Ring-finger protein 5 attenuates oxygen-glucose deprivation and reperfusion-induced mitochondrial dysfunction and inflammation in cardiomyocytes by inhibiting the S100A8/MYD88/NF-κB axis.
Mitochondrial dysfunction is closely intertwined with the progression of heart failure (HF). Ring-finger protein 5 (RNF5) is an E3 ubiquitin ligase, whose deletion induces the enhanced S100A8 expression. S100A8 regulates the mitochondrial dysfunction and S100A8/myeloid differentiation factor 88 (MYD88)/nuclear factor-kappa B (NF-κB) pathway promotes an inflammatory response; however, whether RNF5 modulated mitochondrial dysregulation and inflammation through the S100A8/MYD88/NF-κB axis remains unknown. Here, H9c2 cells were stimulated with oxygen-glucose deprivation/reperfusion (OGD/R) to build a HF model in vitro. RNF5 level was assessed in gene expression omnibus database and in OGD/R-induced H9c2 cells with reverse transcriptase quantitative polymerase chain reaction and western blot. The RNF5 level was overexpressed via transfecting RNF5 overexpression plasmids into H9c2 cells. The role and mechanism of RNF5 in OGD/R-elicited H9c2 cells were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, spectrophotometry, flow cytometry, mitochondrial membrane potential (MMP) measurement, enzyme-linked immunosorbent assay and western blot assays. The RNF5 expression was downregulated both in silico and in OGD/R-stimulated H9c2 cells. OGD/R treatment caused a decrease in the cell viability, the MMP level, and the translational expression of mito-cyt-c and NF-κB-cyto, and an elevation in the concentrations of lactate dehydrogenase and creatine kinase myocardial band, the apoptosis rate, the inflammatory factor release, and the relative protein expression of cyto-cyt-c, S100A8, MYD88 and NF-κB-nuc in H9c2 cells. Upregulation of RNF5 reversed these indicators in OGD/R-stimulated H9c2 cells. Altogether, based on these outcomes, we concluded that RNF5 impeded mitochondrial dysfunction and inflammation through attenuating the S100A8/MYD88/NF-κB axis in OGD/R-stimulated H9c2 cells.


Cleavage of the ALL1 gene in acute lymphoid leukemia before treatment disappears in relapse.
ALL1 gene rearrangements are frequently found in secondary acute leukemias (ALs). A site-specific cleavage of the ALL1 gene in a consensus sequence for topoisomerase II recognition has been considered to be the initial step leading to ALL1 rearrangement and subsequent therapy-related AL. The aim of the present study was to evaluate this cleavage in our patients, to analyze whether it is a laboratory-produced artefact and to check whether it persists or causes a real ALL1 gene rearrangement at relapse. We studied ALL1 rearrangement in 74 cases of AL before treatment by Southern blot avoiding room temperature exposure or delay in processing the samples which could produce ALL1 cleavage. DNA was available for two cases with ALL1 cleavage; it was analyzed by three different Southern blots in one and two in the other. One case with ALL1 cleavage was also studied in relapse. The presence of the cleavage of the ALL1 DNA was found in 3 of 74 (4%) patients. Two of these three patients had the ALL1 cleavage in three and two different analyses. One case was positive for ALL1 cleavage at diagnosis, but negative for both ALL1 cleavage and ALL1 rearrangement at relapse. The fact that a constant pattern was obtained from the same patients in different DNA preparations, supports the notion that ALL1 cleavage is not a laboratory artefact. The absence of the cleavage in a sample from a relapsed patient suggests that the subclone with the ALL1 cleavage, in this case, did not play a clear role in the pathogenesis of disease recurrence.


Paget's disease.
Paget's disease of bone is the most common metabolic bone disease after osteoporosis and affects 2-4% of adults over 55 years of age. Its etiology is only partly understood and includes both genetic and environmental factors. The disease may be asymptomatic and can be uncovered incidentally on x-ray or in biochemical tests performed for another condition. It can also manifest itself with bone pain, deformity, fracture or other complications. Paget's disease is diagnosed by x-rays and in general has very typical radiological features, but occasionally the clinical picture may be unusual and a differential diagnosis of sclerotic or lytic metastases needs to be considered. Plasma total alkaline phosphatase activity is the most clinically useful indicator of disease activity. It is elevated in most untreated patients, but may be within the normal range in patients with monostotic or limited disease. Bisphosphonate therapy is indicated for patients with symptoms and should also be considered in patients with disease sites that suggest a risk of complications, such as long bones, vertebrae or base of the skull. Orthopedic surgery in Paget's disease patients includes almost exclusively the correction of fractures and arthroplasty.


The prevalence of psychiatric morbidity on a coronary care ward.
Numerous studies have documented the high prevalence of psychological and emotional disorders in patients seen in general medical settings. However, despite the emphasis placed on holistic approaches to nursing care in all professional models of nursing practice, much of this distress is still missed by nursing staff. The Hospital Anxiety and Depression (HAD) scale is an easy-to-use self-administered screening instrument purportedly designed to detect psychological distress amongst hospitalized patients with physical illnesses. On using the HAD scale on patients admitted to a coronary care ward of a district general hospital, 44% were found to be suffering high levels of anxiety or depression. This figure is consistent with the results of similar studies in other cardiac wards and out-patient clinics. In most cases, the levels of distress found were not sufficiently severe to warrant seeking specialist psychiatric support. Instead, there is much that the general nurse can do to alleviate the understandable fears and worries of patients being treated for cardiac disease. However, to respond appropriately, nursing staff must be able to identify psychological distress in patients. The HAD scale, if it can be validated in cardiac in-patient settings, provides an instrument which could easily become part of the routine assessment of patients' nursing needs.


[Investigation on in vivo metabolism of n-butyl phthalide].
A GC-MS method for the investigation on the metabolism of n-butyl phthalide (NBP) is described. After oral administration of NBP to rats, urine was collected, hydrolyzed with beta-glucuronidase, extracted and concentrated for TMS derivatization, and then analyzed by GC-MS. HBP and its four oxidative metabolites were determined in 0-24 h, 24-48 h rat urine. The mass spectra of the metabolites and their derivatives were presented and the in vivo metabolic pathway was discussed.


Time lapses between distribution of influenza vaccines to health authorities and their administration by General Practitioners (GPs) to older adults: a retrospective study over five influenza seasons in Italy.
Delays in influenza vaccine delivery and administration can hinder vaccine coverage and protection. This study examines the differentials in distributing and administering adjuvanted trivalent (aTIV) and quadrivalent influenza vaccines (aQIV) to older adults in Italy's primary care setting and its potential impact on hospitalization risk over 5 epidemic seasons. Using a primary care database, individuals aged ≥ 65 years were selected. The proportion of vaccine distribution to regional authorities and subsequent administration by GPs was estimated using census data. Using quantile (median) regression, we examined the relationship between velocities of vaccine distribution and administration (doses/week) and the incidence of hospitalizations. Over the 5 influenza seasons, the velocity of distribution and administration of aTIV/aQIV ranged 341-833 and 152-270 median doses/week; no trend was yielded for the difference between these velocities (p = 0.189) or vaccine coverage (p = 0.142). An association was observed for each differential dose/week between distributed and administered vaccines and all-cause hospitalizations with a 10% increase in 2017-2018, 54% in 2018-2019, and 12% in 2020-2021 season. These findings highlight the importance of minimizing the time lapse between vaccine distribution and administration to mitigate the impact of influenza and address factors that contribute to vaccination barriers.


Kallikrein-related peptidases represent attractive therapeutic targets for ovarian cancer.
Aberrant levels of kallikrein-related peptidases (KLK1-15) have been linked to cancer cell proliferation, invasion and metastasis. In ovarian cancer, the KLK proteolytic network has a crucial role in the tissue and tumor microenvironment. Publically available ovarian cancer genome and expression data from multiple patient cohorts show an upregulation of most KLKs. Areas covered: Here, we review the expression levels of all 15 members of this family in normal and ovarian cancer tissues, categorizing them into highly and moderately or weakly expressed KLKs, and their association with patient prognosis and survival. We summarize their tumor-biological functions determined in cell-based assays and xenograft models, further highlighting their suitability as cancer biomarkers and attractive candidates for drug development. Finally, we discuss some different pharmaceutical approaches, including peptide-based and small molecule inhibitors, cyclic peptides, depsipeptides, engineered natural inhibitors, antibodies, RNA/DNA-based aptamers, prodrugs, miRNA and siRNA. Expert opinion: In light of the results from clinical and tumor-biological studies, together with the available pharmaceutical tools, we suggest KLK4, KLK5, KLK6 and possibly KLK7 as preferred targets for inhibition in ovarian cancer.


Mechanical effect of the Angelchik prosthesis on the competency of the gastric cardia: pathophysiologic implications and surgical perspectives.
The Angelchik prosthesis appears to be effective in preventing gastroesophageal reflux, although its precise mechanism of action remains controversial. In a unique in vitro model, 10 freshly harvested canine esophagogastric specimens were tested for their ability to remain competent against challenges of intragastric pressure under controlled conditions of intra-abdominal pressure, longitudinal esophageal tension, lower esophageal sphincter pressure and overall length and circumference of the cardia (measure of gastric dilatation). Competency of the specimen was assessed by stepwise variation in the overall length of the sphincter, while keeping constant intraabdominal pressure (20 cm H2O), intragastric pressure (20 cm H2O), esophageal tension (physiologic), lower esophageal sphincter pressure (15 cm H2O) and degree of gastric dilatation (3 cm). With each specimen serving as its own control, the effect produced by the application of an Angelchik prosthesis was evaluated. Results consistently demonstrated that at any lower esophageal sphincter length the percent of competency was increased when the prosthesis was applied (P < 0.01). The findings indicate that the Angelchik prosthesis controls reflux by preventing unfolding of the lower esophageal sphincter when challenged by intragastric pressure.


Simultaneous synthesis of mixtures of lactulose and galacto-oligosaccharides and their selective fermentation.
Lactulose and galacto-oligosaccharides (GOS) are well recognized prebiotics derived from lactose. In the synthesis of lactulose with β-galactosidases GOS are also produced, but the ratio of lactulose and GOS in the product can be tuned at will, depending on the operation conditions, so to obtain an optimal product distribution in terms of prebiotic potential. The selectivity of fermentation of each carbohydrate alone as well as mixtures of both was determined using pH-controlled anaerobic batch cultures with faecal inoculum. Within the experimental range considered, lactulose/GOS molar ratio of 4 resulted in the highest selectivity for Bifidobacterium and Lactobacillus/Enterococcus, so this ratio was selected as the target for the synthesis of lactulose from fructose and lactose with Aspergillus oryzae β-galactosidase. Synthesis was optimized using response surface methodology, considering temperature, initial concentrations of acceptor sugars and fructose/lactose molar ratio as key variables, with the aim of maximizing lactulose yield at the optimal product distribution in terms of prebiotic potential (lactulose/GOS molar ratio of 4). Under optimal conditions (50°C, 50%w/w total initial concentrations of sugars and fructose/lactose molar ratio of 6.44), lactulose yield of 0.26g of lactulose produced per g of initial lactose was obtained at the optimal product distribution.


The microvasculature: a target for nutritional programming and later risk of cardio-metabolic disease.
There is compelling evidence that microvascular deficits affecting multiple tissues and organs play an important role in the aetiopathogenesis of cardio-metabolic disease. Furthermore, both in humans and animal models, deficits in small vessel structure and function can be detected early, often before the onset of macrovascular disease and the development of end-organ damage that is common to hypertension and obesity-associated clinical disorders. This article considers the growing evidence for the negative impact of an adverse maternal diet on the long-term health of her child, and how this can result in a disadvantageous vascular phenotype that extends to the microvascular bed. We describe how structural and functional modifications in the offspring microcirculation during development may represent an important and additional risk determinant to increase susceptibility to the development of cardio-metabolic disease in adult life and consider the cell-signalling pathways associated with endothelial dysfunction that may be 'primed' by the maternal environment. Published studies were identified that reported outcomes related to the microcirculation, endothelium, maternal diet and vascular programming using NCBI PubMed.gov, MEDLINE and ISI Web of Science databases from 1980 until April 2013 using pre-specified search terms. Information extracted from over 230 original reports and review articles was critically evaluated by the authors for inclusion in this review.


Intussusception: is floating caecum a causative factor? Analysis of 10 cases.
Ten consecutive cases of intussusceptions treated by the authors at the University of Port Harcourt Teaching Hospital (UPTH) in a five year period are analysed. The median age of occurrence was nine months; average 5.2 years; range: one month to 25 years. The male to female ratio was 2:3. Five patients had ileocaecal, two ileoileal, two colocolic and one ileocolic intussusceptions. Of the two patients with ileoileal intussusceptions one had antegrade with Meckel's diverticulum and the other retrograde with lipoma as lead-points. The two patients with colocolic intussusceptions had mesenteric and mesocolic lymph nodes hypertrophy. The remaining six patients had freely mobile caecum anchored to the posterior peritoneum by a long mesocaecum and such arrangement was believed to be the cause of the intussusceptions. In addition to intraoperative reduction in five cases and resection with end to end ileoileal anastomosis in one, each of these six patients had the caecum fixed to the posterior abdominal wall to prevent recurrence of the intussusception.


Hyperoxia and hypergravity are independent risk factors of atelectasis in healthy sitting humans: a pulmonary ultrasound and SPECT/CT study.
Aeroatelectasis has developed in aircrew flying routine peacetime flights on the latest generation high-performance aircraft, when undergoing excessive oxygen supply. To single out the effects of hyperoxia and hypergravity on lung tissue compression, and on ventilation and perfusion, eight subjects were studied before and after 1 h 15 min exposure to +1 to +3.5 Gz in a human centrifuge. They performed the protocol three times, breathing air, 44.5% O2, or 100% O2 and underwent functional and topographical imaging of the whole lung by ultrasound and single-photon emission computed tomography combined with computed tomography (SPECT/CT). Ultrasound lung comets (ULC) and atelectasis both increased after exposure. The number of ULC was <1 pre protocol (i.e., normal lung) and larger post 100% O2 (22 ± 3, mean ± SD) than in all other conditions (P < 0.001). Post 44.5% O2 differed from air (P < 0.05). Seven subjects showed low- to medium-grade atelectasis post 100% O2 There was an effect on grade of gas mixture and hypergravity, with interaction (P < 0.001, respectively); 100% O2, 44.5% O2, and air differed from each other (P < 0.05). SPECT ventilation and perfusion were always normal. Ultrasound concurred with CT in showing normal lung in the upper third and ULC/atelectasis in posterior and inferior areas, not for other localizations. In conclusion, hyperoxia and hypergravity are independent risk factors of reversible atelectasis formation. Ultrasound is a useful screening tool. Together with electrical impedance tomography measurements (reported separately), these findings show that zones with decreased ventilation prone to transient airway closure are present above atelectatic areas.


Long-term succinylcholine infusion during isoflurane anesthesia.
The characteristics of the neuromuscular blockade produced by prolonged succinylcholine infusion were compared in 40 patients anesthetized with either nitrous-oxide-isoflurane (0.75-1.50% inspired) or nitrous-oxide-fentanyl. Neuromuscular transmission was monitored using train-of-four stimulation and the infusion rate was adjusted to keep the first twitch at 10-15% of its control value. Initially, all patients exhibited a depolarizing-type block, and the infusion rates were similar in the isoflurane (61 micrograms . kg-1 . min-1) and fentanyl (57 micrograms . kg-1 . min-1) groups. Tachyphylaxis developed in both groups and correlated well with the onset of non-depolarizing (phase II) block. Both occurred sooner and at a lower cumulative dose in the isoflurane groups. After 90 min, infusion rates were similar in both groups (isoflurane: 107 micrograms . kg-1 . min-1, fentanyl;: 93 micrograms. kg-1 . min-1). After the infusion was stopped, the recovery of the train-of-four ratio was inversely related to the dose and duration of exposure to succinylcholine, and was slower with nitrous-oxide-isoflurane anesthesia. After 10 min of recovery, patients receiving isoflurane exhibited train-of-four ratios of 0.5 or less after 8.5 mg/kg succinylcholine and 103 min. Corresponding figures for fentanyl patients were 13 mg/kg and 171 min. The block in all 13 patients (eight with isoflurane, five with fentanyl) who did not recover spontaneously was antagonized successfully with atropine and neostigmine. It was concluded that with succinylcholine infusion of 90 min or less, isoflurane accelerates the onset of tachyphylaxis and phase II neuromuscular block without affecting succinylcholine requirements. These results, with isoflurane, were similar to those reported previously with enflurane or halothane.


Association between Helicobacter pylori infection and pancreatic cancer.
In order to determine whether infection with Helicobacter pylori might be associated with pancreatic adenocarcinoma, we performed a study to compare the H. pylori seroprevalence rate between patients with pancreatic carcinoma and matched control subjects. Blood samples from 92 patients with histologically confirmed diagnosis of pancreatic adenocarcinoma admitted to our hospital between January 1994 and July 1995 were analyzed for the presence of IgG antibodies against H. pylori by a commercially available enzyme-linked immunosorbent assay. Thirty patients with gastric cancer, 35 patients with colorectal cancer, and 27 healthy volunteers served as controls. In addition to these serological analyses, tumor specimens from 20 patients with pancreatic adenocarcinoma were microscopically investigated for the presence of H. pylori. 65% of pancreatic cancer patients and 69% of those with gastric cancer were found to be seropositive, while only 45% of the other controls tested positive. Statistical analysis revealed no difference in seropositivity between the cohort of patients suffering from pancreatic and gastric cancer. The rate of seropositivity was more prominent, however, in pancreatic cancer patients when compared with those suffering from colorectal cancer combined with normal controls (p = 0.035), with an odds ratio of 2.1 (1.1-4.1). Microscopic evaluation of human pancreatic cancer specimens showed no evidence for the presence of H. pylori. Our data suggest an association between H. pylori infection and pancreatic cancer. Despite demonstration of a positive relationship and its physiological plausibility, larger prospective studies are needed to confirm our preliminary findings and to assess H. pylori as a potential carcinogenic risk factor.