Vladimir Kaplan

Impact of Physical Activity on Cardiovascular Risk Factors in IDDM

OBJECTIVE To study the impact of physical activity on glycemic control and plasma lipids [HDL cholesterol (HDL-C), HDL-C subfractions, triglycerides, lipoprotein(a)], blood pressure, weight, and abdominal fat and to determine the necessary short-term adaptations in diabetes management during intensive endurance training in patients with IDDM. RESEARCH DESIGN AND METHODS Well-controlled subjects with IDDM (n = 20; HbA1c = 7.6%) engaged in a regular exercise program over a period of 3 months involving endurance sports such as biking, long-distance running, or hiking. Subjects were instructed to exercise at least 135 min per week. If baseline activity exceeded this level, subjects were to increase further their physical activity as much as possible and record the type and time of such activity. RESULTS During the 3-month intervention, physical activity increased from 195 ± 176 to 356 ± 164 min (mean ± SD) per week (P < 0.001). Physical fitness as assessed by VO2max increased from 2,914 ± 924 to 3,092 ± 905 ml/min (P < 0.001), and insulin sensitivity increased significantly (steady-state plasma glucose [SSPG] decreased from 10.5 ± 4.8 to 7.0 ± 3.3 mmol/l; P < 0.01). Subsequently, LDL cholesterol decreased by 14% (P < 0.05), and HDL and HDL3-C subfraction increased by 10 (P < 0.05) and 16% (P < 0.05), respectively. Systolic and diastolic blood pressure decreased significantly from 127 ± 9 to 124 ± 8 (P < 0.05) and from 80 ± 5 to 77 ± 5 mmHg (P < 0.01), respectively. Resting heart rate decreased from 63 ± 6 to 59 ± 7 bpm (P < 0.01). Waist-to-hip circumference ratio decreased from 0.882 ± 0.055 to 0.858 ± 0.053 (P < 0.001), body weight decreased from 70.7 ± 10.4 to 68.7 ± 10.2 kg (P = 0.003), with a consequent decrease in body fat from 21.9 ± 8.2 to 18.0 ± 6.3% (P < 0.001) and an increase in lean body mass from 54.9 ± 12.2 to 56.8 ± 11.0 kg. These effects occurred independently of glycemic control. The overall frequency of severe hypoglycemic episodes was reduced from 0.14 to 0.10 per patient-year during the study period. CONCLUSIONS This study shows that increasing physical activity is safe and does not result in more hypoglycemic episodes and that there is a linear dose-response between increased physical activity and loss of abdominal fat and a decrease in blood pressure and lipid-related cardiovascular risk factors, with a preferential increase in the HDL3-C subfraction.

Identification of a novel loss-of-function calcium channel gene mutation in short QT syndrome (SQTS6)

AIMS Short QT syndrome (SQTS) is a genetically determined ion-channel disorder, which may cause malignant tachyarrhythmias and sudden cardiac death. Thus far, mutations in five different genes encoding potassium and calcium channel subunits have been reported. We present, for the first time, a novel loss-of-function mutation coding for an L-type calcium channel subunit. METHODS AND RESULTS The electrocardiogram of the affected member of a single family revealed a QT interval of 317 ms (QTc 329 ms) with tall, narrow, and symmetrical T-waves. Invasive electrophysiological testing showed short ventricular refractory periods and increased vulnerability to induce ventricular fibrillation. DNA screening of the patient identified no mutation in previously known SQTS genes; however, a new variant at a heterozygous state was identified in the CACNA2D1 gene (nucleotide c.2264G > C; amino acid p.Ser755Thr), coding for the Ca(v)α(2)δ-1 subunit of the L-type calcium channel. The pathogenic role of the p.Ser755Thr variant of the CACNA2D1 gene was analysed by using co-expression of the two other L-type calcium channel subunits, Ca(v)1.2α1 and Ca(v)β(2b), in HEK-293 cells. Barium currents (I(Ba)) were recorded in these cells under voltage-clamp conditions using the whole-cell configuration. Co-expression of the p.Ser755Thr Ca(v)α(2)δ-1 subunit strongly reduced the I(Ba) by more than 70% when compared with the co-expression of the wild-type (WT) variant. Protein expression of the three subunits was verified by performing western blots of total lysates and cell membrane fractions of HEK-293 cells. The p.Ser755Thr variant of the Ca(v)α(2)δ-1 subunit was expressed at a similar level compared with the WT subunit in both fractions. Since the mutant Ca(v)α(2)δ-1 subunit did not modify the expression of the pore-forming subunit of the L-type calcium channel, Ca(v)1.2α1, it suggests that single channel biophysical properties of the L-type channel are altered by this variant. CONCLUSION In the present study, we report the first pathogenic mutation in the CACNA2D1 gene in humans, which causes a new variant of SQTS. It remains to be determined whether mutations in this gene lead to other manifestations of the J-wave syndrome.

Age- and gender-related prevalence of multimorbidity in primary care: the swiss fire project

BackgroundGeneral practitioners often care for patients with several concurrent chronic medical conditions (multimorbidity). Recent data suggest that multimorbidity might be observed more often than isolated diseases in primary care. We explored the age- and gender-related prevalence of multimorbidity and compared these estimates to the prevalence estimates of other common specific diseases found in Swiss primary care.MethodsWe analyzed data from the Swiss FIRE (Family Medicine ICPC Research using Electronic Medical Record) project database, representing a total of 509,656 primary care encounters in 98,152 adult patients between January 1, 2009 and July 31, 2011. For each encounter, medical problems were encoded using the second version of the International Classification of primary Care (ICPC-2). We defined chronic health conditions using 147 pre-specified ICPC-2 codes and defined multimorbidity as 1) two or more chronic health conditions from different ICPC-2 rubrics, 2) two or more chronic health conditions from different ICPC-2 chapters, and 3) two or more medical specialties involved in patient care. We compared the prevalence estimates of multimorbidity defined by the three methodologies with the prevalence estimates of common diseases encountered in primary care.ResultsOverall, the prevalence estimates of multimorbidity were similar for the three different definitions (15% [95%CI 11-18%], 13% [95%CI 10-16%], and 14% [95%CI 11-17%], respectively), and were higher than the prevalence estimates of any specific chronic health condition (hypertension, uncomplicated 9% [95%CI 7-11%], back syndrome with and without radiating pain 6% [95%CI 5-7%], non-insulin dependent diabetes mellitus 3% [95%CI 3-4%]), and degenerative joint disease 3% [95%CI 2%-4%]). The prevalence estimates of multimorbidity rose more than 20-fold with age, from 2% (95%CI 1-2%) in those aged 20–29 years, to 38% (95%CI 31-44%) in those aged 80 or more years. The prevalence estimates of multimorbidity were similar for men and women (15% vs. 14%, p=0.288).ConclusionsIn primary care, prevalence estimates of multimorbidity are higher than those of isolated diseases. Among the elderly, more than one out of three patients suffer from multimorbidity. Management of multimorbidity is a principal concern in this vulnerable patient population.

Triple rule-out CT in patients with suspicion of acute pulmonary embolism: findings and accuracy.

RATIONALE AND OBJECTIVES The aim of this study was to prospectively investigate the diagnostic value of triple rule-out computed tomography (CT) in patients suspected of having acute pulmonary embolism (PE). MATERIALS AND METHODS A total of 125 patients with suspicion of PE, of whom 14 patients had the additional clinical suspicion of acute aortic syndrome, underwent electrocardiogram-gated triple rule-out dual-source CT. The contrast media application protocol was adjusted to obtain a homogenous attenuation of the pulmonary arteries, thoracic aorta, and coronary arteries. The diagnostic performance of triple rule-out CT was assessed by using adjudicated discharge diagnoses as reference standards. RESULTS A total of 161 adjudicated cardiovascular discharge diagnoses were made in the 125 patients (including all true-positive and true-negative findings): acute PE was found in 26 (21%) and was excluded by CT in 99 (79%), coronary artery disease was found in 3 (3%) and was excluded by catheter angiography in 9 (6%), left ventricular systolic dysfunction was found in 2 (2%) and was excluded by echocardiography in 8 (6%), and acute aortic syndrome was found in 5 (4%) and was excluded by CT in 9 (7%) patients. Nonvascular chest disease was found in 34 (27%) and included pneumonia (n = 17), neoplasms (n = 5), fractures/osteolysis (n = 3), pericarditis (n = 2), and post-pneumonectomy syndrome (n = 1). Triple rule-out CT was normal in 53 (42%) patients. Overall sensitivity, specificity, and positive and negative predictive value of triple rule-out CT for cardiovascular disease were 100% (95% confidence interval [CI] 90-100%), 98% (95%CI 94-100%), 95% (95%CI 82-99%), and 100% (95%CI 97-100%, respectively). CONCLUSIONS Triple rule-out CT is feasible in patients with suspicion of PE, reveals a wide range of vascular and non-vascular chest disease, and offers an excellent overall diagnostic performance.

Comparison of Cox and Gray's survival models in severe sepsis

BackgroundAlthough survival is traditionally modeled using Cox proportional hazards modeling, this approach may be inappropriate in sepsis, in which the proportional hazards assumption does not hold. Newer, more flexible models, such as Gray’s model, may be more appropriate. ObjectivesTo construct and compare Gray’s model and two different Cox models in a large sepsis cohort. To determine whether hazards for death after sepsis were nonproportional. To explore how well the different survival modeling approaches describe these data. DesignAnalysis of combined data from the treatment and placebo arms of a large, negative, sepsis trial. SettingIntensive care units at 136 U.S. medical centers. SubjectsA total of 1090 adults aged 18 yrs or older with signs and symptoms of severe sepsis and documented or probable Gram-negative infection. MeasurementsWe considered 27 potential baseline risk factors and modeled survival over the 28 days after the onset of sepsis. We tested proportionality in single-variable Cox analysis using Schoenfeld residuals and log–log plots. We constructed a traditional multivariable Cox model, a multivariable Cox model with time-varying covariates, and a multivariable Gray’s model. ResultsIn single-variable analyses, 20 of the 27 potential factors were significantly associated with mortality, and 10 of 20 had nonproportional hazards. In multivariate analysis, all three models retained a very similar set of significant covariates (two models retained the identical set of nine variables, and the third differed only in that it retained the same nine plus a tenth variable). Four of the nine common covariates had nonproportional hazards. Of the three models, Gray’s model best captured these changing hazard ratios over time. ConclusionWe confirm that many of the important predictors of mortality in severe sepsis are nonproportional and find that Gray’s model seems best suited for modeling survival in this condition.

Community-acquired pneumonia in the elderly

CAP is traditionally considered a medical disease, and is managed with intravenous fluids and antibiotics on medical floors. Recent cost-containment efforts have shifted the provision of care to the outpatient settings, and only those with most severe disease and multiple comorbid illnesses are admitted to hospitals. Therefore, the proportion of hospitalized patients with severe CAP that need intensive care and life support is increasing. Furthermore, the incidence of severe CAP is also rising due to disproportionate growth of the elderly population that is most vulnerable to this deadly disease. Many of these elderly patients have advanced underlying diseases, and CAP might often be a terminal event superimposed on an underlying chronic debilitating illness. As ICU physicians, we need to be familiar with this disease, its complications, and its prognosis to provide intensive care in a timely and rational fashion in some patients, and refrain from life support in others. Just as prior efforts have sought to improve and standardize criteria for hospital admission, future efforts should aim to improve and standardize decisions regarding intensive care and life support in these very sick elderly patients. Future efforts in the management of CAP need to consider the postdischarge period where most deaths occur. Prevention is an important issue especially for those at high risk for CAP.

Effect of training on repeatability of cardiopulmonary exercise performance in normal men and women.

The effect of gender and training on repeatability of cardiopulmonary exercise performance has not been well defined. Therefore, we performed two bicycle exercise tests 1 wk apart in each of two groups: In 19 normal subjects (age 24 to 64 yr, 10 females), with a mean maximal oxygen uptake (VO2max) of 42 mL.kg-1.min-1, who had been in an ongoing training program including bicycle exercise, and in 19 untrained volunteers (23 to 54 yr, 11 females) with a mean VO2max of 36 mL.kg-1.min-1 (P < 0.05). Mean differences in physiologic variables measured during tests 1 and 2 were calculated. Repeatability coefficients were defined as 2 SD in percent of the means. In untrained subjects mean (+/- SD) maximal heart rate decreased by 4 +/- 5 beats.min-1 from the first to the second test (P < 0.05). VO2max and maximal work rate (Wmax) remained unchanged. No significant changes in these or other variables occurred in trained subjects. Repeatability coefficients for VO2max were 8 and 13% in trained and untrained subjects, respectively (P = NS). For Wmax the repeatability coefficient in untrained (11%) exceeded that in trained subjects (4%, P < 0.05). Repeatability coefficients did not differ among males and females. Our study provides normal values for repeatability of various parameters assessed during exercise testing and demonstrates that interpretation of performance during repeated tests has to account for training of the subjects.

Moving to and dying in a nursing home depends not only on health - an analysis of socio-demographic determinants of place of death in Switzerland.

Background In developed countries generally about 7 out of 10 deaths occur in institutions such as acute care hospitals or nursing homes. However, less is known about the influence of non-medical determinants of place of death. This study examines the influence of socio-demographic and regional factors on place of death in Switzerland. Data and Methods We linked individual data from hospitals and nursing homes with census and mortality records of the Swiss general population. We differentiated between those who died in a hospital after a length of stay ≤2 days or ≥3 days, those who died in nursing homes, and those who died at home. In gender-specific multinomial logistic regression models we analysed N = 85,129 individuals, born before 1942 (i.e., ≥65 years old) and deceased in 2007 or 2008. Results Almost 70% of all men and 80% of all women died in a hospital or nursing home. Regional density of nursing home beds, being single, divorced or widowed, or living in a single-person household were predictive of death in an institution, especially among women. Conversely, homeownership, high educational level and having children were associated with dying at home. Conclusion Place of death substantially depends on socio-demographic determinants such as household characteristics and living conditions as well as on regional factors. Individuals with a lower socio-economic position, living alone or having no children are more prone to die in a nursing home. Health policy should empower these vulnerable groups to choose their place of death in accordance to needs and wishes.

Acute autoimmune response in a case of 3yromellitic acid dianhydride-induced hemorrhagic alveolitis

A 17‐year‐old man was occupationally exposed to pyromellitic acid dianhydride dust during the production of epoxy resin in a chemical factory. He was clinically diagnosed as having acute hemorrhagic alveolitis associated with anemia. The serologic analysis revealed a high concentration of IgG antibodies against pyromellitic acid dianhydride‐treated human serum albumin (PMDA‐HSA). Immunoblotting with PMDA‐treated human serum as antigen and the patients serum as the first antibody showed that additional PMDA‐modified serum proteins other than HSA were recognized by the patients IgG antibodies in the higher mol. mass range (>67 kDa). No specific IgG could be detected against other anhydride conjugates (maleic acid, MA; phthalic acid, PA) with the exception of a reaction with the trimellitic acid anhydride‐conjugated HSA (TMA‐HSA). No specific IgE antibodies could be detected against any of the above mentioned antigens, but immunoblotting of the patients serum indicated IgG 4‐type autoantibodies against in vitro PMDA‐treated Ig molecules of normal serum proteins.

Therapeutic Conflicts in Emergency Department Patients with Multimorbidity: A Cross-Sectional Study

Background Patients with multimorbidity are an increasing concern in healthcare. Clinical practice guidelines, however, do not take into account potential therapeutic conflicts caused by co-occurring medical conditions. This makes therapeutic decisions complex, especially in emergency situations. Objective The aim of this study was to identify and quantify therapeutic conflicts in emergency department patients with multimorbidity. Methods We reviewed electronic records of all patients ≥18 years with two or more concurrent active medical conditions, admitted from the emergency department to the hospital ward of the University Hospital Zurich in January 2009. We cross-tabulated all active diagnoses with treatments recommended by guidelines for each diagnosis. Then, we identified potential therapeutic conflicts and classified them as either major or minor conflicts according to their clinical significance. Results 166 emergency inpatients with multimorbidity were included. The mean number of active diagnoses per patient was 6.6 (SD±3.4). We identified a total of 239 therapeutic conflicts in 49% of the of the study population. In 29% of the study population major therapeutic conflicts, in 41% of the patients minor therapeutic conflicts occurred. Conclusions Therapeutic conflicts are common among multimorbid patients, with one out of two experiencing minor, and one out of three experiencing major therapeutic conflicts. Clinical practice guidelines need to address frequent therapeutic conflicts in patients with co-morbid medical conditions.