[Renal aspects of sodium glucose cotransporter 2 inhibitors]. / Les inhibiteurs du cotransporteur SGLT2 comme nouveau traitement du diabète: aspects rénaux.

It has been known for centuries that the kidneys play a role in glucose homeostasis, yet the underlying tubular mechanisms have only been recently identified by studying patients with familial glucosuria. These insights have lead to the commercialization of a novel class of oral antidiabetic agents named gliflozines. Gliflozines induce renal glucosuria by blocking the Na-glucose cotransporter SGLT2, localized in the proximal tubule, and allow a reduction of 0.5 to 1% of glycated hemoglobin. They also diminish proximal sodium reabsorption, and reduce the glomerular hyperfiltration that is often seen in the early stages of diabetes. Preliminary data suggest that they may decrease blood pressure and have renoprotective effects. This article provides an overview of the role of kidneys in glucose homeostasis and the renal effects of SGLT2-inhibitors.

[Diabetes and end stage renal disease. Eight year progression in the Canton de Vaud, Switzerland]. / Diabète et insuffisance rénate terminate. Evolution en huit ans dans le canton de Vaud.

Diabetic nephropathy is the first cause of endstage renal disease. The demographic expansion, the increase in the incidence of diabetes and the prolonged survival rates explain the steep increase observed these last 30 years. In the United States, improved treatment has brought to a decline in the incidence of end-stage renal disease in the diabetic population since the mid nineties. We examined the change in prevalence of diabetics on dialysis from 2001 and 2009 in the Canton de Vaud, Switzerland. The prevalence of diabetics on dialysis increased from 18% to 31% in dialysis centers and increased from 1.1/1000 to 1.9/1000 in the diabetic population. These are strong indicators that efforts are needed to improve the renal outcome of patients with diabetic nephropathy.

Effects of the peroxisome proliferator-activated receptor (PPAR)-gamma agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals.

AIMS/HYPOTHESIS: Glitazones are powerful insulin sensitisers prescribed for the treatment of type 2 diabetes. Their use is, however, associated with fluid retention and an increased risk of congestive heart failure. We previously demonstrated that pioglitazone increases proximal sodium reabsorption in healthy volunteers. This study examines the effects of pioglitazone on renal sodium handling in individuals prone to insulin resistance, i.e. those with diabetes and/or hypertension. METHODS: In this double-blind randomised placebo-controlled four-way crossover study, we examined the effects of pioglitazone (45 mg daily during 6 weeks) or placebo on renal, systemic and hormonal responses to changes in sodium intake in 16 individuals, eight with type 2 diabetes and eight with hypertension. RESULTS: Pioglitazone was associated with a rapid increase in body weight and an increase in diurnal proximal sodium reabsorption, without any change in renal haemodynamics or in the modulation of the renin-angiotensin aldosterone system to changes in salt intake. A compensatory increase in brain natriuretic peptide levels was observed. In spite of sodium retention, pioglitazone dissociated the blood-pressure response to salt and abolished salt sensitivity in salt-sensitive individuals. CONCLUSIONS/INTERPRETATION: Pioglitazone increases diurnal proximal sodium retention in diabetic and hypertensive individuals. These effects cause fluid retention and may contribute to the increased incidence of congestive heart failure with glitazones. TRIAL REGISTRATION: ClinicalTrial.gov NCT01090752 FUNDING: Hypertension Research Foundation Lausanne.

Deep Sedation in Paediatric MR: a Review of Our Case Histories.

Sedation in paediatric MR is a necessary choice because very often we are dealing with uncooperative patients about to undergo lengthy examinations. The aim of this a retrospective study is to demonstrate that profound sedation with halogenated vapour Sevorane, together with specific systems for monitoring vital signs, is a safe and reliable technique. In accordance with current guidelines, it is considered essential to have an expert anaesthetist present in order to reduce the risk of incidents, which, in the case of difficulty in the airways, as seen in literature, could have fatal outcomes.

Erythromycin resistance in Streptococcus pyogenes and macrolide consumption in a central Italian region.

BACKGROUND: The study investigated macrolide resistance in Streptococcus pyogenes in a central Italian area from 2001 to 2006 and the possible correlation between antibiotic consumption and fluctuations of resistance percentages. MATERIALS AND METHODS: Macrolide and lincosamide susceptibility of 1,419 S. pyogenes isolates was tested by Kirby Bauer method. Macrolide consumption was evaluated as defined daily dose/1,000 inhabitants per day (DID), according to the World Health Organization anatomic therapeutic chemical classification. Spearman's correlation coefficient was used to assess the association between resistance and use of (1) all macrolides pooled, (2) once daily, (3) twice daily, and (4) three times daily dosage regimens. RESULTS: : In total, 320 strains (22.6%) were erythromycin-resistant, 11.4% with the M phenotype and 11.2% with the MLS phenotype. There was a significant decrease in erythromycin resistance during the study period-from 28.1% in 2001 to 15.6% in 2006 (p < 0.01). No significant correlation was found between erythromycin resistance and local overall macrolide consumption, neither during the same year nor during the previous year. In contrast, a significant correlation was found between resistance rates and once-daily macrolide use during the preceding 6 months in Siena r = 0.747, p = 0.008). CONCLUSION: The known greater selective effect of long-acting agents could establish a pressure outcome, resulting in a specific local epidemiology during a relatively short time gap.

Activation of electrical triggers of atrial fibrillation in hyperthyroidism.

CONTEXT: A shortening of the atrial refractory period has been considered as the main mechanism for the increased risk of atrial fibrillation in hyperthyroidism. However, other important factors may be involved. OBJECTIVE: Our objective was to determine the activity of abnormal supraventricular electrical depolarizations in response to elevated thyroid hormones in patients without structural heart disease. PATIENTS AND DESIGN: Twenty-eight patients (25 females, three males, mean age 43+/-11 yr) with newly diagnosed and untreated hyperthyroidism were enrolled in a prospective trial after exclusion of heart disease. Patients were followed up for 16 +/- 6 months and studied at baseline and 6 months after normalization of serum TSH levels. MAIN OUTCOME MEASURES: The incidence of abnormal premature supraventricular depolarizations (SVPD) and the number of episodes of supraventricular tachycardia was defined as primary outcome measurements before the start of the study. In addition, heart rate oscillations (turbulence) after premature depolarizations and heart rate variability were compared at baseline and follow-up. RESULTS: SVPDs decreased from 59 +/- 29 to 21 +/- 8 per 24 h (P = 0.003), very early SVPDs (so called P on T) decreased from 36 +/- 24 to 3 +/- 1 per 24 h (P < 0.0001), respectively, and nonsustained supraventricular tachycardias decreased from 22 +/- 11 to 0.5 +/- 0.2 per 24 h (P = 0.01) after normalization of serum thyrotropin levels. The hyperthyroid phase was characterized by an increased heart rate (93 +/- 14 vs. 79 +/- 8 beats/min, P < 0.0001) and a decreased turbulence slope (3.6 vs. 9.2, P = 0.003), consistent with decreased vagal tone. This was confirmed by a significant decrease of heart rate variability. CONCLUSION: Hyperthyroidism is associated with an increased supraventricular ectopic activity in patients with normal hearts. The activation of these arrhythmogenic foci by elevated thyroid hormones may be an important causal link between hyperthyroidism and atrial fibrillation.

[Chronic kidney disease and antidiabetic treatment]. / Insuffisance rénale chronique et médicaments antidiabétiques.

Diabetic nephropathy is the leading cause of chronic renal failure (CRF) in Europe. About fifty percent of diabetic subjects develop microalbuminuria, which progresses towards established diabetic nephropathy in one third of patients. The treatment of type 2 diabetes in a patient with CRF is a challenge for the general practitioner, because of the accumulation of drugs and/or specific metabolites. Sulfonylureas are associated with an increased risk of hypoglycaemia. Biguanides may exceptionally cause life-threatening lactic acidosis. Glitazones have an interesting profile since they decrease microalbuminuria and blood pressure. However, their safety is not well defined in the context of CRF In the case of severe CRF, only insulin and repaglinide can be recommended.

Antimicrobial susceptibility of Streptococcus pyogenes and Streptococcus pneumoniae: surveillance from 1993 to 2004 in Central Italy.

The susceptibility of 1870 Streptococcus pyogenes and 1595 Streptococcus pneumoniae to macrolides and lincosamides has been monitored from 1993 to 2004 in Central Italy. Among S. pyogenes, 30.2% were erythromycin resistant; 18.5% were also resistant to josamycin and clindamycin (MLS phenotype). After an increasing erythromycin resistance rate in 1993-1997 (maximum 53.16%), a definite decrease was observed since 2001 with resistance rates always less than 30%. Thirty six percent of pneumococcal isolates were erythromycin-resistant, with minor temporal fluctuations; the MLS phenotype was the most prevalent overall (32.6%) and in individual years. S. pneumoniae strains were also tested for susceptibility to beta-lactams and other antimicrobial agents: 11.2% were penicillin non-susceptible, with a gradually increasing prevalence after 2001 (maximum rate 17.3% in 2004), 31.15% were resistant to tetracycline, 4.9% to chloramphenicol, 0.74% to rifampin. All pneumococcal isolates were susceptible to teicoplanin and 99.9% to ceftriaxone and ofloxacin.

Epidemiology of streptococcus group A in school aged children in Pemba.

BACKGROUND: In Pemba (Zanzibar) all the risk factors which favour Group A Streptococci spreading, infections and late sequelae are present, though GAS epidemiology is unknown. OBJECTIVE: To determine the prevalence of GAS pharyngeal carriers among school-aged-children. DESIGN: Community-based cross sectional study, carried out at the end of the dry season (January-February 2001). SETTING: Eight primary schools over the four Pemba districts were included in the study. SUBJECTS AND METHODS: Two thousand two hundred and eighty six children aged 7-10 years were selected by random sampling and submitted to throat-swab after informed consent. Swabs were processed according to the "Lennette Manual of Clinical Microbiology" 7th Ed. Isolated were tested for antibiotic susceptibility toward penicillins, erythromycin, clindamycin, josamycin, cloramphenicol, levofloxacin, rifampin and tetracyclines. RESULTS: Twenty seven point six percent of school-aged children harboured beta-haemolytic Streptococci in their pharynx; most of the isolates were serologically identified as non Group A streptococci group C and G represented more than 70% of all strains, 38.8% of whom were identified as group G; the prevalence of group A streptococci carriers among healthy children all over the island was 8.6%; group A streptococci isolates were sensitive to all the antibiotic tested, except tetracyclines, towards which 83.2% of strains were resistant. CONCLUSION: This is the first research in the field of bacteriology carried out in Pemba. According to the epidemiology of group A streptococci and to the environmental and underlying factors which predispose to late group A streptococci sequelae, we suggest to consider antibiotic treatment for children presenting with sore throat with fever and swollen cervical lymphonodes without cough or coryza.

Staphylococcus aureus nasal carriage in the community: a survey from central Italy.

Recently, concern has increased regarding the spread of methicillin-resistant Staphylococcus aureus (MRSA) in the community. We studied 812 subjects from central Italy to establish the rates of nasal carriage of S. aureus, and antibiotic susceptibility patterns, in the community. The prevalence of S. aureus nasal carriage was 30.5%. Only one subject, with predisposing risk factors for acquisition, was identified as carrier of MRSA (prevalence of 0.12%). The presence of MRSA in the community of our area still appears to be a rare event. Among methicillin-susceptible S. aureus (MSSA) isolates, a surprisingly high rate (18%) of resistance to rifampin was observed.

Testing mode of inheritance of a candidate mutation at a quantitative trait locus.

Here is presented an approach to testing whether the effect of a candidate gene on a quantitative trait is dominant and for testing whether the effect is recessive. The approach uses parental genotype information in nuclear families to adjust for bias due to population admixture. The approach is applicable regardless of the nature of the sampling. The results of an application of the methods to a candidate mutation for diabetic nephropathy are used for illustration.

Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism.

UNLABELLED: Risk of advanced diabetic nephropathy in type 1 diabetes is associated with endothelial nitric oxide synthase gene polymorphism. BACKGROUND: Polymorphisms in the endothelial nitric oxide synthase gene (eNOS) may be implicated in the development of nephropathy in patients with type 1 or insulin-dependent diabetes mellitus (IDDM). METHODS: Three groups of IDDM patients were selected to study this hypothesis: cases with advanced diabetic nephropathy (N = 78), cases with overt proteinuria but normal serum creatinine (N = 74), and controls with normoalbuminuria despite 15 years of diabetes (N = 195). Parents of 132 cases and 53 controls were also examined and were used for the transmission disequilibrium test, a family-based study design to test association. RESULTS: We examined four eNOS polymorphisms, and two were associated with diabetic nephropathy in the case-control comparisons: a T to C substitution in the promoter at position -786 and the a-deletion/b-insertion in intron 4. For the former, the risk of developing advanced nephropathy was higher for C allele homozygotes than for the other two genotypes (odds ratio 2.8, 95% CI, 1.4 to 5.6). For the latter polymorphism, it was the a-deletion carriers that had the higher risk (odds ratio 2.3, 95% CI, 1.3 to 4.0) in comparison with noncarriers. Both polymorphisms were analyzed together as haplotypes in a family-based study using the transmission disequilibrium test. The C/a-deletion haplotype was transmitted from heterozygous parents to cases with advanced diabetic nephropathy with a significantly higher frequency than expected (P = 0.004). CONCLUSION: The findings of the case-control and family-based studies demonstrate clearly that DNA sequence differences in eNOS influence the risk of advanced nephropathy in type 1 diabetes.

Patterns of macrolide resistance determinants among community-acquired Streptococcus pneumoniae isolates over a 5-year period of decreased macrolide susceptibility rates.

Erythromycin resistance rates were found to be increased, from 7.1 in 1993 to 32.8% in 1997, among community-acquired Streptococcus pneumoniae isolates from the Siena area of central Italy. Most of the erythromycin-resistant isolates carried ermAM determinants and were also resistant to josamycin and clindamycin, whereas a minority (5.8%) carried mefA determinants and remained susceptible to the latter drugs.

Aortic connexin43 is decreased during hypertension induced by inhibition of nitric oxide synthase.

Connexin43 (Cx43), the predominant gap junction protein in vessels and heart, is involved in the control of cell-to-cell communication and is thought to modulate the contractility of the vascular wall and the electrical coupling of cardiac myocytes. We have investigated the effects of arterial hypertension induced by inhibition of nitric oxide synthase on the expression of Cx43 in aorta and heart as well as on the distensibility of the carotid artery. Administration of 0.4 g/L NG-nitro-L-arginine methyl ester (L-NAME) to rats in their drinking water for 4 weeks increased intra-arterial mean blood pressure, wall thickness of aorta and carotid artery (25%), and heart weight (17%). Analysis of heart mRNA demonstrated increased expression of the fetal skeletal alpha-actin and of atrial natriuretic peptide but not of Cx43. In contrast, Cx43 mRNA and protein were decreased by 50% in the aortas of L-NAME-treated rats that did not show increased carotid distensibility. Because these data contrasted with those obtained in the 2-kidney, 1 clip model of rat hypertension, which is characterized by increased arterial distensibility and Cx43 expression in aorta, we investigated by Western blot analysis the posttranslational modifications of Cx43. We found that Cx43 was more phosphorylated in the aorta of 2-kidney, 1 clip rats than in that of L-NAME or control rats, which indicated a differential regulation of Cx43 in different models of hypertension. The data suggest that the cell-to-cell communication mediated by Cx43 channels may help regulate the elasticity of the vascular wall.

Identification of Aeromonas strains of clinical origin with atypical phenotypical profiles.

A total of 47 strains of Aereomonas isolated from patients with gastroenteritis was analyzed for 40 phenotypical characters and for evaluating the numeric taxonomy based on 27 discriminatory tests. It was proved that the clinical isolates showed a relative phenotypical distance and the groups of strains that had atypical profiles were compared with the type species by the present identification schemes.

Differences in the mechanical properties of the rat carotid artery in vivo, in situ, and in vitro.

The elastic properties of carotid arteries of spontaneously hypertensive rats (SHR) and normotensive controls (Wistar-Kyoto rats [WKY]) were examined in vivo, in situ, and in vitro. The changes of internal diameter were measured with a high-resolution A-mode echo-tracking device simultaneously with the intra-arterial pressure at the carotid. The internal diameter at mean arterial blood pressure (MBP) was substantially smaller in vitro than in vivo in SHR (-33.8%) and WKY (-48.3%). The arterial distensibility was lower in vitro in all arteries compared with in vivo conditions (SHR, -30.1%; WKY, -60.4%; at MBP) despite a reduced incremental elastic modulus in vitro (SHR, -56.9%; WKY, -45.1%; at MBP). However, the in vitro and in vivo measurements show consistent elastic behavior of the carotid arteries between both strains of rats. Carotid arteries from WKY were also examined in situ. Although no significant reduction in internal diameter could be observed in situ, distensibility was dramatically decreased (-87% at MBP). These results emphasize the importance of considering the original vascular geometry when determining elastic properties of arteries. We conclude that experimental conditions are likely to be a critical determinant for the assessment of the mechanical properties of conduit vessels.

Unusual species of campylobacters isolated in the Siena Tuscany area, Italy.

From January 1989 to December 1990, stool samples from 288 children with enteritis were examined for the presence of unusual campylobacters which represented about 20% of all campylobacteria isolated when the filtration technique was used. The isolation percentage was the following: C. jejuni ss. jejuni 6.9%; C. coli 2%; C. jejuni ss. doylei, C. upsaliensis and C. concisus each 0.7%. The atypical Campylobacter isolates were examined for their virulence characteristics. Toxin profiles based on cytotonic, cytotoxic and cytolethal distending factors were determined after analysis responses in Vero, CHO and HeLa cells. Adhesivity and invasivity tests were performed on Intestine 407 cells. No strain was cytotoxic. C. jejuni ss. doylei and C. concisus induced an elongation of CHO cells (a cytotonic-like effect). C. upsaliensis strains provoked a cytolethal distending effect. No strain adhered to cells in vitro. Our results suggest that the filtration technique is excellent for the isolation of atypical campylobacters and indicate that the unusual Campylobacter isolates could be potentially virulent.

Species, biotype and serogroup of Campylobacter spp. isolated from children with diarrhoea over a ten-year period.

From 1981 to 1990, stool samples from 6403 gastroenteritis cases were examined for the presence of campylobacters as well as Salmonella, Shigella, Aeromonas species and Yersinia enterocolitica. The percentages of isolation were the following: campylobacters 10.8 (86.1% of isolates were C. jejuni and 13.9% were C. coli), Salmonella spp. 8.4, Aeromonas spp 1.4, Yersinia enterocolitica 0.3. Shigella spp. were isolated only occasionally. Predominant biotypes of campylobacters were C. jejuni I (69.5%), C. jejuni II (29.5%) and C. coli I (92.7%). The six most common LIO serogroups-36; 4; 1; 28.53; 11; 2-accounted for 50% ca. of typable strains. Campylobacters are the most common etiological agent of bacterial enteritis in children living in this area of Tuscany. The species and serogroup determination can be useful from an epidemiological point of view.

Time course changes of the mechanical properties of the carotid artery in renal hypertensive rats.

Distensibility of the carotid artery is not altered 2 weeks after renal artery clipping despite adaptive vascular hypertrophy related to hypertension. The purpose of this study was to assess arterial wall behavior with hypertension persisting for a longer period. Male Wistar rats were examined 1, 5, 9, and 24 weeks after renal artery clipping (two-kidney, one clip renal hypertension; n = 40) or after sham operation (n = 39). Mean blood pressure increased significantly to 132 +/- 4, 143 +/- 4, 153 +/- 4, and 144 +/- 4 versus 98 +/- 2, 107 +/- 2, 115 +/- 3, and 108 +/- 3 mm Hg, respectively, in 1-, 5-, 9-, and 24-week hypertensive rats and age-matched controls. Cardiac and vascular hypertrophy increased in parallel and were correlated to mean blood pressure. Wall stress at mean blood pressure did not differ between the hypertensive and normotensive groups (3.79 +/- 0.24, 4.60 +/- 0.34, 4.49 +/- 0.27, and 4.14 +/- 0.28 versus 3.15 +/- 0.12, 4.14 +/- 0.25, 4.80 +/- 0.28, and 4.69 +/- 0.32 10(3) dyne/cm2, respectively, in 1-, 5-, 9-, and 24-week hypertensive rats and age-matched controls). Distensibility-pressure data from the two groups fell on a common curve for all study periods. The intrinsic properties of the wall constituents were similar in controls and hypertensive rats at 1 and 5 weeks. However, the arteries became stiffer in the 9- and 24-week hypertensive rats, as illustrated by a shift to higher levels of the incremental elastic modulus-stress curve. Wall stress remains constant at mean blood pressure as a result of the increase in wall tissue mass. With time, even though the distensibility-pressure curve is not shifted downward, the thickened wall becomes stiffer in the hypertensive rats, which may predispose them to accelerated alterations of the wall material.

Age-related changes of the mechanical properties of the carotid artery in spontaneously hypertensive rats.

BACKGROUND: We had previously demonstrated that the distensibility of the carotid artery in spontaneously hypertensive rats (SHR) aged 18 weeks does not differ from that of the carotid artery in normotensive animals for common pressure levels, despite vascular hypertrophy in SHR. OBJECTIVE: To examine the time-course effects of hypertension on the geometry and the mechanical properties of the carotid artery in SHR. METHODS: The mechanical behavior of the carotid arteries of anesthetized SHR, stroke-prone SHR (SHRSP), and Wistar-Kyoto (WKY) rats aged 4, 8, 12, 16, and 32 weeks was examined by simultaneously measuring the internal diameter with an A-mode ultrasonic echo-tracking device and the intra-arterial pressure with a computerized data-acquisition system. Histometric measurements of the carotid artery were performed after death of rats. RESULTS: Blood pressure increased with time in rats of the two genetic hypertensive models. However, it rose earlier and to higher levels in the SHRSP. Cardiac hypertrophy was comparable in the two hypertensive groups whereas vascular hypertrophy was less pronounced in the SHRSP than it was in the SHR. There was an age-related decrease in arterial distensibility in rats of all groups that was more pronounced in the SHRSP than it was in the SHR compared with that in WKY rats (decreases of 57 and 36%, respectively, versus WKY rats aged 32 weeks; P < 0.05). For rats of all ages studied, although aging affected differently the vascular properties of the distinct animal strains, arterial distensibility was increased in the SHR and SHRSP compared with that in control animals for similar blood pressure levels, implying a rightward shift of the distensibility-pressure curves in the two hypertensive models. However, there was a significant reduction in arterial distensibility in rats of the two hypertensive strains at their respective mean blood pressures, compared with that in control animals.