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Clinical trials of renal denervation (RDN) have shown unanticipated changes in non-renal sympathetic activity. It has been hypothesized that this is due to ablation of sympathoexcitatory afferent renal nerves, which are overactive under conditions of renal inflammation. This study sought to investigate the interaction of the inflammatory cytokine, IL-1, and afferent renal nerves in the pathogenesis of hypertension. To test this hypothesis, we compared the effect of afferent RDN (ARDN) to the administration of the IL-1R antagonist anakinra, on the pathogenesis DOCA-salt hypertension. In addition, the combination of ARDN and anakinra treatments in DOCA-salt mice was administered to assess the degree of mechanistic overlap. 10-week-old male C57BL6/J mice were implanted with radio-telemetry probes in the carotid artery for measurement of mean arterial pressure (MAP). DOCA was administered via subcutaneous implantation of a silicon pellet containing 50 mg of DOCA. Sham mice received a drug free silicon pellet. Uni-nephrectomy, pellet insertion, salt treatment, ARDN were all performed or started on the same day. ARDN was performed through peri-axonal application of capsaicin. IL-1R antagonist anakinra was used to suppress activation of IL-1R. Anakinra (75mg/kg) was delivered via intraperitoneal injection daily 10 days post induction of hypertension. Animals in the untreated or monotherapy groups received sham RDN and/or vehicle injections. Baseline MAP was measured 3 days prior to induction of DOCA-salt hypertension by radiotelemetry. MAP increased in untreated DOCA-salt mice by 42 ± 2 mmHg (n=7) from baseline in the final week of the study. In comparison, this response was attenuated by 42% by ARDN (+24 ± 2 mmHg, n=7). IL-1α and IL-1β were both increased in DOCA-salt kidneys (112.4 ± 19.2 pg/mg and 2.1 ± 0.4 pg/mg respectively) compared to sham kidneys (31.98 ± 4.4 pg/mg and 0.36 ± 0.06 pg/mg respectively). The DOCA-salt induced increase of MAP in mice treated with anakinra alone (+23 ± 3 mmHg, n=9), or the combination of ARDN and anakinra (+26 ± 3 mmHg, n=5) was similar to ARDN monotherapy (+24 ± 2 mmHg, n=7). All treatment groups showed statistically significant changes in MAP compared to the SHAM and Vehicle treated group with 2 Way ANOVA and Tukey test for multiple comparisons. The finding that ARDN and anakinra combination therapy provides no additional benefit beyond ARDN or anakinra alone, suggests a common mechanism. We propose that antagonism of IL-1R blocks IL-1 mediated activation of afferent renal nerves resulting in decreased central sympathetic tone and decreased MAP. Further investigation into the mechanisms of cytokine mediated sensory fiber activation in the kidney are the subject of ongoing studies. T32DK083250-01A1, R01HL116476 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Tacrolimus, a macrolide calcineurin inhibitor, is the most widely used immune suppressant medication after solid-organ transplant in humans, however, its use is complicated by nephrotoxicity and the development of chronic kidney disease. Interestingly, transplanted kidneys, which lack renal nerves, enjoy a relative protection from tacrolimus-induced nephrotoxicity. Consistent with this clinical observation, we explored the hypothesis that renal denervation would protect against the development of kidney disease in a rat model of tacrolimus-induced nephrotoxicity.To test this hypothesis, Sprague-Dawley rats underwent either total renal denervation (TRDN) or sham denervation and thereafter were injected with either vehicle (corn oil) or tacrolimus (2 mg/kg) for 14 days. At the end of this protocol plasma blood urea nitrogen (BUN), a marker of renal filtration function, was substantially lower in TRDN rats treated with tacrolimus than in their sham counterparts (24 vs 36 mg/dL, respectively). Similarly, TRDN rats treated with tacrolimus demonstrated substantially less renal fibrosis and glomerular damage than their sham counterparts as demonstrated by trichrome staining and PAS staining.Together our results demonstrate that total renal denervation is protective against the development of tacrolimus-induced nephrotoxicity. This finding suggests that renal denervation of the kidneys of solid-organ transplant recipients could substantially decrease the burden of chronic kidney disease in the transplant population. R01 HL116476. T32HL144472. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Background and Objective: Clinical trials have shown that catheter-based total (efferent and afferent) renal denervation (TRDN) can effectively lower arterial pressure in patients with treatment-resistant hypertension (HTN). The Peregrine catheter infusion system deploys microneedles from the renal artery lumen into the renal artery adventitia to inject the neurolytic agent ethanol. The objective of this study was to utilize this catheter to develop novel renal denervation therapies in a large animal model. In this study our aim was to demonstrate that TRDN lowers arterial pressure in the deoxycorticosterone acetate and high salt diet (DOCA-salt) sheep model of HTN. This will establish the utility of this catheter to deliver the afferent nerve neurolytic agent, capsaicin. Our group has shown that selective afferent renal denervation (ARDN) lowers arterial pressure to the same degree as TRDN in DOCA-salt HTN rats. Our long-term goal is to translate these findings to the DOCA-salt sheep model and eventually humans. Methods: Adult Domestic sheep weighing 60-80 kg were implanted with a subcutaneous silicone pellet containing DOCA (350mg/kg) and given access to salted (0.2% NaCl) drinking water and (180mEq Na+/kg) feed. Stellar radio telemeters were implanted for continuous measurement of MAP. 30 days following induction of DOCA-salt HTN, the Peregrine catheter infusion system was used to perform bilateral TRDN. One month after TRDN, animals were terminated and kidneys were harvested to verify denervation efficacy. Preliminary Results: 30 days following implantation of DOCA, 24hr MAP increased ~25mmHg from a baseline of 99mmHg to 123mmHg (n=2). 30 days following TRDN, 24hr MAP decreased to near control levels of 105mmHg. Conclusion and Future Directions: These preliminary results demonstrate that TRDN with the Peregrine catheter lowers MAP in DOCA-salt HTN sheep. The mechanism underlying this response is still being investigated. Sheep studies are underway to utilize the Peregrine catheter to perform ARDN by injection of capsaicin into the renal artery adventitia. The goal is to conduct a translational study to move catheter-based ARDN into clinical trials. If catheter-based ARDN lowers MAP to the same degree as TRDN, efferent renal nerves could be preserved to maintain MAP and blood volume in response to hemorrhagic or septic shock. Supported by NHLBI R01 HL116476. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Introduction: Post‐traumatic stress disorder (PTSD) is associated with significant cardiovascular disease (CVD) risk. Women are twice as likely as men to develop PTSD after a traumatic event. Although premenopausal women are thought to be protected from CVD, a diagnosis of PTSD increases CVD risk by up to three-fold. Available data in predominantly male cohorts point to autonomic nervous system dysfunction as a potential underlying mechanism. Therefore, the aim of this study was to determine if premenopausal women diagnosed with PTSD, compared to those without, present a blunted parasympathetic control of the heart and elevated cardiovascular hemodynamics. Methods: Thirty-five otherwise healthy young women (18-40 years) with a history of trauma exposure were included in this study, 14 with PTSD and 21 without PTSD diagnostic. The study took place during two visits. At visit one, we collected anthropometric measures, assessed PTSD symptom severity with the PTSD checklist for DSM 5 (PCL5) and depression severity using the Beck Depression Inventory (BDI). At visit two, we measured resting heart rate variability (HRV) using the finger volume pulse waveforms obtained from a peripheral arterial tone signal and central hemodynamics (i.e., aortic blood pressure and augmentation index) via pulse wave analysis using applanation tonometry. We compared the two groups with independent t-tests and we report two-tailed p-values. Results: Age (27±7years) and BMI (27±6 kg/m2) were comparable between the two groups (p>0.05). Women diagnosed with PTSD had higher PCL5 (48±9 vs 32±18 a.u., p=.001) and BDI (27±10 vs 15±7 a.u., p UL1TR002494, NIH K01HL161027 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hypertension (HTN) is a multifactorial disease affecting one-third of adults in western society. It is well established that renal artery stenosis results in secondary renovascular HTN. Experimentally, renovascular HTN is induced in rats by creating stenosis of the left renal artery, thereby decreasing perfusion pressure while the contralateral kidney remains intact (2K1C-HTN). This leads to increases in renin-angiotensin system activity, mean arterial pressure (MAP), sympathetic nerve activity, thirst, and renal inflammation. The organum vasculosum of the lamina terminalis (OVLT) has been implicated in the regulation of MAP, sympathetic activity, and thirst. In the present study, we investigated the role of the OVLT in the rat model of 2K1C-HTN.Male Sprague-Dawley rats (n=6-8/group) were randomly selected to receive either electrolytic lesion of the OVLT (OVLTx) or sham operation. One week after lesion or sham-lesion, rats were instrumented with telemeters to continuously measure MAP. The following week the rats received a silver clip around the left renal artery to generate 2K1C-HTN or sham-clip surgery. MAP was measured for 6 weeks after clip or sham-clip and, once a week, rats were housed in metabolic cages for 24 hours to measure water intake and urine volume. Urine was analyzed for inflammatory cytokines and copeptin, a surrogate marker of vasopressin. Neurogenic pressor activity (NPA) was assessed on the last day of the experiments by measuring the peak MAP response to ganglionic blockade. Upon completion of the study, rats were euthanized, and kidneys removed for measurement of inflammatory cytokine content.At the end of the protocol, MAP was significantly (p JO is funded by NIH R01 HL116476. LE is funded by NIH R01 HL152166. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The risk of hypertension (HTN) in young females is lower than in young males, but this risk increases in postmenopausal females and surpasses that of age-matched males. The mechanisms by which fluctuating ovarian hormone environment during the menopause transition impacts the onset of HTN are poorly understood. Similarly, preventative and rehabilitative strategies to reduce HTN risk in peri- and postmenopausal females are lacking. Purpose: We aim to use an ovary-intact rat model of reproductive aging to accelerate the natural process of follicular loss and determine mechanisms contributing to the development of HTN in the Deoxycorticosterone (DOCA)-salt rat model. We hypothesize that induction of perimenopause by the chemical 4-vinylcyclohexene diepoxide (VCD) administration will increase the susceptibility to development of HTN in DOCA-salt rats. Methods: We repeated a daily dose of VCD for 15 days, which selectively destroys primordial and primary follicles in rodent ovaries to accelerate female rats into perimenopause. We then administered DOCA, in combination with a high-salt diet, to induce HTN in those rats. Female Sprague-Dawley rats at 28 post-natal day (pnd) were weighed and received subcutaneous injection of VCD (160mg/kg) for 15 consecutive days. Control rats were injected with a vehicle (corn oil; 2.5 mL/kg body weight). Under inhaled isoflurane anesthesia, 57 days after the first VCD/oil injection, uninephrectomy and telemetric pressure transducer (DSI) implantation were performed. After 2 weeks of recovery, a 100 mg/kg DOCA silicone or vehicle implant was placed subcutaneously. The animals were divided into oil+DOCA (N=3) and VCD (periestropause rats) +DOCA (N=6). DOCA-salt rats were provided 0.9% saline during the 21 days of DOCA protocol and mean arterial pressure (MAP) was continuously measured. Rats were housed weekly in metabolic cages for 24 hours to measure water intake and urine volume. At the end of the protocol the animals were anesthetized, and blood was collected into heparinized tubes for the measurement of anti-Mullerian hormone (AMH), estradiol (E2), and progesterone (P4) by ELISA. Results: The plasma concentrations of AMH were reduced in the periestropause animals compared to oil (VCD: ± 6.5 ng/mL; Oil: 19 ng/Ml; p= 0.0042) confirming the VCD-induced follicular depletion. The steady state increase in MAP (day 21 of DOCA-salt) was higher in periestropause (±45.7mmHg; p NIH R01 HL116476 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Exceptional orthogonal Laguerre polynomials can be viewed as an extension of the classical Laguerre polynomials per excluding polynomials of certain order(s) from being eigenfunctions for the corresponding exceptional differential operator. We are interested in the (so-called) Type I X1-Laguerre polynomial sequence LnI,αn=1∞, degpn=n and α>0, where the constant polynomial is omitted. We derive two representations for the polynomials in terms of moments by using determinants. The first representation in terms of the canonical moments is rather cumbersome. We introduce adjusted moments and find a second, more elegant formula. We deduce a recursion formula for the moments and the adjusted ones. The adjusted moments are also expressed via a generating function. We observe a certain detachedness of the first two moments from the others.

Nonalcoholic fatty liver disease (NAFLD), historically considered as the hepatic component of the metabolic syndrome, is a spectrum of fat-associated liver conditions in the absence of secondary causes that may progress to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. Disease progression is closely associated with body weight or fatness, dyslipidemia, insulin resistance, oxidative stress, and inflammation. Recently, there has been a significant scientific interest into the relationship between vitamin D status and NAFLD. Because oxidative stress and inflammation might act as the common pathogenic mechanisms of NAFLD and vitamin D deficiency, and as both diseases are associated with insulin resistance, type 2 diabetes and cardiovascular disease, several studies have investigated the association between vitamin D deficiency and NAFLD/NASH, but with conflicting findings. Therefore, we sought to critically review the current evidence on the association between vitamin D deficiency and NAFLD/NASH, and to analyze and discuss some key variables that may interfere with this evaluation, such as host-, environment-, and heritability-related factors regulating vitamin D synthesis and metabolism; definitions of deficient or optimal vitamin D status with respect to skeletal and nonskeletal outcomes including NAFLD/NASH; methods of measuring 25(OH)D; and methods of diagnosing NAFLD as well as quantifying adiposity, e.g. the cardinal link between vitamin D deficiency and NAFLD.

The $X_m$ exceptional orthogonal polynomials (XOP) form a complete set of eigenpolynomials to a differential equation. Despite being complete, the XOP set does not contain polynomials of every degree. Thereby, the XOP escape the Bochner classification theorem. In literature two ways to obtain XOP have been presented. When m=1, Gram-Schmidt orthogonalization of a so-called "flag" was used. For general m, the Darboux transform was applied. Here, we present a possible flag for the X_m exceptional Laguerre polynomials. We can write more about this. We only want to make specific picks when we also derive determinantal representations. There is a large degree of freedom in doing so. Further, we derive determinantal representations of the X_2 exceptional Laguerre polynomials involving certain adjusted moments of the exceptional weights. We find a recursion formula for these adjusted moments. The particular canonical flag we pick keeps both the determinantal representation and the moment recursion manageable., Comment: 15 pages, 2 figures

Altered gastric anatomy following laparoscopic sleeve gastrectomy (LSG) is likely to induce upper gastrointestinal (GI) symptoms. Published studies, however, have focused mainly on gastroesophageal reflux disease (GERD). This study aims to evaluate LSG's impact on the prevalence of upper GI symptoms and to assess the effects of time from surgery, weight loss, and proton pump inhibitor (PPI) therapy.The validated Rome III Criteria symptom questionnaire for upper GI symptoms, including quality of life items, has been self-administered to 97 patients who underwent LSG. Symptoms were analyzed either separately or altogether to classify patients in GERD or dyspepsia, subdivided in epigastric pain (EPS) and post-prandial distress (PDS) syndromes.Before LSG, 52.7% of the patients were asymptomatic, 27.0% had GERD, and 8.1% had dyspepsia (2.7% EPS, 5.4% PDS). After a median follow-up of 13 months, 91.9% of the patients complained of upper GI symptoms, the most prevalent being PDS (59.4 %). GERD prevalence did not differ before and after LSG. The only symptom strongly related to LSG was dysphagia (OR 4.7, 95% CI 1.3-20.4, p = 0.015), which was present in 19.7% of the patients and mainly associated with PDS rather than GERD. GI symptoms, however, did not have a great impact on quality of life. Time from surgery, weight loss after surgery, as well as concomitant PPI, did not influence the symptoms.After a median follow-up of 13 months, PDS-like dyspepsia, rather than GERD, was the main complaint, both poorly responding to PPI therapy. A longer follow-up will be necessary to evaluate their future persistency.

SUMMARYThe objective of this study was to assess the prevalence of Ureaplasma urealyticum and Mycoplasma hominis infections and to investigate associations between their presence in the lower female genital tract and lifestyle characteristics. The study was performed on a population of 3115 women, comparing the demographic and behavioural characteristics of 872 women with U. urealyticum infection and 142 women with M. hominis with uninfected women, using univariate and multiple logistic regression analysis. The prevalence of infection with U. urealyticum was 28% and M. hominis was 4·6%. In multivariate logistic regression analysis, intrauterine device, number of sexual partners and age (U. urealyticum while previous induced abortion, condom use and young age at first intercourse (M. hominis infection. U. urealyticum infection presents the same demographic and behavioural characteristics of a sexually transmitted disease. The unprotective role of condom use suggests a non-sexual mode of transmission of M. hominis infection.

Summary Background Long-term observational studies assessing the incidence of type I gastric carcinoid (typeIGC) in patients with chronic atrophic gastritis are few. Aim To evaluate the occurrence of typeIGC at diagnosis and during follow-up and to identify patient features associated with the presence of typeIGC in a cohort of chronic atrophic gastritis patients. Methods Three hundred and sixty-seven chronic atrophic gastritis patients [245 women, age 54 (18–79) years] underwent regular follow-up by gastroscopy. The incidence of typeIGC was determined in chronic atrophic gastritis patients with at least 2 years of follow-up (n = 214). Baseline clinical and histological features were analysed as factors associated with the presence of typeIGC by univariate analysis. Results Type I gastric carcinoid was diagnosed in nine (2.4%) patients at the moment when chronic atrophic gastritis was diagnosed. After 1463 person-years, six patients developed typeIGC with an annual incidence rate (person-year) of 0.4%. Patients with typeIGC had significantly higher levels of gastrin, chromogranin A and more frequently the presence of body polyps and ECL-dysplasia compared with chronic atrophic gastritis patients without typeIGC. Conclusions This cohort study shows that typeIGC is a rare complication in patients with chronic atrophic gastritis, and the presence of body polyps and ECL-dysplasia at gastroscopic/histologic evaluation is strongly associated with the presence of typeIGC.

The effect of Helicobacter pylori treatment on the potential reversal of atrophic body gastritis (ABG) is controversial. Body atrophy reversal was evaluated in a cohort of H. pylori-negative and treated H. pylori-positive ABG patients.Observational long-term follow-up cohort study including 300 ABG patients with at least one follow-up gastroscopy with three biopsies from the antrum and three from the body performed no earlier than 1 year after diagnosis was included. H. pylori was diagnosed by Giemsa-stain and serology. H. pylori-positive patients (n = 192) were treated with bismuth-based triple regimen.After a mean follow-up of 5.2 years, body atrophy reversal was observed in 42/300 patients (14%). Body atrophy reversal occurred more frequently in patients treated for H. pylori than in H. pylori-negative ones (21.3% vs 0.9%, p0.00001) and was observed between 2 and 8 years after treatment in 52% of cases. Predictive factors for body atrophy reversal at Cox-regression analysis were mild atrophy (HR 2.14; 95% CI 1.12-4.1), moderate-severe inflammation (HR 5.3; 95% CI 1.64-17.3), and absence of intestinal metaplasia (HR 2.4; 95% CI 1.2-4.8).Body atrophy reversal was observed in about 20% of ABG patients treated for H. pylori infection, and about 50% of reversals occurred during long-term follow-up.

Over the last two decades, there have been many studies on children who have sought an effective and safe treatment to eradicate Helicobacter pylori infection, but as yet, no therapy regimen has been found which is always effective and safe. Differences in drug response among pediatric patients are common. Such individual variability in drug response is multifactorial, including environmental, genetic, development and disease determinants that affect the disposition of a given drug. In pediatric efficacy studies for the management of H. pylori eradication in children, the most commonly tested regimen has contained a combination of proton pump inhibitor (PPI), clarithromycin and amoxicillin, followed by triple therapies containing PPI, clarithromycin and nitroimidazoles. Thus, PPIs are an integral part of triple therapy for H. pylori eradication in children with gastroduodenal disease. In this article, we comprehensively review, from a pediatric point of view, the literature on the clinical, pharmacologic and microbiologic properties of PPIs. We also discuss genetic, developmental and other host-related factors that may affect the efficacy of these drugs. Finally, we provide some guidance regarding their potential role and limitations for H. pylori eradication in children.

Background A positive association between maternal occupational exposure to pesticide and spontaneous abortion has been reported in some studies. Work in greenhouses may imply exposure of pregnant women to pesticides continuously and at elevated level. Methods A total of 717 women working in greenhouses provided information on 973 pregnancies, including 110 spontaneous abortions. These pregnancies were classified as exposed or not exposed according to maternal occupation, re-entry activities and application of pesticides in greenhouses during at least 1 month in the first trimester of pregnancy. The ORs for spontaneous abortion were estimated through a generalised estimate equations model for all orders of pregnancy together, and through a logistic regression model limited to first pregnancies. Results Increased risks of spontaneous abortion were found for maternal re-entry activities within 24 hr after pesticides were applied (all orders of pregnancy: OR 3.2, 95% CI 1.3–7.7; first pregnancies: OR 3.8, 95% CI 1.0–13.9) and for those who applied pesticides (all orders of pregnancy: OR 2.6, 95% CI 1.0–6.6; first pregnancies: OR 3.7, 95% CI 0.7–20,6) Conclusions The observed results support the hypothesis of an association between maternal work in greenhouses and spontaneous abortion. The main limitations of the study are lack of information on the specific chemicals used and the small number of pregnancies heavily exposed to pesticides. Am. J. Ind. Med. 51:290–295, 2008. © 2008 Wiley-Liss, Inc.

Background and Aim. Acute respiratory failure (ARF) is a condition that must be treated as quickly as possible. Continuous Positive Airway Pressure (CPAP) is a common method used to treat ARF in hospital. The main objective of our study was to investigate the effect of CPAP prior to admission to the emergency room, on the reduction of endotracheal intubation, in-hospital mortality and on the length of stay in hospital (HLOS). Methods. A prospective, observational (non-randomised) study with a historical control group. Data from 3 groups of patients with ARF, irrespective of cause, was collected: pre-hospital CPAP (PHCPAP) group, i.e. 35 patients treated with a helmet CPAP in the ambulance, by trained nurses (mean age, years 80.1±7.9 SD; 14 males); hospital CPAP (HCPAP) group, i.e. 46 patients treated with helmet CPAP in the hospital emergency room (mean age 78.6±6.9 SD; 27 males), and a historical control group of 125 patients treated with medical therapy only (mean age 76.7±5.5 SD; 52 males). CPAP was delivered via a helmet interface. Results. Compared with standard medical therapy, helmet CPAP (pre and in-hospital) reduced mortality by 77 % (p=0.005), while pre-hospital helmet CPAP reduced it by 94% (p=0.011), after adjustment for age, sex, severity of clinical conditions at entry and diagnosis upon admission. HLOS was reduced, compared with standard medical therapy, by 63.5% and by 66% (adjusting for age, sex, severity of clinical conditions at entry and diagnosis at admission) with helmet CPAP (pre and in-hospital) and with helmet CPAP in the ambulance, respectively (p

We obtain representations of $X_1$ exceptional orthogonal polynomials through determinants of matrices that have certain adjusted moments as entries. We start out directly from the Darboux transformation, allowing for a universal perspective, rather than dependent upon the particular system (Jacobi or Type of Laguerre polynomials). We include a recursion formula for the adjusted moments and provide the initial adjusted moments for each system. Throughout we relate to the various examples of $X_1$ exceptional orthogonal polynomials. We especially focus on and provide complete proofs for the Jacobi and the Type III Laguerre case, as they are less prevalent in literature. Lastly, we include a preliminary discussion explaining that the higher co-dimension setting becomes more involved. The number of possibilities and choices is exemplified, but only starts, with the lack of a canonical flag., Comment: 24 pages

Clinical studies have shown that renal denervation (RDNX) decreases arterial pressure (AP) and improves glucose metabolism in drug resistant obese hypertensive patients. In the present study, we used a murine model of obesity-induced hypertension (HTN) to test the hypothesis that RDNX lowers AP and improves glucose metabolism via an interaction of renal nerves with inflammatory mediators in the kidney. 8-week old C57Bl/6J mice were fed either a low fat diet (LFD; 10 KCal% from fat) or a high fat diet (HFD; 45 KCal% from fat) for 10 weeks. Two parallel protocols were conducted. In a metabolic protocol, body weight, food intake, body-composition and glucose metabolism were measured. In a cardiovascular protocol, radiotelemeters were implanted for measurement of AP. C57Bl6J mice on a HFD exhibited an inflammatory and metabolic syndrome phenotype including increase splenic and renal total T cells, increased fat mass, high blood pressure, hyperglycemia and glucose intolerance as compared to LFD mice. RDNX but not Sham surgery after 12 weeks of HFD normalized AP (116 ± 4 in sham vs. 97± 6 mmHg in RDX HFD mice). RDX had no effect on AP in LFD diet mice. RDX in obese hypertensive mice had no effect on renal T cells or cytokines. Finally, RDX had no effect on glucose metabolism in HFD mice as determined by the glucose tolerance test at 2 weeks after RDX. We conclude that the antihypertensive effect of RDX in obesity-induced hypertension is not associated with improvement in glucose metabolism or renal inflammation in the mouse.

To perform a systematic review assessing accuracy and completeness of diagnostic studies of procalcitonin (PCT) for early-onset neonatal sepsis (EONS) using the Standards for Reporting of Diagnostic Accuracy (STARD) initiative. EONS, diagnosed during the first 3 days of life, remains a common and serious problem. Increased PCT is a potentially useful diagnostic marker of EONS, but reports in the literature are contradictory. There are several possible explanations for the divergent results including the quality of studies reporting the clinical usefulness of PCT in ruling in or ruling out EONS. We systematically reviewed PubMed, Scopus, and the Cochrane Library databases up to October 1, 2014. Studies were eligible for inclusion in our review if they provided measures of PCT accuracy for diagnosing EONS. A data extraction form based on the STARD checklist and adapted for neonates with EONS was used to appraise the quality of the reporting of included studies. We found 18 articles (1998–2014) fulfilling our eligibility criteria which were included in the final analysis. Overall, the results of our analysis showed that the quality of studies reporting diagnostic accuracy of PCT for EONS was suboptimal leaving ample room for improvement. Information on key elements of design, analysis, and interpretation of test accuracy were frequently missing. Authors should be aware of the STARD criteria before starting a study in this field. We welcome stricter adherence to this guideline. Well-reported studies with appropriate designs will provide more reliable information to guide decisions on the use and interpretations of PCT test results in the management of neonates with EONS.

Results concerning the association of adiponectin gene polymorphisms (single-nucleotide polymorphisms, SNPs) with obesity, type 2 diabetes (T2DM), metabolic disorders and insulin resistance have not lead to definite conclusions. The aim of our study was to investigate a possible association between the -11391G>A and -11377C>G SNPs of adiponectin gene and measure of insulin sensitivity evaluated by the hyperinsulinemic-euglycemic clamp in a group of 'uncomplicated' obese subjects (with no associated comorbidities) (n=99, mean age 35 years) with a history of obesity lasting at least 10 years. The study of uncomplicated obese subjects, free of possible confounding factors that could interfere with insulin sensitivity, such as pharmacological treatment, provides a good model to assess insulin sensitivity per se. We observed that subjects homozygous for the G allele at locus -11391 had lower M (mg/kg min)/fat-free mass (FFM) index and adiponectin levels compared to subjects with GA+AA genotypes (P=0.002 and P=0.03, respectively) and subjects carrying the -11377G variant had lower M (mg/kg min)/FFM index and adiponectin levels compared to noncarriers (P=0.003 and P=0.03, respectively). Our results imply that the two promoter SNPs, -11391G>A and -11377C>G, of the adiponectin gene are associated with a reduced insulin sensitivity evaluated by hyperinsulinemic-euglycemic clamp in obese subjects.

Summary Background : Current guidelines recommend non-invasive testing and treatment of young dyspeptic patients without alarm symptoms. Aim : To evaluate the accuracy of a new rapid immunochromatographic stool test to diagnose Helicobacter pylori infection before and after treatment compared with a gold standard. Methods : Prospective, single-blind study, performed in a tertiary care hospital. A total of 303 consecutive dyspeptic patients underwent endoscopy with multiple biopsies. Infected patients were offered a treatment and invited to come back 4–6 weeks after the end of therapy to repeat the endoscopy. Patients were also asked to provide a stool sample before and after therapy. Results : About 149 patients were H. pylori infected. The sensitivity and specificity before treatment were 91.3 and 93.5%; after treatment 92 and 100%. The likelihood ratios were robust enough to produce significant changes from pretest to post-test probability both in pre-treatment (LR+ = 14, LR− = 0.093) and post-treatment (LR+ = 19.6, LR− = 0.095). Conclusions : The novel immunochromatographic stool test is fast, easy to perform and provides good differentiation between positive and negative results. It might become a rapid near patients test easily performed in the doctor office.

Obstetric complications may be an etiologically important factor in the development of schizophrenia. The aim of this study was to evaluate whether the risk for developing schizophrenia in adult life is increased in individuals with more severe obstetric complications at birth.To this end, mothers were interviewed to gather data about obstetric complications. The 'midwife protocol' of Parnas and colleagues was used to quantify the presence and entity of obstetric complications. We studied the frequency distribution and the severity of obstetric complications in 64 male DSM IV schizophrenic patients. The genetic load was reduced by using 81 brothers who were not psychiatric patients as controls. Odds ratios for the effects of obstetric complications, maternal age, birth order and birth weight were calculated using conditional logistic regression.The only factor found to have a significant effect on the risk of schizophrenia was the overall measure of obstetric complications at birth. The history of obstetric complications was higher in schizophrenic patients than in their siblings.The results seem to confirm the hypothesis that obstetric complications may contribute to increased vulnerability to the disease, in addition to genetic risk factors.

Summary Background : A new urea breath test (UBT) has been described which uses a tablet formulation of 13C-urea with citric acid and allows breath sampling to be performed as early as 10 min after ingestion of the tablet. Aim : To assess the diagnostic accuracy of tablet-based 13C-UBTs (50 and 100 mg 13C-urea) before and after Helicobacter pylori eradication treatment, compared with an endoscopy gold standard and a conventional 13C-UBT (75 mg 13C-urea). Methods : Two hundred dyspeptic patients underwent endoscopy, followed by tablet-based 13C-UBTs (50 and 100 mg 13C-urea) and a conventional 13C-UBT (75 mg 13C-urea). H. pylori-infected patients were prescribed treatment and asked to return 4–6 weeks after the end of therapy for repeat endoscopy and 13C-UBTs. Results : One hundred and thirteen patients were infected with H. pylori. The sensitivity and specificity of the conventional 13C-UBT were both 100%; the sensitivity and specificity of the 100-mg tablet-based 13C-UBT were 100% and 98.85%, respectively. For the 50-mg tablet-based 13C-UBT, cut-off values of the difference over baseline of between 1.65 and 3.15 provided a sensitivity and specificity of 100%. At follow-up, the sensitivity and specificity of the conventional and 100-mg tablet-based 13C-UBTs were both 100%. For the 50-mg tablet-based 13C-UBT, cut-off values of the difference over baseline of between 1.49 and 1.56 gave a sensitivity and specificity of 100%. Conclusions : New 10-min 13C-UBTs using tablet formulations of 13C-urea with citric acid are reliable for the assessment of H. pylori status pre- and post-treatment.

Further statistics in dentistry: If one were to go by the explosion of interest in evidence-based clinical practice in the past decade of the second millennium, one could be forgiven for thinking that the idea was new. In fact, a quick search of Medline revealed 9,306 references to 'evidence-based medicine' (EBM) and 291 when the search was restricted to dentistry. It is claimed (Sackett et al., 1996)1 that the origins of EBM date back to mid nineteenth century Paris or earlier although the name EBM was coined in 1992. The inventor of the randomised controlled clinical trial, Sir Austin Bradford Hill, in the 1950s set out the statistical foundations of EBM.

In 1998, a systemic fetal cytokine response, defined as a plasma interleukin-6 (IL-6) value above 11. pg/mL, was reported to be a major independent risk factor for the subsequent development of neonatal morbid events even after adjustments for gestational age and other confounders. Since then, the body of literature investigating the use of blood concentrations of IL-6 as a hallmark of the fetal inflammatory response syndrome (FIRS), a diagnostic marker of early-onset neonatal sepsis (EONS) and a risk predictor of white matter injury (WMI), has grown rapidly. In this article, we critically review: IL-6 biological functions; current evidence on the association between IL-6, preterm birth, FIRS and EONS; IL-6 reference intervals and dynamics in the early neonatal period; IL-6 response during the immediate postnatal period and perinatal confounders; accuracy and completeness of IL-6 diagnostic studies for EONS (according to the Standards for Reporting of Diagnostic Accuracy statement); and recent breakthroughs in the association between fetal blood IL-6, EONS, and WMI.

In order to introduce the concepts underlying multiple linear regression, it is necessary to be familiar with and understand the basic theory of simple linear regression on which it is based.

Further statistics in dentistry: The clinical trial is a planned experiment, strictly on human subjects, which is conducted with a view to investigating the efficacy of one or more treatments for a given condition. It is possible to use statistical techniques to make inferences about the population of patients who will present to the practitioner in the future using information obtained from the sample of patients in the trial. Consequently, the results of the trial may be expected to influence the way in which patients with the condition are treated in the future.

To facilitate statistical discussion, it is essential to have an understanding of factors, effects, interactions, confounding, bias, estimation and hypothesis testing, to name but a few terms commonly used in statistical investigations in dentistry. These terms were explained in the previous paper in this series. This second paper is concerned with describing and differentiating between the various research designs that may be adopted.

Objective To evaluate several alternative measures of forced expiratory volume in 1 second percent predicted (FEV 1 %pred) variability as potential predictors of future FEV 1 %pred decline in patients with cystic fibrosis. Study design We included 13 827 patients age ≥6 years from the Epidemiologic Study of Cystic Fibrosis 1994-2002 with ≥4 FEV 1 %pred measurements spanning ≥366 days in both a 2-year baseline period and a 2-year follow-up period. We predicted change from best baseline FEV 1 %pred to best follow-up FEV 1 %pred and change from baseline to best in the second follow-up year by using multivariable regression stratified by 4 lung-disease stages. We assessed 5 measures of variability (some as deviations from the best and some as deviations from the trend line) both alone and after controlling for demographic and clinical factors and for the slope and level of FEV 1 %pred. Results All 5 measures of FEV 1 %pred variability were predictive, but the strongest predictor was median deviation from the best FEV 1 %pred in the baseline period. The contribution to explanatory power (R 2 ) was substantial and exceeded the total contribution of all other factors excluding the FEV 1 %pred rate of decline. Adding the other variability measures provided minimal additional value. Conclusions Median deviation from the best FEV 1 %pred is a simple metric that markedly improves prediction of FEV 1 %pred decline even after the inclusion of demographic and clinical characteristics and the FEV 1 %pred rate of decline. The routine calculation of this variability measure could allow clinicians to better identify patients at risk and therefore in need of increased intervention.

Background Infections which complicate rheumatic diseases such as Rheumatoid Arthritis (RA) and Spondyloarthropathy (SpA) (Psoriatic Arthritis [PA] and Ankylosing Spondylitis [AS]), may cause significant morbidity and mortality. However, among the studies on the incidence rate (IR) of infections in such patients, very few have involved controls and the results have been controversial, probably due to methodological difficulties. To estimate infection rates in RA and SpA patients under disease-modifying anti-rheumatic drugs (DMARDs), corticosteroids (CS) and tumor necrosis factor (TNF)α antagonists, alone or combined, a single-centre retrospective observational cohort study has been performed. Patients and methods Incidence rates/100 patient-years of any infections were evaluated in RA and SpA outpatients observed in the period November 1, 2003 through December 31, 2009 and stratified according to therapy. Infection incidence rate ratios (IRR) were calculated using Poisson regression models which adjusted for demographic/clinical characteristics of the patients. Results Three hundred and thirtyone infections [318 (96.1%) non-serious and 13 (3.9%) serious] have been registered among 176 of the 341 patients (52%). The IR/100 patient-years of all infections was 36.3 ranging from 12.4 (DMARDs + CS) to 62.7 (anti-TNFα + CS). The most frequent infection site was respiratory tract, and bacteria were responsible for three quarters of all infections. In the multivariate analysis, adding anti-TNFα to DMARDs doubled the IRR compared to DMARDs alone, anti-TNFα + CS significantly tripled it, whereas anti-TNFα + CS + DMARDs only increased the risk 2.5 times. The degree of disease activity was strongly and significantly associated with the infection risk (severe or moderate versus mild, IRR = 4). Female sex was significantly associated with increased infection risk, while duration of disease and anti-influenza vaccination were protective, the latter even for cutaneous/soft-tissue (mainly herpetic) infections. Conclusion The combination anti-TNFα with CS was found to be the most pro-infective treatment, whereas DMARDs alone were relatively safe. Physicians, therefore, should be aware that there may be an increased risk of infection when using anti-TNFα and CS therapy together. Anti-influenza vaccination appears to provide broad protection, adding evidence to support its use in these patients, and deserves further study.

Background: Helicobacter pylori infection, gastric acid hypersecretion and NSAID consumption may cause peptic ulcer. Aim: To investigate the respective roles of H. pylori and acid secretion in bleeding duodenal ulcer. Patients and methods: A total of 99 duodenal ulcer patients were referred for evaluation of acid secretion: seven with Zollinger–Ellison Syndrome; 14 with hypersecretory duodenal ulcer, defined by the coexistence of elevated basal acid output and pentagastrin acid output; and 78 duodenal ulcer patients with normal acid output. All non-Zollinger–Ellison Syndrome patients were H. pylori-positive and cured of infection. All patients were followed-up for a 36-month period, to assess the occurrence of bleeding episodes. Results: Twenty-nine patients had at least one bleeding episode in the 4 years before the study. Bleeding was more frequent in males and in patients on NSAIDs. The mean basal acid output was not higher among bleeders. In the 21 patients (14 hypersecretory duodenal ulcer, seven Zollinger–Ellison Syndrome) with basal acid output > 10 meg/h and pentagastrin acid output > 44.5 meg/h, the risk of bleeding was higher (OR 6.5; 95% CI: 2–21). In the follow-up period, three out of 83 (3.3%) non-Zollinger–Ellison Syndrome patients had a H. pylori-negative duodenal ulcer with bleeding. The risk of bleeding after H. pylori cure was not higher in hypersecretory duodenal ulcer patients (P > 0.3), nor among patients with previous bleeding episodes (P > 0.2). Conclusions: In H. pylori-positive duodenal ulcer patients, the coexistence of elevated basal acid output and pentagastrin acid output leads to a sixfold increase in the risk of bleeding. After H. pylori cure, gastric acid hypersecretion is not a risk factor for bleeding. However, duodenal ulcer recurrence with bleeding may occasionally occur in patients cured of H. pylori, even if acid output is normal.

Hashimoto's thyroiditis (HT) is an autoimmune disease resulting from a complex interaction between genetic and environmental factors. The genetic loci conferring susceptibility need to be still defined. The aim of the present study was to determine whether Cytotoxic T-Lymphocyte-Associated Antigen-4 (CTLA-4), HLA DRB1, and DQB1 genes were associated to HT in an Italian population. We evaluated the allele distribution of the following loci: CTLA-4 exon 1 A49G dimorphism, which resulted in an amino acidic exchange (Thr/Ala) in the leader peptide, CTLA-4 3' microsatellite, HLA DRB1 and DQB1 in 126 patients with HT and in 301 control subjects from an Italian population (Lazio region). CTLA-4 exon 1 A49G dimorphism was typed by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR-RFLP); CTLA-4 3' microsatellite alleles were defined using a fluorescence-based method. HLA DRB1 and DQB1 alleles were typed using a SSO reverse line blot method and a probeless procedure based on allele group-specific amplification followed by DNA heteroduplex analysis, respectively. Data were initially analyzed by chi2 test or Fisher's exact test. Multiple logistic regression analysis was then applied on factors with significant crude odds ratios and on CTLA-4 exon 1 A49G dimorphism to investigate their independent effects. The two polymorphic sites at CTLA-4 gene did not increase the risk for HT. The distribution of HLA DRB1 and DQB1 alleles did not show any significant difference between patients and controls, however, the DRB1*04-DQB1*0301 haplotype was significantly increased in patients. Other factors that increase the risk of disease were gender and age. Females showed approximately 18 times more risk than males; subjects older than 50 years had an odds ratio of 6.6. These data suggest that these two polymorphic sites at CTLA-4 do not play a major role in the susceptibility of the disease in an Italian population while female gender, age over 50 years, HLA DRB1*04-DQB1*0301 haplotype increase the risk of developing HT.

This paper describes the trend in the risk of spontaneous abortion in Italy from 1974 to 1995. There was a dramatic decline in the risk after the law that legalized induced abortion was passed in 1978, which implies that probably many induced abortions performed before 1978 were registered as spontaneous abortions. Data for 1991 have been extracted from the Italian national registers of births and abortions and analyzed to investigate the effects of maternal age, gravidity, marital status, and education on the risk of spontaneous abortion. In comparison with women under age 20 years, the risk is found to be increased for women aged 35-39 (odds ratio = 1.45) and women over age 40 (odds ratio = 3.10). The odds ratio is almost 2 for women who have been pregnant two or more times previously. Unmarried women have an increased risk (odds ratio = 1.33), but no important effect of education was observed. There is an important interaction between maternal age and gravidity. The risk of spontaneous abortion is excessively high for young women with high gravidity. It is hypothesized that this could be due to the effect of short intervals between pregnancies.

Objective: To assess the ability of the SOFA score (Sequential Organ Failure Assessment) to describe the evolution of organ dysfunction/failure in trauma patients over time in intensive care units (ICU). Design: Retrospective analysis of a prospectively collected database. Setting: 40 ICUs in 16 countries. Patients: All trauma patients admitted to the ICU in May 1995. Main outcome measures and results: Incidence of dysfunction/failure of different organs during the first 10 days of stay and the relation between the dysfunction, outcome, and length of stay. Included in the SOFA study were 181 trauma patients (140 males and 41 females).The non-survivors were significantly older than the survivors (51 years ± 20 vs 38 ± 16 years, p 3 in 47 % of non-survivors vs 17 % of survivors), cardiovascular ( > 3 in 24 % of non-survivors vs 5.7 % of survivors), and neurological systems ( > 4 in 41 % of non-survivors vs 16 % of survivors); although the trend was maintained over the whole study period, the differences were greater during the first 4–5 days. After the first 4 days, only respiratory dysfunction was significantly related to outcome. A higher SOFA score, admission to the ICU from the same hospital, and the presence of infection on admission were the three major variables associated with a longer length of stay in the ICU (additive regression coefficients: 0.85 days for each SOFA point, 4.4 for admission from the same hospital, 7.26 for infection on admission). Conclusions: The SOFA score can reliably describe organ dysfunction/failure in trauma patients. Regular and repeated scoring may be helpful for identifying categories of patients at major risk of prolonged ICU stay or death.

The clinically important glycopeptide antibiotic vancomycin binds to bacterial cell wall peptides of Gram-positive bacteria which terminate in -Lys-D-Ala-D-Ala, thereby inhibiting cell wall synthesis resulting in cell death. We have removed the N-terminal leucine residue of vancomycin by an Edman degradation and acylated the exposed amino group of residue 2 with N-Me-Gly, N-Me-D-Ala, acetyl, butyl, and isohexyl groups to generate novel vancomycin analogues. The binding of vancomycin and these vancomycin analogues to the bacterial cell wall analogue di-N-Ac-L-Lys-D-Ala-D-Ala (DALAA) was studied by NMR techniques and UV spectroscopy. The effects that these structural modifications of the carboxylate binding pocket of vancomycin have on the antibiotic-DALAA recognition process show that a cooperative effect between non-polar and ionic forces appears to be partly responsible for the highly efficient sequestering of the DALAA C-terminal carboxylate from aqueous solution.

Summary Background Pernicious anaemia (PA) has an increased risk for gastric cancer (GC). It is not established whether PA patients need to undergo endoscopic/histological follow-up. Aim To provide a systematic overview of the literature on PA and the development of gastric cancer, to estimate the gastric cancer incidence-rate. Methods According to PRISMA, we identified studies on PA patients reporting the incidence of gastric cancer. Quality of studies was evaluated using the Newcastle-Ottawa Quality Assessment Scale. Meta-analysis on annual gastric cancer incidence rates was performed. Results Twenty-seven studies met eligibility criteria. 7 studies were of high, 6 of medium, 10 of low and 4 of very low quality. Gastric cancer incidence-rates ranged from 0% to 0.2% per person-years in 7 American, from 0% to 0.5% in 2 Asiatic, from 0% to 1.2% in 11 Northern European studies and from 0% to 0.9% in 7 studies from other European countries. The incidence-rates of gastric cancer ranged from 0% to 1.2% per person-years in studies which used gastroscopy, from 0.1% to 0.9% in those based on International Classification of Disease. Heterogeneity between studies was not statistically significant at the 5% level (Chi-squared test = 17.9, P = 0.08). The calculated pooled gastric cancer incidence-rate was 0.27% per person-years. Meta-analysis showed overall gastric cancer relative risk in PA as 6.8 (95% CI: 2.6–18.1). Conclusions This systematic review shows a pooled gastric cancer incidence-rate in pernicious anaemia of 0.27% per person-years and an estimated nearly sevenfold relative risk of gastric cancer in pernicious anaemia patients. Further high quality studies are needed to confirm this higher risk.

Summary Background Because of the decrease in the Helicobacter pylori eradication rate after standard triple therapy with a proton pump inhibitor and two antibiotics, bismuth-based therapy has recently been recommended as alternate first-line regimen in children. Aim To comprehensively review the clinical, pharmacologic and microbiologic properties of bismuth salts, and to summarise the evidence for the therapeutic efficacy of bismuth-based therapy for H. pylori eradication in children. Methods Bibliographical searches were performed in MEDLINE. Results on the efficacy of bismuth-containing regimens on H. pylori eradication were combined using the inverse variance method. Results Bismuth monotherapy showed a very low efficacy. Overall, the mean eradication rate with bismuth-based dual therapy was 68% (95% CI, 60–76%) (intention-to-treat analysis-ITT) and 73% (95% CI, 64–81%) (per protocol-PP). In case series, the overall percentages of children with successful eradication for triple therapy containing bismuth were 82% (95% CI, 76–88%) and 86% (95% CI, 80–92%) according to ITT and PP respectively. In comparative studies, H. pylori eradication rates ranged between 69% and 85% according to ITT and between 74% and 96% PP. Side effects included dark stools, urine discoloration, black tongue, burning tongue, and marked darkness of the gums. Conclusions The evidence in favour of bismuth compounds for treating infected children is still not clear. Well-designed, randomised, multi-centre studies of H. pylori eradication trials in children comparing bismuth-based triple therapy with the best available recommended first-line therapies are needed. The evidence obtained from audited case series that produce an eradication rate of >95% on PP analysis should also be considered.

Efficient monitoring of surfaces for spores of filamentous fungi is essential for detecting minor contamination even when air samples test negative for fungi. This study evaluates and compares a pad prepared using a dusting cloth with Rodac contact plates and humidified swabs for detecting mycological contamination, and concludes that the new method is superior and cheaper.

For neonates, assessment of laboratory tests occurs within a context of prenatal growth and neonatal development. This is a significant issue for neonatal reference intervals.