New risk and protective factors for severe hypoglycaemia in people with type 1 diabetes.

AIMS: To evaluate risk factors for severe hypoglycaemia (SH) in patients with type 1 diabetes (T1DM). METHODS AND RESULTS: Retrospective observational and comparative study. All SH occurring between 2007 and 2014 in a German population (Lippe-Detmold) were captured. Characteristics of patients with T1DM and SH were compared with a control group being equivalent concerning age, diabetes duration, HbA1c, comorbidity, and ß-blocker treatment. SH was defined as a symptomatic event requiring treatment with intravenous glucose or glucagon administration and being confirmed by a blood glucose measurement of <2.8 mmol/l. Predictive factors for SH were analysed by a multivariable regression model. As many as 405 cases of SH in T1DM occurred in 206 subjects; 50% of episodes were related to 31 patients who experienced ≥3 SH. Need for nursing care (OR 4.88), treatment with NPH (OR 3.68), and impaired hypoglycaemia awareness (OR 2.06) were the strongest risk factors for SH (all p < 0.05, all pFDR-adjusted < 0.10; false discovery rate (FDR)). Depression (OR 0.14), treatment with CSII (OR 0.39) and short-acting insulin analogues (OR 0.31) appeared to be protective (all p < 0.10; FDR-adjusted). The probability of SH onset was significantly higher in patients who had previously experienced recurrent SH episodes. ß-Blocker treatment did not appear to be a risk factor. CONCLUSION: The complex risk for SH in people with T1DM can be reduced by treatment with CSII and short-acting analogues. Future structures of diabetes care will be challenged by the need of treating increasingly geriatric subjects with T1DM having a high risk of SH.

Number and sex ratio of children and impact of parental diabetes in individuals with Type 1 diabetes.

OBJECTIVE: To assess the number and sex ratio of children in individuals with Type 1 diabetes mellitus and the influence of parental diabetes on age at onset of Type 1 diabetes in our cohort. METHODS: In a cross-sectional study in a German region comprising 350,000 inhabitants, 697 subjects with Type 1 diabetes (364 women, 333 men) underwent a standardized assessment regarding the number and sex of their children and the family history of diabetes. RESULTS: Compared with 1.36 children per woman in the German background population, the total fertility rate in the calendar year of 2010 in our female cohort with Type 1 diabetes (age 18-49 years) was 0.88. Men with Type 1 diabetes had a fertility rate of 0.65. More men (51.1%) than women (35.7%; P < 0.0001) were childless. Twenty per cent of all women aged 41-45 years in the background population were childless compared with 36.2% of all women and 52% of all men in this specific age group from our cohort. The sex ratio of female vs. male offspring of individuals with Type 1 diabetes did not differ significantly from the expected 1:1 ratio. Maternal Type 1 or Type 2 diabetes increased the age at onset of Type 1 diabetes from 22.9 ± 13.7 (no maternal diabetes) to 28.6 ± 16.8 and 30.1 ± 15.1 years (p < 0.0001), respectively. CONCLUSIONS: Compared with the German reference population, individuals with Type 1 diabetes had significantly fewer children and were more often childless. The sex ratio female vs. male offspring of women and men with Type 1 diabetes was unaffected. Maternal history of Type 1 and Type 2 diabetes was associated with a significant later onset of Type 1 diabetes.

Gemcitabine induced digital ischaemia and necrosis.

A 70-year-old woman presented with a 7-day history of severe pain, paresthesia, oedema, acrocyanosis and punctate haemorrhagic lesions on her fingertips. The complaints began 2 days after the second cycle of a first-line chemotherapy consisting of cisplatin or carboplatin, and gemcitabine due to advanced urothelial carcinoma. At the fingertips of both hands, haemorrhagic and partly ulcerative lesions were found; these were attributed to vascular toxicity of gemcitabine. Therapeutically sympathicolysis by bilateral blockade of the brachial plexus was performed, accompanied by intravenous administration of the prostacyclin analog iloprost, fractionated heparin subcutaneously and oral therapy with corticosteroids and aspirin. Digital amputation could be avoided. Acral ischemia is a rare but probably underreported adverse effect of gemcitabine therapy and a potential source of misdiagnosis.

[Prevalence of extended-spectrum beta-lactamases of the CTX-M type producing Escherichia coli and Klebsiella pneumoniae in Bretonneau hospitals (CHRU Tours)]. / Prévalence des souches de Escherichia coli et de Klebsiella pneumoniae productrices de beta-lactamases à spectre étendu de type CTX-M à l'hôpital Bretonneau (CHRU de Tours).

The CTX-M type extended spectrum beta-lactamases constitute a rapidly growing cluster of enzymes that have disseminated geographically. This study evaluates the prevalence of these enzymes in the university hospital in Tours, in 2007. Twenty-eight strains were studied: 21 Escherichia coli and seven Klebsiella pneumoniae. The gene bla(CTX-M) was detected by real-time PCR for 27 strains. The CTX-M-1 group, including CTX-M-15, was the most frequent CTX-M-type enzyme.

[1997-2007, 10 years of monitoring the evolution of resistance of Streptococcus pneumoniae to antibiotics in the region Centre; review of the Pneumococcus network]. / 1997-2007, dix ans de suivi de l'évolution de la résistance de Streptococcus pneumoniae aux antibiotiques en région Centre; bilan de l'observatoire du pneumocoque.

Regional pneumococcal observatories in region Centre, created in 1997, participate with the others pneumococcal observatories alongside the National Reference Center for Pneumococci and the Institut de Veille Sanitaire at the monitoring of the evolution of resistance of pneumococci to antibiotics in France. Between 1997 and 2007, 2427 strains of Streptococcus pneumoniae were isolated in part from cerebrospinal fluids, blood and middle ear fluid, from children and adults. The prevalence of pneumococci with a decreased susceptibility to penicillin (PDSP) decreased strongly in region Centre: 56.8 % in 2001, 39.6 % en 2007. These data are similar to the French national data over the same period.

The E23K variant of KCNJ11 and the risk for severe sulfonylurea-induced hypoglycemia in patients with type 2 diabetes.

Severe sulfonylurea-induced hypoglycemia (SH) is a life-threatening and frequently misdiagnosed condition leading to a mortality of up to 10%. Pharmacogenetic factors could be of critical importance for the risk of SH. We investigated the effects of the E23K variant of KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11) on risk for SH in patients with type 2 diabetes (T2D). In a case-control study, the frequency of the E23K KCNJ11 polymorphism of 43 diabetic patients with SH admitted to the emergency department was compared with a matched control group of 54 patients with T2D, but without a history of SH. All patients have been treated with the sulfonylureas glimepiride or glibenclamide. SH was defined as a symptomatic event requiring treatment with intravenous glucose and was confirmed by a blood glucose measurement of <50 mg/dl. The K variant was significantly more frequent in the control group (46%) than in cases with SH (31%) (p=0.04). However, in multivariate logistic regression analyses, age, HbA(1c) and sulfonylurea dose appeared to be the strongest predictors of SH. Nevertheless, in generalized linear model analyses, the E23K variant was significantly associated with increased HbA(1c) levels (adjusted p=0.04) independent of age, sex, body mass index, diabetes duration and sulfonylurea dose. Our data suggest that patients with T2D carrying the K variant of the E23K polymorphism in KCNJ11 have reduced response to sulfonylurea therapy, which results in increased HbA(1c) and consequently in lower risk for SH.

[Pediatric osteoarticular infections caused by Kingella kingae from 1995 to 2006 at CHRU de Tours]. / Infections ostéo-articulaires pédiatriques à Kingella kingae de 1995 à 2006 au CHRU de Tours.

Use of molecular biology shows that Kingella kingae is a pathogen frequently involved in osteoarticular infections in young children. This study describes the cases of osteoarticular infections due to K. kingae which happened from 1995 to 2006 in the CHRU of Tours. The description is based on clinical and biological features. A K. kingae specific polymerase chain reaction was performed in our laboratory in order to improve K. kingae osteoarticular infections diagnosis, and is detailed here.

The insertion/deletion polymorphism in the angiotensin-converting enzyme gene and hypoglycemia awareness in patients with type 1 diabetes.

Impaired hypoglycemia awareness affects approximately 25% of all patients with type 1 diabetes (T1DM). Duration of diabetes and tight glycemic control represent main risk factors of impaired hypoglycemia awareness. However, even among patients with good glycemic control and longstanding T1DM, awareness of hypoglycemia may be intact. Genetic factors might explain some of this remaining variability. Recently, the insertion/deletion ( I/ D) polymorphism in angiotensin converting enzyme gene ( ACE) was shown to be associated with significantly higher risk of hypoglycemic events in subjects with T1DM. Here, we studied the effects of genetic polymorphisms in the ACE on impaired hypoglycemia awareness in 231 Caucasian T1DM patients. Hypoglycemia awareness status was determined using standardized questionnaires (Clarke et al. and Edinburgh Hypoglycemia Scale). ACE I/ D genotype was determined by PCR amplification of the respective fragments from intron 16 of the ACE and size fractionation (I allele frequency=0.49; P=0.74 for Hardy-Weinberg equilibrium). In the logistic regression analysis, significant risk factors of impaired hypoglycemia awareness were duration of diabetes, C-peptide and HbA (1c) (all P<0.01). However, no significant effect of the I/ D polymorphism on impaired hypoglycemia awareness was observed with and without adjustment for age, diabetes duration, C-peptide and HbA (1c). Even though the study provides a relatively large dataset, it is possible that small differences may have been missed.

Targeted disruption of the Insl3 gene causes bilateral cryptorchidism.

The sexual dimorphic position of the gonads in mammals is dependent on differential development of two ligaments, the cranial suspensory ligament (CSL) and the gubernaculum. During male embryogenesis, outgrowth of the gubernaculum and regression of the CSL result in transabdominal descent of the testes, whereas in the female, development of the CSL in conjunction with failure of the gubernaculum development holds the ovaries in a position lateral to the kidneys. Several lines of evidence suggest that regression of the CSL and induction of gubernaculum development are mediated by testosterone and a yet unidentified testicular factor, respectively. The Insl3 gene (originally designated Ley I-L), a member of the insulin-like superfamily, is specifically expressed in Leydig cells of the fetal and postnatal testis and in theca cells of the postnatal ovary. Here we show that male mice homozygous for a targeted deletion of the Insl3 locus exhibit bilateral cryptorchidism with free moving testes and genital ducts. These malformations are due to failure of gubernaculum development during embryogenesis. In double-mutant male mice for Insl3 and androgen receptor genes, testes are positioned adjacent to the kidneys and steadied in the abdomen by the CSL. These findings demonstrate, that the Insl3 induces gubernaculum development in an androgen-independent way, while androgen-mediated regression of the CSL occurs independently from Insl3.

Steroidogenic capacity of isolated adult mouse Leydig cells does not decrease with age.

Leydig cells were isolated from the testes of adult young (5--7 months), old (21 months), and senile (27 months) mice using a highly preservative Percoll procedure. The yield in Leydig cells per testis from young animals was slightly lower than from the old age groups. hCG-induced testosterone synthesis proceeded in a linear fashion for at least 5 h in all three groups. The maximal steroidogenic capacity of cells from old animals was identical to that from young adults. There was no significant difference between Leydig cells from young and old mice with respect to hCG-induced cAMP accumulation and protein kinase activation. Determination of hCG concentrations required for half-maximal stimulation of testosterone synthesis and cAMP accumulation showed identical, or even lower, values in the old age groups. The phenomenon may be connected with the significant augmentation with age of the DNA content per cell (polyploidization), possibly acting as a compensatory mechanism of age-induced deficiencies. Detailed kinetic studies of cAMP accumulation, protein kinase activation, protein kinase activation, and steroidogenesis as well as ultrastructural analyses support the findings of unimpaired or increased capacities of the testosterone-forming cells in old animals. Thus, the aging of Leydig cells appears to differ from that of other tissues of the mouse (e.g. skeletal muscle), which exhibit decreasing abilities to respond to stimuli.

Evidence for production and functional activity of nitric oxide in seminiferous tubules and blood vessels of the human testis.

Previous studies have demonstrated that nitric oxide (NO) influences Leydig cell function. Here we provide evidence for NO production and activity in seminiferous tubules and blood vessels of the human testis. By immunohistochemistry, the soluble guanylyl cyclase (sGC), the intracellular NO receptor, and the second messenger, cyclic guanosine monophosphate (cGMP), were detected in myofibroblasts of the peritubular lamina propria in Sertoli cells, as well as in endothelial and smooth muscle cells of testicular blood vessels. Performed with isolated tubules and blood vessels, the biological activity of sGC could be proved by cGMP generation in response to treatments with the NO donor, sodium nitroprusside. The endothelial and neuronal subtypes of NO synthase (NOS) were localized immunohistochemically to the same cell types that express sGC and cGMP. In isolated tubules and vessels, the presence of endothelial NOS and neuronal NOS was confirmed by immunoblotting, and NOS activity was demonstrated by decreased cGMP production upon incubation with the NOS inhibitor L-nitro arginine methylester. These findings show that peritubular cells, Sertoli cells, and testicular blood vessels may be sites of NO production and activity, possibly involved in relaxation of seminiferous tubules and blood vessels to modulate sperm transport and testicular blood flow, respectively.

Risk of hypoglycaemia with oral antidiabetic agents in patients with Type 2 diabetes.

In patients with Type 2 diabetes, the appropriate intensity of glucose control is determined by age, life expectancy, and the presence of concomitant disease. Geriatric patients are especially susceptible to hypoglycaemia and therefore particular care should be taken in this group characterized by polypharmacy, renal or hepatic dysfunction, cardiovascular multimorbidity and malnutrition. As hypoglycaemia is a significant cause of morbidity and mortality, treatment regimens for diabetes should minimize the occurrence of hypoglycaemic episodes and be tailored to the patient's individual needs. The pharmacological options for treating Type 2 diabetes have increased considerably and the risk of hypoglycaemia of the currently available drugs varies considerably. Metformin, thiazolidinediones, and acarbose, oral antidiabetic drugs that decrease insulin resistance or postprandial glucose absorption, are associated with a low risk of hypoglycaemia. These drugs can also be used effectively in various combination regimens; however, by improving insulin sensitivity, combinations of metformin and thiolidinediones with sulphonylureas or meglitinides may considerably increase the risk of hypoglycaemia. On account of its complex pharmacoprofile glibenclamide is a problematic substance carrying a high risk of hypoglycaemia. There are limited preliminary data indicating that, under routine conditions, glimepiride may be associated with a lower risk of hypoglycaemia than glibenclamide and is no more likely to cause hypoglycaemia than other shorter-acting agents such as gliclazide and glipizide. Nateglinide and repaglinide as short-acting insulin secretagogues may be associated with a reduced risk of hypoglycaemia compared with glibenclamide, in particular when dosed flexibly. Repaglinide might be beneficial in individuals with renal impairment.

Clinical characterisation of severe hypoglycaemia--a prospective population-based study.

AIM: To determine the clinical characteristics of severe hypoglycaemia (SH) in a nonselected German population. SH was defined as an event requiring intravenous glucose or glucagon injection. METHODS: The prospective population-based study screened sensitively for SH in a region with 200,000 inhabitants between 1997 and 2000. All 30,768 patients who presented to the regional central hospital emergency department, and 6,631 (85 %) of 7,804 patients attended by the emergency medical service in the region were given an initial blood glucose test to detect atypical hypoglycaemia. RESULTS: Altogether, 264 cases of SH were registered, which occurred either spontaneously (n = 14; 5 %), in subjects with type 1 (n = 92; 35 %) or type 2 diabetes (n = 148; 56 %), or in subjects with a non-classified form of diabetes (n = 10; 4 %). On the basis of the estimated local number of diabetic patients the annual rate of SH was 1.5 episodes per 100 patients in insulin-treated type 2 diabetics compared with a rate of 0.4 episodes per 100 patients for the overall group of type 2 diabetic patients. Nocturnal hypoglycaemia accounted for 44 % of episodes in patients with type 1 diabetes on intensified therapy but for only 25 % in patients with type 2 diabetes. 26 % of the hypoglycaemic individuals with type 1 diabetes had an impaired awareness of hypoglycaemia and thus recurrent hypoglycaemic episodes. Irrespective of the treatment, the most frequent contributing factors for SH in type 2 diabetic patients were advanced age (76 +/- 12 years), multimorbidity (3.6 +/- 2.6 concomitant diseases)--in particular renal impairment (54 % [80/148])--and polypharmacy (4 +/- 2.7 concomitant drugs). 34 % (50/148) of the subjects with type 2 diabetes lived in nursing homes or were cared for by a home nursing service. With standardised treatment zero mortality of SH in diabetic patients was achieved, only one non-diabetic died due to hepatic failure. CONCLUSION: In elderly, multimorbid patients approaching the insulin-deficient end of the spectrum of type 2 diabetes the risk of developing SH increases considerably, nearing that in patients with type 1 diabetes. In order to avoid SH in geriatric patients, the treatment targets should be defined critically, taking into account individual quality of life and life expectancy. Hypoglycaemia unawareness is a major risk factor for SH in type 1 diabetes.

Lipodystrophy and metabolic disorders as complication of antiretroviral therapy of HIV infection.

Peripheral lipodystrophy, central adiposity, hyperlipidaemia, insulin resistance, and diabetes mellitus, in varying constellations, are frequent complications of highly active antiretroviral therapy in HIV1-infected patients. The pathogenetic significance of protease inhibitors toxicity has been demonstrated by the partial reversal of metabolic disorders after switching to other antiretroviral regimens. The therapeutic and prognostic implications of these metabolic disorders are not yet clear. The dramatic improvements in the prognosis and quality of life of people with HIV since the introduction of highly active antiretroviral therapy call for evidence based concepts for the management of treatment-related metabolic disturbances.

Hormonal counterregulation during severe hypoglycaemia under everyday conditions in patients with type 1 and insulin-treated type 2 diabetes mellitus.

AIM: To determine the counterregulatory hormonal responses to severe hypoglycaemia (SH) in type 1 versus insulin-treated type 2 diabetic patients under everyday conditions. METHODS: Counterregulatory hormones were determined in 28 consecutive type 1 and thirteen insulin-treated type 2 diabetic patients (age 54 +/- 18 vs. 75 +/- 13 yrs; diabetes duration 27 +/- 16 vs. 21 +/- 6 yrs) with SH requiring emergency treatment. Blood samples were taken prior to and after effective treatment of SH. SH was defined as an event with neuroglycopenic presentation requiring external intervention by administration of intravenous glucose or oral carbohydrates. 68 % (19/28) of type 1 diabetic patients but none of those with type 2 diabetes had reduced awareness of hypoglycaemia. RESULTS: Plasma glucose levels were 30 +/- 14 prior to and 179 +/- 82 mg/dl after treatment of SH; the time between the two measurements was 54 +/- 26 minutes. With the exception of higher levels of human growth hormone in type 1 patients - which were attributed to younger age - the other counterregulatory responses to SH showed no significant differences in type 1 vs. type 2 diabetic patients. In both groups glucagon responses were virtually absent while moderate catecholamine responses could be demonstrated. Treatment with beta-blockers did not affect hormonal counterregulation in type 1 diabetic patients. CONCLUSIONS: In patients approaching the insulin-deficient end of the spectrum of type 2 diabetes the hormonal responses to SH are comparable to those in patients with longstanding type 1 diabetes. Thus, in advanced type 2 diabetes the risk of developing SH may be similar to that in individuals with type 1 diabetes.

Endothelin and endothelin receptors A and B in the human testis.

Human testicular capillaries interconnect Leydig cells and seminiferous tubules. Microcirculation and blood flow are therefore essential for the maintenance of spermatogenesis. The expression and the localisation of ET (endothelin) and its receptors in testicular tissue, in seminiferous tubules and in human testicular capillaries were studied. ET-1 mRNA was detected in whole testicular tissue and in seminiferous tubules whereas isolated testicular capillaries were negative. Big ET-1 (Big endothelin 1) and ET peptides were localised in Leydig and Sertoli cells whereas interstitial and intramural capillaries (within the lamina propria) remained unstained. ET was also found in mature spermatids. ET-A (endothelin receptor A) mRNA was detected in seminiferous tubules and whole testicular tissue whereas testicular blood vessels were negative. ET-A immunostaining was displayed in Leydig and Sertoli cells and in spermatids. ET-B (endothelin receptor B) mRNA was detected in whole testicular tissue, seminiferous tubules and in testicular capillaries. ET-B peptide was prominent in Leydig cells, peritubular cells, endothelial cells and pericytes of interstitial and intramural capillaries as well as in vascular endothelial and smooth muscle cells. From these results we conclude that ET produced in Leydig and Sertoli cells can act in a paracrine manner via ET-B on the human testicular microvasculature and the peritubular cells. The presence of both ET-A and ET-B in Leydig cells and of ET-A in Sertoli cells leads to the assumption that ET could influence these cells as an autocrine factor.

Blood glucose self-monitoring from abdominal skin: a precise and virtually pain-free method.

For many diabetic patients, years of blood glucose self-monitoring (SM) with readings taken several times daily is an inevitable aspect of insulin therapy. We investigated whether SM from abdominal skin might be an alternative to the established fingertip method. A total of 63 diabetic patients and 16 nondiabetic volunteers determined their blood glucose in parallel in capillary blood from the tip of the finger and from abdominal skin 5 times daily on 5 successive days. The blood samples were collected from the two test regions using lancing devices, and the SM determinations were all done with a meter. Consecutive specific enzymatic glucose determinations in blood from the fingertip served as the reference method. The results of the SM from abdominal skin, a method perceived as virtually painless, were in close correlation with the control laboratory determinations and with SM from the finger (Pearson's r, 0.94 and 0.95). The comparison of SM method for abdomen vs. finger laboratory control gave a linear regression equation of y=8.35+0.94x (r=0.94). Error grid analysis revealed: range A, 93.6%; range B, 5.4%; range C, 0.05%; range D, 1.0%; and range E, 0%. Bland and Altman analysis yielded the mean of the differences, 0.2 mg/dl; 2 SD, 32 mg/dl; minimum, -162 mg/dl; maximum, 148 mg/dl. Laboratory glucose determinations in capillary blood from the fingertip and from abdominal skin led in 99.7% of the cases to concordant therapeutic decisions in the diabetics; the sample material was therefore equivalent. The practical aspects (afterbleeding, number of punctures, test strip consumption) of SM from the two regions showed no essential differences. However, only 22% of the diabetic patients investigated continued to perform SM from abdominal skin on a longer basis. In a further 5 adipose diabetic patients (BMI, 32 kg/M2), SM from abdominal skin was not practicable, as there was insufficient blood to collect. SM from abdomal skin is a simple, virtually pain-free and precise method. It provides certain diabetic patients with an alternative to the established method of SM from the fingertip.