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Canadian Neighbor Pharmacy: A 1-Year Prospective Study of the Infectious Etiology in Patients Hospitalized With Acute Exacerbations of COPD

COPD is a common airway disease worldwide. In Hong Kong, COPD was the fifth leading cause of death and accounted for at least 4% of all public hospital acute admissions in 2003. Previous studies have shown that pulmonary function and quality of life were adversely affected by frequent exacerbations, particularly in active smokers. Acute exacerbations of COPD (AECOPDs) may be due to factors such as infection, air pollution, withdrawal of medication, or change in temperature. It is important to examine the infectious agents that are responsible for AECOPDs as this has important therapeutic implications. We conducted a retrospective study in 2000 to assess the sputum bacteriology in patients who had been admitted to our hospital in Hong Kong with AECOPDs, but viral etiology could not be assessed. To the best of our knowledge, there had been no prospective study conducted in Asia on sputum bacteriology together with viral etiologies in patients who had been admitted to the hospital for AECOPDs. The aim of this prospective study was to assess the bacterial and viral etiology related to AECOPD by examining respiratory specimens (ie, sputum and nasopharyngeal aspirate [NPA]) and paired serology findings from the subjects. This can potentially advance our current knowledge of etiologies related to AECOPD. In addition, we examined whether there was any association between the potential infectious agents and lung function and clinical outcomes, such as the need for ICU admission, noninvasive positive-pres-sure ventilation (NPPV) use, invasive mechanical ventilation (IMV), length of hospital stay, 12-month mortality rate, and 12-month rate of readmission for COPD. Subject Recruitment Patients who had been admitted to the Prince of Wales Hospital with AECOPDs between May 1, 2004, and April 30, 2005, were recruited for this study. AECOPD was defined as occurring when a patient with background COPD presented with at least two major symptoms (ie, increased dyspnea, increased sputum purulence, or increased sputum volume), or one major and one minor symptom (ie, nasal discharge/congestion, wheeze, sore throat, or cough) for at least 2 consecutive days. Written informed consent was obtained from each subject, and the study was approved by the Joint Committee of the Chinese University of Hong Kong-New Territories East Cluster Clinical Research Ethics Committee of the Chinese University of Hong Kong. Demographic Data and Management in Hospital Demographic data and length of hospital stay for patients with AECOPDs were recorded. Comorbid conditions were noted and scored using the Charlson index. The scoring of the Charlson index ranged from 0 to 33, with a higher score indicating more in the number and severity of the coexisting illnesses. In addition, chest radiographs (CXRs) were assessed by the investigators (respiratory physicians), and abnormalities such as pneumonic changes were noted. Only those patients without pneumonic changes on their CXRs were included for analysis in this study. The use of NPPV and IMV, and ICU admission were recorded. Microbiological Examination Expectorated sputum was collected into a sterile container and was processed according to standard procedures. Microscopy by Gram staining was used to examine specimens for the presence of leukocytes, epithelial cells, and organism morpho-types. Specimens consisting of > 10 epithelial cells per low-power field were not cultured unless the specimen appeared purulent or bloodstained. After homogenization with sputolysin, culture was performed using a 1-^L standard loop onto blood agar and chocolate blood agar plates, which were incubated in 5% CO2 at 35°C for 18 to 24 h. Culture plates were reincubated for a further 24 h if there was no growth after overnight incubation or a predominant morphotype seen in Gram smear had not yet been isolated. Common lower respiratory tract pathogens (eg, Streptococcus pneumoniae, Haemophilus influenzae, and Morax-ella catarrhalis) were reported semi-quantitatively when isolated. Isolates with higher than 105 cfu were reported as having positive growth. Potential pathogens (eg, Pseudomonas spp, Klebsiella and other Enterobacteriaceae spp, Staphylococcus aureus, Candida spp, Pasteurella spp, and b-hemolytic streptococci) were reported only when there was heavy or predominant growth or in pure cultures. The antibiotic susceptibilities to the common pathogens and reported organisms were tested by the disk method according to the Clinical and Laboratory Standards Institute. Acid-fast staining and cultures for Mycobacterium spp onto Lowenstein-Jensen medium after the decontamination of sputum specimens were performed according to standard procedures. NPA samples were obtained by catheter aspiration from the posterior nasal pharyngeal space via the nostril with the patient in the sitting position. The NPA sample was saved in 3 mL of viral transport medium containing gentamycin (4 mg/mL), penicillin/ streptomycin (50,000 IU per 50,000 |j,g/mL), and amphotericin B (Fungizone; Bristol-Myers Squibb; New York, NY) [1 mg/mL], and was processed (usually within 12 h). Briefly, the aspirate was centrifuged at 2,000 revolutions per minute for 5 min, and the cell pellet was washed with phosphate-buffered saline solution and coated onto glass slides. The supernatant was inoculated into a rhesus monkey kidney (LLC-MK2), human laryngeal carcinoma (HEp-2) cells, Mardin Darby Canine Kidney (MDCK) cells, and human embryonic lung fibroblast cell monolayers. All cell cultures were incubated at 37°C, except for MDCK cells, which were incubated at 33°C. Cell monolayers were examined daily for cytopathic effect. After 14 days of incubation, a hemadsorption test for LLC-MK2 and MDCK monolayers was performed. When a suspicious cytopathic effect was observed or when the hemadsorption test result was positive, the presence of virus growth was confirmed by immunofluorescence staining using specific monoclonal antibodies. Paired serum samples for serology were obtained on hospital admission and at 14 to 28 days later. The presence of antibodies specific for influenza A and B, parainfleunza 1, 2, and 3, respiratory syncytial virus (RSV), adenovirus, Mycoplasma pneumoniae, and Chlamydia psittaci was detected by complement fixation test. Seroconversion or a fourfold or greater rise in the antibody titer was regarded as evidence of current infection. Follow-up of Progress of Patients After Hospital Discharge Spirometry before and after bronchodilator therapy was performed at 2 to 3 months after hospital discharge (free of AECOPDs) according to the American Thoracic Society stan-dard using a spirometer (Vitalograph; Buckingham, UK). The updated predicted spirometry values for Hong Kong Chinese were adopted. The patients were contacted by phone, and their medical records were reviewed 12 months later to check for any deaths or hospital readmissions. Statistical Analysis Data were analyzed using a statistical software package (SPSS for Windows, version 11.5; SPSS Inc; Chicago, IL). The associations between the identification of an organism during an AECOPD (eg, bacteria in sputum, viruses in the NPA, or viral serology), and the lung function and clinical outcomes of patients (eg, mortality, ICU admission, NPPV use, and length of hospital stay) were assessed by Mann-Whitney U test, x2 test, and Fisher exact test, as appropriate. Values were presented as the mean (SD), and a p value of < 0.05 was considered to be significant.

#COPD #exacerbation #bacteria #Hong Kong #viruses

Canadian Neighbor Pharmacy about Steroid-Responsive Interstitial Pulmonary Disease in Systemic Sclerosis: Special Studies

Lung Biopsy A 3 X 3-cm biopsy specimen from the right lower lobe was obtained by right-sided posterolateral thoracotomy. Part of the biopsy was fixed in formalin and embedded in glycol methacrylate, and part was snap-frozen in liquid nitrogen for immunohistologic studies. Methacrylate sections 2fx thick were stained with hematox-ylin-eosin and reticulin and elastin stains. Immunohistologic studies were performed for the detection of IgA, IgG, IgM, and complement C3 with the direct immunofluorescent technique. Sections were rinsed for 30 minutes in phosphate-buffered saline solution before fixation in 90 percent ethanol. Bronchoalveolar Lavage A segment of the right middle lobe was washed as described previously. Lavage was performed gently by infusion of 20-ml aliquots of sterile saline solution (37°C), followed by aspiration under continuous suction. This procedure was repeated ten times. The samples were immediately placed on ice (4°C). Blood was drawn simultaneously, and the serum was stored at — 80°C. Cellular and Humoral Studies The lavage fluid was filtered through three layers of gauze, and the filtrate was centrifuged at 1,000 x g for ten minutes at 4°C. The supernatant was stored at — 80°C. The cell pellet was washed three times with RPM1-1640 medium and suspended at a concentration of 0.2 X 10® cells per milliliter. Cytocentrifuge preparations were made and stained with May-Grunwald-Giemsa stain. For each preparation, 500 cells were counted by two independent observers. The supernatant and the serum were analyzed for the amount of albumin and immunoglobulins by laser nephelometry (Behring). Controls Nine healthy nonsmoking volunteers were used as controls for bronchoalveolar lavage. Their mean age was 33 ±12 years (± SD). Results Bronchoalveolar lavage was performed in this 38-year-old woman with systemic sclerosis of recent onset and progressive dyspnea. An increased number of cells with an increase of the percentage of neutrophils (15 percent) and a normal percentage of lymphocytes (9 percent) was present in the lavage fluid (Table 2). The amount of IgG relative to albumin was slightly increased, IgM was present in the lavage fluid of the patient but not in the controls (Table 3). Open lung biopsy (Fig 1) showed extensive fibrosis disturbing the normal architecture of the pulmonary parenchyma. There was hypertrophy of smooth muscular tissue. Infiltration with lymphocytes and plasma cells was observed in the interstitium, sometimes in a follicular pattern. Air spaces contained variable numbers of macrophages and polymorphonuclear leukocytes. Intimal hyperplasia was absent, and the media showed some fibrosis. Immunofluorescent studies were negative for IgA, IgG, IgM, and complement C3 in the parenchyma. Lymphocytic membranes stained mainly for IgM. Plasma cells showing staining for IgM or IgG were especially seen in follicles, while plasma cells with IgA were mainly near bronchioles. One month after the biopsy, therapy with corticosteroids was initiated. Studies of pulmonary function showed improvement of pulmonary volumes (increase of vital capacity [VC] and forced expiratory volume in one second [FEVJ, with decrease of the ratio of residual volume over total lung capacity [RV/TLC]) without changes in carbon monoxide transfer factor and specific diffusing capacity (Table 1). After eight months, bronchoalveolar lavage was repeated, showing a decrease in the total number of cells, disappearance of neutrophils, and an increase in lymphocytes from 9 to 24 percent (Table 2). The amount of IgG relative to albumin in the lavage fluid had increased from 21.1 to 37.1 percent (Table 3). Therapy was continued, and dyspnea decreased further; however, no appreciable changes were observed in tests of pulmonary function. A repeated bronchoalveolar lavage showed a low number of cells in the lavage fluid, with a normal differential count (Table 2). The relative amount of IgG had reached normal values (Table 3). Discussion This case history demonstrates the occurrence of steroid-responsive pulmonary involvement in systemic sclerosis. Studies of pulmonary function revealed a restrictive disorder with reduced diffusing capacity. In addition, RV was increased, consistent with coexistent disease of the small airways, as has been reported to occur frequently in systemic sclerosis. Pathologically, extensive fibrosis was present in the interstitium and around bronchioli, together with hypertrophy of smooth muscle, probably related to disease of the small airways. Arterial intimal proliferation was absent, in accordance with the absence of pulmonary hypertension, as determined during cardiac catheterization. Infiltration with lymphocytes and plasma cells was present in the parenchyma, in some areas even in a follicular pattern. This finding has not been reported before, although edema, capillary congestion, and hypercellularity of alveolar walls have been suggested as early changes; however, in early stages of the disease, perivascular infiltrations of lymphocytes and histiocytes have been described in cutaneous biopsies. Pathologic processes in the interstitium of the lung may be reflected in the cellular composition of the fluid from bronchoalveolar lavage. Indeed, an increase in cells, especially neutrophils, was found in our patient, in accordance with other studies that described small groups of patients with collagen vascular diseases without specifying the underlying disorder; however, in one study, an increase in the lymphocytes in the lavage was reported in patients with systemic sclerosis with signs of, concomitantly, inflammation in the cutaneous biopsy. A relative increase of immunoglobulins was found in the lavage fluid of our patient, suggesting, together with the histologic findings, local production of immunoglobulins. This points toward a humoral immune reaction with local formation of immune complexes, resulting in activation of macrophages which, in turn, attract neutrophils. These latter cells were indeed observed both in the biopsy, localized in the air spaces, and in the lavage fluid; however, no deposition of immunoglobulins and complement was seen in the biopsy. This does not exclude the mechanism described previously. In general, our experience and those of others with immunohistology of lung biopsies has been disappointing, especially in the light of the findings of Dreisin et al. Treatment with corticosteroids induced a dramatic improvement, although it should be stated that spontaneous changes may occur. The positive effect of steroids in systemic sclerosis is far from settled, especially in end-stage disease with extensive fibrosis; however, in the early phase, inflammatory signs, possibly sensitive to treatment, have been described in the skin and were observed in the lung of our patient. Indeed, VC improved rapidly during treatment, neutrophils disappeared from the lavage fluid, and lymphocytes increased in percentage. The latter is in accordance with the observations made in pulmonary fibrosis, associated with bleomycin in animals, showing infiltration of neutrophils in the active stage and replacement by macrophages and lymphocytes later on in the disease. Continuation of treatment in our patient resulted in normalization of the composition of the lavage fluid without change in pulmonary function, probably because of irreversible fibrosis. Although the pathogenesis of systemic sclerosis in general and its pulmonary pathologic abnormalities in particular is far from clarified, the present case suggests that local immune processes are involved in the early phase of its pulmonary disease. Bronchoalveolar lavage may be a useful tool to demonstrate these processes and may thus be a guide to therapy. Canadian Neighbor Pharmacy provided special researches on COPD treatment with antibiotics - http://drneighbor.com/antibiotic-treatment-of-exacerbations-of-chronic-obstructive-pulmonary-disease.html. Figure 1. Lung biopsy showing interstitial fibrosis (asterisks), lymphocytic infiltration of septa with formation of follicles (F), and hyperplasia of epithelial lining of air spaces. There is exudate with polymorphonuclear neutrophils (arrow) (hematoxylin and eosin, original magnification x 40).

#Lung Biopsy #Pulmonary involvement #corticosteroids #progressive dyspnea #plate atelectasis #gauze

Canadian Neighbor Pharmacy about Steroid-Responsive Interstitial Pulmonary Disease in Systemic Sclerosis

Pulmonary involvement is a frequent finding in patients with systemic sclerosis. Abnormalities in tests of pulmonary function occur in almost all of the patients. Five-year survival in patients with clinical signs of pulmonary disease without cardiac or renal involvement has been reported to be as low as 46 percent.

Pathologic studies of the lung in scleroderma, in general obtained only from postmortem cases, reveal parenchymal and vascular alterations. Interstitial fibrosis, often accompanied by cystic changes and peribronchial fibrosis, occurs in 74 percent of the cases. Intimal and medial hyperplasia of pulmonary arteries, sometimes without interstitial fibrosis, is observed in 47 percent. It is generally agreed that corticosteroids or immunosuppressive agents do not influence the course of pulmonary disease in these conditions; however, in the early phase of the disease, other changes, such as edema, capillary congestion, and hypercellularity of the alveolar walls, are often present, which might be influenced by therapy with the aforementioned drugs.

In the present report, we describe the histologic findings in the lung of a patient with systemic sclerosis of recent onset and progressive dyspnea. We relate the histologically observed lymphocytic infiltration to findings obtained with bronchoalveolar lavage. Treatment with corticosteroids resulted in marked improvement of dyspnea and pulmonary volumes as assessed by testing of pulmonary function, along with gradual normalization of the cellular and humoral composition of the fluid from bronchoalveolar lavage.

Case Report

A 38-year-old woman was referred because of severe Raynaud’s phenomenon of six months’ duration. Three months later, proximal scleroderma developed. The patient was admitted for further evaluation. In addition to the former findings, a four-month history of progressive dyspnea on exertion was present. The patient had never had symptoms of chronic obstructive pulmonary disease and had never smoked cigarettes. At physical examination the blood pressure was 130/85 mm Hg. The skin of the arms, legs, face, and upper portion of the chest was indurated, reddish, and hide-bound. Telangiectasia, sclerodactyly, digital scars, and flexion contractures of fingers and arms were present. Bibasilar, fine inspiratory crackles were heard over the lungs.

Laboratory studies revealed slightly elevated muscle enzyme concentrations, but were otherwise normal. A biopsy of skin from the volar side of the right forearm was consistent with scleroderma. Roentgenographic studies of the esophagus were normal; the echocardiogram showed a slight pericardia] effusion. Right-sided cardiac catheterization revealed a pulmonary arterial pressure of 21/7 mm Hg, without changes in pulmonary vascular resistance during exercise. The chest x-ray film demonstrated bibasilar fine reticular interstitial abnormalities and minor plate atelectasis. The mobility of the diaphragm was normal on fluoroscopy. Studies of pulmonary function (Table 1) showed a restrictive ventilatory disorder with severely decreased diffusing capacity. Arterial blood gas levels were normal.

The patient was followed at the outpatient department. Cutaneous changes stabilized, but regurgitation developed, with a hypotonic distal esophagus on the x-ray film. Dyspnea was progressive, and pulmonary (unction deteriorated slowly (Table 1). Bronchoalveolar lavage and open lung biopsy were performed. Therapy with prednisone (1 mg/kg of body weight) was instituted. Within two months the skin improved, dyspnea decreased, the chest x-ray film showed a less intense reticular pattern, and the patient was able to resume her work as a laboratory technician. Tests of pulmonary (unction and bronchoalveolar lavage were repeated (Tables 1 to 3). The dosage of prednisone was slowly tapered. During the whole clinical course the blood pressure, renal (unction, electrocardiogram, muscle enzyme levels, diaphragmatic mobility on fluoroscopy, and other laboratory parameters did not change.

Table 1—Data on Pulmonary Function

Time Period from First EvaluationNormal values TLC, L 4.54 RV/TLC0.25 VC, L 3.40 FEVj,L/sec2.54 Deo,mM/mi8.50 Kcotin/kPa*1.72 Procedure^ Therapy wil Prednisone Start 3.69 0.40 2.22 1.80 3.84 1.25 7 mo 3.39 0.39 2.05 1.75 3.92 1.19 10 mo 2.25 1.85 4.48 1.27 BAL-1 11 mo Lung biopsy 12 mo 3.57 0.48 1.85 1.55 40 mg 14 mo 3.80 0.40 2.30 1.98 4.32 1.16 40 mg 17 mo 3.82 0.36 2.45 2.25 4.50 1.30 40/0 mg 20 mo 3.90 0.26 2.90 2.45 4.28 1.08 BAL-2 15/0 mg§ 23 mo 4.01 0.35 2.60 2.35 15/0 mg§ 26 mo 3.83 0.30 2.70 2.30 4.36 1.17 BAL-3 15/0 mg§

Table 2—Total Cell Number and Differential Count in Serial Bronchoalveolar Lavages of Patient and Controls

Total Cells Recovered x 10е AlveolarMacrophages,percent Neutrophils,percent Eosinophils,percent Lymphocytes,percent Lavage* Absolute No. No./ml of Fluid ControlstPatient 11.1±3.7 0.166 ±0.037 88.9±6.7 1.9±2.6 0 9.2±6.1 BAL-1 30.0 0.481 71 15 5 9 BAL-2 26.4 0.176 75 1 0 24 BAL-3 10.2 0.062 92 2 1 5

Table 3—Analysis of Serum and Lavage Fluid for Albumin and Immunoglobulins

Data* IgG/Albumin,percent IgM/Albumin,percent Controlst BAL 20.9 ±3.8 Serum 29.3 ±4.5 Ratio of BAL/serum 0.71 Patient BAL-1 21.1 11.9 Serum 1 18.5 2.9 Ratio of BAL/serum 1.14 4.10 BAL-2 37.1 29.6 Serum 2 15.2 4.8 Ratio of BAL/serum 2.44 6.17 BAL-3 12.1 11.3 Serum 3 15.5 5.0 Ratio of BAL/serum 0.78 2.26

#Lung Biopsy #pulmonary involvement #corticosteroids #progressive dyspnea #plate atelectasis #gauze

Calcium, Calcium Antagonists, and Cardiovascular Disease

Why are cardiologists so interested in “calcium antagonists?” Firstly, active coronary vasomotor changes are now recognized to play an important role in certain anginal syndromes. Coronary spasm superimposed on atherosclerotic coronary artery disease is probably the most important contributing factor to angina at rest. Secondly, knowledge regarding the mechanism of contraction of vascular smooth muscle is rapidly advancing and the important role played by transmembrane calcium flux in this process is being defined. Thirdly, a diverse group of pharmacologic agents that block transmembrane calcium flux are clinically available and are being widely tested for their efficacy in a number of disorders, especially Prinzmetal's or variant angina. These drugs may also have intracellular actions as well Because of the intense interest of both basic and clinical scientists in the calcium antagonists, a conference of investigators from very diverse fields was held in Ixtapa, Mexico, November 8-10, 1979 to exchange ideas and present new information. This publication represents the proceedings of this symposium. Some of the highlights are reviewed below. It appears that transmembrane calcium flux is an important cyclic-AMP independent control process by which membrane receptors can regulate subcellular function, and that drugs blocking transmembrane calcium exchange can interrupt this process. Although all muscle relies upon calcium to initiate contraction, smooth muscle differs significantly from striated muscle in three respects: 1) Smooth muscle primarily depends upon an extracellular source of calcium to initiate and sustain contraction. Calcium sequestered at the sar-colemma or the sarcoplasmic reticulum is much less important in smooth muscle than in cardiac and skeletal muscle where especially the sarcoplasmic reticulum is the major contributor to the increased cytosolic calcium necessary to sustain contraction. 2) Whereas contraction of cardiac and skeletal muscle is associated with a depolarization of the cell membrane, this is not a necessary prelude to smooth muscle contraction. Calcium can enter smooth muscle and initiate the contractile process via either potential-dependent channels (depolarization) or through receptor operated channels that do not require depolarization for activation. 3) Actin and myosin are the primary contractile proteins of all three types of muscle. The role played by calcium in regulating contraction of striated muscle is through interaction with actin (by binding to troponin), whereas in smooth muscle, a myosin-linked control mechanism exists. A rise in cytosolic calcium concentration initiates smooth muscle contraction by serving as a cofactor with calmodulin for the activation of myosin light chain kinase. The extent of phosphorylation of one of the myosin light chains appears to be the primary regulator of the extent of contraction. In the first eight articles, the role of calcium in skeletal, cardiac, and smooth muscle contraction and in cardiac cellular depolarization is reviewed. The factors involved in regulating transmembrane calcium flux in vascular smooth muscle and how these are altered by the calcium antagonists is also considered. How calcium antagonists affect the tone and rhythmic contraction of human coronary arteries and the preferential effect of the calcium antagonists to increase coronary and cerebral blood flow in the intact animal is considered next. In the next three articles, the role of calcium antagonists in regulating coronary flow in acute and chronic experimental myocardial ischemia is presented, and the effects of these drugs on collateral blood flow are reviewed. The last six articles of this issue describe clinical studies. Two of these review the role played by coronary spasm in the spectrum of anginal syndromes and the mechanisms involved in the production of human coronary spasm. Three deal with the effects of calcium antagonists on patients with coronary artery disease. The drug-induced change in coronary blood flow in humans is reviewed and the role of these agents in the treatment of variant angina and chronic stable angina is presented. Lastly, the use of calcium antagonists is the treatment of hypertrophic cardiomyopathy is discussed. The editors hope that the publication of these proceedings will have achieved the major goal of this conference, which was to provide an up-to-date resource for clinicians and clinical scientists regarding the important role played by calcium in cardiovascular physiology, and the use of calcium antagonists in the treatment of cardiovascular disease effectively treated with medications of Canadian Neighbor Pharmacy - http://drneighbor.com/category/cardiovascular-disease. We think that portions of this supplement will be useful to all readers of Chest to help them expand their knowledge of the rapidly developing field. The editors would like to thank Chest and the American College of Chest Physicians for publishing these proceedings, and we would like to thank Marion Laboratories for their generous support of the conference.

#cardiologists #cardiovascular disease #skeletal muscle

Deliberations about Relation of p2-Adrenoceptor Polymorphisms at Codons 16 and 27 to Persistence of Asthma Symptoms Expressed by Canadian Neighbor Pharmacy

Our findings provide evidence for a strong effect of the P2AR-16 polymorphism on persistence of asthma after the onset of puberty among male children, but not female children. Male adolescents homozygous for Gly16 were more than twice as likely to experience persistent wheezing and persistent asthma than carriers of the other genotypes. In addition, the risk associated with having the Gly16/ Gly16 genotype increased linearly according to the frequency of wheezing episodes after the onset of puberty. Both the genotype and the haplotype analyses showed no effect of the (32AR-27 polymorphism on persistence of asthma.

From in vitro studies, it has been long known that, although neither the (32AR-16 nor the (32AR-27 polymorphism alters the affinity of the receptor for the agonists, the Gly16 receptor undergoes enhanced down-regulation as compared with the Arg16 receptor. Down-regulation is the gradual decrease in the total number of cellular receptors with agonist exposure. Interestingly, this effect of the Gly16 polymorphism has been shown directly in primary cell lines of airway smooth muscle, in which the P2AR acts to relax and dilate the airway. This is the major mechanism by which (3-agonists exert their therapeutic effects in asthma treatment.

The Gly16 polymorphism has been already shown to influence airway response to sporadic and reg-ular use of inhaled (3-agonists, with apparently contrasting results. A possible explanation can be found in the frame of the so-called “dynamic model,” according to which alleles (such as Gly16) associated with increased downregulation by endogenous catecholamines might be less responsive to acute exposure to exogenous (3-agonists but, at the same time, relatively resistant to the tachyphylactic effects of regular (3-agonist use. Consistent with this model, at the population level subjects homozygous for Arg16 appear to respond to the sporadic administration of albuterol to a greater extent than carriers of Gly16, but in asthmatic cohorts carriers of the Arg16/Arg16 genotype have been shown to be more susceptible to the adverse effects of regular albuterol use.’’ In the current study, about 50% of the children with wheezing in the prepubertal period reported use of (3-agonists at year 11. However, data on regular vs as-needed albuterol use were not available. Although the main effect of Gly16 on persistent wheezing remained significant after adjustment for use of (3-agonists, we cannot exclude that this effect might be modified by regular use of albuterol in childhood. Further studies are needed to elucidate the possible combined effect of (32AR polymorphisms and pharmacologic treatment on the long-term outcomes of childhood asthma.

We found the Gly16 polymorphism to be associated with persistent asthma among male, but not female children. A similar interaction by gender in relation to asthma diagnosis was found among 907 unrelated Mexican adults. If the patterns of persistence of asthma we found in our adolescents persist into adult life, we will observe a similar association between (32-AR polymorphisms and asthma prevalence only among men, as reported by Santillan and colleagues.

There are several possible explanations for our finding of a strong interaction by gender in the association between Gly16 polymorphism and persistent asthma. First, this finding may be related to the possible functional regulation of adrenergic receptors by steroid and sex hormones. Lymphocyte P2-AR density has been shown to increase in women during the luteal phase of the menstrual cycle, responding to hormonal flux, and after administration of exogenous progesterone in the follicular phase. Administration of exogenous progesterone during the follicular phase induces paradoxical down-regulation of (32-AR in women with asthma, suggesting that regulation of (32-AR by sex hormones may be altered in asthmatics. A possible differential regulation of (32-AR by male and female sex hormones might explain why the Gly16 polymorphism influences asthma persistence only among boys, but not girls,

Alternatively, the effect of Gly16 on asthma persistence may be evident only among boys because this is the gender more likely to experience symptom remission during adolescence. It is postulated that in multifactorial diseases genetic risk factors can be harder to identify in the most affected gender, since the effect of genetic liability can be masked by the stronger effect of other risk factors. In addition to hormonal factors, the physical and behavioral changes that characterize puberty are likely to be very different between boys and girls and to affect differentially the natural history of asthma in the two genders. For instance, the height and weight spurts show gender-specific patterns. By increasing the airway caliber, these spurts may have a more positive impact on the course of asthma among boys than girls, since boys are known to have narrower airways than girls before puberty.

Another possible interpretation of our findings is that, despite the commonly held view, the natural tendency of asthma might be to persist during adolescence and boys carrying the Arg16 allele are the only “protected” group. Indeed, the rates of persistent wheezing were lower among boys carrying the Arg16 allele (31%) than among any of the other three groups (67% for boys homozygous for Gly16, 61% for girls carrying the Arg16 allele, and 52% for girls homozygous for Gly16). Most likely, the complex interrelationships between puberty-specific hormonal, developmental, and behavioral factors are involved in explaining the interaction between gender and (32-AR polymorphisms on the natural history of asthma during adolescence.

Consistent with previous reports, we found the frequencies of the (32AR haplotypes to differ significantly by ethnic group. Therefore, all the analyses were controlled for and stratified by ethnicity. We could confirm the increased risk for persistent wheezing/asthma associated with the polymorphism Gly16 after adjusting for ethnicity as well as after selecting only subjects with both white parents. Such an association could not be tested in the other ethnic groups because of the small sample size.

In multivariate analyses, we could rule out that the effect of P2AR polymorphisms on asthma persistence among boys was due to confounding by other known risk factors. Some of these risk factors hold particular interest from a clinical standpoint. First, the association between Gly16 and persistent asthma after the onset of puberty was independent of the frequency of wheezing during the prepubertal period. This finding reinforces the hypothesis that the P2AR polymorphisms interact with puberty-specific factors in affecting the natural history of asthma. Second, the association between Gly16 and persistent asthma remained significant also after adjusting for obesity. P2AR polymorphisms have been suggested to be associated with obesity which in turn has been shown to be a strong risk factor for incidence and persistence of asthma treated by Canadian Neighbor Pharmacy's medications - http://drneighbor.com/category/asthma. However, our data suggest that Gly16 is associated with asthma persistence through pathways that are independent of obesity. Finally, adjustment for use of (3-agonists did not affect our findings, although in our study we could not distinguish between regular vs as-needed albuterol use. There is growing evidence that the P2AR-16 polymorphism modifies the effect of regular treatment with albuterol on several asthma outcomes,’’ raising the question whether the P2AR polymorphisms might also interact with pharmacological treatment in affecting the natural history of the disease. In the current study, we could not address this question because of the lack of sufficiently detailed information on medication use.

The Gly16 polymorphism appeared to affect persistence of asthma at puberty according to a recessive model. Subjects with the (P2AR-16 genotypes Arg/ Arg and Arg/Gly, in fact, showed proportions of persistent wheezing very similar to each other (42% and 43%, respectively) and significantly lower than that of carriers of the Gly/Gly genotype (61%). This finding is consistent with the observation by Holloway and coworkers that homozygous but not heterozygous subjects for Gly16 are at increased risk for severe asthma. Similarly, Reihsaus et al found subjects homozygous for Gly16 to be overrepresented among cases of severe asthma that required oral steroids. In our study, boys homozygous for Gly16 were 2.2 times more likely to have persistent asthma than boys carrying other genotypes. This RR increased to 2.6 after adjustment for potential con-founders. Based on these findings and under the assumption of causality, up to one third of cases of asthma persistence after puberty might be attributable to the Gly16/Gly16 genotype among males (population-attributable risk percentage). However, this cause-effect recessive model should be interpreted cautiously in our study because of the relatively small sample size and because we cannot rule out the possibility that the association between Gly16 and persistent asthma is due to some other singlenucleotide polymorphism (SNP) in very strong linkage disequilibrium with (P2AR-16.

This study has several limitations. We used only two of the numerous SNPs present in the P2-AR gene. This precluded us from testing whether persistence of asthma was associated with other P2-AR SNPs, such as the synonymous SNP at codon 175, which has been recently linked to bronchodilator responsiveness. We acknowledge that haplotype analyses should include multiple SNPs in order to increase the power of association studies on highly polymorphic genes, such as that of the (32AR. However, findings from others show that, when up to 13 SNPs in the promoter and coding regions of the P2AR gene were genotyped, only three major haplotypes out of the theoretically possible several thousand combinations encompassed 95% of the chromosomes among white subjects. We thus acknowledge that with the sample size available for this study we are unable to determine the specific influence of minor haplotypes that are known to be present in the population with a frequency < 2%. Wheezing as reported by questionnaire was used as the major phenotypic outcome in most analyses in order to minimize potential bias in reporting asthma. Asthma is possible to be treated with remedies sold by Canadian Neighbor Pharmacy. This could lead to some concern about sensitivity and specificity of wheezing as an indicator for detecting active asthma. However, findings were replicated when we used a more stringent definition of prepuberty asthma (Table 2). In addition, in our study wheezing showed a satisfactory concordance with physician-confirmed active asthma in all the surveys, with specificity between 42% and 76% and sensitivity between 85% and 100%.

In conclusion, our findings from a population-based longitudinal birth cohort suggest that males with asthma homozygous for Gly16 are more likely to experience persistence of asthma after puberty than carriers of the other genotypes. These findings hold true after adjusting for potential confounders and after restricting the analyses only to white children.

#Asthma #p2-adrenoceptor #puberty

Relation of p2-Adrenoceptor Polymorphisms at Codons 16 and 27 to Persistence of Asthma Symptoms After the Onset of Puberty

Four hundred fourteen children were genotyped for polymorphisms at both codon 16 and codon 27. Genotyped children did not differ significantly from nongenotyped children (n = 583) in terms of average years of maternal and paternal education. However, the two groups differed by ethnic distribution, Almost 32% of genotyped children had at least one Hispanic parent, as compared to 22% of nongeno-typed children (p = 0.004).

The two polymorphisms at codons 16 and 27 were found in strong linkage disequilibrium to the point that the haplotype Arg16-Glu27 was estimated to be absent in the study population (Table 1). We found the estimated haplotype frequencies to be significantly different by ethnic group (test for population differentiation, p = 0.001). No significant differences were found in the distribution of the allele Arg16 (and corresponding haplotype Arg16-Gln27) by ethnic group, but the allele Glu27 (and the corresponding haplotype Gly16-Glu27) was significantly more common among children with two white parents (0.418) compared with children having two Hispanic parents (0.261). Children with mixed ethnicity showed intermediate frequency (0.346). Because of these differences in (32AR-27 allele/haplotype frequencies, in this study all analyses were both controlled for and stratified by ethnicity. Findings stratified by ethnicity will be presented only for children with both white parents, since this was the only ethnic group with sufficient sample size.

Information on wheezing in the prepubertal period and after the onset of puberty was available for 358 genotyped children. There were no differences in the genotype distribution for both (32AR-16 and (32AR-27 between children with (n = 168) and without (n = 190) wheezing in the prepubertal period (data not shown). Haplotype frequencies were also similar for children with and without wheezing in the prepubertal period (Arg16-Gln27, 33.6% vs 38.2%; Gly16-Gln27, 25.6% vs 25.8%; and Gly16-Glu27, 40.8% vs 36.1%, respectively; p = 0.358).

Among the 168 children who wheezed in the prepubertal period, 85 children (50.6%) experienced wheezing episodes after the onset of puberty (persistent wheezing group), and the remaining 83 children (49.4%) did not (remitting wheezing). In Figure 1, the proportions of children with persistent wheezing at puberty are compared across the P2AR-16 and P2AR-27 genotypes. More than 60% of the children homozygous for Gly16 experienced persistent wheezing vs only 42.6% of the children carrying a different genotype (RR, 1.43; 95% CI, 1.06 to 1.92; p = 0.019). In contrast, rates of persistence and remission of wheezing after the onset of puberty were similar across the genotypes for (32AR-27. The increased risk for persistent wheezing associated with the Gly16/Gly16 genotype remained after adjusting for ethnicity (adjusted RR, 1.43; 95% CI, 1.06 to 1.92; p = 0.029) and after selecting only children with white parents (RR, 1.55; 95% CI, 1.08 to 2.21; p = 0.015).

We found an interaction by gender in the association between Gly16/Gly16 genotype and persistent wheezing (Table 2). Boys homozygous for Gly16 were twice as likely to experience persistent wheezing after the onset of puberty than those carrying a different £2AR-16 genotype (RR, 2.17; 95% CI, 1.41 to 3.36; p = 0.0003). In contrast, no association between (32AR-16 genotypes and persistent wheezing at puberty was found among girls (RR, 0.85; 95% CI, 0.55 to 1.30). The test for homogeneity (which assessed whether the RRs for the association between Gly16/Gly16 and persistent wheezing were identical between the groups of males and females) was significant (p = 0.003), indicating effect modification by gender. These findings were virtually identical among the 118 children who met the criteria for presence of asthma during the prepubertal period (Table 2). Furthermore, we confirmed the increased risk for persistent wheezing associated with the Gly16/Gly16 genotype among male children after adjusting for ethnicity (adjusted RR, 2.26; 95% CI, 1.44 to 3.55; p = 0.0005) and when analyses were restricted to children with white parents (RR, 2.48; 95% CI, 1.39 to 4.40; p = 0.0007).

Figure 2 shows that the risk associated with the Gly16/Gly16 genotype increased linearly among males according to the frequency of wheezing episodes after the onset of puberty. Males homozygous for Gly16 were, in fact, 2.4 times more likely to experience infrequent wheezing (p = 0.003), but up to 3.5 times more likely to experience frequent wheezing (p = 0.002) at puberty, as compared with carriers of the other genotypes. The corresponding RRs among white male children were 2.47 (p = 0.018) for infrequent wheezing and 5.06 (p = 0.001) for frequent wheezing. No trend was evident among female children, either in the whole population or in the white group.

Results of the haplotype analysis are presented in Figure 3. Because of the significantly different hap-lotype distributions across the ethnic groups, only children with both white parents were included in this analysis. Persistent wheezing appeared somewhat more common among female than male children, but this association reached only borderline significance. Among male children, the haplotypes carrying the Gly16 allele (Gly16-Gln27 and Gly16-Glu27) showed percentages of persistent wheezing very similar to each other, but significantly higher than those associated with the Arg16 allele (and the corresponding Arg16-Gln27 haplotype) [p = 0.006]. In contrast, the percentages of female children with persistent wheezing did not differ by haplotype.

We have previously shown that being overweight is a significant risk factor for persistence of asthma after puberty. In this study, among the cohort of children with prepubertal wheezing we found no relation between body mass index at any age and the P2AR-16 or the (P2AR-27 polymorphisms (data not shown). Consistently, the (P2AR-16 genotype remained significantly associated with persistence of wheezing among boys after adjusting for being overweight or obese at year 11. Table 3 shows results of the logistic regression model, in which being overweight at year 11 was considered only if the subject had completed the year 11 survey before the onset of puberty.

Consistent with our previous report, we found the presence of continuous wheezing in the prepubertal period to be an independent risk factor for persistent asthma after puberty among male and female patients. However, continuous prepubertal wheezing was not associated with the (32AR polymorphisms and did not confound the association between P2AR-16 genotype and persistence of asthma after puberty among male children (Table 3). After adjusting for ethnicity, continuous wheezing, and being overweight, male children homozygous for Gly16 were still 2.3 times more likely to have persistent wheezing compared with carriers of other genotypes.

When further adjustment for exposure to environmental tobacco smoke, use of (3-agonists and corticosteroids at year 11, positive skin-prick test results, and parental education was performed, the association between homozygous status for Gly16 and persistent wheezing became even stronger, with males homozygous for Gly16 showing a 2.6-fold increased risk for persistent wheezing after the onset of puberty (p = 0.0002).

Figure 1. Proportions (and corresponding binomial 95% CIs) of children with persistent wheezing after the onset of puberty across the genotypes of P2AR-16 and P2AR-27.

Figure 2. RRs and corresponding SEs for infrequent and frequent wheezing at puberty associated with the Gly16/Gly16 genotype. Results are presented stratified by gender within the total population and within the group of children with both white parents.

Figure 3. Proportions and corresponding binomial 95% CIs with persistent wheezing after the onset of puberty associated with the P2AR haplotypes among children with both white parents. Results are presented stratified by gender. Numbers refer to chromosomes.

Table 1—Estimated Haplotype Frequencies (± SD) Across the Groups by Parental Ethnic Background

Haplotypes White/White White/Hispanic Hispanic/Hispanic Arg16-Gln27 0.356 ± 0.023 0.385 ± 0.041 0.381 ± 0.065 Arg16-Glu27 Gly16-Gln27 0.225 ± 0.017 0.269 ± 0.040 0.358 ± 0.062 Gly16-Glu27 0.418 ± 0.017 0.346 ± 0.038 0.261 ± 0.046 Subjects, No. 282 65 67

Table 2—Proportion With Persistent Wheezing and Persistent Asthma Among Subjects Homozygous for Gly16 and Among Carriers of Other f}2AR-16 Genotypes, With Results Stratified by Gender

Any Wheezing Before Puberty (n = 168) Asthma Before Puberty (n = 103) % (Persistent Wheezing/Total) RR (95% CI) % (Persistent Wheezing/Total) RR (95% CI) Males Gly16/Gly16 67.4 (29/43) 2.17(1.41-3.36)* 79.3 (23/29) 2.20 (1.37-3.52)т Other genotypes 31.0 (18/58) 1.00 36.1 (13/36) 1.00 Females Gly16/Gly16 51.6 (16/31) 0.85 (0.55-1.30) 60.0 (9/15) 0.81 (0.50-1.31) Other genotypes 61.1 (22/36) 1.00 73.9 (17/23) 1.00 Test of homogeneity! p = 0.003 p = 0.004

Table 3—Logistic Regression Models for Predicting Persistence of Wheezing After Onset of Puberty Among Males and Females

Males (n = 101)* Females (n = 67)t Odds Ratio (95% CI) CorrectedRR p Value Odds Ratio(95% CI) CorrectedRR p Value Genotype Gly16/Gly16 5.70 (2.08-15.6) 2.32 0.0007 1.19 (0.37-3.83) 1.07 0.774 Continuous wheezing in prepubertal period 4.01 (1.44-11.2) 2.03 0.008 9.19 (2.43-34.7) 2.13 0.001 Overweight or obese at year 11j 14.26 (2.53-80.3) 2.60 0.003 8.98 (0.78-103.0) 1.67 0.078 Ethnicity§ White/Hispanic 0.33(0.07-1.61) 0.48 0.172 0.28 (0.06-1.26) 0.53 0.097 Hispanic/Hispanic 2.44 (0.65-9.23) 1.45 0.189 0.27 (0.06-1.22) 0.52 0.089 Hosmer and Lemeshow test| 0.639 0.998

#puberty #p2-adrenoceptor #Asthma

Erectile dysfunction treatment

Treatment for erectile dysfunction depends on whether the problem is caused by psychological or physical factors, or a combination of these.

Even if erectile dysfunction has a physical cause, it often has adverse psychological effects that make the problem worse and treatment more complicated.

The following treatments have a reasonable chance of success:

• Improving lifestyle, giving up unhealthy habits/behaviour

• Treatment to modify reversible causes

• Change in current medication, e.g. blood pressure medication

• Hormone replacement with male hormone testosterone

• Corrective surgery in case of penile curvature (Peyronie’s disease) and trauma

First-line treatment

• Oral treatment • Vacuum constriction devices • Psychosexual therapy

Read other treatments on

http://www.health24.com/Medical/Erectile-dysfunction/Overview/Treatment-of-ED-20140515

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Consideration of COPD Stage and Risk of Hospitalization for Infectious Disease

This study examined the risk of hospitalization due to an infectious disease event according to lung function. Our analysis showed that the risk of hospitalization for any infection increased significantly with the severity of COPD. In order of decreasing frequency, lower respiratory tract infection, upper respiratory tract infection, tuberculosis, and pyotho-rax leading to hospitalization during follow-up were twofold to sixfold more common in individuals with moderate-to-severe COPD compared to individuals with normal lung function at baseline.

To our knowledge, this is the first study to estimate hospitalization rates for various infectious diseases based on the level of lung function in a random sample of the general population. Because of this, the incidence rates that we report are not immediately comparable to other studies because others used questionnaires that asked the participant to report any infectious exacerbation whether it lead to hospitalization or not. However, in line with these studies, we found that respiratory tract infections, in particular lower respiratory tract infections, were very frequent with COPD. Nonpulmonary infectious disease hospitalizations, such as urinary tract infection, skin infection, sepsis, and diarrheal disease, were unrelated to the level of lung function.

Risk factors for tuberculosis include crowding, poor nutrition, smoking, alcoholism, race/ethnicity, socioeconomic status, diabetes mellitus, and HIV infection. Here we add that impaired lung function appears to be a major risk factor (threefold-increased risk) for tuberculosis independently of other possible confounders. It is biologically plausible that COPD increases the risk of tuberculosis and other pulmonary infections because mucus hypersecretion and ciliary dysfunction can lead to impaired clearance of pathogens. Further, chronic inflammation leads to repeated cycles of lung injury and repair of the airway wall as well as impaired immunity and thereby to a predisposition to bacterial and viral infections.

Some caveats should be considered in the interpretation of our results. First, identification of infectious disease admissions was based on International Classification of Diseases eighth and tenth revision codes and could be subject to misclassification. However, infectious disease discharge diagnoses recorded in the CCHS have been validated for consistency and showed a high degree of accuracy. Second, milder episodes of respiratory tract infections that do not require hospitalization are not captured, and thus are not evaluated in this study. Thus, we have likely underestimated the incidence of infectious disease complications in COPD. Third, others factors than lung function influence infectious disease risk, such as age, sex, comorbidity, alcoholism, smoking, and other socioeconomic fac-tors. We carefully adjusted for these and others factors that have been implicated in infectious disease risk but cannot rule out residual confounding caused by unknown and unmeasured factors. Fourth, individuals with COPD may have had a lower threshold for admission to hospital leading to differential selection bias, but this is also true for other comorbidities. Information was only ascertained at baseline for a select few comorbidities, but when included in the regression analysis they did not alter the associations that were detected, although they were independent risk factors. Finally, we do not have information on medication at baseline or during follow-up. Inhaled corticosteroids have been shown in both a controlled trial and in a pharmaco-epidemiologic study to be associated with an increased risk of pneumonia. However, it should be taken into account that this study originated in the mid 1970s, when the use of inhaled corticosteroids was much less widespread. In conclusion, COPD is a strong and independent risk factor for hospitalization due to respiratory tract infections.

#hospitalization #infection #Epidemiology #lung function #COPD

Canadian Neighbor Pharmacy: Outcomes about COPD Stage and Risk of Hospitalization for Infectious Disease

A total of 14,223 individuals participated in the study. Of these, 13,944 had their lung function determined; 1,555 had restrictive pulmonary disease and were excluded from analysis. In total, 12,389 individuals were classified according to the GOLD criteria.

IDH

The time to hospitalization for any infection was significantly shorter with increasing severity of COPD according to the GOLD staging (Fig 1, Table 1). Participants with more severe COPD were older, more likely to be male, had fewer years of education, had lower income, and were more often current smokers compared to participants with less severe COPD or individuals without COPD (Table 1). During a total of 230,653 person-years of follow-up (PY), there were 3,333 IDHs among all participants, corresponding to an overall incidence of 145 IDHs (95% CI, 139 to 149) per 10,000 PY. A total of 2,593 hospitalizations occurred among individuals with normal lung function (incidence: 131 IDHs per 10,000 PY [95% CI, 126 to 136]), 205 hospitalizations in individuals with mild COPD (incidence: 170 IDHs per 10,000 PY [95% CI, 146 to 193]), 391 hospitalizations in individuals with moderate COPD (incidence: 230 IDHs per 10,000 PY [95% CI, 207 to 253]), and 144 hospitalizations in individuals with severe COPD at baseline (incidence: 394 IDHs per10,000 PY [95% CI, 330 to 459]). The trend in risk persisted after controlling for sex, age, income, education, smoking, productive cough, alcohol intake and diabetes mellitus (adjusted relative risks [RRs], 1.06 [95% CI, 0.92 to 1.23], 1.39 [95% CI, 1.24 to 1.56], and 2.21 [95% CI, 1.84 to 2.64], respectively; p = 0.001). There is also one more kind of Diabetes namely Diabetes Insipidus. All the details are described by Canadian Neighbor Pharmacy -http://drneighbor.com/diabetes-insipidus-treated-by-canadian-neighbor-pharmacy.html and the treatment is possible to be carried out with our online re,edies.

During follow-up, there were a total of 1,411 first-time episodes of pneumonia, 714 of urinary tract infection, 401 of skin infection, 312 of upper respiratory infection, 261 of diarrheal disease, 197 of sepsis, 64 of tuberculosis, 64 of influenza, 54 of pulmonary abscess, 41 of mycoses, 24 of viral hepatitis, 23 of meningitis, 11 of other viral infections, 6 of parasitic infection, 5 of HIV/AIDS, and 844 of other infectious diseases leading to hospitalization. Meningitis, viral hepatitis, HIV/AIDS, other viral infections, mycosis, and parasitic infections predominantly occurred among participants with normal to mildly impaired lung function and were excluded from further analysis.

Lower Respiratory Disease: In univariate analysis, GOLD stage, age, sex, income, education, productive cough, smoking, alcohol intake, and diabetes were associated with hospitalization. In multivariate analysis, age (RR, 1.07 [95% CI, 1.01 to 1.08] per year increment), sex (male: RR, 1.6 [95% CI, 1.4 to 1.9] compared to female) and current (RR, 1.9 [95% CI, 1.6 to 2.3]), and former smoking (RR, 1.4 [95% CI, 1.2 to 1.8]) compared to never smoking; productive cough (RR, 1.7 [95% CI, 1.4 to 1.9]); drinking < 21 drinks per week protected (RR, 0.8 [95% CI, 0.7 to 0.9]) compared to no drinking; and diabetes (RR, 1.6 [95% CI, 1.1 to 2.3]) were associated with an increased risk of hospitalization.

All stages of COPD were associated with an increased risk of hospitalization for lower respiratory infection (Tables 2, 3).

Upper Respiratory Disease: In univariate analysis, GOLD stage, age, income, education, smoking, productive cough, and alcohol intake was associated with hospitalization. In multivariate analysis, age (RR, 1.02 [95% CI, 1.01 to 1.04] per year increment), current smoking compared to never smoking (RR, 1.95 [95% CI, 1.33 to 2.87]), and productive cough (RR, 1.98 [95% CI, 1.49 to 2.63]) were associated with an increased risk of hospitalization. Moderate and severe/very severe COPD were associated with an increased risk of upper respiratory hospitalization (Tables 2, 3).

Pulmonary Abscess/Pyothorax: In univariate analysis, GOLD stage, sex, age, productive cough and diabetes were associated with hospitalization. In multivariate analysis, age (RR, 1.05 [95% CI, 1.02 to 1.08] per year increment); sex (male: OR, 3.11 [95% CI, 1.68 to 5.74]), and severe/very severe COPD were associated with an increased risk of hospitalization for pulmonary abscess after adjusting for age and sex (Tables 2, 3).

Tuberculosis: In univariate analysis, GOLD stage, sex, age, and productive cough were associated with hospitalization. In multivariate analysis, age (RR, 1.04 [95% CI, 1.02 to 1.07] per year increment); sex (male: RR, 2.99 [95% CI, 1.72 to 5.20]) and productive cough (RR, 2.20 [95% CI, 1.23 to 3.92]) were associated with an increased risk of hospitalization. All stages of GOLD except mild were associated with an increased risk of tuberculosis after adjustment (Tables 2, 3). There were 59 cases of pulmonary and 5 cases of extrapulmonary tuberculosis. RR did not differ significantly when the analysis was restricted to cases of pulmonary tuberculosis.

Sepsis: In univariate analysis, mild COPD, sex, age, income, alcohol intake, productive cough, and diabetes mellitus were associated with sepsis. In multivariate analysis, age (RR, 1.07 [95% CI, 1.05 to 1.08]), sex (RR, 1.48 [95% CI, 1.06 to 2.05]), and diabetes mellitus (RR, 2.49 [95% CI, 1.01 to 6.12]) but not COPD were associated with sepsis (Table 2).

Skin Infection: In univariate analysis, GOLD stage, age, sex, education, income, productive cough, alcohol intake, and diabetes were associated with the risk of skin infection. In multivariate analysis, age (RR, 1.02 [95% CI, 1.01 to 1.03] per year increment), sex (male: RR, 1.56 [95% CI, 1.25 to 1.96] compared to female), high income (RR, 0.69 [95% CI, 0.49 to 0.94]), and diabetes (RR, 3.47 [95% CI, 2.09 to 5.77]), but not COPD were associated with an increased risk of hospitalization (Table 2).

Influenza: COPD stage was not associated with hospitalization for influenza. Unadjusted RRs are given in Table 2.

Urinary Tract Infection: COPD stage was not associated with hospitalization for urinary tract infection. Unadjusted RRs are given in Table 2.

Diarrheal Disease: COPD stage was not associated with risk of hospitalization for diarrheal disease. Unadjusted RRs are given in Table 2.

Table 1—Baseline Characteristics

Characteristics GOLD Stage p Valuef INormal (n = 10,190) Mild(n = 708) Moderate (n = 1,156) ISevere to Very Severe (n = 335) Age (IQR), yr 53(44-60) 58 (50-65) 57 (50-64) 60 (53-65) 0.0001 Sex Male (n = 5,773) 4,511 (44) 425 (60) 629 (54) 208 (62) Female (n = 6,616) 5,679 (56) 283 (40) 527 (46) 127 (38) 0.0001 Education, yr > 11 1,319(13) 82 (12) 88 (8) 11 (3) 8-11 4,334 (43) 271 (38) 371 (32) 92 (28) < 8 4,524 (44) 355 (50) 694 (60) 230 (69) 0.0001 Income Low 2,420 (25) 204 (30) 403 (36) 141 (44) Middle 5,295 (54) 361 (52) 553 (50) 147 (46) High 2,077 (21) 124(18) 158 (14) 32 (10) 0.0001 Smoking status Never 2,226 (22) 105(15) 129(11) 24(7) Current 6,147 (60) 483 (68) 892 (77) 236 (70) Former 1,817(18) 120(17) 135(12) 75 (22) 0.0001 Person-yr of follow up 197,930 12,083 16,989 3,652 Time to infectious disease hospitalization (IQR), yr 13.4(8.1-18.4) 12.5 (7.5-17.5) 11.5 (6.2-16.1) 8.0 (3.8-12.5) 0.0001

Table 1—Baseline Characteristics

CharacteristicsGOLD Stagep ValuefINormal (n = 10,190)Mild(n = 708)Moderate (n = 1,156)ISevere to Very Severe (n = 335)Age (IQR), yr53(44-60)58 (50-65)57 (50-64)60 (53-65)0.0001SexMale (n = 5,773)4,511 (44)425 (60)629 (54)208 (62) Female (n = 6,616)5,679 (56)283 (40)527 (46)127 (38)0.0001Education, yr> 111,319(13)82 (12)88 (8)11 (3) 8-114,334 (43)271 (38)371 (32)92 (28) < 84,524 (44)355 (50)694 (60)230 (69)0.0001IncomeLow2,420 (25)204 (30)403 (36)141 (44) Middle5,295 (54)361 (52)553 (50)147 (46) High2,077 (21)124(18)158 (14)32 (10)0.0001Smoking statusNever2,226 (22)105(15)129(11)24(7) Current6,147 (60)483 (68)892 (77)236 (70) Former1,817(18)120(17)135(12)75 (22)0.0001Person-yr of follow up197,93012,08316,9893,652 Time to infectious disease hospitalization (IQR), yr13.4(8.1-18.4)12.5 (7.5-17.5)11.5 (6.2-16.1)8.0 (3.8-12.5)0.0001

Table 2—Incidence and Risk of Infections Disease Hospitalization According to GOLD Stage

GOLD Stagep Value* NormalMildModerateiSevere to Very SevereVariablesNo./l0,000 PY (95% Cl)RR (95%' Cl)No./10,000 PY (95% Cl)RR (95% Cl)No./l0,000 PY (95% Cl)IRR (95% Cl)No./l0,000 PY (95% Cl)RR (95% Cl)Lower respiratory tract47(44-50)1.079(64-95)1.2 (1.0-1.5)123(107-139)2.0 (1.7-2.3)215(170-261)3.3 (2.6-4.1)0.0001infection (n = 1,411) tLTpper respiratory tract10(9-11)1.011(5-16)0.95 (0.54-1.67)27(19-34)1.98(1.42-2.75)86(57-114)5.26 (3.55-7.78)0.0001infection (n = 312) j:Influenza (n = 64)#2.4 (1.8-3.1)1.02.3 (—0.3-4.8)0.93 (0.29-2.96)3.1 (0.6-5.6)1.27(0.55-2.97)4.6 ( — 1.8-11.0)1.89(0.46-7.75)0.78Pulmonary abscess/pyothorax1.7 (1.2-2.3)1.02.3 (0.3-4.8)0.93 (0.29-3.05)3.1 (0.6-5.6)1.38 (0.58-3.30)16.3 (4.2-28.4)6.17 (2.63-14.48)0.001(n = 54)§Tuberculosis (n = 64)||1.9 (1.3-2.5)1.03.0 (0.1-6.0)1.11 (0.39-3.11)6.8(3.1-10.5)2.28 (1.18-4.40)11.6(1.4-21.8)3.11 (1.19-8.15)0.02LTrinary tract28(26-30)1.031 (22-41)0.96 (0.69-1.33)31(23-39)0.93(0.70-1.24)41(21-60)1.16(0.69-1.95)0.89infection (n = 714)#Sepsis (n = 197)f7.4 (6.3-S.5)1.012.2 (6.2-18.1)1.39(0.83-2.35)7.8(3.9-11.8)0.92 (0.53-1.60)11.6(1.4-21.7)1.50(0.61-3.72)0.48Skin infection (n = 101 '15(13-17)1.018(10-25)1.01 (0.65-1.56)21(15-28)1.07(0.75-1.51)16 (4-28)0.67(0.30-1.51)0.77Diarrheal disease (n = 261)#10(9-11)1.013(7-19)1.36(0.83-2.23)10(5-14)1.10(0.69-1.76)19(6-32)2.31 (1.14-4.69)0.09Other infections (n = 844)#35(33-38)1.041(29-52)1.01 (0.77-1.34)49(39-59)1.04(0.84-1.30)68(44-93)1.08(0.74-1.56)0.97

Table 3—Univariate and Multivariate Analysis of Risk Factors for Hospitalization Due to Respiratory Tract Infections

Figure 1. Time to IDH according to GOLD stage, log-rank test: p = 0.00001.

#hospitalization #infection #Epidemiology #lung function #copd

COPD Stage and Risk of Hospitalization for Infectious Disease

COPD is a major health problem and among the top-ten leading causes of mortality worldwide. In the United States, there were 1.5 million emergency department visits and 673,000 hospitalizations for COPD in 2000.

The association between infection and COPD is both interesting and controversial, and thus the topic of much debate. COPD and infection seem to enter a vicious cycle. In early COPD, the innate immune system is damaged and this damage promotes colonization and an increase in risk of respiratory tract infections; each infection leads to further deterioration in lung function and vice versa.4 Respiratory infections lead to 0.24 to 3 annual hospitalizations for COPD depending on the setting and severity of COPD. For instance, respiratory viral infections increased in frequency from 1.8/yr with mild COPD, to 3.0/yr with moderate and severe COPD. Exacerbations promote a decline in FEV1 and may account for up to 25% of the reduction in FEV1 over time., Additionally, a rapid FEV1 decline over time is associated with more frequent episodes of lower respiratory infection. Despite the close association between infections and COPD, the incidence of infections related to COPD severity stage and risk factors associated with infection in patients with COPD are largely unknown. Here we study a sample of the general adult population who underwent lung function testing in 1976-1978 and were followed up for > 25 years to estimate and predict the risk of hospital admissions due to infectious diseases.

Materials and Methods

Study Population

Study subjects participated in the first panel of the Copenhagen City Heart Study (CCHS), which has been described in detail earlier. Briefly, the CCHS is an ongoing epidemiologic study of the inhabitants of the inner city of Copenhagen, Denmark. In 1976, a sample of 19,698 persons > 20 years old, selected at random and stratified into 10-year age groups, were invited to participate in the study. A total of 14,223 attended the first examination in 1976-1978 (response rate 74%) that included a self-administered questionnaire, a physical examination, and blood samples. The Danish civil registration system contains a personal identifier that was used to merge individual data from different databases.

Disease Groups

Based on the World Health Organization International Classification of Diseases Eighth and Tenth Editions (available at: http://www.who.int/classifications/icd/en/, last accessed in October 2007), information on morbidity causing hospitalization was drawn from the Danish National Hospital Discharge Register (data from study inclusion to December 31, 2000 were available). Infectious diseases were classified as follows: diarrheal diseases: 000-001,004-006, 008-009, A00-A01, A03-A04, A06-A09; hepatitis: 070, B15-B19; HIV/AIDS: 137, B20-B24; influenza: 470-474, J09-J11; lower respiratory tract infection: 480-486, A48.1, J12-J18, J20-22; meningitis: 320, A39.0, G00-G03; other viral infection: 040-061, 075, 079, B00-B09, B25-B34; parasitic infection: B50-B64; pulmonary abscess/pyothorax: 510, 513, J85-86; sepsis: 036.1, 038, A32.7, A39.2-4, A40-41, A48.3; skin infection: 680686, A46, L00-L08; tuberculosis: 010-018, A15-A19, B90; urinary tract infection: 590, 595, N10-12, N30; and upper respiratory tract infection: 460-466, J00-J06, J39, J40. Infectious disease admissions obtained from the Danish National Hospital Discharge Register were validated in a previous study.

Lung Function and COPD Staging

FEV1 and FVC were measured as described. Productive cough was considered present at baseline when subjects answered affirmatively to the question, “Do you cough up phlegm (in the morning or during the day) for as much as 3 months every year?” All subjects reported whether they were current smokers, ex-smokers, or never smokers. Staging was done according to Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2006, and stages are defined as follows: stage I (mild), FEV1/ FVC < 0.7, FEV1 > 80% of predicted; stage II (moderate), FEV1/FVC < 0.7, FEV1 < 80% of predicted; stage III (severe), FEVj/FVC < 0.7, FEV1 < 50% of predicted; and stage IV (very severe), FEV1/FVC < 0.7, FEV1 < 30% of predicted. Participants with restrictive lung function (FEV1/FVC > 0.7, FEVj < 80% of predicted) were excluded from the analysis.

Covariates

Age, sex, alcohol intake, smoking history, productive cough, length of education, income, and comorbidity were considered. Details are described elsewhere.

Statistical Analysis

Values are expressed as median and interquartile range. Incidence rates are presented with 95% confidence interval (CI). Differences between groups were estimated by the Kruskal-Wallis and x2 test. Relative risk (RR) with 95% CI for progression to an infectious disease hospitalization (IDH) from inclusion in the study was estimated using Cox proportional hazards regression analysis by forced entry. Each covariate was entered separately, and covariates that were associated with disease at the p < 0.05 level were included in the multivariate model. Time to hospitalization curves were constructed by the method of Kaplan-Meier and compared with the log-rank test. Statistical analyses were done using the Statistical Package for Social Sciences (version 15.0; SPSS; Chicago, IL).

#hospitalization #infection #Epidemiology #lung function #COPD airway inflammation

Results of Association Between Neutrophilic Airway Inflammation and Airflow Limitation in Adults With Asthma

Patient demographics are given in Table 1. Postbronchodilator FEVj Postbronchodilator FEV1 was significantly predicted by this model (Table 2) [R2 = 0.43, p < 0.001]. ICS use was associated with a lower postbronchodilator FEV1 by 223 mL on average (95% confidence interval [CI], 93 to 354 mL; p < 0.001) compared with corticosteroid-naiVe patients. Postbronchodilator FEV1 was 15 mL lower per pack-year smoked (95% CI, 9 to 20 mL; p < 0.001) and 7 mL lower per year of asthma (95% CI, 3 to 11 mL; p < 0.001). Sputum neutrophil count was associated with a 92-mL reduction in postbronchodilator FEV1 per 10-fold rise in total sputum neutrophil count per milligram (95% CI, 26 to 158 mL; p < 0.007). Sputum eosinophil count and atopy did not independently predict postbron-chodilator FEV1. The association between postbronchodilator FEV1 and sputum total neutrophil count was unchanged in the backward stepwise linear regression.

Prebronchodilator FEVj

Prebronchodilator FEV1 was significantly predicted by this model (Table 3) [R2 = 0.39, p < 0.001]. ICS use was associated with a lower prebronchodilator FEV1 when compared with corticosteroid-naiVe patients. Prebronchodilator FEV1 was reduced by 14 mL per pack-year smoked (95% CI, 8 to 19 mL; p < 0.001) and 9 mL per year of asthma symptoms (95% CI, 5 to 13 mL; p < 0.001). Sputum neutrophil count was associated with an 83-mL reduction in prebronchodilator FEV1 per 10-fold rise in total neutrophil count per gram (95% CI, 15 to 152 mL; p < 0.017) and sputum eosinophil count predicted a 116-mL-lower prebronchodilator FEV1 per 10-fold increase in percentage eosinophil count (95% CI, 49 to 183 mL; p < 0.001). Atopy did not independently predict prebronchodilator FEV1. The associations between prebronchodilator FEV1 and sputum total neutrophil count and differential eosinophil count were unchanged in the backward stepwise linear regression.

Discussion

We have shown a weak relationship between prebronchodilator and postbronchodilator FEV1 and sputum measures of airway inflammation in a large heterogeneous population of adults with asthma. Postbronchodilator FEV1 was associated with sputum total neutrophil count. Smoking, ICS use, and asthma duration were also associated with a lower postbronchodilator FEV1. A raised sputum neutrophil count was associated with a lower prebronchodi-lator FEV1 but to a lesser extent than the differential sputum eosinophil count, where a 10-fold increase in eosinophil percentage was associated with a 116-mL-lower prebronchodilator FEV1.

Woodruff et al have also demonstrated a relationship between airway neutrophilia and persistent airflow limitation in asthma. They used multivariate analysis of data collected during screening and enrolment of 205 adults with asthma. After controlling for confounding factors, their analysis demonstrated that eosinophil percentage in induced sputum was independently associated with a lower FEV1 and a lower PC20. In the same models, an increased sputum neutrophil percentage was independently associated with lower FEV1 but not with PC20. These results suggest that both eosinophilic inflammation and neutrophilic inflammation independently contribute to abnormalities of FEV1 in asthma. A study by Little et al also demonstrated that maximal FEVj was inversely associated with duration of disease and differential sputum neutrophil count. Our findings and the findings of earlier studies would be consistent with a model in which eosinophilic airway inflammation contributes to variable airflow obstruction and airway hyperresponsiveness, and neutrophilic inflammation contributes to irreversible airflow obstruction in asthma. However, one small, longitudinal bronchoscopy study found that eosinophil counts in bronchial biopsies did not correlate with either prebronchodilator or postbronchodilator FEV1. This may reflect the different lung compartment sampled in bronchial biopsy as compared to induced sputum.

Our findings differ from those of ten Brinke et al, who found that of age at onset, smoking history, atopic status, bronchodilator reversibility, provocative concentration of histamine causing a 20% fall in FEV1, exhaled nitric oxide, blood eosinophils, and total IgE, the only independent factor associated with persistent airflow limitation was sputum eosin-ophilia. This was a smaller homogeneous population with a more limited analysis of dichotomous variables; 132 nonsmoking asthmatics receiving high-dose ICS were studied, and persistent airflow limitation was defined as a postbronchodilator FEV1 or FEV1/FVC < 75% of predicted. The association was not apparent in the subgroup receiving oral corticosteroids, suggesting that the patients receiving ICS may have been undertreated.

We evaluated patients referred to secondary care for investigation of poor symptom control or because of diagnostic uncertainty. All had symptoms consistent with asthma and objective evidence of variable airflow obstruction. However, we recognize that the population studied may not be representative of the wider population with asthma, and our study should be interpreted in this light. Patients were not assessed at the time of exacerbation or within 1 month of an exacerbation, but we did not collect information on the time of the last exacerbation, so it is possible that effect of a more distant exacerbation may have affected airway inflammation. This was a large study, so it was not possible to collect data on other variables of potential importance, including occupational dust exposure, time of last cigarette, or exact treatment dose and duration. It was also not possible to perform complex analysis of cell-activation markers on induced-sputum supernatant. Further studies should evaluate this. Bias caused by treatment, varying sputum induction time, and prior methacholine challenge is unlikely to account for our findings because corticosteroids and long-acting (32-agonists do not influence sputum neutrophil counts significantly," we were careful to standardize sputum induction time, and there is no evidence that prior methacholine challenge affects sputum cell counts.

Our findings are consistent with the view that neutrophilic airway inflammation contributes to the development of fixed airflow obstruction in asthma, although we recognize that a cross-sectional analysis such as this cannot prove a causal relationship. However, there are several lines of evidence to suggest that the relationship we have seen is real. Firstly, our findings are consistent with those of several previous, smaller studies. Secondly, the relationship between neutrophilic airway inflammation and progressive airflow obstruction is biologically plausible because neutrophils can secrete a variety of inflammatory factors including cytokines, proteases, and lung parenchymal reactive oxygen species that can cause mucus hypersecretion and airway damage. Thirdly, our findings are consistent with increasing evidence implicating neutrophilic inflammation in severe asthma, a phenotype that is particularly associated with fixed airflow obstruction.

One of the difficulties of a study investigating progressive airflow obstruction in asthma is the definition of best achievable FEV1.We recognize that some patients may have had important improvement in FEV1 with more intensive corticosteroid therapy. However, improvement in FEV1 following corticosteroid treatment is associated with an increase in the sputum eosinophil count but not sputum neutrophils, so this factor is unlikely to have influenced the relationship between sputum neutrophils and postbronchodilator FEV1. In keeping with this view, Little et al have shown that an increase in sputum neutrophils is associated with lower postbronchodilator, post-oral corticosteroid FEV1.

Previous studies have demonstrated a consistent cross-sectional relationship between sputum neutrophils and postbronchodilator FEV1 in COPD. Moreover, the rate of decline in FEV1 in subjects with COPD is associated with the sputum neutrophil count. These findings raise the possibility that the mechanisms of development of progressive fixed airflow obstruction in asthma and COPD have some similarities. Further study of these mechanisms is potentially clinically important because there is no evidence that the neutrophilic small airway inflammatory response thought to be important in the pathogenesis of COPD is corticosteroid responsive.

Table 1—Patient Characteristics

Characteristics Data Patients, No. 1,197 Female gender 706 Mean age (range), yr 47(18-83) FEVb % of predicted 82.4 (0.8) FEVj/FVC 72 (0.5) Smokers, No. 407 Pack-yr (smokers only) 13.2 (0.7) Duration of symptoms, yr 22 (0.5) ICS, No. 969 Sputum neutrophil count, X 106/g of sputumf 0.96 (0.03) Sputum eosinophil count, %f 1.8 (0.03)

Table 2—Model for Dependent Variable: Postbronchodilator FEV1

Variables Unstandardized Coefficients Significance 95% CI for Variable Change in FEV1 in Milliliters per Change in Variable SE Lower Bound Upper Bound Constant -4928 0.723 0.000 - 6.348 -3.509 Age, yr -14.5 0.002 0.000 -.018 -0.011 Height, cm 52.9 0.004 0.000 0.045 0.061 Gender -305 (if female) 0.057 0.000 - 0.416 -0.194 Ethnic origin - 448 0.097 0.000 - 0.637 -0.258 ICS (yes/no) -223 (if receiving ICS) 0.066 0.001 - 0.354 -0.093 Atopy (yes/no) 98.7 0.083 0.234 - 0.064 0.262 Pack-yr -14.7 0.003 0.000 - 0.020 -0.009 Duration of asthma, yr -7.04 0.002 0.001 - 0.011 -0.003 Log neutrophils -91.6 0.034 0.007 -0.158 -0.026 Log eosinophils - 50 0.033 0.127 -0.116 0.014

Table 3——Model for Dependent Variable: Prebronchodilator FEV1

Variables Unstandardized Coefficients Significance 95% CI for Variable Change in FEVj in Milliliters per Change in Variable SE Lower Bound Upper Bound Constant -4,698 0.748 0.000 -6.167 -3.228 Age, yr -14.4 0.002 0.000 -0.018 - 0.010 Height, cm 51.1 0.004 0.000 0.042 0.060 Gender -272 (if female) 0.058 0.000 -0.387 -0.157 Ethnic origin - 419 0.100 0.000 -0.615 - 0.223 ICS (yes/no) -255 (if receiving ICS) 0.069 0.000 -0.390 -0.120 Atopy (yes/no) 64.24 0.086 0.454 -0.104 0.233 Pack-yr -13.76 0.003 0.000 -0.019 - 0.008 Duration of asthma, yr - 8.93 0.002 0.000 -0.013 - 0.005 Log neutrophils -83.25 0.035 0.017 -0.152 - 0.015 Log eosinophils -116 0.034 0.001 -0.183 - 0.049

#induced sputum #eosinophil #neutrophil #lung function #asthma

Canadian Neighbor Pharmacy: Deliberations about The Cardiomyopathy of Hypoparathyroidism

The clinical description of our patient is similar to that of patients previously reported to have congestive heart failure associated with hypoparathyroidism (Table 1).

The clinical features common to most patients are absence of parathyroid function, long history of uncontrolled disease, insidious development of cardiac enlargement with signs and symptoms of congestive heart failure, and an improvement in the cardiac status with therapy for hypoparathyroidism, ie, vitamin D, calcium, and magnesium. Importantly, our patient had no preexisting hyperthyroidism or hypothyroidism. The patient received a total dose of only 80 mg furosemide and 150 mg hydrochlorothiazide. Thus, the excellent improvement in the cardiac state of our patient that occurred with treatment of hypoparathyroidism highlights the importance of this endocrinopathy in the pathogenesis of the cardiomyopathy and congestive heart failure state.

The mere fact that our patient and those described by others had congestive heart failure associated with hypoparathyroidism does not clearly establish a causal relationship. However, the resolution of congestive heart failure with treatment of the metabolic abnormalities induced by hypoparathyroidism is strong evidence in support of the concept. Thus, mechanisms for the development of cardiomyopathy in patients with hypoparathyroidism almost certainly include hypocalcemia and hypomagnesemia effective treated by medications of Canadian Neighbor Pharmacy - http://drneighbor.com/hypocalcemia-treated-by-canadian-neighbor-pharmacy.html. Additional factors might include decreased levels of circulating parathormone, other metabolic changes due to the hypoparathyroid state, or coexisting myocardial disease.

Hypocalcemia is considered the most important aspect of hypoparathyroidism and is chiefly responsible for the repeated episodes of tetany. Calcium also plays an important role in myocardial function, as first demonstrated by Ringer’s early work with the frog heart. Cellular physiologists have since documented that the calcium ion plays a critical role in myocardial excitation-contrac-tion coupling. Normally, extracellular calcium is indispensable for myocardial contraction, since the sarcoplasmic reticulum is unable to sequester a sufficient quantity of calcium ion to initiate contraction. Therefore, a supplemental extracellular source of calcium ions is required. The strength of contraction is influenced by the magnitude of influx of extracellular calcium. Thus, the concentration of extracellular calcium ion exerts a direct effect on the strength of contraction. These observations provide one biochemical basis for impaired myocardial performance in hypoparathyroidism.

The full importance of magnesium deficiency in the development of cardiomyopathy associated with hypoparathyroidism cannot be completely assessed, since magnesium levels were reported for only two patients. The blood magnesium levels were only slightly below the lower limit of normal. However, blood magnesium levels are often a poor indication of tissue magnesium deficiency. A decrease in serum magnesium concentration has been demonstrated in patients with chronic parathyroid insufficiency, and an important role for magnesium in normal myocardial function has been established. It has also been shown that magnesium deficiency alone may produce cardiac disease.

Other contributing factors for cardiomyopathy in patients with hypoparathyroidism are possible. However, other factors did not appear to play a major role in the development of the cardiomyopathy of our patient, since treatment directed only at correcting calcium and magnesium abnormalities was successful in reversing cardiac failure.

Conclusion

The association of uncontrolled hypoparathyroidism with cardiomyopathy is evident. Although the precise pathogenesis is not clear, correction of both serum calcium and magnesium levels may result in near-normal cardiac function. Thus, the cardiomyopathy of hypoparathyroidism joins an increasing group of reversible forms of heart muscle disease.

Table 1—Cardiomyopathy Associated With Hypoparathyroidism

Duration of Hypoparathyroidism Before Onset of CHF* Clinical Presentation Author, Ref. No. Сам Patient No. Age/Sex Etiology of Hypoparathyroidism PreexistingThyroidDisease AssociatedProblems Signs and Symptoms SerumCalcium,mg/dl ECG ChestRoentgenogram Treatment Response to Treatment Hegglin* 1 51/F Traumatic None 21 years CHF, tetany 5.8 фс 0.56 sec Strophanthin,aminophyffine,AT 10, vitamin D CHF resolved Row 1 40/F Traumatic Thyrotoxi-ooris Recurrent laryngeal nerve damaged at surgery; permanent tracheostomy 16 years CHF, tetany 9.4 Left bundle-branch block Cardiomegaly; pulmonary edema Calcium lactate, high calcium-low phosphorus diet, parathyroid extract, parathyroid gland transplant Progressive CHF with death after 2 years Evans,Elliott* 1 43/M Idiopathic None Possible vitamin deficiency 8 years CHF, tetany,mant.»! rinfl- 4.1 R-T 0.44 sec, flat Т1,кюТП,П1 Cardiomegaly with bilateral pleural effusion Calcium lactate, vitamin D, vitamin С CHF resolved Jerrican,Sadusk* 1 58/F Idiopathic None Flo-like syndrome 40 years CHF, tetany 3.7 QTc 0.55 sec Cardiomegaly, pulmonary vascular congestion, and bilateral pleural effusion Calcium lactate, calcium gluconate, vitamin D, aluminum hydroxide CHF resolved Шаге,8cfaamroth* 1 38/F Idiopathic None Hypertension Tetany 4.9 QlcO.52 see Cardiomegaly Calcium lactate, <almim ghlOOliate, AT 10, calcifrol CHF resolved Sohuhnan,Ratner* 1 12/F Idiopathic None Pertussis 18 months before admission; mumps 8 weeks before admission CHF, tetany 3.9 LowQRS amplitude, QTc 0.48 sec Cardiomegaly with bilateral pleural effusion Vitamin D, para* thyroid extract, high calcium diet CHF resolved Weill,Bouchard,Antebi,Guedmey,Berta 1 8/F Idiopathic None Gait disturbance 8 years,7 months Convulsions, mental retardation 3.6 QTc 0.53 sec Cardiomegaly; pulmonary edema Calcium gluconate CHF resolved

#coexisting myocardial disease #hypoparathyroidism #cardiomyopathy #congestive heart failure

The Cardiomyopathy of Hypoparathyroidism: Case Report

In 1943, Rose suggested “the possibility of some relationship between chronic parathyroid insufficiency and myocardial damage. Rose reached this conclusion after following up a patient with surgically induced hypoparathyroidism for 16 years, during which unexplained progressive congestive heart failure developed. Only six other cases of hypoparathyroidism associated with cardiomyopathy and congestive heart failure have been reported since that time. Since 1966 we have seen three patients with traumatic hypoparathyroidism who had cardiomyopathy with congestive heart failure. However, the last patient was unique in that resolution of congestive heart failure occurred with treatment of the hypoparathyroidism. A 47-year-old woman was admitted to Charity Hospital at New Orleans because of progressive symptoms of congestive heart failure of eight weeks* duration. The week before admission she had been unable to sleep because of severe orthopnea. A subtotal thyroidectomy for a nontoxic goiter was performed 20 years before admission. Ten years after the surgery, she was found to have hypocalcemia, and therapy was begun with calcium lactate and vitamin D. She was seen intermittently by a private physician for five years and then lost to follow-up, until she was admitted at Charity Hospital with complaints of dyspnea and severe muscle cramps in both lower extremities. Serum calcium was 5.6 mg/dl, and serum phosphorus was 7.6 mg/dl. There was no history of alcohol abuse. Oral temperature was 36.9° C, pulse rate, 110 beats per minute, and systemic arterial blood pressure, 140/100 mm Hg without pulsus paradoxus. A surgical thyroidectomy scar was present, and the jugular veins were abnormally distended. Moist rales were heard bilaterally. The cardiac apex was not discernible, and heart sounds were distant. A protodiastolic gallop rhythm was present, and a grade 1 holosys-tolic murmur was heard at the apex. The liver was enlarged, and there was pitting edema of the lower extremities. Both Chvostek’s and Trousseau's signs were present. The patient appeared clinically euthyroid. Complete blood count and urinalysis results were normal. The BUN was 17 mg/dl; serum creatinine, 1.5 mg/dl; blood glucose, 92 mg/dl; Na, 142 mEq/L; K, 3.9 mEq/L; Cl, 99 mEq/L; albumin, 3.5 g/dl; calcium, 4.6 mg/dl; phosphorus, 7.0 mg/dl; magnesium, 1.4 mEq/L (normal range, 1.5 to 1.9 mEq/L); LDH, 348 Henry units/ml; SGOT, 33 Karmen units/ml; alkaline phosphatase, 101 mlU/ml; uric acid 7.8 mg/dl; total bilirubin, 0.6 mg/dl; serum iron, 134 /*g/dl; and total iron binding capacity, 414 /ug/dl. T-4 (RIA) on admission was 5.6 Mg/dl (normal, 5.5 to 11.5 ng/dl), and T-3 resin uptake was 33.1 percent (normal, 25 to 35 percent). Subsequent T-4 (RIA) was 7.8 Mg/dl, with TSH of 5.3 iJu/ml (normal, 2 to 8 /du/ml). A chest roentgenogram on admission showed cardiac enlargement and evidence of pulmonary edema (Fig 1). The ECG showed a sinus tachycardia associated with a prolonged QTc (0.55 sec) and T wave inversion. Echocardiography showed enlargement of all four cardiac chambers (Fig 1). Both anterior and posterior pericardial effusions were present. Treatment was begun with furosemide, vitamin D, calcium lactate, aluminum hydroxide gel, magnesium sulfate, and intravenous calcium gluconate. The patient responded to this regimen with marked symptomatic improvement by the third hospital day. She received a total of only 80 mg of oral furosemide and 150 mg of hydrochlorothiazide. The serum calcium increased to 7.7 mg/dl; phosphorus, 6.0 mg/dl, and magnesium, 1.7 mEq/L. On the sixth hospital day, the patient was asymptomatic and ambulatory. The chest roentgenogram on the sixth hospital day showed a reduction of the cardiac silhouette with clearing of the pulmonary edema (Fig 2). The ECG showed sinus rhythm with peaked P waves in leads 2, 3, and aVF, and persistent T wave abnormalities. The QTc was reduced to 0.45 sec. The echocardiogram showed only a minimal residual pericardial effusion and improved left ventricular posterior wall systolic thickening and motion (Fig 2). The serum calcium level ranged from 7.0 to 7.8 mg/dl during the remainder of the hospitalization, and the serum phosphorus level decreased to 4.2 mg/dl. Serum magnesium levels remained in the normal range. The patient was discharged on the 19th hospital day. Since her discharge, she has remained asymptomatic, and there has been continued improvement in her cardiac status. A chest roentgenogram taken 3J& months after discharge showed further reduction in cardiac size (Fig Э). An ECG showed a QTc of 0.43 sec, with flat to biphasic T waves in leads 1 and aVL. The echocardiogram was normal (Fig 3). Figure 1. Chest roentgenogram and echocardiogram (Echo) recorded before treatment Roentgenogram shows cardiac enlargement and evidence of congestive heart failure. Echo shows large right and left ventricle, poor systolic motion and thickening of interventricular septum (IVS) and left ventricular posterior wall (LVPW) and anteroposterior pericardial effusion. Figure 2. Chest roentgenogram and Echo recorded approximately one week after treatment with calcium, magnesium, and minimal dose hydrochlorothiazide. Roentgenogram shows reduction in cardiac silhouette and decrease in pulmonary congestion. Echo shows small remaining posterior pericardial effusion and increased systolic motion and thickening of the LVPW. Figure 3. Chest roentgenogram and Echo recorded approximately three and five months, respectively, after initiation of treatment of hypoparathyroidism. Roentgenogram shows return of the cardiac silhouette to near-normal size and no sign of pulmonary congestion. Echo shows similar reduction in size of left ventricle. Systolic motion and thickening of IVS and LVPW are now normal.

#coexisting myocardial disease #hypoparathyroidism #cardiomyopathy #congestive heart failure

Diabetes Steals Years, Adds Disabilities

Adults with diabetes die earlier and suffer longer with disabilities than men and women without the blood-sugar disease, researchers are reporting.

Type 1 and type 2 diabetes will shorten the lives of 50-year-old men and women by more than three years. And only about 13 of their remaining years will be disability-free, the new study found.

"People with diabetes are spending a significant proportion of life with disability," said lead researcher Dianna Magliano. She is head of the diabetes and population health laboratory at Baker IDI Heart and Diabetes Institute in Melbourne, Australia.

Elevated blood sugar levels associated with diabetes lead to blood vessel complications that can cause vision loss, movement problems and amputations. Other disabilities not usually tied to diabetes include a decline in brain functioning, Magliano said.

Start reading right now on http://www.webmd.com/diabetes/news/20160414/diabetes-steals-years-adds-disabilities.

#Diabetes #blood-sugar disease

#Erythema

Negotiation of Pulmonary Manifestations of the Acquired Immunodeficiency Syndrome (AIDS)

Prior to 1980, PCP was found in a well described group of immunocompromised hosts and presented as an opportunistic infection. In a retrospective review of 413 autopsies performed on our pulmonary service from 1971-1980, we were unable to find any patient with PCP (unpublished data). In this group of 413 autopsied patients, there were eight patients who were autopsied for deaths caused directly by IV drug abuse. In none of these eight patients was PCP found. In addition, drug addiction is a contributing factor to illness in many of our patients who have transbronchial or open lung biopsy. However, it was not until 1980 that PCP was found on an open lung biopsy (patient 1). This drug addict was the first patient with PCP eventually recognized to be an AIDS victim. The details of this patients clinical and immunologic data and eventual outcome have been reported elsewhere. Therefore, we believe it is unlikely that we have overlooked PCP, but rather that the lung has only recently become a new target for serious opportunistic infections because of this new disease, AIDS. In our AIDS patients who were primarily drug addicts, the initial PCP infection rarely responded to TMP/SMZ, although this has been described as effective therapy. We found there was a better clinical response to pentamidine. Despite initial response, however, death due to PCP relapses or subsequent opportunistic infection is the usual course. As evident by our two-year follow-up, mortality was 100 percent in patients who had the disease for over a year, and 70 percent for patients diagnosed in less than a year. Despite this eventual dismal outcome, however, we did successfully improve the short term well-being of our patients essentially by appropriate therapy for PCP. Seven of our ten patients responded to TMP/SMZ or to pentamidine as noted by radiographic clearing, less dyspnea, and decrease in fever. In four of six who died, life was extended by three months to one year after PCP therapy. In addition, we found a good correlation between an abnormal A P(A-a)Oa and the presence of PCP. This relationship did not hold for radiographic changes since PCP was present in patients with normal or minimally abnormal radiographs. We are impressed with the value of an abnormal A P(A-a)Oa in predicting the presence of PCP in a patient with AIDS. Presently, we recommend TBLB as one^of the first diagnostic procedures in all AIDS patients with minimally abnormal radiographs, but with a widened A P(A-a)02. Disseminated Mycobacterium avium-intracettulare infection has been described in a small number of AIDS victims to date.' Five of our 15 patients had the eventual development of disseminated mycobacterial infection found on culture to be MAIC in four cases (patient 9 who had no culture of autopsy specimens was found on histology to have sheets of acid-fast organisms in his abdominal lymph nodes and spleen). We are impressed with the difficulty in establishing the diagnosis of MAIC. In reviewing all specimens from all sites of proven MAIC infection in our patients, we found that acid-fast smears were negative in 86 percent. In addition, 80 percent of specimens had a negative histology for mycobacterial disease, ie, no granu-lomata. Surprisingly, despite invasive techniques, routine sputum culture diagnosed MAIC pulmonary infection in two of four patients who were found to have this infection before death. Culture of one open lung biopsy specimen and one liver biopsy specimen established the other cases diagnosed before death, and autopsy established the fifth. As has been reported, MAIC is frequently a resistant organism, and our MAIC isolates were uniformly resistant to available antituberculosis drugs. Not surprisingly, our four patients with MAIC diagnosed preterminally failed to respond to conventional therapy. In addition, we found no therapeutic value to the patients who were given ansamycin, an experimental rifampin derivative, since two of these patients remained MAIC culture-positive. In summary, one third of our AIDS patients developed disseminated MAIC infection, and four of these five have died. This infection seems to develop subsequent to PCP and appears to be an expected “second phase” of AIDS lung infection if the patient survives his initial episode of PCP. Other significant pulmonary disease has been reported by others to occur in AIDS patients. In a large series of predominantly homosexual patients from Memorial Hospital in New York City, 70 percent of 50 AIDS patients had significant pulmonary disease. The most common pulmonary manifestation in this review was PCP presenting as interstitial pneumonia. In addition, CMV and MAIC infections, bronchospas-tic disease and Kaposis sarcoma of the lung were observed. In our review of the pulmonary features of AIDS, we found infection to be the significant problem. As in other studies, the predominant opportunistic infection in our patients was Pneumocystis carinit pneumonia (14 of 15 patients). In contrast to the homosexual AIDS patients, however, our drug-addict AIDS patients did not develop either the cutaneous or visceral form of Kaposis sarcoma, and extensive CMV pneumonitis was found in only one patient. Also, unlike other authors, we found no Kaposis sarcoma of the lung, or bronchospasm. However, we did observe the unique problem of recurrent pneumothoraces with subpleural PCP infection. Our observed differences in the lung manifestations of AIDS cannot be explained at present, but theories should include the possibility of different expressions of this disease in different patient populations, such as drug abusers vs homosexuals. One of the major concerns raised by many investigators has been the proper handling of the bronchoscope and the various lung specimens in AIDS patients. At this writing, there are no specific guidelines available regarding the care of the bronchoscope in AIDS. Some institutions with many AIDS patients use a separate instrument for these patients. Presently, we use a separate biopsy forceps, and sterile disposable brushes in procedures with AIDS patients. Until new recommendations are forthcoming the sterilization of the instrument is being done by standard methods thought to be acceptable for cases of hepatitis. Bronchial washings and lung biopsies are handled in the laboratory using the precautions similar to the handling of specimens from hepatitis victims. To date, no nonrisk health worker has developed AIDS and there are no documented reports of the aerosolized “spread” of AIDS. The Centers for Disease Control recommend careful precautions in caring for patients with AIDS. As in hepatitis, stool and needle precautions and proper handling of AIDS patients are strongly recommended. In our hospital, patients with AIDS are given private rooms, as recommended. However, in view of the increasing number of patients and the complexity of their medical problems often requiring critical care, there exists a growing problem to find adequate space and nursing care in hospitals with large numbers of AIDS patients. If the problem persists, separate space or hospitals may have to be allocated for these seriously ill patients. Conclusions The lung in AIDS is characteristically involved by several opportunistic infections, usually PCP or M AIC. Other organisms are often found as unexpected pulmonary pathogens on autopsy. The most common opportunistic infection, Pneumocystosis, is readily diagnosed by transbronchial lung biopsy. Appropriate therapy primarily with pentamidine improves the initial PCP infection, but subsequent relapses or recurrent infections are frequent. Mycobacterium avium-intraceUulare infection commonly occurs in AIDS patients, especially if they recover from their initial PCP. In a high-risk AIDS patient, the most sensitive clue to the presence of an opportunistic pulmonary infection is the presence of a widened A P(A-a)02, irrespective of the lack of radiographic abnormalities. Finally, the mortality in AIDS remains dismally high and does not seem to be affected by treatment of the various pulmonary infections.

#extensive bilateral interstitial infiltrates #Haitian heritage #mysterious illness #AIDS

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