The clinical potentials of adjunctive fluvoxamine to clozapine treatment: a systematic review.
New clozapine optimization strategies are warranted, as some patients do not achieve sufficient response and experience various adverse effects. Fluvoxamine is a potent CYP1A2 inhibitor and may increase the ratio of clozapine to its primary metabolite N-desmethylclozapine (NDMC). This study aims to review all pharmacodynamic effects and the adverse effect profile of changing the clozapine/NDMC ratio with adjunctive fluvoxamine. MEDLINE, Embase, and the Cochrane Library were searched with the search terms "clozapine" and "fluvoxamine" without any time limit. Language was restricted to English, Scandinavian, Polish, and German. Studies were sorted for relevance based on title and abstract. Clinical recommendations of potential indications/effects were graded as level A, B, C, or D depending on studies of high, moderate, low, or very low quality, respectively. Based on data from 24 case reports/series, seven cohort studies, and two randomized controlled trials, 241 patients were studied. Evidence (A) supported that adjunctive fluvoxamine increased clozapine plasma levels. This may increase the probability of response in patients, where sufficient clozapine plasma levels cannot be achieved. Adjunctive fluvoxamine reduced metabolic adverse effects of clozapine (B) but not agranulocytosis risk (B). Although depressive or obsessive-compulsive symptoms may improve, a SSRI with no CYP1A2 inhibition should rather be used (C). No studies investigated the effect of adjunctive fluvoxamine to minimize clozapine rebound psychosis (D) or to reduce the effects of smoking on clozapine plasma levels (D). Adjunctive fluvoxamine may have clinical potentials for optimizing clozapine treatment but further clinical studies are warranted to explore the clinical implications.


Hierarchical porous "skin/skeleton"-like MXene/biomass derived carbon fibers heterostructure for self-supporting, flexible all solid-state supercapacitors.
Two-dimensional transition metal carbide and nitride are promising energy storage materials. However, the aggregation and rearrangement of two-dimensional nanosheets limit their electrochemical performance. In this paper, a novel hierarchical porous "skin/skeleton"-like MXene/biomass derived carbon fibers (MXene/CF) heterostructure is prepared by one-step pyrolysis, which efficiently weakens the stacking of MXene nanosheets. Moreover, MXene/CF has a well-defined hierarchical porous structure, thereby facilitating electrolyte penetration and providing efficient and stable channels for rapid diffusion/transfer of ions to the electrode and producing functional MXene-based electrodes. When MXene/CF heterostructure is applied as a self-supporting electrode for supercapacitors, the electrode has high volumetric capacitance of 7.14 F cm-3, good rate characteristics (63.9% from 0.5 to 100 A g-1), and excellent cyclic stability (99.8% after 5000 cycles). In addition, all solid-state symmetric supercapacitors based on MXene/CF electrodes are also assembled, which not only exhibits high capacitance and rate performance, but also has good flexibility and long durability. The device still maintains structural integrity and steady capacitance even after 2500 cycles at different bending angles. This work is expecting to guide the design of the next generation of flexible, portable and highly integrated supercapacitors with high capacity and rate performance to further meet the requirements of sustainable development.


Arterial stiffness and plasma creatinine in untreated hypertensive patients.
Increased arterial stiffness is a common feature of hypertensive subjects with renal failure, independently of age, office blood pressure (BP), and traditional cardiovascular risk factors including atherosclerosis but not diabetes mellitus. Recently a reduction in creatinine clearance was shown to be associated with increased arterial stiffness in patients with normal or elevated BP and mild renal failure, and the association was noted to be stronger in subjects <55 years of age. We wanted to study this relationship in a population of newly recognized hypertensive subjects with preserved renal function using another method to assess arterial stiffness and to see whether it was independent of 24-h BP. In 263 untreated hypertensive subjects with plasma creatinine <135 micromol/L, 24-h ambulatory BP was measured before any treatment using a validated device enabling automatic measurement of arterial stiffness in parallel. The age median was 48 years in this population. Accordingly the population was split into two groups: those < 48 and those > or =48 years of age. Arterial stiffness and plasma creatinine were positively and significantly correlated, independently of age, height, gender, traditional risk factors and 24-h BP measurements. A significant correlation was observed whether subjects were younger (< 48 years) or older (> or =48 years). In untreated hypertensive subjects with preserved renal function, arterial stiffness and plasma creatinine were found to be positively related, independent of age and ambulatory BP, suggesting an independent link between the two parameters at an early phase of hypertensive vascular disease.


SPLUNC1/BPIFA1 contributes to pulmonary host defense against Klebsiella pneumoniae respiratory infection.
Epithelial host defense proteins comprise a critical component of the pulmonary innate immune response to infection. The short palate, lung, nasal epithelium clone (PLUNC) 1 (SPLUNC1) protein is a member of the bactericidal/permeability-increasing (BPI) fold-containing (BPIF) protein family, sharing structural similarities with BPI-like proteins. SPLUNC1 is a 25 kDa secretory protein that is expressed in nasal, oropharyngeal, and lung epithelia, and has been implicated in airway host defense against Pseudomonas aeruginosa and other organisms. SPLUNC1 is reported to have surfactant properties, which may contribute to anti-biofilm defenses. The objective of this study was to assess the importance of SPLUNC1 surfactant activity in airway epithelial secretions and to explore its biological relevance in the context of a bacterial infection model. Using cultured airway epithelia, we confirmed that SPLUNC1 is critically important for maintenance of low surface tension in airway fluids. Furthermore, we demonstrated that recombinant SPLUNC1 (rSPLUNC1) significantly inhibited Klebsiella pneumoniae biofilm formation on airway epithelia. We subsequently found that Splunc1(-/-) mice were significantly more susceptible to infection with K. pneumoniae, confirming the likely in vivo relevance of this anti-biofilm effect. Our data indicate that SPLUNC1 is a crucial component of mucosal innate immune defense against pulmonary infection by a relevant airway pathogen, and provide further support for the novel hypothesis that SPLUNC1 protein prevents bacterial biofilm formation through its ability to modulate surface tension of airway fluids.


Tetramethylammonium hydroxide poisoning during a pallet cleaning demonstration.
The purpose of this study was to examine the cause of an accidental death from acute poisoning resulting from exposure to a cleaner containing tetramethylammonium hydroxide (TMAH) and to consider measures to prevent future cases. The authors examined the details and the reason for the accidental death from acute poisoning based on the autopsy report. The victim was a 39-year-old male researcher with 7 years of work experience employed by a surfactant production company. The accident occurred when he was conducting a field test of a newly developed cleaner, containing 8.75% TMAH solution. The researcher spilled the cleaner on his work clothes in the area of both the hands/arms and legs. He was unconscious when discovered. An autopsy found no damage or injury that could have resulted in death other than burns to 12% of his body, and the cause of death was found to be acute poisoning by TMAH. TMAH is widely used in the electronics industry as a developer or cleaner. It is a dangerous material, causing neurotoxicity leading to respiratory failure by ganglion block that occurs through skin absorption, and no antidote has been developed yet. For this reason, it is best to completely prevent exposure by wearing proper personal protective equipment. Despite this fatal toxicity of TMAH, it is not classified in Korea as a "chemical requiring legal control". For this reason, it is urgent to raise awareness of the toxic properties of TMAH to prevent additional cases of TMAH poisoning


Results and predictors of early and late outcome of coronary artery bypass grafting in patients with severely depressed left ventricular function.
Coronary artery bypass grafting (CABG) is a well-accepted therapeutic approach in patients with symptomatic multivessel coronary artery disease and severely depressed left ventricular function. However, the potential impact of off-pump CABG in this group of patients remains unknown. In addition, there are only scarce data regarding long-term survival and its predictors in this patient population. We retrospectively analyzed prospectively collected data of 2,725 consecutive patients (mean age, 65 +/- 11 years; 843 (31%) female) undergoing CABG between January 1998 and December 2005 (ejection fraction [EF] < or = 0.30; n = 495, 18%). Outcome measures included hospital mortality, major complications, and long-term survival. Multivariate analysis was performed to identify predictors of hospital mortality and late survival. Subgroup analysis for patients with EF less than or equal to 0.30 undergoing conventional CABG (n = 424, 86%) versus off-pump CABG (n = 71, 14%) was performed. Hospital mortality was 1.8% (EF < or = 0.30, 3.6%; EF > 0.30, 1.4%; p = 0.002). Off-pump CABG did not have an impact on operative mortality (on-pump, 4%; off-pump, 3%; p = 0.509). Ejection fraction of 0.30 or less was not an independent risk factor of hospital mortality but predicted respiratory failure (odds ratio [OR] = 2.3) and sepsis (OR, 1.4). Long-term survival was significantly decreased in patients with EF of 0.30 or less: 1-year and 5-year survival 88% +/- 1.5% and 75% +/- 2.2% versus 96% +/- 0.4% and 81% +/- 1.2%, respectively (p = 0.001). Reoperation (OR, 6.9), peripheral vascular disease (OR, 3.2), chronic obstructive pulmonary disease (OR, 3.0), congestive heart failure (OR, 2.7), and female sex (OR, 2.1) were independent predictors of long-term survival. Excellent results after CABG can be expected in patients with EF of 0.30 or less, with minimal increase in mortality and acceptable postoperative morbidity. Long-term survival remains limited, but recent results are substantially better than historical reports. Careful preoperative patient selection and perioperative management are essential in these patients undergoing CABG.


Long-term retention on treatment with lumiracoxib 100 mg once or twice daily compared with celecoxib 200 mg once daily: a randomised controlled trial in patients with osteoarthritis.
The efficacy, safety and tolerability of lumiracoxib, a novel selective cyclooxygenase-2 (COX-2) inhibitor, has been demonstrated in previous studies of patients with osteoarthritis (OA). As it is important to establish the long-term safety and efficacy of treatments for a chronic disease such as OA, the present study compared the effects of lumiracoxib at doses of 100 mg once daily (o.d.) and 100 mg twice daily (b.i.d.) with those of celecoxib 200 mg o.d. on retention on treatment over 1 year. In this 52-week, multicentre, randomised, double-blind, parallel-group study, male and female patients (aged at least 40 years) with symptomatic primary OA of the hip, knee, hand or spine were randomised (1:2:1) to lumiracoxib 100 mg o.d. (n = 755), lumiracoxib 100 mg b.i.d. (n = 1,519) or celecoxib 200 mg o.d. (n = 758). The primary objective of the study was to demonstrate non-inferiority of lumiracoxib at either dose compared with celecoxib 200 mg o.d. with respect to the 1-year retention on treatment rate. Secondary outcome variables included OA pain in the target joint, patient's and physician's global assessments of disease activity, Short Arthritis assessment Scale (SAS) total score, rescue medication use, and safety and tolerability. Retention rates at 1 year were similar for the lumiracoxib 100 mg o.d., lumiracoxib 100 mg b.i.d. and celecoxib 200 mg o.d. groups (46.9% vs 47.5% vs 45.3%, respectively). It was demonstrated that retention on treatment with lumiracoxib at either dose was non-inferior to celecoxib 200 mg o.d. Similarly, Kaplan-Meier curves for the probability of premature discontinuation from the study for any reason were similar across the treatment groups. All three treatments generally yielded comparable results for the secondary efficacy variables and all treatments were well tolerated. Long-term treatment with lumiracoxib 100 mg o.d., the recommended dose for OA, was as effective and well tolerated as celecoxib 200 mg o.d. in patients with OA. clinicaltrials.gov NCT00145301.


Extracellular volume expansion and the preservation of residual renal function in Korean peritoneal dialysis patients: a long-term follow up study.
In chronic peritoneal dialysis patients, preservation of residual renal function (RRF) is a major determinant of patient survival, and maintaining sufficient intravascular volume has been hypothesized to be beneficial for the preservation of RRF. The present study aimed to test this hypothesis using multifrequency bioimpedence analyzer (MFBIA), in Korean peritoneal dialysis patients. A total of 129 patients were enrolled in this study. The baseline MFBIA was checked, and the patients were divided into the following two groups: group 1, extracellular water per total body water (ECW/TBW) < median, group 2, ECW/TBW > median. We followed up the patients, and then we analyzed the changes in the urine output (UO) and the solute clearance (weekly uKt/V) in each group. Data associated with patient and technical survivor were collected by medical chart review. The volume measurement was made using Inbody S20 equipment (Biospace, Seoul, Korea). We excluded the anuric patients at baseline. The median value of ECW/TBW was 0.396. The mean patient age was 49.74 ± 10.01 years, and 62.1 % of the patients were male; most of the patients were on continuous ambulatory peritoneal dialysis (89.1 %). The mean dialysis vintage was 26.20 ± 28.71 months. All of the patients were prescribed hypertensive medication, and 48.5 % of the patients had diabetes. After 25.47 ± 6.86 months of follow up, ΔUO and Δweekly Kt/V were not significantly different in the two groups as follows: ΔUO (-236.07 ± 185.15 in group 1 vs -212.21 ± 381.14 in group 2, p = 0.756); Δ weekly Kt/v (-0.23 ± 0.43 in group 1 vs -0.29 ± 0.49 in group 2, p = 0.461). The patient and technical survivor rate was inferior in the group 2, and in the multivariable analysis, initial hypervolemia was an independent factor that predicts both of the patient mortality [HR 1.001 (1.001-1.086), p = 0.047] and the technical failure [HR 1.024 (1.001-1.048), p = 0.042]. Extracellular volume expansion, measured by MFBIA, does not help preserve residual renal function, and is harmful for the technical and patient survival in Korean peritoneal dialysis patients.


Practical method development for the separation of monoclonal antibodies and antibody-drug-conjugate species in hydrophobic interaction chromatography, part 1: optimization of the mobile phase.
The goal of this work is to provide some recommendations for method development in HIC using monoclonal antibodies (mAbs) and antibody-drug conjugates (ADCs) as model drug candidates. The effects of gradient steepness, mobile phase pH, salt concentration and type, as well as organic modifier were evaluated for tuning selectivity and retention in HIC. Except the nature of the stationary phase, which was not discussed in this study, the most important parameter for modifying selectivity was the gradient steepness. The addition of organic solvent (up to 15% isopropanol) in the mobile phase was also found to be useful for mAbs analysis, since it could provide some changes in elution order, in some cases. On the contrary, isopropanol was not beneficial with ADCs, since the most hydrophobic DAR species (DAR6 and DAR8) cannot be eluted from the stationary phase under these conditions. This study also illustrates the possibility to perform HIC method development using optimization software, such as Drylab. The optimum conditions suggested by the software were tested using therapeutic mAbs and commercial cysteine linked ADC (brentuximab-vedotin) and the average retention time errors between predicted and experimental retention times were ∼ 1%.


Assessment of adenosine deaminase levels in rheumatoid arthritis patients receiving anti-TNF-alpha therapy.
Anti-TNF-alpha agents are increasingly used in rheumatoid arthritis (RA) treatment and that is known to increase the risk of tuberculosis (TB) reactivation. Adenosine deaminase (ADA) levels are shown to increase to high levels in TB patients. Our aim is to investigate the serum ADA levels in RA patients being treated with anti-TNF-alpha and to compare the results with the patients on DMARD therapy. The study groups comprised of 56 RA patients (45 female, mean age 49) who were treated either with two or three DMARDs, 32 RA patients with anti-TNF-alpha treatment (26 female, mean age 46) and 20 healthy controls (10 female, mean age 48). All patients fulfilled the 1987 ACR criteria for RA. DAS28 score was calculated for all subjects. When compared to healthy controls, ADA levels were measured statistically higher both in patient groups (P = 0.046, 0.002). ADA levels in anti-TNF-alpha group were similar to conventional therapy (11.3 +/- 2.7, 10.9 +/- 4.01; P = 0.76). PPD was positive in 17 RA patients in the anti-TNF-alpha treatment group (%53). The ADA levels were found to be similar in the anti-TNF-alpha group when compared according to the PPD positivity (positive, 12.4 +/- 3.7; negative, 10.5 +/- 2.1; P = 0.02). No correlation was found between the ADA levels and age, disease duration, ESR, CRP, DAS 28 and HAQ score. In this study, we observed that RA patients at remission taking DMARD or anti-TNF-alpha therapy have similar levels of serum ADA. Although serum ADA levels during TB infection increase much higher, in our study, ADA levels of all RA patients were lower than 15 IU/L. Elevated ADA levels may be a clue for diagnosis of TB in patients who were on anti-TNF-alpha therapy.


Topographic organization of the central projections of the spiral ganglion in cats.
The morphological organization of inputs from restricted sectors of the cat cochlear spiral ganglion into the cochlear nucleus was studied by making focal extracellular injections of horseradish peroxidase (HRP) into the spiral ganglion. Injections resulted in Golgi-like labeling of a small cluster of spiral ganglion cells and their peripheral and central axons. Large injections involved most of the cells within Rosenthal's canal in sectors of the spiral ganglion innervating greater than or equal to 1 mm of the basilar membrane and resulted in narrow, complete laminae of labeled axons and preterminal fields within each cochlear nucleus subdivision. The positions of these bands were consistent with the "isofrequency laminae" appropriate for the frequencies represented at the injection sites, with high frequency laminae situated more dorsally, and lower frequencies progressively more ventral. A discrete projection to the small cell cap area was observed that was discontinuous with the main projection laminae in the ventral cochlear nuclei (VCN). In the dorsal cochlear nucleus, projecting fibers and terminals were excluded from the molecular cell layer. No labeled fibers entered the granule cell areas. In contrast to larger injections, very small HRP deposits labeled only part of an isofrequency lamina. Specifically, injections restricted to the scala tympani aspect of the spiral ganglion labeled only the lateral part of VCN isofrequency laminae, whereas injections limited to the scala vestibuli aspect of the ganglion labeled the medial aspect of the isofrequency planes. Thus these data indicate a previously unrecognized topographic representation of the vertical dimension of the spiral ganglion across VCN isofrequency laminae. Some possible functional implications of this projection organization are discussed.


Immunological evidence of an early seroconversion to oncogenic Merkel cell polyomavirus in healthy children and young adults.
Oncogenic Merkel cell polyomavirus (MCPyV) provokes a widespread and asymptomatic infection in humans. Herein, sera from healthy children and young adults (HC, n = 344) aged 0-20 years old were evaluated for anti-MCPyV immunoglobulin G (IgG) and IgM antibodies employing a recently developed immunoassay. Serum MCPyV IgG data from healthy subjects (HS, n = 510) and elderlies (ES, n = 226), aged 21-65/66-100 years old, from our previous studies, were included. The anti-MCPyV IgG and IgM rates in HC sera were 40.7% and 29.7%, respectively. A lower prevalence of anti-MCPyV IgGs was found in HC aged 0-5 years old (13%) compared to 6-10 (52.3%), 11-15 (60.5%) and 16-20 years old (61.6%) cohorts. Age-stratified HCs exhibited similar anti-MCPyV IgM rates (27.9%-32.9%). Serological profiles indicated that anti-MCPyV IgGs and IgMs had low optical densities (ODs) during the first years of life, while IgM ODs appeared to decrease throughout young adulthood. A lower anti-MCPyV IgGs rate was found in HC (40.7%) than HS (61.8%) and ES (63.7%). Upon the 5-years range age-stratification, a lower anti-MCPyV IgGs rate was found in the younger HC cohort aged 0-5 years old compared to the remaining older HC/HS/ES cohorts (52.3%-72%). The younger HC cohort exhibited the lowest anti-MCPyV IgG ODs than the older cohorts. Low anti-MCPyV IgMs rates and ODs were found in the 21-25 (17.5%) and 26-30 (7.7%) years old cohorts. Our data indicate that, upon an early-in-life seroconversion, the seropositivity for oncogenic MCPyV peaks in late childhood/young adulthood and remains at high prevalence and relatively stable throughout life.


A Novel Home-Based Study of Circadian Rhythms: Design, Rationale, and Methods for the Circadia Study.
The Circadia Study (Circadia) is a novel "direct-to-participant" research study investigating the genetics of circadian rhythm disorders of advanced and delayed sleep phase and non-24 hour rhythms. The goals of the Circadia Study are twofold: (i) to create an easy-to-use toolkit for at-home circadian phase assessment for patients with circadian rhythm disorders through the use of novel in-home based surveys, tests, and collection kits; and (ii) create a richly phenotyped patient resource for genetic studies that will lead to new genetic loci associated with circadian rhythm disorders revealing possible loci of interest to target in the development of therapeutics for circadian rhythm disorders. Through these goals, we aim to broaden our understanding and elucidate the genetics of circadian rhythm disorders across a diverse patient population while increasing accessibility to circadian rhythm disorder diagnostics reducing health disparities through self-directed at-home dim light melatonin onset (DLMO) collections.


Psychodermatology in Lithuania. A survey on knowledge, awareness, and practice patterns in Lithuanian dermatovenereologists.
The aim of this study was to evaluate the knowledge, awareness, and practice patterns of Lithuanian dermatovenereologists regarding psychocutaneous medicine. An online survey questionnaire was distributed to the members of the Lithuanian Association of Dermatovenereologists and to dermatovenereologists through public and private healthcare institutions in Lithuania. The questionnaire consisted of questions related to dermatovenereologists' awareness, knowledge, experience, and training needs regarding psychocutaneous disorders. 50% of respondents reported having a good or excellent understanding and knowledge of psychodermatology, and 42% feel prepared to consult psychodermatology patients. 54% of doctors rated their preparedness to prescribe psychopharmacological treatment as poor. The most frequent diagnoses referred to mental health professionals were dermatitis artefacta, acne excoriée, other self-inflicted dermatoses, trichotillomania, and pruritus. The most common course of action with patients at high risk of suicide or other acute psychiatric condition was trying to provide psychological support during dermatovenereology consultation. The most frequent management tactic for patients with chronic psychological problems was a referral to a psychiatrist. 85% of all respondents would participate in educational events about psychodermatology. 70% expressed interest in events about psychopharmacological treatment in dermatology. Lithuanian dermatovenereologists have a good understanding and knowledge of psychodermatology and are willing to further their education in this field. However, some gaps remain. Many doctors reported feeling poorly prepared to administer psychopharmacological treatment to their patients and there seems to be a lack of formal training in psychodermatology in Lithuania.


Probing the structure-holding interactions in cheeses by dissociating agents - A review and an experimental evaluation with emmental cheese.
Interactions holding protein structure in cheese has been a subject of considerable investigation, with conclusions varying among studies. We present a review on this topic, covering fresh curds, ripened cheeses, and processed cheeses. We discuss the usual chemicals and conditions used to probe different types of interactions. Furthermore, we did our own study with solutions of urea, SDS, EDTA, NaCl, and NaOH, at different concentrations and combinations, for Emmental cheese. To quantify solubilized protein, we developed a modification of a spectrometric-based method that can be conveniently employed to quantify total protein in cheese, with statistically similar results to those obtained by the Kjeldahl method. Our results point out that caseins in the Emmental cheese are held together by a set of hydrophobic interactions, hydrogen bonds, and other electrostatic ones, including ionic bonds. Hydrogen bonds seem to have an important role, comparable to hydrophobic interactions, a conclusion not commonly reported for cheese structures.


A transmembrane domain of Andrias davidianus ranavirus 13R is crucial for co-localization to endoplasmic reticulum and viromatrix.
13R, a core gene of Andrias davidianus ranavirus (ADRV), encoded a protein containing a transmembrane domain (TMD) and a restriction endonuclease-like domain. However, the characterization and function of 13R and the protein it encodes remain unclear. In this study, Chinese giant salamander thymus cell (GSTC) was used to investigate the function of 13R. The results showed that the 13R transcripts were detected first at 8 h post-infection (hpi) by RT-PCR and the protein was detected first at 24 hpi by western blot, but the transcription was inhibited by cycloheximide and cytosine arabinofuranoside, indicating that 13R is a viral late gene. Subcellular localization showed that the 13R was co-localized with endoplasmic reticulum (ER) in the cytoplasm, while 13R deleting TMD (13RΔTM) was distributed in cytoplasm and nucleus. During ADRV infection, 13R was observed first in the cytoplasm and nucleus, and later aggregated into the viromatrix, whereas 13RΔTM remain dispersed in cytoplasm and nucleus. Western blot analysis suggested that 13R was a viral non-structural protein and its overexpression did not affect the viral titer in GSTC. All these indicated that the TMD of 13R is crucial for the co-localization into the ER and the viromatrix.


Increased myofibrillar protein catabolism in Duchenne muscular dystrophy measured by 3-methylhistidine excretion in the urine.
Myofibrillar protein catabolic rate was calculated in seven patients with Duchenne muscular dystrophy from the amount of 3-methylhistidine excreted in the urine, and found to be over three times that found in a control series when expresses as the percentage of myofibrillar protein catabolised per day. It is suggested that measurement of myofibrillar protein catabolic rate may add a useful parameter in the study of muscle disorders.


The early career researcher collaboration mindset.
Everyone knows that science is about collaboration, but the degree to which one embraces collaboration can have an outsized impact on the value one derives from collaboration. In this article, different aspects of collaboration are discussed and a list of action-oriented principles is presented to help readers understand what can be done to develop more of a collaboration mindset to get the maximal value out of collaboration.


Long-term Trends in the Clinicopathologic Features of Kidney Transplant Recipients With Graft Dysfunction.
Graft biopsy is the gold standard for the differential diagnosis of graft dysfunction. The time interval between transplant surgery and biopsy often provides clinicians with diagnostic clues. However, the clinicopathologic features of late graft biopsy, especially those obtained at more than 5 years after kidney transplant, are not well understood. We retrospectively collected graft biopsy tissues obtained from kidney transplant recipients who underwent indication biopsy between February 2012 and March 2017. Patients were divided according to their post-transplant period, and their clinical characteristics, pathologic diagnosis, and Banff scores were compared across groups. A total of 410 indication biopsy specimens obtained from 321 kidney transplant recipients were analyzed in this study. Overall, the incidence of T cell-mediated rejection, borderline rejection, and BK virus-associated nephropathy decreased while that of antibody-mediated rejection, nonspecific interstitial fibrosis and tubular atrophy, and glomerulonephritis increased over time. Most samples obtained over 5 years after kidney transplant exhibited chronic glomerular and tubulointerstitial injuries irrespective of their pathologic diagnosis. In patients whose post-transplant period was less than 5 years, urine protein-to-creatinine ratio was significantly elevated in the glomerulonephritis and chronic active antibody-mediated rejection groups only. In contrast, patients who underwent graft biopsy more than 5 years after kidney transplant showed significantly high levels of proteinuria irrespective of the pathologic diagnosis, and there was no statistical difference between groups. We demonstrated that the etiology of graft dysfunction is largely influenced by the biopsy time point.


Evolutionary analysis of JC polyomavirus in Misiones' population yields insight into the population dynamics of the early human dispersal in the Americas.
JC polyomavirus (JCV) has an ethno-geographical distribution across human populations. Study the origins of the population of Misiones (Argentina) by using JCV as genetic marker. Viral detection and characterization was conducted by PCR amplification and evolutionary analysis of the intergenic region sequences. 22 out of 121 samples were positive for JCV, including 5 viral lineages: MY (n = 8), Eu-a (n = 7), B1-c (n = 4), B1-b (n = 2) and Af2 (n = 1). MY sequences clustered within a branch of Native American origin that diverged from its Asian counterpart about 21,914 years ago (HPD 95% interval 15,383-30,177), followed by a sustained demographic expansion around 5000 years ago. JCV in Misiones reflects the multiethnic origin of the current population, with an important Amerindian contribution. Analysis of the MY viral lineage shows a pattern consistent with the arrival of early human migrations to the Americas and a population expansion by the pre-Columbian native societies.


Epidermal Notch signalling: differentiation, cancer and adhesion.
The Notch pathway plays an important role in regulating epidermal differentiation. Notch ligands, receptors and effectors are expressed in a complex and dynamic pattern in embryonic and adult skin. Genetic ablation or activation of the pathway reveals that Notch signalling promotes differentiation of the hair follicle, sebaceous gland and interfollicular epidermal lineages and that Notch acts as an epidermal tumour suppressor. Notch signalling interacts with a range of other pathways to fulfil these functions and acts via RBP-Jkappa dependent and independent mechanisms. The effects on differentiation can be cell autonomous and non-autonomous, and Notch contributes to stem cell clustering via modulation of cell adhesion.


Inhibition of sperm migration through cervical mucus in vitro.
The effectiveness of inhibiting bovine sperm migration through cervical mucus in vitro by prior treatment of semen with 45 to 150 micrograms of soybean trypsin inhibitor, univalent (papain-digested, nonagglutinating) and bivalent (undigested) rabbit anti-bovine sperm immunoglobulin, and heat-treated heifer serum was studied. Sperm head-to-head agglutination resulted from treatment of semen with bivalent immune antibody and heat-treated heifer serum. Migration through cervical mucus was inhibited only by treatment resulting in spermagglutination. It is postulated that in vivo inhibition of sperm migration may be influenced by secretory immunoglobulins from the cervix.


Arthrogryposis multiplex with deafness, inguinal hernias, and early death: a family report of a probably autosomal recessive trait.
We report on three male newborn infants of a highly inbred Lebanese family presenting with a characteristic phenotype: arthrogryposis multiplex, deafness, large inguinal hernia, hiccup-like diaphragmatic contractions, and inability to suck, requiring nasogastric gavage feeding. All three boys died from respiratory failure during the first 3 months of life. Intra vitam or post mortem examinations revealed myopathic changes and elevated glycogen content of muscle tissue. This new syndrome is probably transmitted in an autosomal recessive mode, although X-linked inheritance cannot be excluded.


Elevated white blood cell synthesis of leukotriene C4 in chronic myelogenous leukaemia but not in polycythaemia vera.
Leukotriene (LT) formation was studied in ionophore A23187-stimulated white blood cell (WBC) preparations from patients with chronic myelogenous leukaemia (CML; n = 14), polycythaemia vera (PV; n = 10) and two control groups consisting of patients with non-malignant inflammatory disease (n = 4) and normal healthy donors (n = 25). The synthesized products were identified and quantitated using high-performance liquid chromatography combined with computerized UV-spectroscopy. White blood cell preparations from the CML patients produced more LTC4 (40.2 +/- 7.9 pmol/10(6) WBC, mean +/- SEM) than WBC from the healthy donors (9.0 +/- 1.8), P less than 0.0005. In contrast, the formation of LTB4 was normal and there was no increase in the total leukotriene synthesis (the sum of LTC4, LTB4, 20-OH-LTB4 and the delta 6-trans-isomers of LTB4). The ratio between leukotrienes C4 and B4 was strongly elevated in the CML group; 1.67 +/- 0.25 v. 0.37 +/- 0.07 in the controls, P less than 0.0005. No significant correlation was observed between the levels of LTC4 and the number of known LTC4 producing cells (such as monocytes, eosinophils and basophils) in the CML WBC preparations. In contrast, a correlation was found between the sum of neutrophilic granulocytes and metamyelocytes in these suspensions and the amount of LTB4 formed; r = 0.600, P less than 0.05. A number of other laboratory or clinical variables of the CML patients (including total white blood cell and platelet counts, differential counts, previous cytotoxic treatment, time from diagnosis, time from last treatment, post study survival and age) did not significantly correlate with the formation of leukotrienes. No abnormality in the production of LTB4 or LTC4 was observed in granulocyte and WBC preparations from the patients with polycythaemia vera and non-malignant inflammatory disease, respectively. The results indicate a selectively increased LTC4 producing capacity in CML.


Synthesis and antibacterial activity of [6,5,5] and [6,6,5] tricyclic fused oxazolidinones.
A series of conformationally restricted, [6,5,5] and [6,6,5] tricyclic fused oxazolidinones were synthesized and tested for antibacterial activity. Several compounds in the trans-[6,5,5] series demonstrated potent in vitro and in vivo activity. This work provides valuable information regarding the preferred conformational orientation of the oxazolidinones at the binding site.


Radiopharmaceutical development of radiolabelled peptides.
Receptor targeting with radiolabelled peptides has become very important in nuclear medicine and oncology in the past few years. The overexpression of many peptide receptors in numerous cancers, compared to their relatively low density in physiological organs, represents the molecular basis for in vivo imaging and targeted radionuclide therapy with radiolabelled peptide-based probes. The prototypes are analogs of somatostatin which are routinely used in the clinic. More recent developments include somatostatin analogs with a broader receptor subtype profile or with antagonistic properties. Many other peptide families such as bombesin, cholecystokinin/gastrin, glucagon-like peptide-1 (GLP-1)/exendin, arginine-glycine-aspartic acid (RGD) etc. have been explored during the last few years and quite a number of potential radiolabelled probes have been derived from them. On the other hand, a variety of strategies and optimized protocols for efficient labelling of peptides with clinically relevant radionuclides such as (99m)Tc, M(3+) radiometals ((111)In, (86/90)Y, (177)Lu, (67/68)Ga), (64/67)Cu, (18)F or radioisotopes of iodine have been developed. The labelling approaches include direct labelling, the use of bifunctional chelators or prosthetic groups. The choice of the labelling approach is driven by the nature and the chemical properties of the radionuclide. Additionally, chemical strategies, including modification of the amino acid sequence and introduction of linkers/spacers with different characteristics, have been explored for the improvement of the overall performance of the radiopeptides, e.g. metabolic stability and pharmacokinetics. Herein, we discuss the development of peptides as radiopharmaceuticals starting from the choice of the labelling method and the conditions to the design and optimization of the peptide probe, as well as some recent developments, focusing on a selected list of peptide families, including somatostatin, bombesin, cholecystokinin/gastrin, GLP-1/exendin and RGD.


Comparative Analysis of Bacterial Diversity between the Liquid Phase and Adherent Fraction within the Donkey Caeco-Colic Ecosystem.
Donkey hindgut is an enlarged fermentative chamber that harbors a highly complex and extremely abundant community of anaerobic bacteria. It can be divided into two different ecological sites: liquid (Lq) phase and adherent fraction (Ad) colonized by bacteria. However, the Ad bacteria have not previously been specifically collected or directly compared with the Lq bacteria. In the present study, the digesta collected from the caecum, ventral colon and dorsal colon of nine Dezhou donkeys was separated into Lq and Ad fractions. The bacterial community structure was comparatively determined using 16S rRNA gene sequences by Illumina MiSeq. The Ad bacteria had a higher bacterial diversity than Lq bacteria due to the higher Chao and ACE index (p < 0.05). The predominant bacteria at the phylum level were Firmicutes (55.4~74.3%) and Bacteroidota (13.7~32.2%) for both the Lq and Ad fraction. The relative abundance of Bacteroidota, Spirochaetota, Fibrobacterota and Patescibacteria in the Ad fraction was greater than Lq (p < 0.05), suggesting that bacteria associated with feed particles were mainly responsible for plant fiber degradation. At the genus level, the abundance of Lactobacillus in Lq was greater than that in the Ad fraction (p < 0.05), indicating that the bacteria in the Lq fraction were better at hydrolyzing readily fermentable carbohydrates. PICRUSt showed that the activities of enzymes related to fiber degradation in the Ad fraction were also greater than Lq. In addition, the hindgut region also had a significant effect on the bacterial community composition. The relative abundance of Rikenellaceae_RC9_gut_group, Clostridium_sensu_stricto_1, Christensenellaceae_R-7_group and norank_Bacteroidales_BS11_gut_group was increased (p < 0.05) along the donkey hindgut. In summary, the present study provides evidence that bacteria adherent to plant biomass were different to those in the liquid phase within the donkey caeco-colic digesta, and bacteria associated with feed particles may mainly be responsible for plant fiber degradation.


Current results of esophageal cancer surgery. Time trends in operative mortality and long term survival.
This paper represents a historical analysis of the results achieved by esophageal cancer surgery over the last three decades, as they appear in the literature of the years 1954-1985, and in our own experience between 1965 and 1985, with the aim of assessing the evolution of operative mortality and long-term survival. In a review of 4930 resections reported in western literature, mean values of perioperative mortality went down from 30% to 9%, while the five-year survival increased from 8% to 19%. Similar changes were evident in Japanese and Chinese literature where the survival rose from 9% to 23% in unscreened populations and up to 90% in early cancers. In our experience, dividing the series in two decades (1965-74 and 1975-85), the overall perioperative mortality changed from 28% to 13%. The actuarial survival for the two periods was 8% vs 18% at 5 years, with a median survival of 9 and 18 months. A greater difference was evident for N0 patients where the survival rose from 15% to 35% at 5 years, with a median survival of 15 vs 38 months.


Rash, fever, and chills after intravenous fluorescein angiography.
To report a previously unreported complication associated with intravenous injection of fluorescein dye. Case report. A 75-year-old man developed a unique complication after intravenous injection of fluorescein dye for angiography. Two hours after receiving an intravenous injection of fluorescein for angiography, the patient developed a fever, rash, and chills. Admission to a hospital and careful systemic evaluation determined that this reaction was a noninfectious allergic response to intravenous fluorescein dye injection. A delayed allergic response to intravenous fluorescein dye injection can occur.


Adhesion and kinetics of biofilm formation and related gene expression of Listeria monocytogenes in response to nutritional stress.
Listeria monocytogenes is a gram-positive pathogen, that usually adheres to stainless steel (SS), and other abiotic surfaces in food processing that undergo repeated cleaning and cause the spread of Listeria. Through the enumeration of biofilm cells, extracellular polymeric substance (EPS) component and the scanning electron microscopy (SEM) analysis of biofilms, it was found that the ratio of cells and extracellular matrix is affected by nutrition status. Regardless of the temperature, all strains exhibited a higher adhesion ability when exposed to 10-fold diluted TSB-YE (DTSB-YE, nutrition deficiency). Three hour initial adhesion was significantly positively correlated with biofilm formation (p<0.01). DTSB-YE enhances initial attachment and subsequently promotes biofilm formation. The SEM analysis also showed that in DTSB-YE the adhesion and covered area of the attached cells were higher than those in TSB-YE (rich media). The amount of both extracellular polysaccharides and proteins was significantly higher when incubated in DTSB-YE than TSB-YE. The highest biofilm formation of Lm83 was observed in DTSBYE independent of temperature. The effects of nutrition deficiency on the expression of critical biofilm-associated genes of Lm 83 planktonic and biofilm cells were measured. The gene expression levels of inlA and sigB in biofilm cells in TSB-YE and DTSB-YE were approximately 95.7% and 88.0% and 42.2% and 45.7% lower than those in planktonic cells, respectively. However, the expression of inlA in DTSB-YE was significantly higher (p<0.05) than that in TSB-YE for the same cell state. Interestingly, the gene expression of motB was considerably higher in DTSB-YE than in TSBYE, regardless of the state. These results indicate that better cell motility in nutrient deficiencies might facilitate the cell aggression to promote biofilm formation.


Insulin-like growth factor type-1 receptor down-regulation associated with dwarfism in Holstein calves.
Perturbations in endocrine functions can impact normal growth. Endocrine traits were studied in three dwarf calves exhibiting retarded but proportionate growth and four phenotypically normal half-siblings, sired by the same bull, and four unrelated control calves. Plasma 3,5,3'-triiodothyronine and thyroxine concentrations in dwarfs and half-siblings were in the physiological range and responded normally to injected thyroid-releasing hormone. Plasma glucagon concentrations were different (dwarfs, controls>half-siblings; P<0.05). Plasma growth hormone (GH), insulin-like growth factor-1 (IGF-1) and insulin concentrations in the three groups during an 8-h period were similar, but integrated GH concentrations (areas under concentration curves) were different (dwarfs>controls, P<0.02; half-siblings>controls, P=0.08). Responses of GH to xylazine and to a GH-releasing-factor analogue were similar in dwarfs and half-siblings. Relative gene expression of IGF-1, IGF-2, GH receptor (GHR), insulin receptor, IGF-1 type-1 and -2 receptors (IGF-1R, IGF-2R), and IGF binding proteins were measured in liver and anconeus muscle. GHR mRNA levels were different in liver (dwarfs<controls, P<0.002; dwarfs<half-siblings, P=0.06; half-siblings<controls, P=0.08) but not in muscle. IGF-1R mRNA abundance in liver in half-siblings and controls was 2.4- and 2.5-fold higher (P=0.003 and P=0.001, respectively) and in muscle tissue was 2.3- and 1.8-fold higher (P=0.01 and P=0.08, respectively) than in dwarfs. Hepatic IGF-1R protein levels (Western blots) in muscle were 2.5-fold higher (P<0.05) and in liver and muscle (quantitative immunohistochemistry) were higher (P<0.02 and P<0.07, respectively) in half-siblings than in dwarfs. The reduced presence of IGF-1R may have been the underlying cause of dwarfism in studied calves.


[Pain, analgesic intake and mental health of German intensive care unit nurses].
Since nurses in general are frequently affected by pain and depressive episodes, the aim of this study was to analyze the prevalence of pain, frequency of analgesic intake and the mental health of intensive care nurses. This study was a survey study of German intensive care nurses and the questionnaire comprised self-developed items and the short version of the Depression Anxiety Stress Scale (DASS-21). A total of 432 intensive care nurses (82.97% female) were included in the analysis. Recurrent pain was reported by 36.81% (95% confidence interval [CI]: 31.31%; 42.99%) of study participants and chronic pain by 18.52% (95% CI: 14.68%; 23.05%). Body weight (adjusted odds ratio (AOR): 1.02 [95% CI: 1.01; 1.03]; p = 0.006) and sex (male AOR: 0.33 [95% CI: 0.14; 0.78]; p = 0.012) were significantly associated with chronic pain, and sex (male AOR: 0.59 [95% CI: 0.31; 1.00]; p = 0.049) and the presence of sleeping problems (AOR: 2.16 [95% CI: 1.41; 3.31]; p ≤ 0.001) with recurrent pain. Analgesics were used by 52.61% of study participants with chronic/recurrent pain (most frequently used substance: ibuprofen [81.67%]). Study participants with chronic and recurrent pain indicated significantly higher depression, anxiety and stress levels compared to those without pain. This study indicates that a large number of participating intensive care nurses are suffering from chronic and recurrent pain. Pain in this population was associated with a variety of factors.


A human ICAM-1 antibody isolated by a function-first approach has potent macrophage-dependent antimyeloma activity in vivo.
We isolated a tumor B-cell-targeting antibody, BI-505, from a highly diversified human phage-antibody library, using a pioneering "function-first" approach involving screening for (1) specificity for a tumor B cell surface receptor, (2) induction of tumor programmed cell death, and (3) enhanced in vivo antitumor activity compared to currently used treatments. BI-505 bound to intercellular adhesion molecule-1, identifying a previously unrecognized role for this receptor as a therapeutic target in cancer. The BI-505 epitope was strongly expressed on the surface of multiple myeloma cells from both newly diagnosed and relapsed patients. BI-505 had potent macrophage-dependent antimyeloma activity and conferred enhanced survival compared to currently used treatments in advanced experimental models of multiple myeloma.


Pseudogout: an unusual and forgotten metabolic sequela of parathyroidectomy.
Parathyroidectomy is increasingly being performed by otolaryngology units. The well-known metabolic sequela is hypocalcaemia; it may be transient or permanent depending on presence and/or activity of any residual parathyroid tissue. A more unusual metabolic sequela of a parathyroidectomy is the development of pseudogout. We summarize the clinical presentation and pathophysiology of pseudogout following parathyroidectomy. We present a case of a 71-year-old woman who developed pseudogout following removal of a parathyroid adenoma. Although infrequent, pseudogout predominantly occurs in the immediate postoperative period. We propose that otolaryngology units should be more aware of the unusual sequelae of pseudogout following parathyroidectomy; it can lead to a prompt referral and commencement of early treatment.


Low intensity exercise in humans accelerates mitochondrial ATP production and pulmonary oxygen kinetics during subsequent more intense exercise.
We undertook this study to determine whether low intensity exercise (55 % (O2,max) would significantly alter the metabolic and ventilatory responses observed during 10 min of subsequent moderate intensity exercise (75 % (O2,max). By executing this work, we hoped to further our understanding of the mechanisms that limit mitochondrial ATP production at the onset of exercise. Seven healthy human subjects performed 10 min of moderate intensity exercise in the presence and absence of 10 min of low intensity exercise, which preceded the moderate intensity exercise by 3 min. Muscle biopsy samples were obtained from the vastus lateralis at pre-determined time points and oxygen consumption kinetics were determined at rest and during low and moderate intensity exercise. Following low intensity exercise and 3 min of passive recovery, muscle lactate and acetylcarnitine concentrations were elevated above basal levels, but (O2) had returned to the resting rate. When moderate intensity exercise was preceded by low intensity exercise, there was a significant sparing of phosphocreatine (PCr, approximately 25 %, P < 0.05) and reductions in glucose 6-phosphate (G-6-P, approximately 50 %, P < 0.05) and lactate (approximately 50 %, P < 0.05) accumulation during the first minute of moderate intensity exercise. No differences were observed after 10 min of moderate intensity exercise. The (O2) on-kinetic response over the first minute of moderate intensity exercise was accelerated when preceded by low intensity exercise. Collectively, our results suggest the lag in the oxidative ATP delivery at the onset of moderate intensity exercise can be overcome by prior low intensity exercise. Furthermore, our findings support the view that this lag is at least in part attributable to a limitation in acetyl group delivery/availability at the onset of exercise, rather than delayed oxygen supply.


Neuroprotective effects of astaxanthin against oxygen and glucose deprivation damage via the PI3K/Akt/GSK3β/Nrf2 signalling pathway in vitro.
Astaxanthin (ATX), which is the most abundant flavonoid in propolis, has previously shown neuroprotective properties against cerebral ischaemia-induced apoptosis. However, the mechanisms by which ATX mediates its therapeutic effects are unclear. At present, we explored the underlying mechanisms involved in the protective effects of ATX via the phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase 3 beta (GSK3β)/nuclear factor erythroid 2-related factor 2 (Nrf2) signalling pathway in SH-SY5Y cells. The PI3K/Akt inhibitor LY294002 and GSK3β inhibitor LiCl were employed in this study. Pre-treatment with ATX for 24 hours significantly decreased the oxygen and glucose deprivation (OGD)-induced viability loss, reduced the proportion of apoptosis and regulated OGD-mediated reactive oxygen species (ROS) production. Furthermore, ATX suppressed OGD-caused mitochondrial membrane potential and decomposition of caspase-3 to cleaved caspase-3, and heightened the B-cell lymphoma 2 (Bcl-2)/Bax ratio. PI3K/Akt/GSK3β/Nrf2 signalling pathway activation in SH-SY5Y cells was verified by Western blot. ATX and LiCl treatment raised the protein levels of p-Akt, p-GSK3β, nucleus Nrf2 and haeme oxygenase 1 (HO-1). However, these protein expression levels decreased by treatment of LY294002. The above in vitro data indicate that ATX can confer neuroprotection against OGD-induced apoptosis via the PI3K/Akt/GSK3β/Nrf2 signalling pathway.


Quality of Life After Endoscopic Skull Base Surgery: Validation and Reliability of the Italian Version of the Sino-Nasal Outcome Test for Neurosurgery (SNOT-NC).
Expanded endonasal approaches (EEA) have become the main approach to the anterior skull base. A specific questionnaire, the Sino-Nasal Outcome Test for Neurosurgery (SNOT-NC), was developed in German to assess quality of life after EEA. The aim of this study was the cross-cultural adaptation and validation of the Italian version of SNOT-NC. Three hundred patients who underwent EEA for anterior skull base diseases were included in the study. An Italian version of SNOT-NC was cross-culturally adapted. Internal consistency, test-retest reliability, construct, and clinical and group validity were analyzed. The Short-Form 36 questionnaire was used for construct validity analysis. The Cronbach α coefficient was 0.862. Only 1 subscale (olfactory disturbance) showed an insufficient internal consistency. The test-retest reliability was excellent (intraclass correlation coefficient between 0.934 and 0.997). The good correlation between SNOT-NC and Short-Form 36 scores (P < 0.05) showed the construct validity of the questionnaire. SNOT-NC was able to distinguish between patients with more or fewer nasal symptoms (P < 0.05). Patients who underwent a transtuberculum/transplanum approach had greater olfactory disturbances compared with other approaches (P < 0.05). The Italian version of SNOT-NC showed good internal consistency, test-retest reliability, construct, and clinical and group validity, as well as original version. It can be considered a good instrument to evaluate the impact of endoscopic EEA to the anterior skull base.


Adsorption of anions to zirconium(IV) and titanium(IV) chemically immobilized on gel-phase.
Adsorption behaviors of 25 anions to zirconium(IV) and titanium(IV) chemically immobilized on a gel-phase were studied by ion chromatography and by batch adsorption experiments. The affinities of Zr(IV) to iminodiacetate as an anchoring group and to anions as a sample are much stronger than those of Ti(IV). On a Zr(IV) column, fourteen anions showed no retention, four anions showed pH-dependent retention in a low pH region, and seven anions were irreversibly adsorbed at pH <7. In the last group, fluoride was adsorbed both by the ligand exchange mechanism and the addition mechanism, while phosphate, arsenate and selenite were only by the ligand exchange mechanism. The structures of the adsorbed species are discussed.


Comparison of Emergency Preparedness Practices between Food Assistance Program Participants and Non-Participants in the United States.
Previous research has suggested many households are meeting the Federal Emergency Management Agency's 3-day emergency food and water storage recommendations. The impact of limited economic household resources on emergency preparedness practices related to food and water is uncertain. The purpose of this study was to compare emergency preparedness practices in households participating in United States' food assistance programs with households not participating in these programs. A convenience sample of adults (n = 572) completed an online Qualtrics survey. Descriptive statistics, chi-square statistics, and independent t-tests were used to measure differences between households participating in food assistance programs vs. non-participating households. Most households participating in food assistance programs felt prepared to provide household members with food and water during an emergency, which did not significantly differ from non-participating households. Households using food assistance programs had less accessible cash but had similar foods on-hand for an emergency compared to non-participating households. However, they more frequently reported having baby formula/food and less frequently reported having vitamin/mineral supplements compared to non-participating households. Food assistance programs may be effective in providing enough food and water to help low-income families be prepared for an emergency.


Point mutations in the upstream region of the alpha-galactosidase A gene exon 6 in an atypical variant of Fabry disease.
Single point mutations in the upstream region of exon 6 of the alpha-galactosidase A gene were found in two Japanese cases of the cardiac form of Fabry disease; 301Arg----Gln (902G----A) in a case that has already been published and 279Gln----Glu (835C----G) in a new case. They both expressed markedly low, but significant, amounts of residual activity in COS-1 cells. In contrast, two unrelated cases with classic Fabry disease were found to have different point mutations, which showed a complete loss of enzyme activity in a transient expression assay; 328Gly----Arg (982G----A) in the downstream region of exon 6 in one case and two combined mutations, 66Glu----Gln (196G----C)/112Arg----Cys (334C----T), in exon 2 in the other. We conclude, on the basis of the results recorded in this study and those in previous reports, that the pathogenesis of atypical Fabry disease is closely associated with point mutations in the upstream region of exon 6 of the alpha-galactosidase A gene.


Co-proxamol overdose is associated with a 10-fold excess mortality compared with other paracetamol combination analgesics.
To assess the relative toxicity of co-proxamol in overdose in comparison to the 2 other paracetamol-opioid combination products, co-codamol and co-dydramol. Data collected over a 2-year period (July 2000-June 2002) was used to estimate the frequency of overdose and death for the three most popular paracetamol-opioid compound analgesics. Prescription data for Scotland and Edinburgh, the number of overdoses (derived from overdose admissions in Edinburgh) or Poisons Information Service contacts in Scotland, and national death records were used to calculate a series of indicators relating morbidity (admissions), surrogates of morbidity (poisons enquiries by telephone or internet) and mortality to prescriptions. When related to prescription volume overdoses involving co-proxamol in Scotland were 10 times more likely to be fatal (24.6 (19.7, 30.4)) when compared with co-codamol (2.0 (0.88, 4.0)) or co-dydramol (2.4 (0.5, 7.2)). In contrast there was no difference in the presentation rate or enquiry rates for these analgesics when corrected for prescriptions. The excess hazard from co-proxamol is due to inherent toxicity rather than increased use in overdose. We estimate from this study that withdrawal of co-proxamol would prevent 39 excess deaths per annum in Scotland alone.


Catheter-Based Renal Denervation for Hypertension.
This review was undertaken to update readers on the field of therapeutic renal denervation for hypertension during the 2016 through 2018 period. After the failure of Symplicity HTN-3 to meet its top line objective, intense scrutiny revealed several possible concerns addressed by the newer investigations into the area of renal denervation. These included better device technology, more intense subject monitoring for off-protocol antihypertensive drug usage, and deeper penetration into the renal vasculature by the interventionist. Whether untreated by medication for hypertension or on antihypertensive medication, renal denervation shows a clear, though moderate, blood pressure reduction. The failure of roughly one out of three patients with hypertension to respond to denervation procedures argues that there is room for improvement in choosing the optimal patient for this approach to hypertension management.


Mitochondrial DNA depletion in Leigh syndrome.
Leigh syndrome is a heterogenous neurologic disease characterized by seizures, developmental delay, muscle weakness, respiratory abnormalities, optic abnormalities, including atrophy and ophthalmoplegia, and progressive cranial nerve degeneration with early onset in infants and children. Diagnosis can be confirmed by characteristic pathologic findings of necrosis in the basal ganglia, thalamus, and brainstem. Severe dysfunction of mitochondrial energy metabolism is generally present and involved in the etiology of this degenerative central nervous system disease. At the molecular level, a number of point mutations have been located in mitochondrial DNA genes, including ATPase6 and tRNA(Lys) genes, and in nuclear genes encoding subunits of oxidative enzymes, such as pyruvate dehydrogenase. Biochemically these mutations are responsible for enzymatic defects in either respiratory complexes (I, IV, or V) or pyruvate dehydrogenase. We describe here the first case of Leigh syndrome with marked depletion of mitochondrial DNA levels in skeletal muscle and abnormal activities in skeletal muscle of mitochondrial respiratory complexes I, III, IV, and V.


A novel sialic acid binding lectin with anti-bacterial activity from the Hong Kong oyster (Crassostrea hongkongensis).
Lectins play an important role in immune recognition and host defense. In the present study, a full-length cDNA encoding a novel sialic acid binding lectin was cloned from Crassostrea hongkongensis (designated Ch-salectin) by rapid amplification of cDNA ends (RACE). It is 531 bp in length, containing a 21 bp 5' UTR, a 39 bp 3' UTR and a 468 bp ORF coding for 156 amino acids. The Ch-salectin protein contains a signal peptide and a conserved complement component C1q domain. The purified recombinant MBP-tagged Ch-salectin protein can bind to a sialic acid containing protein fetuin and significantly inhibit the growth of both Gram-negative and Gram-positive bacteria. Furthermore, the transcription of Ch-salectin was inducible and significantly up-regulated during Vibrio alginolyticus infection. Thus, these results highlight the essential roles of Ch-salectin in immune recognition and host defense against bacterial infection in C. hongkongensis.


Cross-cultural adaptation and validation of the reliability of the Thai version of the Hip disability and Osteoarthritis Outcome Score (HOOS).
HOOS was developed as an extension of the Western Ontario and McMaster Universities' Osteoarthritis Index questionnaire for measuring symptoms and functional limitations related to the hip(s) of patients with osteoarthritis. To determine the validity and reliability of the Thai version of the Hip disability and Osteoarthritis Outcome Score (HOOS) vis-à-vis hip osteoarthritis, the original HOOS was translated into a Thai version of HOOS, according to international recommendations. Patients with hip osteoarthritis (n = 57; 25 males) were asked to complete the Thai version of HOOS twice: once then again after a 3-week interval. The test-retest reliability was analyzed using the intraclass correlation coefficient (ICC). Internal consistencies were analyzed using Cronbach's alpha, while the construct validity was tested by comparing the Thai HOOS with the Thai modified SF-36 and calculating the Spearman's rank correlation coefficients. The Thai HOOS produced good reliability (i.e., the ICC was greater than 0.9 in all five subscales). All of the Cronbach's alpha showed that the Thai HOOS had high internal consistency (Cronbach's alpha greater than 0.8), especially for the pain and ADL subscales (0.89 and 0.90, respectively). The Spearman's rank correlation for all five subscales of the Thai HOOS had moderate correlation with the Bodily Pain subscale of the Thai SF-36. The pain subscale of the Thai HOOS had a high correlation with the Vitality and Social Function subscales of the Thai SF-36 (r = 0.55 and 0.54)-with which the symptom subscale had a moderate correlation. The Thai version of HOOS had excellent internal consistency, excellent test-retest reliability, and good construct validity. It can be used as a reliable tool for assessing quality of life for patients with hip osteoarthritis in Thailand.


Early prediction of twin-to-twin transfusion syndrome: systematic review and meta-analysis.
To assess the role of first- and early second-trimester markers in the prediction of twin-to-twin transfusion syndrome (TTTS) in monochorionic twin pregnancies. Electronic databases MEDLINE, EMBASE and ClinicalTrials.gov were searched from inception to April 2014, using the MeSH term 'fetofetal transfusion' in combination with phrases 'predictive value', 'sensitivity', 'specificity', 'false positive', 'false negative', 'screening', 'accuracy' and 'ROC'. Study quality was assessed using the PRISMA guidelines and QUADAS-2 tool. A meta-analysis was planned for the following predictive factors: intertwin nuchal translucency (NT) discrepancy; NT > 95th percentile in at least one twin; intertwin crown-rump length (CRL) discrepancy as a percentage of the larger CRL; abnormal ductus venosus (DV) flow in at least one twin. The outcome assessed was TTTS, defined according to the presence of a twin oligohydramnios-polyhydramnios sequence. The diagnostic performance of the predictive factors was evaluated for each included study. The electronic search identified 152 records, of which 23 were assessed in full for eligibility. We identified 13 eligible studies that reported the predictive accuracy of ultrasound parameters, measured before 16 weeks, for the development of TTTS, including a total of 1991 pregnancies, of which 323 developed TTTS. An increased risk of TTTS was associated with: intertwin NT discrepancy (positive likelihood ratio (LR+), 1.92 (95% CI, 1.25-2.96); negative likelihood ratio (LR-), 0.65 (95% CI, 0.50-0.84)); NT > 95th percentile (LR+, 2.63 (95% CI, 1.51-4.58); LR-, 0.85 (95% CI, 0.75-0.96)); CRL discrepancy > 10% (LR+, 1.80 (95% CI, 1.05-3.07); LR-, 0.92 (95% CI, 0.81-1.05)); abnormal DV flow (LR+, 4.77 (95% CI, 1.33-17.04; LR-, 0.49 (95% CI, 0.17-1.41)). The highest sensitivities were observed for intertwin NT discrepancy (52.8% (95% CI, 43.8-61.7%)) and abnormal DV flow (50.0% (95% CI, 33.4-66.6%)). Monochorionic twin pregnancies with intertwin NT discrepancy, NT > 95th percentile, intertwin CRL discrepancy > 10% or abnormal DV flow on first-trimester ultrasound examination are at significantly increased risk of developing TTTS. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.


Microscopic estimation of bacteria and cells in urine. II. A clinical study on the application of the theoretical considerations to clinical practice.
An improved technique for diagnosing acute urinary tract infections (UTI) by means of microscopic estimation of bacteria, leucocytes, erythrocytes and epithelial cells in urine was tested clinically in a total of 1,807 samples obtained from hospital departments. Marked bacteriuria (greater than or equal to 10(5) bacteria per ml of urine) was found microscopically in 13.1% of the urines. Of these 1.9% were falsely positive. Altogether 3.5% of the samples were falsely negative. When the sample collection was controlled carefully and detailed information on possible collection errors was given regularly, sensitivity and specificity indices of the microscopic technique were 85.3 and 98.1, respectively. Microscopic finding of cocci, e.g. Enterococci and Str. agalactiae, was more difficult than that of rods. Alongside bacteriuria, finding of leucocytes (greater than 5 leucocytes per microscopic field) was of great importance for UTI diagnostics, and it strengthened further the microscopic diagnosis, while erythrocytes and epithelial cells were of very poor significance for UTI diagnosis. The results show that the microscopic technique described here is a reliable and suitable method for UTI diagnostics in routine clinical laboratories which examine daily large numbers of samples, most of them negative.


Oxidative stress in the blood of patients with active localized vitiligo.
Vitiligo is an acquired skin disease characterized by white areas on the skin. The pathogenesis of the disease is still unclear. Some findings show that oxidative stress could be an important phenomenon in the pathophysiology of vitiligo. We evaluated 16 consecutive localized vitiligo patients and 16 healthy controls of a similar age and sex distribution. We measured their indicators of oxidative stress such as catalase (CAT), superoxide dismutase (SOD), glucose 6-phosphate dehydrogenase (G6PD) in erythrocytes, and plasma malondialdehyde (MDA) by spectrophotometry. SOD activities and MDA levels of patients were significantly higher than controls (p < 0.001). CAT and G6PD activities of patients were significantly lower than controls (p < 0.05 and p < 0.001, respectively). Our results confirmed that oxidative stress may play an important role in the pathogenesis of vitiligo. Melanocyte damage in vitiligo might be linked to generalized oxidative stress. This study is the first report on some antioxidant parameters of localized-type vitiligo patients.


Characteristics of Encelia species differing in leaf reflectance and transpiration rate under common garden conditions.
The performance of coastal and desert species of Encelia (Asteraceae) were evaluated through common garden growth observations. The obectives of the study were to evaluate the roles of leaf features, thought to be of adaptive value (increased leaf reflectance and/or transpirational cooling), on plant growth in the hot, arid, desert garden versus their impact on growth under cooler, relatively more moist coastal garden conditions. E. californica native to the coast of southern California and E. farinosa, and E. frutescens, interior desert species, were grown in common gardens at coastal (Irvine, California) and interior (Phoenix, Arizona) sites under both irrigated and natural conditions. Although all species survived in both gardens during the two and a half year study period, there were large differences in their sizes. In the desert garden, leaf conductance and leaf water potential were both lower than at the coastal site. E. californica shrubs were leafless much of the time under natural conditions in the desert garden and had the smallest size there as well. Under natural conditions, E. farinosa, with its reflective leaf surface, was able to maintain lower leaf temperatures and attained a large size than the other two species in the desert garden. The green-leaved species (E. californica and E. frutescens) were not able to maintain leaves into the drought periods in the desert garden, with the exception of the irrigated E. frutescens which did maintain its leaf area if provided with supplemental watering to maintain transpirational leaf cooling. In the coastal garden, all species survived and there were few clear differences in the physiological characteristics among the three species. E. californica, the coastal native, attained a larger size in the coastal garden when compared with either of the two desert species.


Iatrogenic factors in acute renal failure: can vigilance equal avoidance?
Physicians can aid substantially in reducing morbidity and mortality from acute renal failure by exercising particular care when using potentially nephrotoxic procedures or agents, by identifying patients at high risk before undertaking elective surgical procedures, and by acting promptly to correct predisposing conditions.


Genomic analysis of vaccinia virus strain TianTan provides new insights into the evolution and evolutionary relationships between Orthopoxviruses.
Vaccinia virus (VACV) strain TianTan was used for much of China's modern history to vaccinate against smallpox, however the only genome sequence contains errors. We have sequenced additional examples of TianTan to obtain a better picture of this important virus. We detected two different subclones. One (TP03) encodes large deletions in the terminal repeats that extend into both VEGF genes and create a small plaque variant. The second clone (TP05) encodes a nearly intact complement of genes in the terminal repeats, except for an insertion of sequences resembling the telomeric 69 bp repeats. The TP05 genome spans 196,260 bp and encodes 219 genes. The revised sequence documents the integrity of all the genes in the conserved virus core. Phylogenetic methods show that TianTan belongs to a unique clade of VACV, but probably also share a common origin with strains belonging to the Copenhagen/Lister lineage and distinct from the Wyeth/Dryvax lineage.


Animal Models of Nonalcoholic Steatohepatitis: Eat, Delete, and Inflame.
With the obesity epidemic, nonalcoholic fatty liver disease (NAFLD) has become a public health problem with increasing prevalence. The mechanism of disease progression remains obscure and effective therapy is lacking. Therefore, there is a need to understand the pathogenic mechanisms responsible for disease development and progression in order to develop innovative therapies. To accomplish this goal, experimental animal models that recapitulate the human disease are necessary, especially, since causative mechanistic studies of NAFLD are more difficult or unethical to perform in humans. A large number of studies regarding the pathophysiology and treatment of nonalcoholic steatohepatitis (NASH) have been undertaken in mice to model human NAFLD and NASH. This review discusses the known dietary, genetic, and inflammation-based animal models of NASH described in recent years, with a focus on the major advances made in this field.


Family resemblance for fasting blood glucose: the Jerusalem Lipid Research Clinic.
Familial aggregation of fasting plasma glucose was studied in a sample of families examined at the Jerusalem Lipid Research Clinic. We first examined homogeneity of familial correlations across major origin groups in the Israeli sample. Correlations were generally homogeneous across origin groups, except for mother-son pairs. The pooled familial correlations were relatively low for unadjusted blood glucose values, and somewhat higher upon adjustment for sex, age, ethnicity, education, seasonality, body mass, cigarette smoking, alcohol consumption and dietary intake. Genetic and cultural determinants of blood glucose were estimated utilizing a path model with 10 parameters to be estimated from a total of 16 correlations. Under a reduced model genetic heritability (h2) was estimated to be 0.18 +/- 0.08 and cultural heritability (c2) was 0.10 +/- 0.02. However, within this population the additive variation could be explained by a cultural model of inheritance without introducing genetic parameters, and most of the variance is due to "random" unmeasured environmental factors. Commingling analysis was also performed, and our findings imply that there is no evidence for admixture in the distribution of fasting blood glucose in this Israeli population sample.


Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) expression during induced luteolysis in the bovine corpus luteum.
Angiogenic factors, like vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), and their receptors, are strongly regulated during the development of bovine corpus luteum (CL). The aim of this study was to investigate real-time changes of these factors in luteal tissue of cows (n = 4-5 per group) in the mid-luteal phase (day 8-12) after intramuscular injection of the PGF2alpha-analog Cloprostenol. Before (control) and 2, 4, 12, 48, and 64 hr after prostaglandin (PG) injection, CL were collected by transvaginal ovariectomy. RT-PCR for VEGF, VEGF-receptor type 1 (VEGF-R1), VEGF-R2, acidic FGF (FGF-1), basic FGF (FGF-2), and FGF-receptor (FGF-R) was performed. Additionally, the protein concentration for VEGF was determined. The mRNA expression of VEGF and its two receptors (VEGF-R1 and -R2) was significantly downregulated during structural luteolysis (after 12 hr). VEGF protein concentration already significantly declined 2 hr after PGF2alpha. Surprisingly FGF-1 and FGF-2 were significantly and maximally upregulated during functional luteolysis (until 12 hr). Furthermore, FGF-R mRNA was significantly upregulated at 2 hr after PGF2alpha, when compared with the control group. During structural luteolysis, the expression of FGFs and their receptors was not significantly different from control, except FGF-2 mRNA, which was downregulated at 64 hr. We conclude that the cessation of VEGF-support for the CL plays a role during structural luteolysis, whereas FGFs seem to have a major impact on functional luteolysis. The possible role of these growth factors could be a transient counter-regulation of luteolysis, but also an involvement in preventing inflammatory reactions during luteal regression.


Adjuvant botulinum toxin A in dyshidrotic hand eczema: a controlled prospective pilot study with left-right comparison.
Dyshidrotic hand eczema is a therapeutic challenge. A prospective pilot study was performed with left-right comparison in order to investigate whether chemical de-innervation of sudoriferic nerves would be superior to standard therapy with topical corticosteroids. Botulinum toxin A (BTXA) is a potent inhibitor of acetylcholine release, that induces eccrine sweat production and release. Inhibition of sweating by other measures such as tap water iontophoresis has been shown to be beneficial in dyshidrotic hand eczema. Eight adult patients suffering from dyshidrotic hand eczema (atopic type) were included in a prospective, side-by-side controlled clinical pilot study using topical corticosteroids on both hands in combination with intracutaneous injections of 100 units of BTXA (Botox) on the more severely affected hand on day 1. The dyshidrotic hand eczema was classified using the DASI (Dyshidrotic Eczema Area and Severity Index) before treatment (0), after 1 week, 4 weeks and 8 weeks. Six patients completed the study, two dropped out because of social and personal reasons. The mean DASI score changed from 28 to17 with topical therapy alone and from 36 to 3 with adjuvant BTXA (P < 0.01). Itching and vesiculation were inhibited earlier when using the combination of corticosteroids and BTXA. There was one relapse in the corticosteroid group. Relapses have not been seen in the BTXA group. Interruption of sweating by BTXA improves the outcome and reduces relapses in patients with dyshidrotic hand eczema. BTXA is antipruritic as well suggesting that it does not only interact with acetylcholine release but substance P.


Colorectal Cancer and Polyp Detection Using a New Preparation-Free, Colon-Scan Capsule: A Pilot Study of Safety and Patient Satisfaction.
Current strategies to prevent colorectal cancer (CRC) vary considerably regarding safety, invasiveness, and patient satisfaction. A known deterrent for patients is the required bowel cleansing for colonoscopy. A new colon-scan capsule system is a unique preparation-free approach that provides structural information on colonic mucosa intended for detection of colorectal polyps and masses. The aim of this study was to determine safety and patient satisfaction with the colon-scan capsule. Prospective single-arm pilot study conducted at two tertiary care centers. Patients with a pre-scheduled colonoscopy for CRC screening or surveillance were included. Patients participating in this study underwent the colon-scan capsule and colonoscopy. Safety was defined by the occurrence of procedure or device-related adverse events. Satisfaction was based on survey questionnaires using a scoring system 1 (strongly disagree) to 5 (strongly agree). Patient satisfaction with the colon-scan capsule was compared to colonoscopy. Forty patients were included (52.9 [5.7] years; 64.1% females). There were no serious adverse events and no occurrences of capsule retention. The most common (12.5%) complaint was self-limiting abdominal cramping. Satisfaction questionnaires were completed by more than 87% of patients, with patients likely to recommend the capsule (score 4.1 [1.03]) compared to colonoscopy (score 2.8 [1.2]), p = 0.001. The new prepless colon-scan capsule system is an innovative, minimally invasive technology with demonstrated safety and high patient satisfaction. A multicenter pivotal study is planned to validate the performance, safety, and accuracy of polyp detection using the capsule system in comparison with colonoscopy.


The appearance of normal and abnormal arterial morphology on intravascular ultrasound.
The ultrasonic appearance of in vitro normal and atherosclerotic arterial wall was investigated with an intravascular ultrasound (IVUS) probe. Fresh cadaver specimens were used: two carotid, two aorta, four iliac and eight superficial femoral arteries. The wall of muscular arteries has a three-layered sonographic appearance. The central hypoechoic layer corresponds to the media, which is primarily composed of smooth muscle. Elastic arteries whose media have a high elastin content appear uniformly echogenic. Calcified plaque is strongly echogenic with acoustic shadowing, fibrous plaque is moderately echogenic, and where there is no cellular matrix the plaque is poorly echogenic. IVUS can provide information about internal plaque architecture. Three-dimensional reconstructions can be generated using a transputer-based workstation coupled to the transducer, providing detailed views of surface contour.


Apoptosis and necrosis of human breast cancer cells by an aqueous extract of garden cress (Lepidium sativum) seeds.
Conventional treatments for breast cancer are costly and have serious side effects. Non-conventional natural treatments have gained wide acceptance due to their promise of a cure with minimal or no side effects, but little scientific evidence exists. One such common remedy is the seed of the Lepidium sativum plant. Presented here is the first reported use of the aqueous extract of Lepidium sativum seeds on breast cancer cells. The ability of the extract to induce apoptosis and necrosis in the human breast cancer cell line MCF-7, compared to normal human skin fibroblasts (HFS), was determined by morphological changes in the cells using light microscopy, DNA fragmentation assay, and florescent stains (Annexin V and propidium iodide) using flow cytometry and fluorescent microscopy. Apoptosis was induced in both cells, and more in MCF-7, when they were treated with 25% and 50% extract, while necrosis was observed mainly after exposure to elevated extract concentrations (75%). DNA fragmentation resulted for both cells, in a time and dose-dependent manner. Both cells, at all extract concentrations, showed no significant differences in the number of living, dead, apoptotic, and necrotic cells. Finally, the results may indicate that apoptotic changes in MCF-7 may be independent of caspase-3, which is involved in apoptosis and is lacking in MCF-7 cells.


Immunotherapy for advanced melanoma.
Immunotherapy for melanoma has undergone significant change since the first attempts to treat patients with high dose IL-2. Herein, strategies to boost patient antitumor immunity through vaccination, treatment with agents that augment host immunity, and adoptive cell transfer will be discussed. The first two strategies have yielded only limited clinical success, but adoptive cell transfer therapy, particularly following a lymphodepleting, preconditioning regimen has resulted in objective response rates approaching 50%. For a number of reasons, lymphodepletion appears to be critical for maintenance of circulating antitumor T cells following adoptive cell transfer. Balancing antitumor efficacy, autoimmunity, and reconstitution of a functioning immune system remain challenging and potentially life-threatening issues.


Degradation of cyanidin-3-O-glucoside induced by antioxidant compounds in model Chinese bayberry wine: Kinetic studies and mechanisms.
The degradation kinetic of cyanidin-3-O-glucoside was determined in combination with different antioxidants, namely ascorbic acid, cysteine, reduced glutathione, and sodium sulfite at different concentrations and temperatures (4, 20, and 37 °C) in model Chinese bayberry wine. Ascorbic acid, cysteine, and reduced glutathione accelerated cyanidin-3-O-glucoside degradation; half-life times decreased by ca. 46 ∼ 93%, 0.39 ∼ 88%, and 1.6 ∼ 92% respectively when the concentrations of antioxidants were 0.1 ∼ 5 mM. Thiols with more -SH groups lead to faster degradation of cyanidin-3-O-glucoside. Interactions of oxidized cyanidin-3-O-glucoside with antioxidants were evaluated in aqueous solution and methanol to investigate the degradation mechanism of anthocyanin after oxidation. An anthocyanin-cysteine adduct was identified by LC-MS and formation pathways are proposed, along with mechanisms of anthocyanin degradation induced by antioxidants.


Ca2+-independent feedback inhibition of acetylcholine release in frog neuromuscular junction.
The effect of membrane potential on feedback inhibition of acetylcholine (ACh) release was studied using the frog neuromuscular junction. It was found that membrane potential affects the functional affinity (K(i)) of the presynaptic M2 muscarinic receptor. The K(i) for muscarine shifts from approximately 0.23 microm (at resting potential) to approximately 8 microm (at a high depolarization). Measurements of Ca2+ currents in axon terminals showed that the depolarization-mediated shift in K(i) does not stem from depolarization-dependent changes in Ca2+ influx. Pretreatments with pertussis toxin (PTX) abolished the depolarization-dependent shift in K(i); at all depolarizations K(i) was the same and higher (approximately 32 microm) than before PTX treatment. The inhibitory effect of muscarine on ACh release is produced by two independent mechanisms: a slow, PTX-sensitive process, which prevails at low to medium depolarizations and operates already at low muscarine concentrations, and a fast, PTX-insensitive and voltage-independent process, which requires higher muscarine concentrations. Neither of the two processes involves a reduction in Ca2+ influx.


A morphological study of the effects of ozone on rat lung. I. Short-term exposure.
In order to determine the effects of ozone on lungs and the course of cell renewal after damage, young male rats were exposed to 3 ppm of ozone for 4 hr. They were killed at 1, 6, 12, and 18 hr and 1, 2, 3, 4, 7, and 14 days after exposure. One hour before the killing, dividing cells were labeled with tritiated thymidine. Type 1 cells of centriacinar location and bronchiolar cells were severely damaged after exposure. Labeling indices of type 2 cells and bronchiolar nonciliated cells increased 1 day after exposure. Hyperplasia of type 2 cells and bronchiolar nonciliated cells was observed 2 and 3 days after exposure. Ciligenesis of bronchiolar ciliated cells occurred 4 days after exposure. Our study shows that injured type 1 cells are repaired by proliferation of type 2 cells and that injured bronchiolar ciliated and Clara cells are repaired by proliferation of bronchiolar nonciliated cells. These undifferentiated cells are probably progenitors of ciliated cells and Clara cells, and some nonciliated cells are in a transitional form between nonciliated and type 2 cells.


LigaSure vessel sealing system in vaginal hysterectomy: safety, efficacy and limitations.
The aim of this study is to compare vaginal hysterectomy performed with standard technique versus the one performed with LigaSure. Observational-longitudinal-cohort study on 42 women candidates to vaginal hysterectomy because of benign uterine pathology. Outcome variables, methods of analysis, inclusion and exclusion criteria were determined prospectively. Eligible patients were subdivided in Group-A (LigaSure-21 patients), or in Group-B (classical-21 patients). Group-A was divided into Subgroup-A1 (10 patients) and Subgroup-A2 (11 patients), depending on the point where the stump of the uterosacral-ligament was transfixed: Subgroup-A1 at cervical portion, Subgroup-A2 at intermediate portion. For all patients were reported: pre-post surgery haemoglobin and hematocrit, number of sutures, duration of intervention and blood loss, NRS-score on first/third post-operative days. All patients underwent gynaecological examination 30 and 180 days after surgery. General characteristics did not show significant differences between the two groups. Statistically significant differences emerged from the comparison between Group-A versus Group-B in terms of: intraoperative bleeding, post-operative value of haemoglobin, Δ-Hb, number of sutures, surgical time, pain at first and third post-operative day. The 180 days follow-up demonstrated four cases of vaginal vault prolapse, only in the Subgroup-A1 related to thermal damage of the uterosacral ligament. LigaSure vessel sealing system is a safe alternative for securing pedicles in vaginal hysterectomy with significant improvement in patients outcome. Following vaginal vault prolapse, we determined the optimal fixation-site to perform the colposuspension in the intermediate portion of the uterosacral-ligament, especially if the cervical portion received a thermal damage, as occurs during the LigaSure use.


Effect of sialoadenectomy and salivary gland extracts on gastrointestinal mucosal growth and gastrin levels in the rat.
We have examined gastrointestinal mucosal growth 30 days after surgical removal of the submandibular-sublingual salivary glands and ligation of the parotid ducts of rats. The rate of [3H]thymidine uptake in vitro as an estimation of DNA synthesis and the content of DNA and RNA were examined in the oxyntic, duodenal and proximal colonic mucosa. DNA synthesis, DNA and RNA content of oxyntic mucosa were reduced in sialoadenectomized rats when compared to sham-sialoadenectomized control animals. There was no change in the degree of [3H]thymidine incorporation or DNA content of the duodenal or colonic mucosa. Intraperitoneal injection of an aqueous extract of the submandibular-sublingual salivary glands of rats (4.0 mg tissue protein in 0.1 M-sodium phosphate buffer administered twice a day for 15 days) increased the rate of DNA synthesis and the total mucosal DNA and RNA content in the oxyntic mucosa. Injections of extracts of spleen or muscle did not produce consistent results. Administration of epidermal growth factor (10 micrograms/kg) or pentagastrin (250 micrograms/kg) resulted in an increase of the level of DNA synthesis observed in the oxyntic mucosa of sialoadenectomized rats. Plasma and antral tissue levels of the trophic hormone, gastrin, were not significantly decreased in sialoadenectomized rats treated with 0.1 M-sodium phosphate-buffered saline. However, treatment with the salivary tissue extract did result in significant reductions in both plasma and tissue levels of gastrin. We conclude that elimination of the major salivary glands in the rat results in a decrease in [3H]thymidine uptake and DNA content of the gastric oxyntic mucosa. These effects are not mediated via a reduction in endogenous levels of the trophic hormone, gastrin. Administration of an aqueous extract of salivary tissue exerted a small but significant trophic influence on the oxyntic mucosa of the rat.


A very particular case of long-term non-progressor: nineteen consecutive years of follow-up in the absence of any detectable HIV-1 viraemia.
A case of extremely prolonged non-progression of HIV-1 infection, characterized by 19 consecutive years of persistently undetectable viraemia (or no laboratory markers of HIV replication) is presented and discussed based on recent literature issues regarding virological and immunological outcome of the natural history of HIV-1 infection.


[Associations to promote access to care and recognition of obesity].
Patient associations bring many benefits to people suffering from obesity. What's more, through their actions, these associations contribute to the recognition of obesity as a pathology.


Stepwise phosphorylation of vesicular stomatitis virus P protein by virion-associated kinases and uncoupling of second step from in vitro transcription.
Transcription-competent cores of vesicular stomatitis virus (VSV) contain two tightly bound protein kinase activities capable of phosphorylating the viral P protein (Beckes and Perrault, Virology 184, 383-386, 1991). We examined here the specificity of these kinases for the P protein substrate and their activity during the in vitro transcription process. Conditions favoring the VSVK1 kinase activity resulted in phosphorylation of the P1 species predominantly whereas conditions favoring VSVK2, or transcription conditions, led to an increase in the proportion of the faster migrating P2 and P3 species. A minimum of 2 mol phosphate/mol P protein was incorporated in 1 hr under optimal transcription conditions. Pulse-chase experiments revealed that the VSVK2 activity converted phosphorylated P1 to P2/P3 species. Most or all of the sites modified by VSVK1 (serines only) mapped to the 78 amino acid-long N-terminal fragment of the P protein; additional serine acceptor sites of undetermined location were also phosphorylated under VSVK2 conditions. Pretreatment of virion cores with 5'-p-fluorosulfonylbenzoyl adenosine had little or no effect on P1 phosphorylation but inhibited P1 to P2/P3 conversion nearly completely, with no effect on subsequent transcription. Likewise, the addition of cell extracts had relatively little effect on P1 phosphorylation but strongly inhibited the appearance of P2/P3, without affecting concurrent transcription. We conclude that phosphorylation of the P protein during transcription in vitro is a two-step process carried out by two distinct kinase activities, but only the first step may be essential for viral mRNA synthesis.


Seborrheic keratosis that follows Blaschko's lines.
A 66-year-old Japanese man had skin lesions on the left side of his trunk and the left upper extremity for approximately 10 years. The skin lesions were asymptomatic but increased gradually, which brought the patient to our hospital. On the initial examination, we noticed 5 mm x 5 mm to 15 mm x 5 mm, round or oval, light to dark brown keratotic papules on the left side of chest and abdomen and the left upper extremity. The papules were aligned in an S-shaped line on the trunk and in a straight line on the upper extremity. Clinical and histopathological findings led to a diagnosis of seborrheic keratosis that followed Blaschko's lines. To our knowledge, no such a case has been reported previously. Our case supports the hypothesis that seborrheic keratosis can be associated with genetic mosaicism.


Critical care medicine update: essentials for the nonintensivist, part 2.
In Part 2 of this update on the essentials of critical care medicine for the nonintensivist, we continue our review of common problems encountered in the intensive care unit (ICU). The focus of this part is on renal failure, acid-base disturbances, common ICU complications, nutrition management, endocrine disorders, prognostic indicators and principles of patient- and family-centered care.


Indications and outcome of salvage surgery for oesophageal cancer.
Some patients with localised oesophageal cancer are treated with definitive chemoradiotherapy (CRT) rather than surgery. A subset of these patients experiences local failure, relapse or treatment-related complication without distant metastases, with no other curative treatment option but salvage oesophagectomy. The aim of this study was to assess the benefit/risk ratio of surgery in such context. Review of a single institution experience with 24 patients: 18 men and 6 women, with a mean age of 59 years (+/-9). Histology was squamous cell carcinoma in 18 cases and adenocarcinoma in 6. Initial stages were cIIA (n=5), cIIB (n=1) and cIII (n=18). CRT consisted of 2-6 sessions of the association 5-fluorouracil/cisplatin concomitantly with a 50-75 Gy radiation therapy. Salvage oesophagectomy was considered for the following reasons: relapse of the disease with conclusive (n=11) or inconclusive biopsies (n=7), intractable stenosis (n=3), and perforation or severe oesophagitis (n=3), at a mean delay of 74 days (14-240 days) following completion of CRT. All patients underwent a transthoracic en-bloc oesophagectomy with 2-field lymphadenectomy. Thirty-day and 90-day mortality rates were 21% and 25%, respectively. Anastomotic leakage (p=0.05), cardiac failure (p=0.05), length of stay (p=0.03) and the number of packed red blood cells (p=0.02) were more frequent in patients who received more than 55 Gy, leading to a doubled in-hospital mortality when compared to that of patients having received lower doses. A R0 resection was achieved in 21 patients (87.5%). A complete pathological response (ypT0N0) was observed in 3 patients (12.5%). Overall and disease-free 5-year survival rates were 35% and 21%, respectively. There was no long-term survivor following R1-R2 resections. Functional results were good in more than 80% of the long-term survivors. Salvage surgery is a highly invasive and morbid operation after a volume dose of radiation exceeding 55 Gy. The indication must be carefully considered, with care taken to avoid incomplete resections. Given that long-term survival with a fair quality of life can be achieved, such high-risk surgery should be considered in selected patients at an experienced centre.