Maternal supplementation with citrulline increases renal nitric oxide in young spontaneously hypertensive rats and has long-term antihypertensive effects

NO deficiency is associated with development of hypertension. Defects in the renal citrulline-arginine pathway or arginine reabsorption potentially reduce renal NO in prehypertensive spontaneously hypertensive rats (SHRs). Hence, we investigated genes related to the citrulline-arginine pathway or arginine reabsorption, amino acid pools, and renal NO in 2-week-old prehypertensive SHRs. In addition, because perinatally supporting NO availability reduces blood pressure in SHRs, we supplemented SHR dams during pregnancy and lactation with citrulline, the rate-limiting amino acid for arginine synthesis. In female offspring, gene expression of argininosuccinate synthase (involved in renal arginine synthesis) and renal cationic amino acid Y-transporter (involved in arginine reabsorption) were both decreased in 2-day and 2-week SHRs compared with normotensive WKY, although no abnormalities in amino acid pools were observed. In addition, 2-week-old female SHRs had much less NO in their kidneys (0.46+/-0.01 versus 0.68+/-0.05 nmol/g of kidney weight, respectively; P<0.001) but not in their heart. Furthermore, perinatal supplementation with citrulline increased renal NO to 0.59+/-0.02 nmol/g of kidney weight (P<0.001) at 2 weeks and persistently ameliorated the development of hypertension in females and until 20 weeks in male SHR offspring. Defects in both the renal citrulline-arginine pathway and in arginine reabsorption precede hypertension in SHRs. We propose that the reduced cationic amino acid transporter disables the developing SHR kidney to use arginine reabsorption to compensate for reduced arginine synthesis, resulting in organ-specific NO deficiency. This early renal deficiency and its adverse sequels can be corrected by perinatal citrulline supplementation persistently in female and transiently in male SHRs.     

Radiographic outcomes of intertrochanteric hip fractures treated with the trochanteric fixation nail

BACKGROUND: Intertrochanteric hip fractures have become more common as the elderly population continues to increase, and surgical stabilisation of these fractures remains a persistent challenge. The purpose of this study was to analyse the ability of a new helical blade device to stabilise intertrochanteric hip fractures, and to further determine which factors are important in implant stability. METHODS: Two hundred and fifty-five patients with an intertrochanteric hip fracture were treated with a trochanteric fixation nail (TFN), 97 of whom fit strict radiographic and follow-up criteria and were included in the study group. After adjusting for magnification and rotation, blade migration within the femoral head and telescoping of the blade along its axis were measured using a custom-designed grid system. Multivariate regression analyses were performed to determine which variables predicted blade migration and telescoping. RESULTS: Fifty-nine fractures were classified as stable, and the remaining 38 were unstable. Mean telescoping was 4.3 mm in the unstable group, compared to 2.6 mm in the stable group (p<0.05). Blade migration within the femoral head averaged 2.2 mm overall, with no difference between stable and unstable fractures. For both telescoping and blade migration, no significant change occurred after the 6-week time point in the stable or unstable group. Nail length, age, and gender did not have a significant effect on either blade migration or telescoping implant position change. Of the initial cohort of 255 patients, five cutouts and one nonunion occurred, three of which required subsequent procedures. CONCLUSIONS: Subtle migration ( approximately 2mm) of the tip of the blade within the femoral head occurred in all fractures, but this did not preclude maintenance of reduction and fracture healing, and was not predicted by fracture type, reduction quality, age, or gender. More telescoping occurred in unstable compared to stable fractures, but this averaged 4mm and did not affect stable fixation or fracture healing. All position changes occurred within the first 6 weeks postoperatively, with no subsequent detectable migration or telescoping. Clinical correlations will be needed in the future to determine the significance of small amounts of migration or differences in telescoping, but this device appears to provide effective fixation in both stable and unstable intertrochanteric hip fractures.     

Serum Antibodies Positivity to 12 Helicobacter pylori Virulence Antigens in Patients with Benign or Malignant Gastroduodenal Diseases – Cross-sectional Study

Aim

To investigate the association of gastric histological and endoscopic findings in patients with Helicobacter pylori (H. pylori), according to presence of seropositivity to 12 bacterial virulence antigens.

Methods

This is a cross-sectional single-center study of 360 consecutive outpatients referred in the period of one year to upper gastrointestinal endoscopy because of dyspeptic complaints. Patients sera were tested by Western blot method to determine the presence of serum antibodies to bacterial virulence antigens – p120 (CagA – cytotoxin-associated antigen), p95 (VacA – vacuolating cytotoxin), p67 (FSH – flagellar sheath protein), p66 (UreB – urease enzyme heavy subunit), p57 (HSP homologue – heath shock protein homologue), p54 (flagellin), p33, p30 (OMP – outer membrane protein), p29 (UreA – urease enzyme light subunit), p26, p19, and p17. Upper gastrointestinal endoscopy was performed, endoscopic diagnosis recorded, and 4 mucosal biopsy samples were obtained and assessed according to Updated Sydney protocol.

Results

The sera of 207 patients were analyzed. Thirty patients had gastric adenocarcinoma, 126 peptic ulcers, and 51 normal finding. p120 (CagA) seropositivity was significantly more often present in patients with higher activity grade in the antrum (P = 0.025), p30 in patients with greater inflammation in the antrum (P = 0.025) and the corpus (P = 0.010), p33 in patients with greater inflammation in the corpus (P = 0.050), and p19 (OMP) in patients with lower intestinal metaplasia grades in the corpus (P = 0.025). Seroreactivity to all other bacterial proteins showed no association with the histological status of the stomach mucosa. Except for the seropositivity to protein p95 (VacA), which was more often present in patients with duodenal ulcer (P = 0.006), there was no difference in seroreactivity to other bacterial proteins and upper gastrointestinal endoscopic findings.

Conclusions

p120 (CagA), p33, p 30 (OMP), and p19 (OMP) seropositivity was more often present in patients with higher grades of the histological parameters of gastritis and seropositivity to protein p95 (VacA) with endoscopic presence of duodenal ulcer. Histological parameters of gastritis are more associated with bacterial virulence than endoscopic findings.Helicobacter pylori (H. pylori) is recognized as a major gastric pathogen with worldwide distribution (1). Estimated prevalence of H. pylori infection in Croatia is 60.4% (2). The persistent colonization induces gastritis and in some patients peptic ulcer disease, atrophic gastritis, or gastric carcinoma (3). However, most of patients infected with H. pylori never develop cancer or ulcer disease and there is a need to identify additional factors that may influence the risk for development of such diseases. The outcome of H. pylori infection is associated with specific (virulence associated) bacterial genotypes, environmental factors, and host’s immune status (4). A number of putative virulence factors for H. pylori infection have been identified, including CagA (cytotoxin-associated antigen), VacA (vacuolating cytotoxin), IceA (induced by epithelium antigen), BabA (blood-group antigen-binding adhesin), etc. It is likely that every other factor that results in increased inflammation will also consequently increase the risk of a disease occurrence.Presently, the only reliable way to identify the disease associated with H. pylori infection remains endoscopic examination combined with histological assessment of the gastric mucosa (5). The bacterial virulence antigens elicit specific antibodies during infection. However, the value of these antibodies as predictive factors for the severity of the disease remains controversial (6-15). So far, several investigations on the subject have been done, such as detecting the level, specificity, or presence of isotypes of serum H. pylori antibodies (16-22). Because disease outcome depends on both the strain characteristics and the host’s response, the serum antibody response to virulence antigens could provide clues in predicting the presence and severity of associated diseases (23,24). On the other hand, since subjects without manifest disease also have strains bearing this or other virulence antigens, it seems that the disease could not be attributed to one virulence antigen alone. Thus, other virulence antigens may also be important. The exact role of other bacterial virulence antigens – p67 (FSH – flagellar sheath protein), p66 (UreB – urease enzyme heavy subunit), p57 (HSP homologue – heath shock protein homologue), p54 (flagellin), p33, p30 (OMP – outer membrane protein), p29 (UreA – urease enzyme light subunit), p26, p19 (OMP), and p17 in the pathogenesis of gastrointestinal diseases is still unclear.In this study, we aimed to investigate the association of gastric histological and endoscopic findings in H. pylori-positive patients according to presence of seropositivity to 12 bacterial virulence antigens. Since both bacterial virulence antigens and pattern of H. pylori gastritis may contribute to development of clinically relevant gastroduodenal disease, we wanted to determine the antibodies which are most associated with higher grades of histology findings of gastritis, atrophy, or intestinal metaplasia and different clinical diseases (peptic ulcer, gastric cancer, and non-ulcer dyspepsia).     

Mechanisms of Disease: erythropoietin resistance in patients with both heart and kidney failure

Anemia is common in patients who have both heart failure and chronic kidney disease, and there is an association between anemia and progression of both diseases. The main causes of anemia are deficient production of erythropoietin (EPO), iron deficiency, and chronic disease with endogenous EPO resistance. EPO has been successfully used for over a decade to treat anemia in patients with chronic kidney disease. Less obvious are the safety and efficacy of EPO treatment in patients with both heart failure and renal disease. Up to 10% of patients receiving EPO are hyporesponsive to therapy and require large doses of the agent. Several mechanisms could explain resistance to endogenous and exogenous EPO. Proinflammatory cytokines antagonize the action of EPO by exerting an inhibitory effect on erythroid progenitor cells and by disrupting iron metabolism (a process in which hepcidin has a central role). EPO resistance might also be caused by inflammation, which has a negative effect on EPO receptors. Furthermore, neocytolysis could have a role. As resistance to exogenous EPO is associated with an increased risk of death, it is important to understand how cardiorenal failure affects EPO production and function.     

Similar effects of long-term exogenous growth hormone (GH) on bone and muscle parameters: a pQCT study of GH-deficient and small-for-gestational-age (SGA) children

BACKGROUND AND AIMS: Treatment with GH in short children has focused on height development. Little is known about the concomitant changes in muscle mass, bone structure and bone strength. METHODS: Muscle area as well as parameters of bone architecture (bone mineral content, BMC; volumetric cortical density, total bone area, TBA; cortical area, cortical thickness, CT; and marrow area) were measured by means of pQCT (Stratec) at 65% of the proximal length of the forearm. The strength-strain index (SSI) was calculated as an indicator of bone strength. RESULTS: Prepubertal children with GHD (mean values: age; 7.2 years; height SDS=-2.9 SDS; GH dose: 30 microg/kg/d) were followed at 0, 6, 12 (n=74) and 24 (n=55) months. Prepubertal children with SGA (mean values: age: 7.1 years; height SDS=-3.4 SDS; GH dose: 55 mug/kg/d) were followed at 0, 6, 12 (n=47) and 24 (n=35) months. Both groups showed a similar increase in height. At GH start, muscle mass and bone characteristics were lower than normal but similar in SGA vs. GHD. Muscle area (mean values, SDS) increased from -3.0 to -1.5 in SGA and from -2.4 to -1.0 in GHD. Bone geometry changed in a biphasic mode, with an increase in total bone area and lowering of bone mineral content (BMC) during the first 12 months, followed by an increase of BMC and CT thereafter. SSI (mean values, mm(3)) improved from 78 to 114 in GHD and from 62 to 101 in SGA after 24 months on GH. The increment in terms of SDS did not reach significance in SGA. SSI correlated positively with muscle area before and during GH treatment. CONCLUSIONS: Bone strength and muscle mass are impaired in prepubertal children with GHD and SGA. Exogenous GH can indirectly improve bone structure and strength by inducing an increase in muscle mass. Our findings support the assumption that, in SGA, there is impaired tissue responsiveness to GH.     

Gap junction coding genes and schizophrenia: a genetic association study

The aim of this study was to evaluate the association of genes that encode gap junction forming proteins and schizophrenia. Representative genetic candidates (Panx2 and Cx36) from two families of gap junction genes were selected for analysis. According to the present findings these genes represent both functional and positional candidates for schizophrenia. The sample was comprised of 381 schizophrenic patients, and the same number of matched controls was tested in this study in order to evaluate the possible influence of the aforementioned genes on the pathogenesis of schizophrenia. Four SNPs in the case of Panx2 and two SNPs in the case of Cx36 were selected for analysis. Allele-, genotype- and haplotype-wise association did not yield statistically significant results. These data do not suggest that Panx2 or Cx36 could increase the risk of schizophrenia in the Japanese population.     

Oral teicoplanin versus oral vancomycin for the treatment of severe <Emphasis Type="Italic">Clostridium difficile</Emphasis> infection: a prospective observational study

The aim of this study was to compare clinical cure rate, recurrence rate and time to resolution of diarrhea in patients with severe and severe-complicated Clostridium difficile infection (CDI) treated with teicoplanin or vancomycin. This two-year prospective observational study included patients with first episode or first recurrence of CDI who had severe or severe-complicated CDI and were treated with teicoplanin or vancomycin. Primary outcomes of interest were clinical cure rate at discharge and recurrence rate after eight weeks follow up, and secondary outcomes were all-cause mortality and time to resolution of diarrhea. Among 287 study patients, 107 were treated with teicoplanin and 180 with vancomycin. The mean age of patients was 73.5?±?10.6 years. One hundred eighty six patients (64.8%) had prior CDI episode. Severe complicated disease was detected in 23/107 (21.5%) and 42/180 (23.3%) patients treated with teicoplanin and vancomycin, respectively. There was no statistically significant difference in time to resolution of diarrhea between two treatment arms (6.0?±?3.4 vs 6.2?±?3.1 days, p?=?0.672). Treatment with teicoplanin resulted in significantly higher clinical cure rate compared to vancomycin [90.7% vs 79.4%, p?=?0.013, odds ratio (OR) (95% confidence interval (CI)) 2.51 (1.19–5.28)]. Recurrence rates were significantly lower in patients treated with teicoplanin [9/97 (9.3%) vs 49/143 (34.3%), p?<?0.001, OR (95%CI) 0.20 (0.09–0.42)]. There was no statistically significant difference in overall mortality rate. Teicoplanin might be a good treatment option for patients with severe CDI. Patients treated with teicoplanin experienced remarkably lower recurrence rates compared to vancomycin-treated patients.