Israel Medical Association Journal

Background: The TANTALUS^™ System (MetaCure Ltd.) is a minimally invasive implantable device for the treatment of type 2 diabetes. The system detects food intake by sensing gastric electrical variations and applies electrical stimulation to the gut synchronized to natural gastric activity. The system is commercially available in Europe and Israel and is in clinical trials in the United States. It has been tested in 132 patients worldwide to date.

Objectives: To re-analyze previously reported data from different studies. This retrospective analysis of the type 2 diabetes subpopulation analyzed the expected benefit and characterize the significance of baseline A1c in the determination of the expected clinical outcome.

Methods: From the total cohort of 132 patients implanted with the TANTALUS device in 10 different centers in Europe and the U.S., 50 subjects (27 females, 23 males) who were obese with uncontrolled T2DM[1] on a stable regime of oral medication for 3 months prior to implant were identified. This population had similar inclusion/exclusion criteria as well as treatment protocols and were all treated for at least 24 weeks. The analysis was based on the A1c change compared to baseline.

Results: Data after 24 weeks demonstrate a reduction in A1c in 80% of the patients with average drop in A1c of 1.1 ± 0.1%. The average weight loss was 5.5 ± 0.7 kg.

Conclusions: The results suggest that the TANTALUS stimulation regime can improve glucose levels and induce moderate weight loss in obese T2DM patients.

Background: Insulin-dependent diabetes mellitus is dominated by a Th1 response whereas atopic diseases such as asthma, eczema and allergic rhinitis are characterized by a Th2 response. Because it is known that Th1 and Th2 cells reciprocally counteract each other, it can be speculated that the prevalence of Th2-mediated diseases is lower in patients with a Th1-mediated disease.

Objectives: To compare the prevalence of atopic diseases among children with IDDM[1] and age-matched controls.

Methods: The study group comprised 65 children with IDDM attending the pediatric endocrinology clinic at the Wolfson Medical Center. The control group consisted of 74 non-diabetic children who presented at the emergency room due to an acute illness (burns, abdominal pain, fever, head trauma). Patients were asked to complete a detailed questionnaire on their history of personal and familial atopic and autoimmune diseases. In addition, a total serum immunoglobulin E concentration and the presence of IgE[2] antibodies to a panel of relevant inhalant allergens were analyzed.

Results: Children with IDDM and their first-degree relatives had a significantly higher prevalence of other autoimmune diseases such as thyroiditis and celiac as compared to controls. The two groups had a similar prevalence of atopic diseases with respect to history, total serum IgE, or the presence of IgE antibodies to a panel of relevant inhalant allergens.

Conclusions: The prevalence of atopic diseases in IDDM patients was similar to that in the normal population. Our results suggest that the traditional Th1/Th2 theory to explain the complexity of the immune response is oversimplified. 

Background: Ocular hypotony is a common unexplained feature of myotonic dystrophy type 1. Spuriously low applanation tonometric readings can be caused by thin corneas, flat corneal curvature and corneal edema.

Objectives: To determine whether structure abnormalities of the cornea cause spuriously low readings in applanation tonometry.

Methods: We utilized a TMS-2N corneal topographer, a NonconRobo SP-6000 Specular microscope and a Corneo-Gage Plus 1A Pachymeter to examine seven patients with DM1[1] and eight healthy controls. Intraocular pressure, central corneal thickness, and endothelial cell density were measured, and simulated keratometry readings were made. Cornea guttata and irregularity of corneal topography patterns were also sought.

Results: The mean intraocular pressure was 9.86 ± 1.29 mmHg for all patients (intraocular operated and non‑operated eyes) and 12.88 ± 1.89 mmHg for the controls (P = 0.000021, two-tailed t-test). Central corneal thickness was 530.57 ± 35.30 micron for all patients and 535.00 ± 39.62 micron for the controls (P = 0.75, two-tailed t-test). Endothelial cell density was 3164 ± 761 cells/mm² for all patients and 3148 ± 395 cells/mm² for the controls (P = 0.94, two-tailed t-test). Simulated keratometry readings were similar in both groups when the operated eyes were excluded. Cornea guttata and irregularity of corneal topography patterns were also noted in the study group.

Conclusions: Corneal thickness, corneal curvature and corneal hydration were within normal limits and thus were not the cause for the low applanation tonometry reading in DM1. The presence of cornea guttata and irregularity of corneal topography patterns in DM1 warrants further investigation. 

Background: Surgical repair of tetralogy of Fallot may leave the patient with pulmonary regurgitation causing eventual right ventricle dilatation and dysfunction. Predicting clinical deterioration may help to determine the best timing for intervention.

Objectives: To assess whether the clinical and humoral status of patients in the second decade after repair of ToF[1] is worse than that of patients in the first decade after repair.

Methods: Twenty-one patients with repaired ToF underwent clinical assessment, electrocardiogram, echocardiogram and measurement of plasma B-type natriuretic peptide and N-terminal pro-BNP[2] as well as the 6 minute walk distance test. Patients were divided into two groups: group A – less than 10 years after repair (n=10, age < 12 years old), and group B – more than 10 years after repair (n=11, age > 12 years old). The age at repair was similar in both groups.

Results: In all but one patient the distance in the 6 min walk test was less than the minimum for age. RV[3] end-diastolic volume and the 6 min walk test correlated with age. NT-proBNP[4] levels were significantly higher in the ToF group compared to 26 healthy controls (P < 0.0001) and were inversely correlated with RV ejection fraction. Comparison of the two groups showed no difference in RV end-diastolic volume indexed for body surface area, pulmonary regurgitation severity, right or left ventricular myocardial performance index, RV ejection fraction, QRS duration, or 6 min walk indexed to minimum for age.

Conclusions: In this group of patients with similar age at operation and pulmonary regurgitation severity, most clinical, echocardiographic and humoral parameters were not worse in the second decade after repair of ToF. These data suggest that very early pulmonary valve replacement may not be of benefit.

Background: Diabetes mellitus is associated with microvascular and macrovascular diseases, potentially manifested as endothelial dysfunction. In adults with type 2 diabetes the haptoglobin genotype 1-1 has been shown to have a protective role in inhibiting the development of complications. Although complications from type 1 diabetes are infrequent during childhood, endothelial dysfunction, which is an early marker of vascular complications, may occur.

Objectives: To evaluate endothelial function in adolescents with type 1 diabetes before the development of complications and to test for potential relationships between endothelial dysfunction and haptoglobin genotype.

Methods: The study group comprised 15 adolescents with type 1 diabetes. All underwent a general physical examination, diabetes control evaluation (including HbA1c levels), endothelial function assessment and haptoglobin genotype determination.

Results: There was a significant negative correlation between HbA1c levels and endothelial function (r = -0.48, P < 0.05), and HbA1c was significantly higher in patients with endothelial dysfunction than in those with normal endothelial function (9.9 ± 2.2 vs. 7.7 ± 1.0 mg/dl, P < 0.05). In addition, there was a tendency toward a positive correlation between high density lipoprotein and endothelial function (r = 0.4, P < 0.1). There was no correlation between the haptoglobin genotype and endothelial function.

Conclusions: These results show that even in patients without complications, uncontrolled type 1 diabetes is associated with endothelial dysfunction, which may lead to microvascular complications in the future.
 

Background: Type 2 diabetes, an extreme state of glucose intolerance, has been found to be associated with cancer mortality; less is known about impaired glucose tolerance and cancer incidence.

Objectives: To examine the association between fasting and post-load plasma glucose and insulin, and the 20 year incidence of cancer.

Methods: We followed a sample of the Jewish Israeli population (n=2780), free of cancer at baseline,

from 1977-1980 to 1999 for cancer incidence and mortality. Baseline fasting and 1 and 2 hour post-load plasma glucose levels were recorded, as was insulin in 1797 of them.

Results: During 20 years, 329 individuals (11.8%) developed cancer. Cancer incidence for all sites differed between men and women (13.0% and 10.7%, P = 0.03), and among different glucose tolerance status groups (P = 0.01). Cancer incidence hazard ratio, by glucose status adjusted for gender, age, ethnicity, smoking and body mass index, was 1.24 (95%CI 0.96–1.62, P = 0.10) for impaired fasting glucose or impaired glucose tolerance, and 1.32 (95%CI 0.96–1.81, P = 0.09) for type 2 diabetes mellitus, compared to those who were normoglycemic at baseline. Fasting insulin and cancer incidence were not associated.

Conclusions: An increased long-term cancer risk for individuals with impaired fasting glucose or glucose tolerance, or diabetes, is suggested. Even this modest association could have substantial public health consequences.
 

Background: The global spread of tuberculosis necessitates the development of an effective vaccine and new treatment modalities. That requires a better understanding of the differences in regulation of the immune responses to Mycobacterium tuberculosis between individuals who are susceptible or resistant to the infection. Previous immune studies in young Ethiopian immigrants to Israel did not demonstrate anergy to purified protein derivative or a Th2-like cytokine profile.

Objectives: To evaluate the profile of Th1 and Th2 cytokine production in immigrant TB patients, in comparison with asymptomatic control subjects.

Methods: The present study included (part 1): 39 patients with acute TB[1] (group 1), 34 patients with chronic relapsing TB (group 2), 39 Mantoux-positive asymptomatic TB contacts (group 3), and 21 Mantoux-negative asymptomatic controls (group 4). Patients were mainly immigrants from Eastern Europe and Ethiopia. Levels of interferon gamma, interleukin 2 receptor, IL-6[2] and IL-10 were measured in serum and in non-stimulated and PPD[3]-stimulated peripheral blood mononuclear cell culture supernatants, using commercial ELISA kits. In addition (part 2), levels of IFNg[4] and IL-12p40 were evaluated in 31 immigrant Ethiopian patients and 58 contact family members.

Results: Patients with acute disease tended to secrete more cytokines than contacts, and contacts more than chronic patients and controls, without a specific bias. None of the patients showed in vitro anergy. Discriminant probability analysis showed that from the total of 12 available parameters, a cluster of 6 (IFNg-SER[5], IFNg-PPD, IL-2R[6]-SER, IL-10-SER, IL-10-NS[7] and IL-6-PPD) predicted an 84% probability to become a TB contact upon exposure, 71% a chronic TB patient and 61% an acute TB patient. Family-specific patterns of IFNg were demonstrated in the second part of the study.

Conclusions: Firstly, no deficiency in cytokine production was demonstrated in TB patients. Secondly, acute TB patients secreted more cytokines than contacts, and contacts more than unexposed controls. Thus, neither anergy nor a cytokine dysregulation explains susceptibility to acute TB disease in our cohort, although chronic TB patients produced less cytokines than did acute patients and less than asymptomatic contacts. Thirdly, a certain cytokine configuration may predict a trend of susceptibility to acquire, or not acquire, clinical TB. It is presently unclear whether this finding may explain the disease spread in large populations. Finally, the familial association of IFNg secretion levels probably points towards a genetic regulation of the immune response to Mycobacterium tuberculosis. 

Background: In 2003 a total of 43 soldiers in the Israel Defense Forces committed suicide; only 20% of them were known to the IDF[1] mental health services. Somatic symptoms are often the only presentation of emotional distress during the primary care visit and may be the key to early identification and treatment.

Objectives: To examine whether the information in the medical records of soldiers can be used to identify those suffering from anxiety, affective or somatoform disorder.

Methods: We conducted a case-control study using the information in the electronic medical records of soldiers who during their 3 year service developed affective disorder, anxiety, or somatoform disorder. A control group was matched for recruitment date, type of unit and occupation in the service, and the Performance Prediction Score. The number and reasons for physician visits were collated.

Results: The files of 285 soldiers were examined: 155 cases and 130 controls. The numbers of visits (mean SD) during the 3 and 6 month periods in the case and control groups were 4.7 ± 3.3 and 7.1 ± 5.0, and 4.1 ± 2.9 and 5.9 ± 4.6 respectively. The difference was statistically significant only for the 6 month period (P < 0.05). The variables that remained significant, after stepwise multivariate regression were the Performance Prediction Score and the presenting complaints of back pain and diarrhea.

Conclusions: These findings may spur the development of a computer-generated warning for the primary care physician who will then be able to interview his or her patient appropriately and identify mental distress earlier. 

Objectives: To evaluate the safety and efficacy of external counter-pulsation therapy in heart failure patients.

Methods: Fifteen symptomatic heart failure patients (subsequent to optimal medical and device therapy) underwent 35 hourly sessions of ECPT[1] over a 7 week period. Before and after each ECPT session we performed pro-B-type natriuretic peptide and brachial artery function studies, administered a quality of life questionnaire, and assessed exercise tolerance and functional class.

Results: Baseline left ventricular ejection fraction was 28.1 ± 5.8%. ECPT was safe and well tolerated and resulted in a reduction in pro-BNP[2] levels (from 2245 ± 2149 pcg/ml to 1558 ± 1206 pcg/ml, P = 0.022). Exercise duration (Naughton protocol) improved (from 720 ± 389 to 893 ± 436 seconds, P = 0.0001), along with functional class (2.63 ± 0.6 vs. 1.93 ± 0.7, P = 0.023) and quality of life scores (54 ± 22 vs. 67 ± 23, P = 0.001). Nitroglycerine-mediated brachial vasodilatation increased (11.5 ± 7.3% vs. 15.6 ± 5.2%, P =0.049), as did brachial flow-mediated dilation (8.35 ± 6.0% vs. 11.37 ± 4.9%, P = 0.09).

Conclusions: ECPT is safe for symptomatic heart failure patients and is associated with functional and neurohormonal improvement. Larger long-term randomized studies with a control arm are needed to confirm these initial encouraging observations.

Background: The Muslim Circassians in Israel represent a unique ethnic community, distinct from Jews and Arabs. This endogamous group has a limited genetic variability that allows studying risk factors associated with type 2 diabetes.

Objectives: To estimate the prevalence of type 2 diabetes among Israeli Circassians and its correlation to obesity and genetic susceptibility.

Methods: Israeli Circassian women (n=450) and men (n=289) older than 35 were included in the study. They were classified as having or not having diabetes, and their risk factors, including hypertension, body mass index, family history of diabetes, and laboratory tests, were examined retrospectively.

Results: The age-adjusted prevalence of diabetes among the 739 participants was 12% (men 14.6%, women 10.7%). It was higher among those with BMI[1] > 30 than in those with lower BMI and a family history of diabetes without high BMI. But the risk of diabetes with BMI > 30 plus a family history was three times higher than when these factors were missing (odds ratio 2.96, 95% confidence interval 1.30–6.6). Multivariate analysis, however, found familial history of diabetes to be the strongest risk factor, independent of obesity (OR[2] 2.47, 95% CI[3] 1.45–4.20).

Conclusions: The results yielded by this homogeneous Circassian population, sharing the same environmental influences and having an endogamous pattern of marriage, suggest a role of genetic risk factors for diabetes. Israeli Circassians are suitable for additional genetic studies that may lead to the identification of susceptibility genes for type 2 diabetes.

Objectives: To assess the risk of microvascular complications associated with the metabolic syndrome in diabetes subjects.

Methods: The study group comprised 415 diabetic subjects attending a primary care clinic. The prevalence of microvascular complications was compared between 270 diabetic subjects with metabolic syndrome (NCEP-III criteria) and 145 diabetic patients without.

Results: We found that as a group, diabetic subjects with metabolic syndrome had significantly higher frequency of microvascular-related complications than diabetic subjects without the syndrome (46.6% and 26.8% respectively, P = 0.0005). These include microalbuminuria (41.5% vs. 23.9%, P = 0.013), neuropathy (10.4% vs. 7.5%, P = 0.38), retinopathy (9.6% vs. 4.1%, P = 0.046) and leg ulcers (7.9% vs. 2.8%, P = 0.044). After adjustment for age, gender, glycemic control, disease duration, lipid profile and blood pressure, metabolic syndrome was associated with a significantly higher risk of microvascular complications: odds ratio (95% confidence interval) for nephropathy 2.27 (1.53–3.34), neuropathy 1.77 (0.79–4.0), retinopathy 3.42 (1.2–9.87), and leg ulcers 3.57 (1.08–11.95).

Conclusions: In addition to hyperglycemia and disease duration, the metabolic syndrome is a significant risk factor for the development of microvascular complications in diabetic subjects.