Review article: after gastritis--an imaginary journey into a Helicobacter-free world.
This article explores the consequences of the world-wide trend that may result--at different times for different populations--in the disappearance of Helicobacter pylori and gastritis. After a brief historical introduction, some of the factors that contribute to the decrease in the prevalence of H. pylori are presented. The most apparent results of this trend in the industrialized world have been a decrease in the incidence of peptic ulcer and distal gastric adenocarcinoma. However, some other conditions of the upper digestive tract, such as acid reflux disease and adenocarcinoma of the cardio-oesophageal junction have been increasing. This simultaneous increase has led to the speculation that it may be causally related to the decreased prevalence of gastritis, and currents of thought supporting a laissez faire attitude with regards to H. pylori infection have developed. If these trends continue, future research aimed at understanding the pathogenesis of H. pylori-related conditions, including gastric carcinogenesis, will hinge on access to populations in which H. pylori is still highly prevalent, and on further refinement of the recently introduced Mongolian gerbil model.


Patients' perceptions of medical urgency: does deprivation matter?
Consultation behaviour is recognized as having numerous determinants, but patients' perceptions of medical urgency have been neglected as a variable of potential importance. We aimed to describe the variation in patients' perceptions of medical urgency, and to investigate the influence of socio-economic deprivation on such perceptions. We also aimed to investigate the association between patients' perceptions of urgency and their perception of doctor availability. We carried out a questionnaire survey (incorporating 10 clinical vignettes) of patients attending one of 17 participating practices during a 1-week study period. A medical urgency score was calculated for each patient, and compared for patients sharing similar characteristics. The setting was West Lothian, Scotland. Patients' perceptions of medical urgency as measured by the urgency score were normally distributed amongst a sample of 4999 patients attending their GP. Whilst socio-economic deprivation was a significant determinant of perceptions of medical urgency, the effect was small and can probably be discounted as an important variable determining such perceptions. An association was observed between patients' perceptions of doctor availability following a non-urgent consultation request and a heightened sense of medical urgency. Further work is required to explain the differences in the population with regard to perceptions of medical urgency, and to examine the association between patients' perceptions of the seriousness of symptoms and the urgency of consultation requests.


Arthritis knowledge: a survey of health professional students.
Recent reports indicate that disease-specific educational modules have resulted in improved knowledge among resident physicians. These findings suggest that graduate level health professional students may also benefit from similar strategies focused on arthritis, the leading cause of disability in the United States. The purpose of this pilot study was to examine arthritis knowledge among healthcare professional students whose current curriculums include didactic arthritis content. A survey of arthritis knowledge was developed to examine general arthritis knowledge and the epidemiological impact of arthritis among healthcare professional students. The survey was administered to 164 first, second, and third year students enrolled in graduate occupational and physical therapy programs. The findings of the current study address risk factors recognition and arthritis knowledge. Risk factors recognition -- 94% identified age; 68% identified gender; 94% identified genetics; 90% identified joint injuries; 73% identified obesity as a risk factor; and 55% identified occupation. More than 50% of the students identified the six risk factors most likely to lead to arthritis. ARTHRITIS KNOWLEDGE: prevalence, disability impact, and cost -- 100% correctly identified arthritis symptoms; 26% of the students surveyed reported arthritis as the third leading cause of disability; 85% of the survey respondents reported that in the US women have higher rates of arthritis; and 31% knew the health care cost of arthritis in the US. All students recognized the symptoms of arthritis and most recognized its individual risk factors, but few exhibited knowledge of the financial and disability burden associated with arthritis. These findings suggested that despite didactic arthritis content in both the occupational and physical therapy programs arthritis risk factors recognition and arthritis knowledge were mixed. Further research examining arthritis knowledge among a broader range of health professional students may be important to determine if disease-specific educational modules are needed in all graduate health professional programs.


Long non‑coding RNA SLNCR1 regulates non‑small cell lung cancer migration, invasion and stemness through interactions with secretory phospholipase A2.
Long non‑coding RNA (lncRNA) SRA‑like non‑coding RNA (SLNCR1; also known as linc00673) is a recently identified oncogenic lncRNA. The role of SLNCR1 in non‑small cell lung cancer (NSCLC), a common malignancy, remains poorly understood. The present study aimed to investigate the involvement of long non‑coding RNA SLNCR1 in the pathogenesis of NSCLC. Reverse transcription‑quantitative PCR (RT‑qPCR) and ELISA were performed to measure the levels of lncRNA SLNCR1 and secretory phospholipase A2 (sPLA2) in lung biopsies, respectively. Correlations between expression levels of lncRNA SLNCR1 and sPLA2 were analyzed by Pearson's correlation analysis. Diagnostic value of lncRNA SLNCR1 for NSCLC was evaluated by receiver operating characteristic curve analysis. lncRNA SLNCR1 small interfering (si)RNA and sPLA2 overexpression vector were transfected into NSCLC cells. Cell migration, invasion and stemness were examined by Transwell migration assay, Matrigel invasion assay and flow cytometric assay, respectively. Following transfection, expression of lncRNA SLNCR1 and sPLA2 was detected by RT‑qPCR and western blotting, respectively. The results demonstrated that lncRNA SLNCR1 expression levels were upregulated in tumor tissues compared with adjacent healthy tissues of patients with NSCLC. Plasma lncRNA SLNCR1 and sPLA2 expression levels were upregulated in patients with NSCLC compared with healthy controls. Plasma lncRNA SLNCR1 and sPLA2 were positively correlated in patients with NSCLC, but not in healthy controls. lncRNA SLNCR1 siRNA silencing inhibited, whereas sPLA2 overexpression promoted cell migratory and invasive abilities and stemness. lncRNA SLNCR1 siRNA silencing led to downregulated sPLA2 expression, whereas sPLA2 overexpression did not significantly affect lncRNA SLNCR1 expression. sPLA2 overexpression attenuated the inhibitory effects of lncRNA SLNCR1 siRNA silencing on cell migration, invasion and stemness. In conclusion, lncRNA SLNCR1 may regulate cancer cell migration, invasion and stemness in NSCLC through interactions with sPLA2.


An Autopsy Case of Primary Biliary Cholangitis with Histological Submassive Hepatic Necrosis Caused by Acute Hepatitis E Virus Infection.
A 59-year-old woman who had been diagnosed with cirrhotic primary biliary cholangitis (PBC) 5 years earlier was admitted for severe jaundice (total bilirubin: 30.1 mg/dL). We suspected that her cirrhotic PBC had deteriorated acutely for some reason. Her general condition deteriorated quickly, and she passed away on day 18 of admission. Hepatitis E virus (HEV)-IgA antibodies were positive, and Genotype 3b HEV involvement was confirmed from a blood sample taken on admission. Histopathological findings revealed cirrhosis and submassive loss and necrosis of hepatocytes. Clinicians should consider the possibility of acute HEV infection as a trigger for acute PBC exacerbation.


Nizatidine, a new histamine H2-receptor antagonist, and hepatic oxidative drug metabolism in the rat: a comparison with structurally related compounds.
The effects of nizatidine (a new H2-receptor antagonist) and of related compounds were studied on oxidative drug metabolism in the rat both in vivo and in vitro. Nizatidine is a structural analog of the H2-receptor antagonists ICI 125,211 (Tiotidine) and ranitidine (Zantac). Nizatidine (120 mg/kg, ip) had no effect on the [14C]aminopyrine (ABT) or [14C]caffeine breath (CBT) tests, nor on the clearance from plasma of aminopyrine despite high tissue and plasma concentrations of nizatidine. Binding of nizatidine (1 mM) to rat hepatic microsomal P-450 determined by spectral analysis was not observed. In vitro aminopyrine demethylation was inhibited by nizatidine only at high concentrations (Ki = 92 mM). Cimetidine, ICI 125,211, and imidazole bind avidly to rat hepatic microsomal cytochrome P-450 and are potent inhibitors of aminopyrine demethylation in vitro. Imidazole inhibited the aminopyrine breath test, while imidazole, ranitidine, and ICI 125,211 inhibited the caffeine breath in vivo. These data indicate that nizatidine has no acute inhibitory effect on hepatic oxidative drug metabolism in the rat, both in vitro and in vivo. The composite structural-activity data suggest that inhibition of in vivo oxidative drug metabolism by H2-antagonists may not depend primarily on either the imidazole ring side chain or the thiazole ring per se. Furthermore, the in vivo inhibition may not correlate with in vitro data.


Influence of Intraocular Lens Asphericity and Blue Light Filtering on Visual Outcome, Contrast Sensitivity, and Aberrometry after Uneventful Cataract Extraction.
To evaluate the effect of asphericity and blue light filter (BLF) of three different intraocular lenses (IOLs) on the visual performance, second- and third-order aberrations (defocus, coma, trefoil), and contrast sensitivity after uneventful cataract surgery. One hundred and twenty eyes of 60 patients with clinically significant cataract were randomly assigned to receive one of the three IOL types: Bioline Yellow Accurate (aspheric, with BLF, i-medical, Germany), BioAcryl 60125 (spherical, without BLF, Biotech, France), and H65C/N (aspheric, without BLF, PhysIOL, Belgium). Each IOL was implanted in 40 eyes. Complete ophthalmologic examination, functional acuity contrast testing and wavefront analysis were performed 60 days postoperatively. The mean postoperative best-corrected visual acuity (BCVA) was 0.95 ± 0.08, not differing statistically among the IOL groups (P = 0.83). Mean defocus and coma values did not yield any statistically significant difference through the IOL groups varying from -0.784 to -0.614 μm and 0.129 to 0.198 μm (P = 0.79 and 0.34, respectively). Bioline Yellow Accurate IOL presented less trefoil aberrations, 0.108 ± 0.05 μm, compared to the other two IOL types (BioAcryl [0.206 ± 0.19 μm] and Physiol [0.193 ± 0.17 μm], P < 0.05). Contrast sensitivity values did not differ among the groups under all lighting conditions. Bioline Yellow IOL showed a statistically higher loss of contrast sensitivity (between mesopic and mesopic with glare conditions) compared to the BioAcryl and PhysIOL in 12 and 3 cpd spatial frequencies, respectively (P < 0.05). Bioline Yellow IOL indicated lower contrast sensitivity under mesopic conditions when glare was applied but resulted in less trefoil aberrations after uneventful cataract surgery. No further differences were noted in postoperative visual performance among three IOL groups.


Publication of clinical drug trials.
Clinical drug trials are the best means for establishing the efficacy and safety of drug therapy. Peer-reviewed publications are the most efficient and reliable means for wide dissemination of the results. The investigators and industry have an obligation to publish the data obtained from these trials so that patients may receive the most effective treatment in the safest possible way.


Comparison of mechanical cardiopulmonary support strategies during lung transplantation.
Lung transplantation outcomes are influenced by the intraoperative mechanical cardiopulmonary support strategy used. This surgery was historically done either on cardiopulmonary bypass (CPB) or off pump. Recently, there has been increased interest in intraoperative support with veno-arterial (VA) or veno-venous (VV) extracorporeal membrane oxygenation (ECMO). However, there is a lack of consensus on the relative risks, benefits and indications for each intraoperative support strategy. This review includes information from cohort studies, case-control studies, and case series that compare morbidity and/or mortality of two or more intraoperative cardiopulmonary support strategies during lung transplantation. The optimal strategy for intraoperative cardiopulmonary support during lung transplantation remains an area of debate. Current data suggest that off pump is associated with better outcomes and could be considered whenever feasible. ECMO is generally associated with preferable outcomes to CPB, but the data supporting this association is not robust. Interestingly, whether CPB is unplanned or prolonged might influence outcomes more than the use of CPB itself. These observations can help guide surgical teams in their approach for intraoperative mechanical support strategy during lung transplantation and should serve as the basis for further investigations.


Specialty board certification and clinical outcomes: the missing link.
Specialty board certification status is often used as a standard of excellence, but no systematic review has examined the link between certification and clinical outcomes. The authors evaluated published studies tracking clinical outcomes and certification status. Data sources consisted of studies cited between 1966 and July 1999 in OVID-Medline, psychological abstracts (PsycLit), and the Educational Research Information Clearinghouse (ERIC). Screening criteria included: only U.S. patients and physicians used as subjects; verified specialty board certification status by an American Board of Medical Specialties' (ABMS') member board using the ABMS database or derivative sources; described selection criteria for patients and physicians; selected nationally recognized standards of care for outcomes; and nested patient data by individual physician. The computerized searches that were conducted in 1999 identified 1,204 papers; one author and a research assistant selected 237 papers based on subject relevance, and reduced the list to 56 based on study quality. The authors independently applied inclusion and exclusion criteria to identify 13 of the 56 papers containing 33 separable relevant findings. Of the 33 findings, 16 demonstrated a significant positive association between certification status and positive clinical outcomes, three revealed worse outcomes for certified physicians, and 14 showed no association. Three negative findings and one finding of no association were identified in two papers with insufficient case-mix adjustments in the analyses. Meta-analytic statistics were not feasible due to variability in outcome measures across studies. Few published studies (5%) used research methods appropriate for the research question, and among the screened studies more than half support an association between board certification status and positive clinical outcomes.


Polytypism in mcalpineite: a study of natural and synthetic Cu3TeO6.
Synthetic and naturally occurring forms of tricopper orthotellurate, CuII3TeVIO6 (the mineral mcalpineite) have been investigated by 3D electron diffraction (3D ED), X-ray powder diffraction (XRPD), Raman and infrared (IR) spectroscopic measurements. As a result of the diffraction analyses, CuII3TeVIO6 is shown to occur in two polytypes. The higher-symmetric CuII3TeVIO6-1C polytype is cubic, space group Ia3, with a = 9.537 (1) Å and V = 867.4 (3) Å3 as reported in previous studies. The 1C polytype is a well characterized structure consisting of alternating layers of CuIIO6 octahedra and both CuIIO6 and TeVIO6 octahedra in a patchwork arrangement. The structure of the lower-symmetric orthorhombic CuII3TeVIO6-2O polytype was determined for the first time in this study by 3D ED and verified by Rietveld refinement. The 2O polytype crystallizes in space group Pcca, with a = 9.745 (3) Å, b = 9.749 (2) Å, c = 9.771 (2) Å and V = 928.3 (4) Å3. High-precision XRPD data were also collected on CuII3TeVIO6-2O to verify the lower-symmetric structure by performing a Rietveld refinement. The resultant structure is identical to that determined by 3D ED, with unit-cell parameters a = 9.56157 (19) Å, b = 9.55853 (11) Å, c = 9.62891 (15) Å and V = 880.03 (2) Å3. The lower symmetry of the 2O polytype is a consequence of a different cation ordering arrangement, which involves the movement of every second CuIIO6 and TeVIO6 octahedral layer by (1/4, 1/4, 0), leading to an offset of TeVIO6 and CuIIO6 octahedra in every second layer giving an ABAB* stacking arrangement. Syntheses of CuII3TeVIO6 showed that low-temperature (473 K) hydrothermal conditions generally produce the 2O polytype. XRPD measurements in combination with Raman spectroscopic analysis showed that most natural mcalpineite is the orthorhombic 2O polytype. Both XRPD and Raman spectroscopy measurements may be used to differentiate between the two polytypes of CuII3TeVIO6. In Raman spectroscopy, CuII3TeVIO6-1C has a single strong band around 730 cm-1, whereas CuII3TeVIO6-2O shows a broad double maximum with bands centred around 692 and 742 cm-1.


[Sialic acid--an acute phase reactant and a concomitant of tumors].
Sialic acid is an acute phase reagent with tumour burden reflecting fluctuations of serum level. The parameter is unsuitable for an early recognition of cancer. Sialic acid could be used as a parameter in questions concerning tumour burden: the diagnosis of tumour stage, the control of growth after therapy, the prediction of recidivation. The small specificity of an increased serum level of sialic acid will presumably be only of little use in tumour diagnostics.


Neuronal ceroid lipofuscinosis in Merino sheep.
To characterise neuronal ceroid lipofuscinosis (NCL) in Merino sheep. A prospective clinical, pathological, biochemical and genetic study. NCL cases were studied from a medium-wool Merino flock, the stud of origin of its replacement rams, and an experimental flock established at the University of Sydney. Behavioural changes and visual impairment were first detected at 7 to 12 months of age and progressed, with associated motor disturbances and at later stages seizures, to premature death by 27 months of age. At necropsy there was severe cerebrocortical atrophy associated with neuronal loss, astrocytosis and the presence in neurons of eosinophilic intracytoplasmic storage bodies with the characteristics of a lipopigment. In the retina there was progressive loss of photoreceptor cells. Storage bodies isolated from fresh brain, liver and pancreas formed electron-dense aggregates and coarse multilamellar and fine fingerprint profiles ultrastructurally, and consisted mainly of the hydrophobic protein, subunit c of mitochondrial ATP synthase. A homozygosity mapping approach localised the gene causing the disease in Merino sheep to the chromosomal region (OAR7q13-15) associated with NCL in South Hampshire sheep. NCL in Merino sheep is a subunit c-storing disease, clinically and pathologically similar to NCL in South Hampshire sheep. We propose that the disease in both breeds represents mutation at the same gene locus in chromosomal region OAR7q13-15.


Liver Regeneration after Partial Hepatectomy Is Not Impaired in Mice with Double Deficiency of Myd88 and IFNAR Genes.
Liver regeneration is known to occur in mice lacking one or more Toll-like receptors (TLRs) or the adaptor protein MyD88. Though MyD88 is required for signaling by many TLRs, others signal via MyD88-independent pathways, leading to the induction of type I interferons (IFNs). Here, we assessed liver regeneration after partial hepatectomy (PH) in mice lacking both MyD88 and the type I IFN receptor (Myd88-IFNAR double-KO). Approximately 28% of Myd88-IFNAR double-KO mice had gross liver lesions prior to surgery. In mice without lesions, Myd88-IFNAR deficiency abrogated the increase in circulating IL-6 after PH but did not impair hepatocyte BrdU incorporation, mitotic figure counts, or recovery of liver-to-body weight ratios. These results indicate that type I IFNs are not responsible for the preservation of liver regeneration in Myd88-deficient mice, and they also cast doubt on the idea of microbial products being essential triggers of liver regeneration in mice undergoing PH.


Prophylactic femoral varization osteotomy for contralateral stable hips in non-ambulant individuals with cerebral palsy undergoing hip surgery: decision analysis.
This study was undertaken to determine the need for concurrent prophylactic femoral varization osteotomy (FVO) of contralateral stable hips at the time of hip reconstructive surgery on unstable hips in non-ambulant individuals with cerebral palsy (Gross Motor Function Classification System levels IV and V). A decision analysis model was constructed that included (1) the probability of unstable hips during observation of the contralateral stable hips, (2) unstable hip rate (subluxation or dislocation rate) after prophylactic FVO or after delayed reconstructive surgery (including FVO) for unstable hips, and (3) complication rates after concurrent prophylactic FVO or after hip reconstructive surgery. The final outcome score was based on pain utility measures. The probabilities of all cases and the utility score were obtained by literature review. The decision model favoured concurrent prophylactic FVO for the contralateral stable hips over observation (pain utility measure scores 0.814 vs 0.781). In a one-way sensitivity analysis, the decision model favoured concurrent prophylactic FVO when the unstable hip rate of contralateral stable hips during observation was 27% or over. Concurrent prophylactic surgery also demonstrated higher utility scores than observation when the unstable hip rate after FVO was between 0% and 29%. The decision analysis model demonstrated that concurrent prophylactic FVO for a contralateral stable hip in individuals with cerebral palsy undergoing hip reconstructive surgery was beneficial from a medical perspective, which was based on current evidence.


LC-MS/MS bioanalytical challenge: ultra-high sensitivity assays.
Anne-Françoise Aubry is Director of Bioanalytical Sciences at Bristol-Myers Squibb Co., leading a team in developing bioanalytical methods for early development drug candidates in support of toxicology and clinical studies. Her main research interests are high-speed, high-resolution LC and new approaches for LC-MS/MS drug bioanalysis in regulated laboratories. Anne Aubry is on the executive board of the Eastern Analytical Symposium and on the organizing committee of the Applied Pharmaceutical Analysis and Chemical and Pharmaceutical Structure Analysis (Shanghai 2011) conferences. The challenges of developing and running low pg/ml LC-MS/MS bioanalytical assays in a regulated laboratory are reviewed. The practical problems encountered in implementing ultrasensitive assays are less in reaching a suitable sensitivity on the instrument than in implementing procedures to control losses and contamination, eliminate matrix interferences and ensure assay robustness so that the assay can be validated to industry standards. Solutions to these problems can be found in each of the three facets of the bioanalytical assay: the sample preparation, the chromatographic separation and the mass spectrometric detection. The key to developing an ultrasensitive assay is to optimize each of these elements. Progress in MS instrumentation has been essential in our ability to reach the low pg/ml limits.


The osmolyte trimethylamine N-oxide (TMAO) increases the proteolytic activity of botulinum neurotoxin light chains A, B, and E: implications for enhancing analytical assay sensitivity.
Botulism, the disease caused by botulinum neurotoxins (BoNTs), secreted by the spore-forming, anaerobic bacteria Clostridium botulinum, has been associated with food poisoning for centuries. In addition, the potency of BoNTs coupled with the current political climate has produced a threat of intentional, malicious poisoning by these toxins. The ability to detect and measure BoNTs in complex matrixes is among the highest research priorities. However, the extreme potency of these toxins necessitates that assays be capable of detecting miniscule quantities of these proteins. Thus, signal-boosting strategies must be employed. A popular approach uses the proteolytic activity of the BoNT light chain (LC) to catalyze the cleavage of synthetic substrates; reaction products are then analyzed by the analytical platform of choice. However, BoNT LCs are poor catalysts. In this study, the authors used the osmolyte trimethylamine N-oxide (TMAO) to increase the proteolytic activities of BoNT LCs. Their data suggest that concentrated solutions of TMAO induce complete folding of the LCs, resulting in increased substrate affinity and enhanced enzyme turnover. The authors observed increases in catalysis for BoNT serotypes A, B, and E, and this increased proteolytic activity translated into substantial increases in analytical assay sensitivity for these medically relevant toxins.


Multi-targeted histone deacetylase inhibitors in cancer therapy.
The heterogeneous nature of cancer requires a comprehensive approach for attacking the multiple mechanisms underlying the initiation and progression of cancers. Histone deacetylase inhibitors (HDACi) have emerged as a new class of anticancer agents, targeting the biological processes including cell cycle, apoptosis and differentiation. Studies have revealed that HDACi are synergistic with diverse classes of anticancer therapies including targeted therapeutics and conventional anticancer agents. Extensive medicinal chemistry efforts have yielded a wide range of chemical structures, indicative of the structural flexibility of HDACi. These findings have supported a strategy to generate multi-targeted HDACi by combining structural features from HDACi and other anticancer agents. HDACi can also be connected to a motif that allows for a selective delivery. Highlighting current examples, this brief review focuses on the rational design of multi-targeted inhibitors based on the examination and manipulation of chemical structures.


[Continuous renal replacement therapy in children with acute renal failure--5 years of experience].
Continuous renal replacement therapy (CRRT) has became a modality of choice in chidren with acute renal failure (ARF), especially in cases of multiorgan failure (MOF) and in hemodynamically unstable patients in whom regular hemodialysis is difficult to reform. Newborns and infants with contraindications to peritoneal dialysis are another group of patients treated with CRRT. Retrospective analysis of CRRT therapy in 112 patients treated with (CVVHD, CVVH, CVVHDF, SCUF-continuous veno-venous hemodialysis/hemofiltration/ hemodiafiltration/ultrafiltration) between 2000-2005 is presented. Indication to CRRT was MOF (n=23, 20%), complications post-liver transplant (n=33, 29%), congenital metabolic defects (n=5, 4.5%), complications of cancer or chemotherapy (n=11, 9.8%) and other causes of ARF (n=40, 36.7%). Overall mortality was 36.6%. The highest rate was seen in children between 0-2 years of age (52,3%) and in patients with congenital metabolic diseases (80%). When adjusted to specific modality--the highest mortality was seen in patients treated with CVVHF (55.4%), while lower was in cases treated with CVVHD (37.8%) and CVVHDF (35.4%). Among older children higher mortality was seen in patients with mean arterial pressure (MAP) <70 mmHg (68.4%), compared to patients with MAP >70 mmHg (23.1%).


Radiology resident selection: results of a survey.
The author determined which criteria were important to program directors for selecting candidates for diagnostic radiology residency. A questionnaire was sent to all radiology residency program directors. They were asked to rank 20 criteria they considered important in a written application. Miscellaneous questions about their program's selection process, including the interview, also were asked. The overall response rate was 69%. Statistical analysis of responses showed significant differences between geographic regions and types of programs (university versus private hospital). Class rank and medical school grades were found to have the highest rating of importance. Nearly half of responding programs use a score sheet to evaluate the written application. On average, almost 60 candidates are invited to interview for approximately five available positions. Criteria believed to be important for selection and the radiology resident selection process show significant differences among programs. These can be correlated partially with the location and type of program.


Nitric oxide modulates and adenosine mediates the tubuloglomerular feedback mechanism.
The tubuloglomerular feedback (TGF) mechanism is an important regulator of the glomerular filtration rate (GFR) and urine excretion rate. It operates by sensing the distal delivery of fluid at the macula densa site and adjusting the tone of the glomerular arterioles to control GFR. We found evidence that nitric oxide is an important modulator of the setting of the sensitivity of the TGF mechanism. Studies on adenosine A1 receptor deficient mice have shown that these animals lack the TGF response and have an increased renin release. These findings show the important role of adenosine as a mediator of the signal for the TGF mechanism and as an inhibitor of renin release.


Two different mechanisms are involved in the heat-shock regulation of chaperonin gene expression in Bradyrhizobium japonicum.
Heat-shock regulation was detected for three out of the five members of the groESL multigene family in Bradyrhizobium japonicum. The results uncovered the simultaneous presence of two distinct heat-shock control systems which so far have not been reported to co-exist in a single prokaryotic organism. The first system concerns groESL1 whose transcription is controlled in a sigma32-dependent manner similar to that known from work done with Escherichia coli. Heat-shock control of groESL4 is mediated by the second system, which is characterized by an inverted-repeat DNA structure originally described as a heat-shock regulatory element (CIRCE) in Bacillus subtilis. This element represses expression of groESL4 under non-stress conditions, as inferred from the increased expression of a groESL4'-'lacZ fusion suffering a 4 bp deletion within the CIRCE element. The two control systems clearly differ with respect to the temperature dependence and the kinetics of the heat-shock response, and they also respond differently to the stress signal elicited by incorporation of the amino acid analogue p-F-phenylalanine into cellular protein. Knock-out mutations in groEL4 resulted in an increased expression of groESL4, suggesting that repression via CIRCE depends, itself, upon the cellular level of GroEL4 protein.


Comparative efficacy, safety and durability of dolutegravir relative to common core agents in treatment-naïve patients infected with HIV-1: an update on a systematic review and network meta-analysis.
The objective of this study was to assess the durability of response of dolutegravir (DTG) as an antiretroviral core agent by comparing its efficacy and safety with other recommended or commonly used core agents up to 96-weeks (W96). A previously published systematic review was updated to identify phase 3/4 randomised controlled trials (RCTs) of core agents in treatment-naïve HIV-1 patients. Efficacy [virologic suppression (VS), CD4+ cell change from baseline] and safety [adverse events [AEs], discontinuations, drug-related AEs [DRAEs]] were analysed at W96 using Bayesian network meta-analysis (NMA) adjusting for nucleoside/nucleotide reverse transcriptase inhibitors' (NRTIs') backbone. Subgroups of patients with VL > 100,000 copies/mL or CD4+ ≤ 200 cells/μL at baseline were analysed separately. The NMA included 20 studies reporting data at W96. A higher proportion of patients receiving DTG achieved VS compared to those on protease inhibitors [PI:Range:8.7%(CrI:3.1,16.0)-19.9%(10.8,30.5)], efavirenz [EFV:6.9%(1.3,10.8)] and cobicistat-boosted elvitegravir [EVG/c:8.2%(0.2,17.4)], and similar but numerically higher compared to rilpivirine [RPV:5.0%(- 2.8,12.5)], raltegravir [RAL:2.9%(- 1.6,7.7)] and bictegravir [BIC:2.7%(- 2.7,10.6)]. The probability that more patients on DTG would achieve VS at W96 compared to any other core agent was greater than 80%. A higher proportion of patients on DTG achieved VS compared to PI/rs [Range:33.1%(13.6,50.4)-45.3%(24.1,61.6)] and RAL [16.7%(3.3,31.2)] in patients with VL > 100,000 copies/mL at baseline, and similar VS was achieved in patients with CD4+ ≤ 200 cells/μL at baseline. DTG also achieved greater increase in CD4+ cells from baseline compared to EFV [32.6(10.7,54.7)], ritonavir-boosted darunavir [DRV/r:25.7(3.6,48.1)] and BIC [24.7(1.5,47.7)]. Patients receiving DTG had lower odds of discontinuing therapy by W96 compared to PI/rs, EFV, RAL and EVG/c. Patients on DTG had lower odds of experiencing an adverse event (AE) compared to patients on EFV [odds ratio:0.6(0.3,0.9)], ATV/r [0.4(0.3,0.6)] and LPV/r [0.3(0.2,0.5)]. For patients on DTG, the odds of experiencing a drug-related AE were lower than the odds for patients on EFV [0.3(0.2,0.4)], comparable to patients on RAL [1.1(0.8,1.4)] and higher than those on BIC [1.5(1.1,2.0)]. Un-boosted integrase inhibitors had better efficacy and similar safety compared to PI/rs at W96 in treatment-naïve patients with HIV-1, with DTG being among the most efficacious core agent, particularly in patients with baseline VL > 100,000 copies/mL or ≤ 200 CD4+ cells/μL, who can be difficult to treat.