More recent, better designed studies have weakened links between antidiabetes medications and cancer risk.

BACKGROUND: An increasing number of studies have investigated associations of antidiabetes medications with cancer risk. Antidiabetes medications are classified by their mechanisms of action on tissues and organs. They potentially act as both causative and confounding factors in the temporal association of diabetes and cancer. AIM: To present the current evidence regarding both the carcinogenic and anti-carcinogenic effects of antidiabetes medications on cancer in humans. METHODS: A review of the scientific literature. RESULTS: The most conclusive evidence shown of an association of antidiabetes medication with a specific cancer was for that of the thiazolidinedione pioglitazone with bladder cancer. Currently, there is inconclusive evidence regarding a possible association of incretin therapies, drugs of the dipeptidyl peptidase-4 inhibitor class, with the risk of pancreatic cancer. Insulin, sulfonylureas, metformin and sodium-glucose co-transporter-2 inhibitors appear not to be associated with increased risk of any cancer. Sparse evidence suggests possible protective effects against cancer incidence of metformin, sulfonylureas, thiazolidinediones, incretin-based drugs and sodium-glucose co-transporter-2 inhibitors. CONCLUSION: The conflicting evidence regarding associations of antidiabetes medications with cancer risk is apparently attributable to both methodological issues and to the complexity of the subject. More recent and better-designed studies have weakened the evidence for links between antidiabetes medications and cancer risk.

A historical cohort study on glycemic-control and cancer-risk among patients with diabetes.

AIMS: This population-based historical cohort study examined whether poor glycemic-control (i.e., high glucose and HbA1c blood levels) in patients with diabetes is associated with cancer-risk. METHODS: From a large healthcare database, patients aged 21-89 years, diagnosed with diabetes before January 2002 (prevalent) or during 2002-2010 (incident), were followed for cancer during 2004-2012 (excluding cancers diagnosed within the first 2 years since diabetes diagnosis). Risks of selected cancers (all-sites, colon, breast, lung, prostate, pancreas and liver) were estimated according to glycemic-control in a Cox regression model with time-dependent covariates, adjusted for age, sex, ethnic origin, socioeconomic status, smoking and parity. Missing glucose or HbA1c values were imputed. RESULTS: Among 440,000 patients included in our analysis, cancer was detected more than 2 years after diabetes diagnosis in 26,887 patients (6%) during the follow-up period. Associations of poor glycemic-control with all-sites cancer and most specific cancers were either null or only weak (hazard ratios (HRs) for a 1% HbA1c or a 30 mg/dl glucose increase between 0.94 and 1.09). Exceptions were pancreatic cancer, for which there was a strong positive association (HRs: 1.26-1.51), and prostate cancer, for which there was a moderate negative association (HRs: 0.85-0.96). CONCLUSION: Overall, poor glycemic-control appears to be only weakly associated with cancer-risk, if at all. A substantial part of the positive association with pancreatic cancer is attributable to reverse causation, with the cancer causing poorer glycemic-control prior to its diagnosis. The negative association with prostate cancer may be related to lower PSA levels in those with poor control.

The joint association of self-rated health and diabetes status on 14-year mortality in elderly men and women.

PURPOSE: Low self-rated health (SRH) has been found to be associated with increased risk of type 2 diabetes (T2D) and with mortality. We examined the possible interaction between SRH and diabetic state on all-cause mortality in a large cohort of elderly subjects, followed for 14 years. METHODS: During the years 2000-2004, survivors of the nationwide longitudinal Israel Study of Glucose Intolerance, Obesity and Hypertension were interviewed and examined for the third follow-up. The 1037 participants (mean age 72.4 ± 7.2 years) were asked to rate their health as: excellent, good, fair, poor, or very poor. Glucose categories were as follows: Normoglycemic, Prediabetes, T2D and Undiagnosed diabetes. Survival time was defined as the time from interview to date of death or date of last vital status follow-up (August 1, 2013). Multivariate Cox proportional hazards models were performed in order to assess whether SRH interacts with glycemic state in the association with mortality. RESULTS: A better SRH was reported by those with undiagnosed than known diabetes, and best for normoglycemic and prediabetic individuals. While all individuals with fair or poor/very poor SRH were at increased risk of mortality compared to those with excellent/good SRH, in the known diabetic individuals a greater hazard was observed in the excellent/good SRH (HR 3.32, 95 % CI 1.71-6.47) than in those with fair or poor/very poor SRH (HR 2.19, 95 % CI 1.25-3.86), after adjusting for age, sex, ethnic origin, marital status, education, BMI, physical activity, CVD, tumors, and creatinine level (p for interaction = 0.01). CONCLUSIONS: Self-rated health is not a sensitive tool for predicting mortality in elderly men and women with known T2D.

One-hour post-load plasma glucose level during the OGTT predicts mortality: observations from the Israel Study of Glucose Intolerance, Obesity and Hypertension.

AIMS: The relationship between 1- and 2-h glucose levels following an oral glucose tolerance test (OGTT) and long-term mortality was evaluated. METHODS: Over a 33-year period, 2138 individuals were followed for all-cause mortality. Fasting and post-OGTT glucose parameters categorized the cohort according to baseline glycaemic status. Four categories were established according to 1- and 2-h glucose levels (in mmol/l): group A = 1 h ≤ 8.8 and 2 h < 7.8; group B = 1 h > 8.6 and 2 h < 7.8; group C = 1 h ≤ 8.6 and 2 h = 7.8-11.1 (impaired glucose tolerance); group D = 1 h > 8.6 and 2 h = 7.8-11.1 (impaired glucose tolerance). Individuals with diabetes at baseline were excluded from the cohort. RESULTS: By August 2013, 51% of the study cohort had died. The worst prognosis occurred in group D (73.8% mortality), followed by groups C (67.5%), B and A (57.9% and 41.6%, respectively). When the 2-h glucose value is 'normal' (< 7.8 mmol/l), the 1-h glucose value > 8.6 mmol/l is an important predictor of mortality (28% increased risk) compared with group A, controlling for sex, age, smoking, BMI, systolic and diastolic blood pressures. A gradual increased hazard for mortality was seen by study group (hazard ratio = 1.28, 1.60 and 1.76, for groups B, C and D, respectively; group A = reference). CONCLUSIONS: A 1-h glucose value > 8.6 mmol/l predicts mortality even when the 2-h level is < 7.8 mmol/l. However, when the 2-h level is in the impaired glucose tolerance range, the hazard for mortality rises significantly independent of the 1-h value. Individuals at risk for developing diabetes could be identified earlier using the 1-h threshold value of 8.6 mmol/l, which could avert progression to diabetes and increased mortality.‬.

Cardiovascular and all-cause mortality in relation to various anthropometric measures of obesity in Europeans.

BACKGROUND AND AIMS: Cardiovascular and all-cause mortality in relation to various anthropometric measures of obesity is still controversial. METHODS AND RESULTS: Body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), waist-to-hip ratio (WHR), A Body Shape Index (ABSI) and waist-to-hip-to-height ratio (WHHR) were measured at baseline in a cohort of 46,651 European men and women aged 24-99 years. The relationship between anthropometric measures of obesity and mortality was evaluated by the Cox proportional hazards model with age as a time-scale and with threshold detected by a piecewise regression model. Over a median follow-up of 7.9 years, 2381 men and 1055 women died, 1071 men (45.0%) and 339 women (32.1%) from cardiovascular disease (CVD). BMI had a J-shaped relationship with CVD mortality, whereas anthropometric measures of abdominal obesity had positive linear relationships. BMI, WC and WHtR showed J-shaped associations with all-cause mortality, whereas WHR, ABSI and WHHR demonstrated positive linear relationships. Accordingly, a threshold value was detected at 29.29 and 30.98 kg/m(2) for BMI, 96.4 and 93.3 cm for WC, 0.57 and 0.60 for WHtR, 0.0848 and 0.0813 m(11/6) kg(-2/3) for ABSI with CVD mortality in men and women, respectively; 29.88 and 29.50 kg/m(2) for BMI, 104.3 and 105.6 for WC, 0.61 and 0.67 for WHtR, 0.95 and 0.86 for WHR, 0.0807 and 0.0765 for ABSI in men and women, respectively, and 0.52 for WHHR in women with all-cause mortality. CONCLUSION: All anthropometric measures of abdominal obesity had positive linear associations with CVD mortality, whereas some showed linear and the others J-shaped relationships with all-cause mortality. BMI had a J-shaped relationship with either CVD or all-cause mortality. Thresholds detected based on mortality may help with clinical definition of obesity in relation to mortality.

Comparison of various surrogate obesity indicators as predictors of cardiovascular mortality in four European populations.

BACKGROUND/OBJECTIVES: Body mass index (BMI) is the most commonly used surrogate marker for evaluating the risk of cardiovascular disease (CVD) mortality in relation to general obesity, while abdominal obesity indicators have been proposed to be more informative in risk prediction. SUBJECT/METHODS: A prospective cohort study consisting of 46 651 Europeans aged 24-99 years was conducted to investigate the relationship between CVD mortality and different obesity indicators including BMI, waist circumference (WC), waist-to-hip ratio (WHR), waist-to-stature ratio (WSR), A Body Shape Index (ABSI) and waist-to-hip-to-height ratio (WHHR). Hazard ratio (HR) was estimated by the Cox proportional hazards model using age as timescale, and compared using paired homogeneity test. RESULTS: During a median follow-up of 7.9 years, 3435 participants died, 1409 from CVD. All obesity indicators were positively associated with increased risk of CVD mortality, with HRs (95% confidence intervals) per standard deviation increase of 1.19 (1.12-1.27) for BMI, 1.29 (1.21-1.37) for WC, 1.28 (1.20-1.36) for WHR, 1.35 (1.27-1.44) for WSR, 1.34 (1.26-1.44) for ABSI and 1.34 (1.25-1.42) for WHHR in men and 1.37 (1.24-1.51), 1.49 (1.34-1.65), 1.45 (1.31-1.60), 1.52 (1.37-1.69), 1.32 (1.18-1.48) and 1.45 (1.31-1.61) in women, respectively. The prediction was stronger with abdominal obesity indicators than with BMI or ABSI (P<0.05 for all paired homogeneity tests). WSR appeared to be the strongest predictor among all the indicators, with a linear relationship with CVD mortality in both men and women. CONCLUSIONS: Abdominal obesity indicators such as WC, WHR, WSR and WHHR, are stronger predictors for CVD mortality than general obesity indicator of BMI.

A simplified severity score for acute asthma exacerbation.

BACKGROUND: To evaluate a simplified severity score designed to facilitate decision making in the Emergency Department (ED) regarding hospital admission of young adult patients with acute asthma exacerbation (AAE). METHODS: All AAE-related ED encounters during two calendar years of patients aged 17-35 years were retrospectively classified as "mild", "moderate" or "severe", according to vital and readily available signs and symptoms, including pulse rate, presence of respiratory wheezes, rales or prolonged expirium, oxygen saturation, and the use of accessory muscles, measured upon arrival to the ED. All medical records of ED and hospital admissions were reviewed for treatment and outcomes. RESULTS: During the study period, 723 AAE-related ED encounters were recorded among 551 asthma patients. Of them, 35.0% were classified as "mild", 37.9% "moderate" and 27.1% "severe". For increasing levels of AAE severity, hospital admission rate increased (11.5%, 42.0%, 61.2%, respectively, p < 0.001). Adjusting for age and sex, odds ratios for hospitalization were 12.2 (95% CI: 7.5-19.9) and 5.6 (95% CI: 3.5-8.9) for the "severe" and "moderate" categories, respectively, compared to the "mild" category. "Mild" asthma patients also had shorter length of hospital stay and none required mechanical ventilation or died during hospitalization. CONCLUSION: The simplified asthma severity score requires no additional tests or costs in the ED, and could facilitate the decision of whether to hospitalize or discharge adult AAE patients. Prospective validation of this tool is needed.

Basal state hyperinsulinemia in healthy normoglycemic adults heralds dysglycemia after more than two decades of follow up.

BACKGROUND: In a preliminary report, we found an association between hyperinsulinemia in the basal (fasting) state and the development of diabetes. OBJECTIVES: The current analysis further explored the long term link between basal hyperinsulinemia and conversion to dysglycemia. METHODS: This is a prospective study with up to 24 years of follow-up of 515 normoglycemic individuals (mean age at follow up = 70.3 ± 7.0; range 58-94) of an Israeli cohort. Fasting glucose and insulin were measured, and dysglycemia was defined as fasting glucose > 100 mg/dL. RESULTS: At the end of the follow-up period, almost half had progressed to dysglycemia. Male sex and elevated baseline levels of basal insulin, body mass index, blood glucose and blood pressure each favoured progression to dysglycemia over the subsequent two decades. A multivariate logistic regression model identified basal hyperinsulinemia as the strongest predictor for progression to dysglycemia (odds ratio = 1.79; 95% confidence interval 1.12-2.88), while controlling for ethnicity, blood pressure, fasting glucose, male sex, body mass index and age. CONCLUSIONS: Basal hyperinsulinemia in normoglycemic adults constitutes an independent risk factor for metabolic deterioration to dysglycemia over adulthood, and may help to identify apparently healthy subjects at increased risk for diabetes.

How the immunoassay transformed C-peptide from a duckling into a swan.

This edition of 'Then and now' re-examines Lise Heding's very highly cited paper 'Radioimmunological determination of human C-peptide in serum', which was published in Diabetologia in 1975. We show how this article and other related articles by Heding contributed to heightened respect for C-peptide (and transformation of Heding's research programme). Initially thought of as an inert discard, C-peptide in blood is now recognised as an excellent surrogate measure of insulin secretion under a wide range of conditions. The assay is especially valuable for acute ascertainment of the insulin secretory capabilities of patients with type 1 diabetes or of transplanted beta cells. The assay is also being used to monitor endogenous beta cell loss or in vivo expansion of beta cell mass over the long term. We conclude with two promising future applications: (1) measurements of C-peptide in blood (along with insulin, glucose, and HbA(1c)) at annual intervals as a potential approach to earlier diagnosis of diabetes; and (2) among many recent advances in recognising properties of C-peptide (including status as a candidate hormone), most promising is C-peptide as a possible therapy for diabetic neuropathy and nephropathy.

Various contract settings and their impact on the cost of medical services.

OBJECTIVES: This study analyzes the effect of outsourcing healthcare on career soldiers in the Israel Defense Forces (IDF) in different settings, so as to develop a model for predicting per capita medical costs METHODS: Demographic information and data on healthcare utilization and costs were gathered from three computerized billing database systems: The IDF Medical Corps; a civilian hospital; and a healthcare fund, providing services to 3,746; 3,971; and 6,400 career soldiers, respectively. Visits to primary care physicians and specialists, laboratory and imaging exams, number of sick-leave days, and hospitalization days, were totaled for men and women separately for each type of clinic. A uniform cost was assigned to each type of treatment to create an average annual per capita cost for medical services of career soldiers. RESULTS: Significantly more visits were recorded to primary care physician and to specialists, as well as imaging examinations by Leumit Healthcare Services (LHS), than visits and tests in hospitals or in military clinics (p < 0.001). The number of referrals to emergency rooms and sick-leave days were lowest in the LHS as compared to the hospital and military clinics (p < 0.001). The medical cost per capita/year was lowest in LHS as well. CONCLUSIONS: Outsourcing primary care for career soldiers to a civilian healthcare fund represents a major cost effective change, lowest consumption and lower cost of medical care. Co-payment should be integrated into every agreement with the medical corps.

A survey of sports injuries among a convenience sample of Israeli athletes.

BACKGROUND: Israel lacks a systematic surveillance of sports injuries, and knowledge of risk factors and specific patterns of injury is inadequate. In order to promote prevention of sports-related injuries, the magnitude of the problem must first be identified and the incidence and severity of sports injuries described. OBJECTIVE: To conduct a survey on previous sports injuries among a sample of Israeli athletes. METHODS: A convenience sample of Israeli amateur athletes participating in the 1997 15th Maccabiah Games was randomly selected. The study group answered an anonymous self-administered questionnaire that included sociodemographic data, and information regarding their sports activity and sports-related injuries that had occurred during the previous 2 years. RESULTS: The study group, aged 12-73 years (median age 21), comprised 301 consenting athletes in 28 different sports. Of these athletes 56.1% reported having had at least one injury. Most injuries (75.6%) involved the upper and lower extremities, and 37.8% of the injured sportsmen had received medical attention from a physician. Half of the athletes participated in contact sports--both collision and limited impact. This group had a much greater proportion of reported injuries in all age groups. CONCLUSION: Surveillance of sports injuries should be expanded in order to develop appropriate prevention programs in Israel.

Cultural elements of postpartum depression. A study of 327 Jewish Jerusalem women.

OBJECTIVE: To examine the social, cultural and religious factors underlying postpartum depression within a cultural cross-section of Jewish Jerusalem women. STUDY DESIGN: A prospective, repeated-measures study of 327 women. The Edinburgh Postpartum Depression Scale (EPDS) was administered immediately postpartum and 6-10 weeks later. Detailed sociodemographic information included perceptions of the pregnancy, community supports and religious affiliation. Odds ratios, 95% confidence interval and P values were calculated for all covariates. Multiple logistic regression was performed to estimate the degree of independent association between religiosity and postpartum depression. RESULTS: Postpartum depressive symptoms significantly associated with secular affiliation (odds ratio [OR] 2.9 [1.3-6.3] and tended toward an inverse association with orthodox affiliation (OR 0.6 [0.3-1.3]). Across secular, traditional, religious and orthodox groups, there was a decreasing trend in EPDS mean scores. Other predictors of depressive symptoms were psychiatric history, immigrant status and poor support with newborn care. CONCLUSION: Our study sample was particularly suitable for the assessment of cultural and religious elements of postpartum depression. We found religiosity, with its associated social and community structuring and well-defined social roles, to be significantly associated with self-reported postpartum depressive symptoms. These findings suggest that cultural factors, including role definitions, community support and rituals, may explain discrepancies found in the incidence of postpartum depression.

A retrospective study of epinephrine administration for anaphylaxis: how many doses are needed?

The precise amount of epinephrine needed to reverse severe symptomatology due to an anaphylactic reaction is unknown. We tried to determine how frequently more than one injection of epinephrine is required to treat an anaphylactic reaction. A retrospective review of patient charts with anaphylactic reactions requiring epinephrine, in response to inhalant allergen and hymenoptera venom immunotherapy as well as live hymenoptera stings, examined type of reaction; number, doses, and timing of epinephrine administered; and ancillary treatment. A total of 105 anaphylactic reaction events of varying severity (Ring's classification) were recorded (54--Grade I, 29--Grade II, 18--Grade III, 0--Grade IV, 4--unknown). The median epinephrine dose administered was 0.3 cc (range 0.1 to 0.8 cc, 1:1000). The timing of the first epinephrine injection was < or = 5 minutes in 27, 6-10 minutes in 13, 11-30 minutes in 16, < or = 30 minutes in 32, 31-60 minutes in 12, and > 60 minutes in five epinephrine treated patients. Overall, 38 patients (35.5%; CI95, 26.4-44.6%) required > 1 epinephrine injection. Of these, 11 experienced Grade I (11/54-20.3%; CI95, 9.6-31.0%), 12--Grade II (12/29-41.5%, CI95, 23.5-59.3%), and 13--Grade III (13/18-72.2%, CI95, 51.5-92.9%); reactivity was unknown in 2 patients. Forty-four patients also received an antihistamine, 10 received corticosteroids, and 30 received both medications and/or other ancillary therapy. A significant number of patients (> 35%) with anaphylactic reactions received greater than one epinephrine dose to manage events for the three classes of severity. Patients at risk for anaphylaxis and their caregivers need to recognize that more than one dose of epinephrine may be required for treatment of anaphylaxis.

Gynecomastia following spinal cord disorder.

Gynecomastia, an excessive development of the mammary glands in men, is a known phenomenon among patients with spinal cord disorder, yet in the last 50 years it has not been fully described in relation to spinal cord disorder. Over a period of 2 years, six patients with spinal cord disorder (4 secondary to a traumatic injury, 1 to decompression sickness, and 1 to transverse myelitis) manifested gynecomastia. The onset of gynecomastia occurred between 1 to 6 months after injury. These patients are presented along with a review of the possible causes for gynecomastia and a suggested workup routine. A clinical examination for the presence of gynecomastia should be performed for every patient with spinal cord disorder and a thorough endocrinological workup should follow to rule out malignancy and reassure the anxious patient undergoing a disruption of his body image.

Postnatal depression: a prospective study of its prevalence, incidence and psychosocial determinants in an Israeli sample.

OBJECTIVE: To assess the prevalence and incidence of postnatal depression and its relation to certain psychosocial factors. METHOD: A questionnaire was administered to 327 randomly selected pregnant women on the first or second postpartum day A and again 6 to 12 weeks later B. The questionnaire comprised a psychosocial and demographic self-report, and the 10-item Edinburgh Postnatal Depression Scale (EPDS). RESULTS: At time A the prevalence of postnatal depression was 9.9-22.3%, and at time B it was 5.2-12.4% (p < 0.0001). Four of the psychosocial determinants examined correlated significantly with depression at times A and B. These factors were: a positive psychiatric history, Oriental ethnic origin, being foreign born, inconvenient timing of pregnancy. CONCLUSION: Postnatal depression was less common than in most reported series. It was related to marital and social support, the circumstances of the pregnancy, and the degree of religious observance. Postnatal depression is a specific disorder, not equivalent to depression in the prenatal period.

Aspirin desensitization in aspirin-sensitive asthma: failure to maintain a desensitized state during prolonged therapy.

A patient with a history of asthma induced by acetylsalicylic acid (ASA) was found to be ASA sensitive when orally challenged with ASA. She was successfully desensitized using incremental doses of ASA given orally and maintained on ASA or other nonsteroidal antiinflammatory (NSAI) agents for the treatment of arthritis. After 6 months of uninterrupted therapy the patient developed asthmatic symptoms that were related to ASA and NSAI drug therapy. Although desensitization may be achieved in patients with ASA-sensitive asthma, sensitivity may recur despite continuous therapy.

Suggestive evidence for both stimulatory and inhibitory domains on human lymphocytes, as indicated by phospholipid turnover studies with wheat germ agglutinin and other lectins.

Short term effects (1 hours or less) of various lectins on phospholipid turnover in human lymphocytes were studied. As expected, concanvalin A and phytohemagglutinin produced 1,5-4.0 fold increases in incorporation of 32PO4 radioactivity into phospholipids (primarily phosphatidylinositol). Wheat germ agglutinin, a nonmitogenic lectin, not only failed to produce a response but actually inhibited phospholipid turnover, both in the presence and absence of PHA or con A. Since wheat germ agglutinin did not appear to be cytotoxic, as defined by a failure to see changes in vital dye uptake, and other evidence from our laboratory indicates that this lectin also inhibits aminisobutyric acid transport and DNA synthesis in human lymphocytes we would tentatively interpret its negative action as indicating the existence of specific inhibitory domains on the cell surface.

Cyclic GMP and lectin-induced lymphocyte activation.

Purified human peripheral lymphocytes incubated with the mitogenic plant lectins phytohemagglutinin and concanavalin A were examined for alterations in intracellular cGMP and cAMP under a variety of experimental conditions and using multiple techniques for the isolation and purification of cGMP and cAMP before assay of the cyclic nucleotides by radioimmunoassay. In contrast to work reported by others, we have been unable to demonstrate consistent increases in cGMP under any of the experimental conditions used and with any of the various purification schemes. In these same experiments exogenous cGMP added to the lymphocytes could be measured, and the immunoreactive material was destroyed by cyclic nucleotide phosphodiesterase, indicating that our inability to measure increases in cGMP was not caused by our inability to measure cGMP. Under identical experimental conditions, small but consistent and statistically significant increases in cAMP were noted. In addition, other parameters of lymphocyte activation, 45Ca uptake (an early parameter), and incorporation of 3H thymidine into DNA were unimpaired. These data call to question the concept of cGMP as the second messenger in lectin-stimulated human peripheral lymphocytes.