Memory for emotional images across sleep versus wake in school-aged children.
Sleep is important for emotional well-being, memory, and development in children. Regarding memory, sleep has been shown to advantage accuracy for declarative tasks but not procedural tasks. There is some evidence to suggest that sleep provides a relatively greater benefit for memory of negative emotional versus neutral images. However, the extent to which sleep benefits emotionally positive memories in children is not clear. This study assessed memory after nocturnal sleep versus daytime wake in a within-person design involving a sample of 40 children aged 7 to 14 years (M = 10.6 ± 1.9 years; 18 boys and 22 girls) for images of negative, neutral, and positive valences. Results show that after accounting for response time, memory accuracy overall was greater after sleep compared with equivalent time of wake and memory accuracy was greatest for positive images compared with both negative and neutral images. However, there was no difference between memory for negative images and that for neutral images in children, and there was no condition by valence interaction. Sleep characteristics as recorded using actigraphy, diary, and parent report were not predictive of memory performance after sleep when correcting for multiple comparisons. Overall, the results suggest that sleep may benefit memory in otherwise healthy children but that despite a bias toward memory for positive items over both negative and neutral items, there is not a relatively greater benefit for emotional versus neutral memory consolidation across sleep periods compared with wake periods.


Risk of MGUS in relatives of multiple myeloma cases by clinical and tumor characteristics.
We and others have shown increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of patients with multiple myeloma (MM). Whether familial risk of MGUS differs by the MM proband's age at onset, tumor or clinical characteristics is unknown. MM and smoldering MM (SMM) cases (N = 430) were recruited from the Mayo Clinic in Rochester, Minnesota between 2005-2015. First-degree relatives over age 40 provided serum samples for evaluation of MGUS (N = 1179). Age and sex specific rates of MGUS among first-degree relatives were compared to a population-based sample. Cytogenetic subtypes were classified by Fluorescence in situ hybridization. MGUS was detected in 75 first-degree relatives for an age- and sex- adjusted prevalence of 5.8% (95% CI: 4.5-7.2). Prevalence of MGUS in first-degree relatives was 2.4 fold (95% CI: 1.9-2.9) greater than expected rates. Familial risk did not differ by proband's age at diagnosis, gender, isotype, IgH translocation, or trisomy. This study confirms first-degree relatives of MM cases have a significantly higher risk of MGUS compared to the general population, regardless of age, gender, or tumor characteristics. In selected situations, such as multiple affected first-degree relatives, screening of first-degree relatives of MM cases could be considered for follow-up and prevention strategies.


Outcome of total knee arthroplasty in hemophilic arthropathy.
The clinical histories of 45 consecutively performed TKAs in 32 patients with hereditary bleeding disorders were reviewed retrospectively. The mean follow up was 88.7 (range, 24-232) months. The cumulative probability of infection free-survival was 87.8% after 180 months. When removal of component was defined as endpoint, the survival probability was 86.4% after 180 months. In regression analysis no significant independent risk factors for infection or aseptic loosening were identified. The HSS score improved significantly from 45 to 85 points. Hemophilic patients can be considered to be at high risk for prosthetic failure, our study has demonstrated favorable functional results of total knee arthroplasty in hemophilic patients.


Myoclonus and adult coeliac disease.
A 56-year-old woman with coeliac disease developed myoclonus of cortical origin and palatal myoclonus with lesions of subcortical white matter on magnetic resonance imaging. Myoclonus can thus be a prominent feature of coeliac disease encephalopathy. A slight vitamin E deficiency was found but does not satisfactorily explain this myoclonic encephalopathy, which remains of unknown origin.


[Identification of the origin of single nucleated red blood cells and free DNA in peripheral blood of pregnant women].
To investigate the feasibility of using single fetal nucleated red blood cells (FNRBCs) and free DNA for noninvasive prenatal diagnosis. 116 samples of maternal blood were analyzed. Single FNRBCs were isolated from the peripheral blood samples of 51 pregnant women with the gestational period of 14 to 26 weeks by micromanipulation techniques after density gradient centrifugation. Nested polymerase chain reaction method was used to amplify the SRY gene. Plasma DNA in blood samples of 65 pregnant women with the gestational period of 5 approximately 40 weeks were extracted and primer extension preamplification (PEP) and nested polymerase chain reaction were employed to amplify the SRY gene. Chorionic tissue/amniotic cells were extracted to compare the concordance between the examination result of the meternal blood and that of chorionic tissue/amniotic cells. Venous blood of healthy men and unpregnant women were used as controls. (1) The detection rate of single nucleated red blood cells was 90.20% (46/51). (2) The concordance rate of SRY gene amplification results of single cells with real fetal sex was 82.61% (38/46), the sensitivity rate was 80.00% (24/30), and the specificity rate was 87.50% (14/16). (3) The concordance rate of SRY gene amplification results of free DNA with real fetal sex was 90.77% (59/65), the sensitivity rate was 89.13% (41/46), and the specificity rate was 94.74% (18/19). (1) The single nucleated red blood cells and free DNA in maternal blood are of fetal origin and can be one of the valuable material sources for prenatal diagnosis. (2) The detection purity of FNRBC by using micromanipulation techniques is nearly 100% and it provides a new way for noninvasive prenatal diagnosis.


Membrane specializations in the peripheral retina of the housefly Musca domestica L.
Membrane specializations of the peripheral retina of the housefly (Musca domestica) are revealed in thin sections and freeze fracture/etch replicas. Septate junctions are abundant in corner areas of the pseudocone enclosure bonding: between homologous corneal pigment cells (CPC); between homologous large pigment cells (LPC); between CPC-LPC; between Semper cells (SC); between SC-CPC. Spot desmosomes are present between Semper cells. It is likely that septate junctions function as strengthening adhesions in this area. A new membrane specialization similar to a continuous junction was observed between retinular cells of the same or adjacent ommatidium. This junction has indistinct septa in the 115 A intermembrane cleft and is intermittent in character. When this junction is absent, the apposed cells gape apart. In freeze fracture studies, this junction is characterized by bridges composed of fused membrane particles and randomly arranged particles on the P face, and noncorresponding grooves on the E face. The ridges are elongate and roughly parallel and sometimes they form enclosures. Mitochondria line up along these junctions, often within 90 A of the unit membrane. This membrane specialization has characteristics of tight and continuous junctions. In line with previous findings, we suggest that this junction assists in retinular cell orientation, possibly in enforcing the ommatidial twist and in maintaining localized ionic concentration gradients between retinular cells.


Pancreatic fistula after pancreatic head resection.
Pancreatic resections can be performed with great safety. However, the morbidity rate is reported to be 40-60 per cent with a high prevalence of pancreatic complications. The aim of this study was to analyse complications after pancreatic head resection, with particular attention to morbidity and pancreatic fistula. From November 1993 to May 1999, perioperative and postoperative data from 331 consecutive patients undergoing pancreatic head resection were recorded prospectively. Data were analysed and grouped according to the procedure performed: classic Whipple resection, pylorus-preserving pancreatoduodenectomy (PPPD) or duodenum-preserving pancreatic head resection (DPPHR). Pancreatic head resection had a mortality rate of 2.1 per cent; the difference in mortality rate between the three groups (0.9-3.0 per cent) was not significant. Total and local morbidity rates were 38.4 and 28 per cent respectively. DPPHR had a lower morbidity, both local and systemic, than pancreatoduodenectomy. The prevalence of pancreatic fistula was 2.1 per cent in 331 patients, and was not dependent on the procedure or the aetiology of the disease. Reoperations were performed in 3.9 per cent of patients, predominantly for bleeding and non-pancreatic fistula. None of the patients with pancreatic fistula required reoperation or died in the postoperative course. A standardized technique and a continuing effort to improve perioperative management may be responsible for low mortality and surgical morbidity rates after pancreatic head resection. Pancreatic complications occur with Whipple, PPPD and DPPHR procedures with a similar prevalence. Pancreatic fistula no longer seems to be a major problem after pancreatic head resection and rarely necessitates surgical treatment.


A new species of Scelidopetalon Delkeskamp (Coleoptera, Erotylidae) from China with a key to world species of the genus.
A new species Scelidopetalon biwenxuani sp. n. is described from China, representing the first occurrence of the genus in Hainan province. A key to the world species of this genus is provided.


N⁴-(3-Bromophenyl)-7-(substituted benzyl) pyrrolo[2,3-d]pyrimidines as potent multiple receptor tyrosine kinase inhibitors: design, synthesis, and in vivo evaluation.
With the goal of developing multitargeted receptor tyrosine kinase inhibitors that display potent inhibition against PDGFRβ and VEGFR-2 we designed and synthesized eleven N(4)-(3-bromophenyl)-7-(substitutedbenzyl) pyrrolo[2,3-d]pyrimidines 9a-19a. These compounds were obtained from the key intermediate N(4)-(3-bromophenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine 29. Various arylmethyl groups were regiospecifically attached at the N7 of 29 via sodium hydride induced alkylation with substituted arylmethyl halides. Compounds 11a and 19a were potent dual inhibitors of PDGFRβ and VEGFR-2. In a COLO-205, in vivo tumor mouse model 11a demonstrated inhibition of tumor growth, metastasis, and tumor angiogenesis that was better than or comparable to the standard compound TSU-68 (SU6668, 8).


IGF-I and IGFBP-3 serum levels in patients hospitalized for complications of liver cirrhosis.
IGF-I and IGFBP-3 are part of IGF system and, due to their predominantly hepatic synthesis, they seem to correlate with hepatic dysfunction intensity. To investigate the significance of IGF-I and IGFBP-3 in patients with decompensated liver disease. Cross-sectional study that included cirrhotic patients admitted to hospital due to complications of the disease, in whom IGF-I and IGFBP-3 serum levels were measured by chemiluminescence. Seventy-four subjects with a mean age of 53.1 ± 11.6 years were included in the study, 73% were males. IGF-I levels were positively correlated with IGFBP-3 and albumin, and negatively correlated with Child-Pugh, MELD, creatinine, INR and aPTT ratio. IGFBP-3 levels were positively correlated with IGF-I and albumin, and negatively correlated with Child-Pugh, MELD, creatinine, INR, total bilirubin and aPTT ratio. Significantly lower scores of IGF-I and IGFBP-3 were observed in patients with higher MELD values and higher Child-Pugh classes (P < 0.05). In cirrhotic patients admitted to hospital due to complications of the disease, IGF-I and IGFBP-3 serum levels were associated with variables related to liver dysfunction and to more advanced liver disease. The levels of these markers seem to undergo little influence from other clinical and laboratory variables, therefore mainly reflecting hepatic functional status.


Host-parasite relationship of Trypanosoma corvi in Ornithomyia avicularia.
The first description of an electron microscopic study of Trypanosoma corvi in the vector Ornithomyia avicularia is reported. There is a close association between vector and parasite in the midgut, ileum and rectum of the vector. The midgut distribution of parasites is determined by the peritrophic membrane, which confines the early infection to the endoperitrophic space. Parasites escape from the ruptured region of the peritrophic membrane at the pylorus to gain access to the ectoperitrophic space, where intense multiplication occurs. The resulting, smaller epimastigotes attach to the cuticle in the pylorus, ileum and rectum, where they continue multiplying to give rise to mature, short, stumpy trypomastigotes (metacyclics) that are not attached. Attachment to these cuticularly lined regions occurs by the formation of dense, hemidesmosome-like plaques at the extremities of the expanded flagella. A fibrous matrix surrounds the parasites in the ileum. For the first time, intracellular midgut forms are reported for T. corvi in O. avicularia. These parasites enter the cells between the microvilli and penetrate deeply between the folds of the midgut. In the midgut of O. avicularia, the cells of a mycetome region are packed with Rickettsia-like organisms. The significance of these intracellular parasites in the relationship of T. corvi in O. avicularia remains unknown.


Adapting the mealtime environment: setting the stage for eating.
In long-term care facilities, mealtime should be an important and exciting event that residents and staff look forward to three times a day. Providing residents with a homelike, pleasant dining atmosphere should promote socialization, enhance awareness, and increase appetites, thereby improving the residents' quality of life. This paper discusses the subtle but strong influence that the environment has in preparing residents for eating. Environmental factors that promote a positive mealtime experience are discussed.


Observations of ejecta clouds produced by impacts onto Saturn's rings.
We report observations of dusty clouds in Saturn's rings, which we interpret as resulting from impacts onto the rings that occurred between 1 and 50 hours before the clouds were observed. The largest of these clouds was observed twice; its brightness and cant angle evolved in a manner consistent with this hypothesis. Several arguments suggest that these clouds cannot be due to the primary impact of one solid meteoroid onto the rings, but rather are due to the impact of a compact stream of Saturn-orbiting material derived from previous breakup of a meteoroid. The responsible interplanetary meteoroids were initially between 1 centimeter and several meters in size, and their influx rate is consistent with the sparse prior knowledge of smaller meteoroids in the outer solar system.


Advanced stable lipid-based formulations for a patient-centric product design.
Multiparticulate dosage forms are a recent strategy to meet the special needs of children, elderly people and patients suffering from dysphagia. Our study presents a novel and cost-efficient approach for the manufacturing of a taste-masked multiparticulate system with a stable immediate release profile by applying lipid-based excipients in a solvent-free hot melt coating process. The thermosensitive N-acetylcysteine (N-ac) was used as model drug and hot-melt coated with a mixture of tripalmitin and polysorbate 65. A predictive in vitro method for the evaluation of the taste masking efficiency was developed based on the deprotonation of the carboxyl group of N-ac and the decline of pH, responsible for the unpleasant sour taste of the compound. The method was confirmed using in vivo studies. Differential scanning calorimetry and X-ray scattering experiments revealed polymorphic transformation and its dependency on transformation time, temperature and emulsifier concentration. During the process, the coating was transformed almost completely into the stable β-polymorph, leading to an unaltered dissolution profile during storage. A statistical design was conducted that revealed the critical process parameters affecting the taste masking efficiency and drug release. This study shows the successful application of solvent-free hot-melt coating in the development of a taste-masked and stable formulation.


Expression of neurochondrin in the developing and adult mouse brain.
Here we describe a detailed analysis of the expression of neurochondrin ( ncdn) in the developing and adult mouse brain. Ncdn is first expressed in the hindbrain and spinal cord at embryonic day 10.5 (E10.5) followed by expression in the midbrain at E11.5. By E18 ncdn is also expressed in the diencephalon and telencephalon. However, strongest expression is still observed in the hindbrain. In adults, the expression in the forebrain is as strong as in the hindbrain. Ncdn is highly expressed in the hippocampus, piriform cortex, septum, amygdaloid complex, medial geniculate nucleus, inferior colliculus, cerebellar nuclei and the nuclei of the Vth, VIIth, and XIIth cranial nerves.


Unusual bacterial infections and colorectal carcinoma--Streptococcus bovis and Clostridium septicum: report of three cases.
Several types of unusual bacterial infections have been reported in association with colorectal malignancy. In the three cases described, uncommon infections resulted in further workup and subsequent resection for occult colonic malignancy. Awareness of this association is critical for early diagnosis and management.


War's long shadow: masculinity, medicine, and the gendered politics of trauma, 1914-1939.
War is an inherently traumatizing experience, and during the First World War more than 15,000 Canadian soldiers were diagnosed with some form of war-related psychological wounds. Many more went unrecognized. Yet the very act of seeking an escape from the battlefield or applying for a postwar pension for psychological traumas transgressed masculine norms that required men to be aggressive, self-reliant, and un-emotional. Using newly available archival records, contemporary medical periodicals, doctors' notes, and patient interview transcripts, this paper examines two crises that arose from this conflict between idealized masculinity and the emotional reality of war trauma. The first came on the battlefield in 1916 when, in some cases, almost half the soldiers evacuated from the front were said to be suffering from emotional breakdowns. The second came later, during the Great Depression, when a significant number of veterans began to seek compensation for their psychological injuries. In both crises, doctors working in the service of the state constructed trauma as evidence of deviance, in order to parry a larger challenge to masculine ideals. In creating this link between war trauma and deviance, they reinforced a residual conception of welfare that used tests of morals and means to determine who was deserving or undeserving of state assistance. At a time when the Canadian welfare state was being transformed in response to the needs of veterans and their families, doctors' denial that "real men" could legitimately exhibit psychosomatic symptoms in combat meant that thousands of legitimately traumatized veterans were left uncompensated by the state and were constructed as inferior, feminized men.


A Phase II Trial of the CD40 Agonist Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Disease Progression on Anti-PD-1.
Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with unique epitope specificity and Fc-receptor binding profile optimized for activation of CD40-expressing antigen presenting cells. Preclinical data indicated that CD40 agonists combined with anti-PD1 could overcome resistance to anti-PD-1. We conducted a multi-center, open-label, phase II trial to evaluate the combination of sotigalimab 0.3mg/kg and nivolumab 360mg q3wk in patients with advanced melanoma following confirmed disease progression on anti-PD-1. The primary objective was to determine the objective response rate (ORR). Thirty-eight subjects were enrolled and evaluable for safety. Thirty-three were evaluable for activity. Five confirmed partial responses (PR) were observed for an ORR of 15%. Two PRs are ongoing at 45.9+ and 26+ months while the other 3 responders relapsed at 41.1, 18.7, and 18.4 months. Median duration of response was at least 26 months. Two additional patients had stable disease for > 6 months. Thirty-four patients (89%) experienced at least one adverse event (AE) and 13% experienced a grade 3 AE related to sotigalimab. The most common AEs were pyrexia, chills, nausea, fatigue, pruritus, elevated liver function, rash, vomiting, headache, arthralgia, asthenia, myalgia, and diarrhea. There were no treatment-related SAEs, deaths, or discontinuation of sotigalimab due to AEs. Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting.


Associations Between Atherosclerosis and Elevated Serum Alkaline Phosphatase in Patients With Coronary Artery Disease in an Inflammatory State.
Serum alkaline phosphatase (ALP) has been shown to be associated with cardiovascular disease (CVD) risk. Inflammation is the initiator of atherosclerosis, throughout the life of atherosclerosis. This study investigated the relationship between serum ALP and atherosclerosis in patients with coronary artery disease (CAD) in an inflammatory state. This was a multicentre retrospective study including 22,989 patients with CAD. Serum alkaline phosphatase was converted into the quartiles. C-reactive protein (CRP) was assayed as a marker of systemic inflammation. The atherosclerosis index (AI) was used to assess the degree of atherosclerosis. Binary logistic regression was used to analyse the relationship between ALP and AI. Stratified analysis was performed according to sex and age. Elevated serum ALP was associated with the risk of atherosclerosis in patients with CAD, and after quartiling ALP, the OR for Q4 was 1.17 (95% CI 1.08-1.26; p<0.001) when using Q1 as reference. The odds ratio (OR) for ALP and risk of atherosclerosis was higher in patients aged ≤60 years (OR 1.33, 95% CI 1.15-1.53; p<0.001) than in patients aged >60 years (OR 1.11, 95% CI 1.01-1.23; p<0.05), and higher in males (OR 1.21, 95% CI 1.09-1.35; p<0.001) than in females (OR 1.16, 95% CI 1.03-1.31; p<0.05). Q4 (ALP >83.00 U/L) was significantly associated with increased risk of atherosclerosis in the inflammatory state (OR 1.48, 95% CI 1.18-1.86; p<0.001), and it remained after stratified analysis according to sex and age. The risk of atherosclerosis tended to increase with increasing ALP levels and the correlation between ALP and the degree of atherosclerosis was significantly stronger when ALP was >83.00 U/L. This relationship was more pronounced in inflammatory states, and there were sex and age differences. URL: https://www. gov; Unique identifier: NCT04026724.


Randomized clinical trial: A phase 2b controlled study of the efficacy and safety of trazpiroben (TAK-906) for idiopathic or diabetic gastroparesis.
Previous clinical studies of trazpiroben, a dopamine D2 /D3 receptor antagonist for long-term treatment of moderate-to-severe idiopathic and diabetic gastroparesis, have shown improved symptoms of fullness. This study assessed trazpiroben efficacy, safety, and tolerability in adults with idiopathic and diabetic gastroparesis versus placebo. This global, multicenter, double-blind, parallel-group, phase 2b study (NCT03544229) enrolled eligible adults aged 18-85 years with symptomatic idiopathic or diabetic gastroparesis. Randomized participants received either oral placebo or trazpiroben 5, 25, or 50 mg, administered twice daily over 12 weeks, and completed the American Neurogastroenterology and Motility Society Gastroparesis Cardinal Symptom Index-Daily Diary. Change in weekly composite score from baseline to week 12 (primary endpoint) and treatment-emergent adverse events were assessed. Data were summarized descriptively. Overall, 242 participants were enrolled (mean [standard deviation] age 55.7 [14.2] years; 75.6% female); 193 completed the study. No significant differences in change from baseline in weekly average of the daily diary composite score occurred at week 12 between placebo (least-squares mean [standard error] -1.19 [0.12]) and trazpiroben (5, 25, and 50 mg: -1.11 [0.22], -1.17 [0.12], and -1.21 [0.12], respectively). Overall, 41.4% of participants receiving trazpiroben reported treatment-emergent adverse events (placebo, 39.7%). No serious events were considered trazpiroben-related; no life-threatening or fatal events were reported. There was no clinically meaningful difference in efficacy between trazpiroben and placebo in treating gastroparesis, based on the primary endpoint analysis. Trazpiroben was well tolerated with no new safety concerns identified, strengthening evidence supporting its favorable safety profile. NCT number: NCT03544229.


Perception of nurses in expanded role.
This is a study aimed at identifying nurses' responsibilities and the perceptions of consumers of health care regarding the expanded roles of nurses in the delivery of primary health care through institutional clinics. Questionnaires were distributed to various categories of workers and students who were receiving care in the selected clinics attached to higher educational institutions, in order to determine the acceptability of nurses in expanded role. Responses of consumers revealed a high degree of acceptability of the nurse's expanded role, with Users scoring higher than Non-users. All the nurses involved had a positive perception of their role which they felt could be improved with the provision of necessary equipment and refresher courses at regular intervals. Other factors necessary for enhancing their role in the provision of primary health care are highlighted.


Hypertension, concurrent cardiovascular risk factors and mortality: the Singapore Cardiovascular Cohort Study.
The current hypertension (HTN) guidelines recommend the assessment of other cardiovascular disease (CVD) risk factors in individuals with HTN for further management. Few studies in Asian populations have been published to identify the outcome of individuals with HTN and other CVD risk factors. This study aims to assess the effect of HTN alone, and in combination with other CVD risk factors on all-cause and CVD mortality. Three cross-sectional studies carried out in Singapore (baseline 1982--1995) consisting of 5830 persons were grouped by the absence or presence of HTN and CVD risk factors. They were followed-up (mean 14.1 years) by linkage with the National Death Register. Cox's proportional hazards model was used to obtain adjusted hazard ratios (HRs) for risk of mortality. HTN individuals with either <2 CVD risk factors (adjusted HR 1.4; 95% confidence interval (CI) 1.0-1.8) or > or =2 CVD risk factors (adjusted HR 2.3; 95% CI 1.9-3.0) were at increased risk of all-cause mortality compared to normotensive individuals. The findings were similar for CVD mortality. HTN individuals who also smoked or had diabetes were at highest risk of all-cause mortality, whereas those with elevated total cholesterol/high-density lipoprotein cholesterol, smoked or diabetes had the highest risk for CVD mortality. These findings show that in HTN individuals it is important to assess the presence of other CVD risk factors and manage accordingly.


Analysis and screening of combinatorial libraries using mass spectrometry.
Mass spectrometry is a highly selective and high throughput analytical technique that is ideally suited for the identification and purity determination of large numbers of compounds prepared using combinatorial chemistry or for the dereplication of natural products. Compounds may be characterized based on molecular weight, elemental composition and structural features based on fragmentation patterns. When coupled to a separation technique such as high-performance liquid chromatography (HPLC) or capillary electrophoresis, mass spectrometric applications may be expanded to include analysis of complex mixtures. However, the slower speed of the separation step reduces the throughput of the analysis. This review concerns the application of mass spectrometry to the characterization of combinatorial libraries and the screening of library and natural product mixtures. Strategies to enhance the throughput of LC-MS are discussed including fast HPLC and parallel LC-MS. Also, mass spectrometry-based screening methods are described including frontal affinity chromatography-mass spectrometry, gel permeation chromatography LC-MS, direct electrospray mass spectrometry of receptor-ligand complexes, affinity chromatography-mass spectrometry, and pulsed ultrafiltration mass spectrometry.


The teaching of primary prevention: concluding thoughts and a call to action.
Commentary is provided on the papers in this special issue on the teaching of primary prevention. We present further thoughts on prevention curricula, and we conclude with the need to elevate the importance of prevention training within our professional organizations.


Enhanced stability of berry pomace polyphenols delivered in protein-polyphenol aggregate particles to an in vitro gastrointestinal digestion model.
Stability of protein-polyphenol aggregate particles, created by complexing polyphenols from blueberry and muscadine grape pomaces with a rice-pea protein isolate blend, was evaluated in an in vitro gastrointestinal model. Recovery index (RI; % total phenolics present post-digestion) was 69% and 62% from blueberry and muscadine grape protein-polyphenol particles, compared to 23% and 31% for the respective pomace extracts. Anthocyanins RI was 52% and 42% from particles (6% and 13% from pomace extracts), and proanthocyanidins RI was 77% and 73% from particles (25% and 14% from pomace extracts), from blueberry and grape, respectively. Protein-polyphenol particle digests retained 1.5 to 2-fold higher antioxidant capacity and suppressed the expression of pro-inflammatory cytokines, iNOS, IL6, and IL1β, compared to unmodified extract digests, which only suppressed IL6. Protein-polyphenol particles as a delivery vehicle in foods may confer better stability during gastrointestinal transit, allow protected polyphenols to reach the gut microbiota, and preserve polyphenol bioactivity.


Proteome characterization of the unsequenced psychrophile Pedobacter cryoconitis using 15N metabolic labeling, tandem mass spectrometry, and a new bioinformatic workflow.
Organisms without a sequenced genome and lacking a complete protein database encounter an added level of complexity to protein identification and quantitation. De novo sequencing, new bioinformatics tools, and mass spectrometry (MS) techniques allow for advances in this area. Here, the proteomic characterization of an unsequenced psychrophilic bacterium, Pedobacter cryoconitis, is presented employing a novel workflow based on (15) N metabolic labelling, 2DE, MS/MS, and bioinformatics tools. Two bioinformatics pipelines, based on nitrogen constraint (N-constraint), ortholog searching, and de novo peptide sequencing with N-constraint similarity database search, are compared based on proteome coverage and throughput. Results demonstrate the effect of different growth temperatures (1°C, 20°C) and different carbon sources (glucose, maltose) on the proteome. Seventy-six and 69 proteins were identified and validated from the glucose- and maltose-grown bacterium, respectively, from which 21 and 22 were differentially expressed at different growth temperatures. Differentially expressed proteins are involved in stress response and carbohydrate metabolism, with higher expression at 20°C than at 1°C, while antioxidants were upregulated at 1°C. This study provides an alternative workflow to identify, validate, and quantify proteins from unsequenced organisms distantly related to other species in the protein database. Furthermore, it provides further understanding on bacterial adaptation mechanisms to cold environments, and a comparative proteomic analyses with other psychrophilic microorganisms.


Search for missing schizophrenia genes will require a new developmental neurogenomic perspective.
Even the most powerful experimental designs in search of genetic causes of schizophrenia have not met the desired goal. It is imperative to review the reasons for such an outcome and to formulate novel strategies for the future direction of this research in the new era of individual genomes. Here, we will review aspects of neurodevelopmental hypothesis of schizophrenia in the light of novel genomic and epigenomic insights. Specifically, we will argue for the involvement of de novo mutations and epigenetic modifications during neurodevelopment that may result in schizophrenia. Our conclusion is that the successful elucidation of hereditary mechanisms in neuropsychiatric disorders must begin with attention to discrete endophenotypes; consideration of ontogeny, forethought of genome structure including temporal and spatial patterns of (epi) mutations and the use of judicious techniques that go beyond association studies.


Inhibition of protein synthesis, pulmonary localization and pulmonary tumour formation by drug-treated tumour cells as a means of predicting their chemosensitivity.
Mouse mammary carcinoma cells were exposed in vitro to increasing concentrations of doxorubicin hydrochloride [adriamycin (ADR)] or 5-fluorouracil (5-FU). Uptake of [75Se]selenomethionine (75SeM) in a methionine-deficient medium measured the resulting inhibition of protein synthesis by the tumour cells. This was compared with the ability of the 75SeM labelled tumour cells to localize in mouse lungs and to form pulmonary tumours following intravenous (i.v.) injection into isogenic hosts. These parameters were also related to the ability of the drugs to inhibit pulmonary tumour formation in vivo when injected into mice which had received tumour cells i.v. Results from five different tumours were pooled for analysis. At the highest drug concentration (10 micrograms/ml ADR, 100 micrograms/ml 5-FU) inhibition of protein synthesis was significantly related to the in vivo action of the drugs in limiting formation of pulmonary tumors (P less than 0.02 using the rank difference coefficient). There was also a direct relationship between pulmonary localization of tumour cells following exposure to drugs, their ability to form tumour nodules (P less than 0.025) and the in vivo action of the drugs in inhibiting tumour formation (P less than 0.05). Thus inhibition of protein synthesis in vitro and pulmonary localization following i.v. injection may be of value in predicting the in vivo effect of cytotoxic drugs.


Myeloid-Specific SIRT6 Deletion Protects Against Particulate Matter (PM2.5)-Induced Airway Inflammation.
Particulate matter (PM2.5) is a common risk factor for airway inflammation. Alveolar macrophages play a critical role in airway inflammation. Sirtuin 6 (SIRT6) is a class Ill histone deacetylase that exerts an anti-inflammatory effect in airway diseases. However, the role of SIRT6 on PM2.5-induced airway inflammation in macrophages remains unclear. We aimed to determine whether SIRT6 protects against PM2.5-induced airway inflammation in macrophages. The effect of SIRT6 on PM2.5-induced airway inflammation was assessed by using THP1 cells or bone marrow-derived macrophages (BMDMs) exposed to PM2.5 in vitro and myeloid cell-specific SIRT6 conditional knockout mice (Sirt6fl/fl-LysMCre) in vivo. PM2.5 increased SIRT6 expression in THP1 cells, but SIRT6 gene silencing decreased PM2.5 induced inflammatory cytokines in THP1 cells. Moreover, the expression of SIRT6 and inflammatory cytokines was also decreased in BMDMs with myeloid-specific deletion of SIRT6 after stimulation of PM2.5. In vivo, Sirt6fl/fl-LysMCre mice substantially decreased airway inflammation in response to PM2.5 exposure. Our results revealed that SIRT6 promotes the PM2.5-induced airway inflammation in macrophages and indicated that inhibition of SIRT6 in macrophages may represent therapeutic strategy for airway disorders induced by airborne particulate pollution.


Discovery of IRL 3461: a novel and potent endothelin antagonist with balanced ETA/ETB affinity.
IRL 3461, N-butanesulfonyl-[N-(3,5-dimethylbenzoyl)-N-methyl-3-[4-(5-+ ++isoxazolyl) -phenyl]-alanyl]-(L)-valineamide, a potent and bifunctional (ETA + ETB) [Ki(ETA) = 1.8 nM, Ki(ETB) = 1.2 nM] antagonist was discovered by structural modification of IRL 2500, an ETB selective antagonist. IRL 3461 was found to be stable on incubation with human, rat, mouse, and guinea pig plasmas.


Image quality of photon counting and energy integrating chest CT - Prospective head-to-head comparison on same patients.
To prospectively compare the image quality of high-resolution, low-dose photon-counting detector CT (PCD-CT) with standard energy-integrating-detector CT (EID) on the same patients. IRB-approved, prospective study; patients received same-day non-contrast CT on EID and PCD-CT (NAEOTOM Alpha, blinded) with clinical protocols. Four blinded radiologists evaluated subsegmental bronchial wall definition, noise, and overall image quality in randomized order (0 = worst; 100 = best). Cases were quantitatively compared using the average Global-Noise-Index (GNI), Noise-Power-Spectrum average frequency (fav), NPS frequency-peak (fpeak), Task-Transfer-Function-10%-frequency (f10) an adjusted detectability index (d'adj), and applied output radiation doses (CTDIvol). Sixty patients were prospectively imaged (27 men, mean age 67 ± 10 years, mean BMI 27.9 ± 6.5, 15.9-49.4 kg/m2). Subsegmental wall definition was rated significantly better for PCD-CT than EID (mean 71 [56-87] vs 60 [45-76]; P < 0.001), noise was rated higher for PCD-CT (48 [26-69] vs 34 [13-56]; P < 0.001). Overall image quality was rated significantly higher for PCD-CT than EID (66 [48-85] vs 61 [42-79], P = 0.008). Automated image quality measures showed similar differences for PCD-CT vs EID (mean GNI 70 ± 19 HU vs 26 ± 8 HU, fav 0.35 ± 0.02 vs 0.25 ± 0.02 mm-1, fpeak 0.07 ± 0.01 vs 0.09 ± 0.03 mm-1, f10 0.7 ± 0.08 vs 0.6 ± 0.1 mm-1, all p-values < 0.001). PCD-CT showed a 10% average d'adj increase (-49% min, 233% max). PCD-CT studies were acquired at significantly lower radiation doses than EID (mean CTDIvol 4.5 ± 2.1 vs 7.7 ± 3.2 mGy, P < 0.01). Though PCD-CT had higher measured and perceived noise, it offered equivalent or better diagnostic quality compared to EID at lower radiation doses, due to its improved resolution.


How the size of motoneurones determines their susceptibility to discharge.
The susceptibility of motoneurones to discharge by physiological inputs varies inversely with their size. This relationship has far-reaching consequences for the control of muscular tension, and also accounts for significant differences in the properties of muscle fibres and motor units. The probable basis for the relationship is that the amplitude of excitatory postsynaptic potentials (e.p.s.ps) is also correlated inversely with cell size, but no satisfactory explanation for this finding is known. We now describe experiments which indicate that afferent impulses invade the relatively simple ramifications of fibres going to small motoneurones more completely than the extensive arborisations going to large cells. This results in activation of a higher percentage of the synaptic endings on small cells, which produces larger e.p.s.ps in them and accounts for their greater susceptibility to discharge.


Effects of enzymatic dephosphorylation on infant in vitro gastrointestinal digestibility of milk protein concentrate.
This study investigated the effects of dephosphorylation extent on infant in vitro gastric clotting property and gastrointestinal digestibility of milk protein concentrate. Dephosphorylation was affected by phosphatase type and incubation pH. A series of milk protein concentrate with 0-69% dephosphorylation were obtained by incubation with calf intestinal alkaline phosphatase at pH 6.5 for 0-420 min. Both β- and αs1-caseins in the modified milk protein concentrate showed multiply dephosphorylated isoforms with different numbers of phosphate groups depending on the extent of dephosphorylation. With increased dephosphorylation of milk protein concentrate, the gastric clotting extent decreased and the gastrointestinal digestibility increased under infant in vitro conditions. These results suggested the potential of developing a dephosphorylated milk protein concentrate, with improved gastric clotting property and gastrointestinal digestibility, to simulate the multiply phosphorylated patterns of human casein and hence to further the humanization of infant formula on a molecular level.


Subsurface cisterns in paraventricular nuclei of the hypothalamus of the rat.
Structures identified as subsurface cisterns (SSC's) were found in neurons of the paraventricular nuclei of the rat hypothalamus. They appeared as cytoplasmic organelles consisting most often of stacks of parallel cisterns apposed to the neuronal plasmalemma. These SSC's were located in the interneurons of the parvocellular system, but not in neurosecretory cells and glial cells. SSC's were seen at zones of cytoplasm apposed to neuronal or glial cell processes, showing in some instances specific relationships with synaptic areas. The morphological features of these SSC's are described, and their possible functional significance is briefly discussed.


Occupational soft-tissue and tendon disorders.
Reports of work-related musculoskeletal disorders have increased. The cause of the problem has yet to be determined. Thus far, only cross-sectional case and controlled studies exist. It is important for the physician to develop a thought process to separate patients with subjective complaints and real objective findings from those with unreasonable subjective complaints and minimal or no findings.


Influence of running pace upon performance: effects upon treadmill endurance time and oxygen cost.
Three possible patterns of pacing (type 1, fast/slow; type 2, slow/fast; and type 3, steady rate) were compared over a 1400 m, 4 min run. The subsequent running time to exhaustion at 370 m . min-1 was significantly longer with a type 1 than with a type 2 protocol (P less than 0.05). The steady rate pattern gave results intermediate between type 1 and type 2 pacing. Data for oxygen debt and recovery heart rate confirmed the superiority of type 1 pacing. Possible explanations included (1) a reduction of inefficient anaerobic work, and (2) a greater mechanical efficiency associated with the better matching of required effort to a tapering physiological power. Runners should aim at a steady physiological rather than a steady physical load.


Congenital parameatal urethral cyst in the male.
Three cases of parameatal cysts in boys are reported. Two cysts were present at birth and the other was found in early infancy. Aetiology and treatment are discussed.


Additional Evidence to Establish Existence of Two Stem Cell Populations Including VSELs and SSCs in Adult Mouse Testes.
Present study aims to describe a simple and robust protocol to delineate the presence of pluripotent, very small embryonic-like stem cells (VSELs) in addition to spermatogonial stem cells (SSCs) in adult mouse testes. Testicular seminiferous tubules were subjected to enzymatic dissociation to obtain single cells suspension. Stem cells were enriched by spinning at different speeds wherein majority of somatic cells were pelleted at 1000 rpm (250 g, Pellet A) and putative stem cells by spinning the supernatant (obtained after separating Pellet A) at 3000 rpm (1000 g, Pellet B). Viable (7AAD-ve), 2-6 μm, LIN-CD45-SCA-1+ VSELs were studied after doublets exclusion by flow cytometry in both Pellets A & B. Almost ten-fold enrichment of VSELs was obtained in Pellet B (0.27 + 0.05%) compared to Pellet A (0.03 + 0.003%). SCA-1 expressing SSCs (>6 μm, 0.18 + 0.06%) were clearly distinguished from VSELs (2-6 μm, 0.07 + 0.003%) by flow cytometry studies on total testicular cells suspension collected by spinning at 3000 rpm. Enriched stem cells from Pellet B were used to study expression of OCT-4, NANOG, SCA-1, SSEA-1, LIFR, GFRa, c-KIT, ERα and ERβ. Cells in Pellet B were also subjected to RT-PCR to study pluripotent (Oct-4a, Sox2, Nanog), primordial germ cells (Stella, Fragilis), SSCs (Oct-4) and estrogen receptors (ERα and ERβ) specific transcripts. qRT-PCR analysis showed >2 folds up-regulation of stem cell markers in Pellet B (Oct-4A, Oct-4, Sox2, Nanog) compared to Pellet A. To conclude, spinning at higher speed led to successful enrichment of pluripotent VSELs from testes which have remained ignored till now. Expression of ERα & β on VSELs/SSCs makes them vulnerable to endocrine disruption.


Collisions of halo nuclei within a dynamical eikonal approximation.
The dynamical eikonal approximation unifies the semiclassical time-dependent and eikonal methods. It allows calculating differential cross sections for elastic scattering and breakup in a quantal way by taking into account interference effects. Good agreement is obtained with experiment for 11Be breakup on 208Pb. Dynamical effects are weak for elastic scattering.


Mental health research, ethics and multiculturalism.
In this paper we examine ethical issues relevant to conducting mental health research with refugees and immigrant communities that have cultural orientations and social organisation that are substantially different to those of the broader Australian community, and we relate these issues to NH&MRC Guidelines. We describe the development and conduct of a mental health research project carried out recently in Melbourne with the Somali community, focusing on ethical principles involved, and relating these to the NH&MRC National Statement on Ethical Conduct in Research Involving Humans, and the NH&MRC document Values and Ethics: Guidelines for Ethical Conduct in Aboriginal and Torres Strait Islander Health Research. The experience of conducting mental health research with the Somali community highlights the fact that the principles of inclusion and benefit enunciated in the NH&MRC document Values and Ethics are particularly pertinent when conducting research with refugees and immigrant communities that are culturally distant to those of the broader Australian community. These principles inform issues of research design and consent, as well as guiding respectful engagement with the participating community and communication of the research findings.


Screening and identification of cellulose-degrading bacteria from soil and leaves at Kerman province, Iran.
Cellulosic biomass is considered one of the most promising sources for the production of alternative renewable bioenergy and other valuable products. Identification and optimization of strains with high enzymatic activity that can overcome constraints imposed by the cellulosic structure is an essential step in the development of new biotechnologies. The aim of this study was to isolate and identify thermophilic (50 °C) and mesophilic (37 °C) cellulolytic bacteria from soil and leaves samples at Kerman, Iran. Degrader bacteria were isolated using serial dilution and pour plate method. Media contained carboxymethylcellulose (CMC), and filter paper was used as sources of carbon. Totally 22 mesophilic and 17 thermophilic bacterial strains which produced clear zones were further identified by morphological and biochemical tests. Screening of purified bacteria was performed to identify cellulase-producing bacteria by Congo red test. These bacteria were compared to each other based on cellulase activity, the percentage of growth, and extracellular protein amounts. The strains with the highest enzymatic activity were determined by the DNS method. The isolated US5 and US7 grew rapidly, and produced cellulase. The US5 created the largest clear zones (7 mm). Besides, these strains were selected for analysis of 16S rRNA sequence. The results showed that selected bacteria strains belong to Brevibacillus borstelensis. The B. borstelensis strains isolated in this study showed a suitable cellulase enzyme activity.


Comparison of IgA versus IgG monoclonal antibodies for passive immunization of the murine respiratory tract.
The protective efficacy of anti-Sendai virus IgA was compared to that of IgG after topical application of monoclonal antibodies (MAb) to the respiratory tract of mice. BALB/c mice were passively intranasally immunized with 50 microliters ascites containing equivalent ELISA titers of MAb 1 h before and 4 and 24 h after intranasal challenge with Sendai virus. Lung viral titers were determined by plaque assay 3 days following challenge. In most instances IgA MAb afforded equivalent protection to IgG MAb in that there was no significant difference in virus recovery from the lungs of animals treated with either IgA or IgG MAb, including subclasses of IgG. When IgA MAb was fractionated into monomers and oligomers, there was no inherent advantage to the oligomeric form with respect to passive protection against viral challenge. The data indicate that IgA and IgG antibodies are equally efficacious in protecting the airways from viral infection. The experiments suggest that the advantage of IgA for protecting mucosal surfaces, such as the respiratory tract, relates to the presence of a specialized mechanism for transporting oligomeric IgA across epithelial surfaces. The results also support the rationale for active mucosal immunization protocols designed to generate an IgA response.


Systematic review: non-adherence and non-persistence in intravitreal treatment.
Intravitreal injection of VEGF inhibitors has become the standard of care for different macular diseases within the last years resulting in improved visual outcomes. Under real-life conditions, however, the necessity for frequent retreatments and reexaminations poses a burden for patients and treatment centers. Non-adherence and non-persistence to intravitreal treatment may lead to inferior clinical outcomes, and knowledge of contributing factors is crucial to improve adherence. This systematic review analyzes current literature for potential factors involved in non-adherence and non-persistence. A systematic search was conducted in PubMed and Embase including three different aspects of intravitreal injection therapy: (1) diseases with intravitreal injections as treatment, (2) intravitreal injection, and (3) aspects of therapy adherence or therapy persistence. Data from identified quantitative studies were further extracted and grouped according to WHO criteria (condition, socio-economy, therapy, patient, and health system). The methodological quality of identified studies was graded. Identified qualitative studies (i.e., interviews) were descriptively analyzed and their findings narratively reported. Twenty-four publications were included. In 16 of those publications, a quantitative data analysis was conducted, analyzing factors associated with non-adherence. Worse visual acuity at baseline and unfavorable development of visual acuity, higher age, and greater distance to the treatment center were associated with non-adherence, while there was inconsistent evidence for an association of comorbidity. In qualitative studies, high follow-up/treatment burden, fear and anxiety, disappointed patient expectations, and lack of motivation to continue treatment were reported as reasons for non-persistence. Knowledge of potential barriers in IVT treatment may improve adherence and potentially clinical results. Improvements can be achieved particularly in the healthcare complex (organizational improvements) and the "patient" complex by establishing realistic expectations. Recurrent education of the patient may be necessary.


[Eosinophilic ulcer of the mouth mucosa. Differential mouth ulcer diagnosis].
Eosinophilic ulcers of the oral mucosa represent a rare, self-limiting disease of unknown origin. Single lesions occur typically in the oral cavity or on the lower lip. Characteristically, they have a short history and resolve spontaneously. Diagnosis is verified by the histologic feature of a deep polymorphic inflammatory infiltrate with numerous eosinophils. The clinical aspect shows a usually nontender ulcer with a white or yellowish base and elevated indurated borders or a tumor with central ulceration. Lymphadenopathy is not found. Differential diagnoses include malignant tumors and the primary stage of syphilis. We present three cases recently diagnosed in our department to show the characteristics and the different appearances of the disease. A 74-year-old woman presented with an ulcer at the base of the tongue, a 59-year-old man had one on the lower lip, and in a 48-year-old man the lesion was atypically located at the edge of the mouth. Here we demonstrate the importance of knowledge of the disease, its course, and the characteristic histology to avoid troublesome diagnostic and therapeutic procedures.


Uptake of cell-penetrating peptides in yeasts.
The uptake of different cell-penetrating peptides (CPPs) in two yeast species, Saccharomyces cerevisiae and Candida albicans, was studied using fluorescence HPLC-analyses of cell content. Comparison of the ability of penetratin, pVEC and (KFF)(3)K to traverse the yeast cell envelope shows that the cellular uptake of the peptides varies widely. Moreover, the intracellular degradation of the CPPs studied varies from complete stability to complete degradation. We show that intracellular degradation into membrane impermeable products can significantly contribute to the fluorescence signal. pVEC displayed highest internalizing capacity, and considering its stability in both yeast species, it is an attractive candidate for further studies.


[Multi-centre register study of hip fractures in Orthogeriatric Units in the Community of Madrid (Spain)].
To describe the characteristics of patients with hip fractures admitted over a period of two years (from January 2015 to December 2016) in eight Orthogeriatric Units in public hospitals of the Community of Madrid. This is a descriptive, prospective and multi-centre study. In 2014, all hospitals in Madrid providing joint Geriatric and Traumatology assistance were invited to a recently created orthogeriatric work group. Geriatricians in charge of the Orthogeriatric Unit from eight hospitals took part in this study. The participants established a database including all variables that influenced health outcomes (socio-demographic and clinical variables). The study includes 3,995 patients, with a mean age of 85.3years (range: 58-108years old). Two-thirds of them were ASA (American Society Physical Status Classification System) III-IV. Almost all (96.7%) of the patients underwent a surgical operation, and 35.9% of them were operated during the first 48hours. The delay was mainly due to logistic problems (43.5%). The mean hospital stay was 11.2days. Just over half (53.1%) of the patients required a blood transfusion. In-hospital mortality was 5.3%. Hip fracture registries are essential tools to monitor the healthcare process of these patients, as well as to improve the quality of care. Our results are similar to other records. It would be necessary to improve pre-operative time, which must be less than 48hours in patients without clinical instability. We also need more resources for functional recovery and more uniformity.


Formation of reactive oxygen species and of 8-hydroxydeoxyguanosine in DNA in vitro with betel quid ingredients.
The formation of reactive oxygen species (ROS) from betel quid ingredients, namely areca nut, catechu and tobacco, was studied using a chemiluminescence (CL) technique. Aqueous extracts of areca nut and catechu were capable of generating superoxide anion and hydrogen peroxide at pH greater than 9.5. The formation of O2 was enhanced by Fe2+, Fe3+ and Cu2+ but inhibited by Mn2+. Tobacco extract failed to generate ROS under similar conditions. Saliva was found to inhibit both O2 and H2O2 formation from betel quid ingredients. Upon incubation of DNA at alkaline pH with areca nut extract and Fe3+ or catechu, 8-hydroxydeoxyguanosine was formed as quantified by high performance liquid chromatography (HPLC)/electrochemical detection. The data suggest a possible role of reactive oxygen species in the etiology of oral cancer in betel quid chewers.


Ligand binding properties of hemoglobin 3 of the trout, Salmo gairdneri. The occurrence of an acid Bohr effect in the absence of heme-heme interaction.
The four components of hemoglobin from the rainbow trout (Salmo gairdneri) have been isolated. The oxygen affinities of the first two components eluted from the DEAE-cellulose column have much smaller pH dependencies than the last two components. These components have very low O2 affinities at low pH. The effect of pH on the equilibrium and kinetics of ligand binding to the third fraction, the pH-dependent component present in greatest amounts, has been studied. Measurements of ligand binding equilibria demonstrate the presence of both an alkaline and an acid Bohr effect. In the region of the alkaline Bohr effect the value of n in the Hill equation is a function of ligand affinity. For CO binding n decreases as the pH is decreased until at pH 6, the minimum ligand affinity is reached. At this pH there is also a complete loss of cooperative ligand binding. Decreasing the pH further results in an increase of ligand affinity, but this acid Bohr effect is not associated with a reappearance of cooperativity. This suggests that Fraction 3 of S. gairdneri is frozen in the low affinity, deoxygenated conformation at low pH and that the quaternary structure does not change even when fully liganded. However, the properties of the low affinity conformation of this hemoglobin are pH-dependent.


A comparative trial of lisinopril and nifedipine in mild to moderate hypertension in general practice.
to compare lisinopril and nifedipine in the management of essential hypertension in 52 patients in general practice with respect to the obtaining of target diastolic blood pressure and freedom from side effects. an open label, parallel randomised trial over an eight week period. lisinopril and nifedipine were found to effectively lower diastolic blood pressure with the latter having a significantly higher level of withdrawals and clinical side effects. lisinopril is equivalent to nifedipine in its hypertensive effect and has a better side effect profile.


Sleep-disordered breathing and lung function abnormalities in adults with congenital heart disease.
Advances in treatment enables most patients with congenital heart diseases (CHD) to survive into adulthood, implying the need to address comorbid conditions in this growing cohort of patients. The aim of this study was to evaluate the prevalence of sleep-disordered breathing (SDB) and lung function abnormalities in patients with adult congenital heart disease (ACHD). Patients with ACHD underwent level 3 sleep testing (Embletta MPR polygraphy) and pulmonary function testing. Results were stratified by the underlying haemodynamic ACHD lesion group. Patients with ACHD (n = 100) were middle-aged (42.3 ± 14.6 years), 54% male and slightly overweight (BMI 25.9 ± 5.5 kg/m2). Polygraphy revealed a prevalence of sleep apnoea of 39% with 15% of patients presenting with predominantly obstructive apnoeic episodes, while 23% of patients presenting primarily with central sleep apnoea. The distribution of mild, moderate, and severe sleep apnoea in the total study population was 26%, 7% and 6%, respectively. Comparison of apnoea-hypopnoea index, presence of sleep apnoea, and apnoea severity did not offer significant differences between the four ACHD lesion groups (p = 0.29, p = 0.41 and p = 0.18, respectively). Pulmonary function testing revealed obstructive lung disease in 19 of 100 patients. Concomitant chronic obstructive pulmonary disease and obstructive sleep apnoea were diagnosed in 3% of patients and were associated with profound nocturnal desaturation. The findings suggest a mild propensity amongst patients with ACHD to develop SDB that seems to be unaffected by the specific underlying congenital lesion.


Application of molecular biology studies to gene therapy treatment strategies.
The diagnosis of pancreatic cancer continues to produce fear in both patients and practitioners in large part owing to the likely incurability in all for whom the diagnosis is made. It is this reality that continually motivates the surgical and medical oncologists who endeavor to treat these patients. Currently, the cure rate for pancreatic cancer has improved only minimally, and the overall survival of patients remains dismal, with fewer than 5% of patients alive at 5 years and 92% of these patients dead at 2 years. This current treatment status has stimulated numerous studies endeavoring to understand the diverse mechanisms of cell growth in this tumor. Intensive investigative efforts have produced the understanding of new tumor suppressor genes such as DPC4 and an increasing understanding of tyrosine kinase receptors and signal transduction and their regulation of programmed cell death (apoptosis). Detection of these numerous genetic defects may give new insights and understanding of the highly chemo- and radioresistant nature of pancreatic cancer. These same findings also provide the basis for the development of new potential therapies for pancreatic cancer through gene therapy. This paper reviews the significant molecular biologic findings and their influence on the development of gene therapy strategies in the treatment of pancreatic adenocarcinoma.


Neurofibroma of the ovary.
We report an unusual example of ovarian neurofibroma in a woman with neurofibromatosis (von Recklinghausen's disease). The neoplasm caused ovarian enlargement which surgically simulated malignant neoplasm. Ovarian neurofibromas are extremely rare and may arise from small myelinated nerves in the ovarian hilum.


Comparison of bupivacaine and alkalinized bupivacaine in brachial plexus anesthesia.
To define the effect of alkalinization of bupivacaine 0.5% in subclavian perivascular brachial plexus blockade, the time to onset, time to peak effect, and 6-hour regression of sensory and motor blockade were determined. Sixty physical status ASA I and II patients were randomly allocated to one of two groups and a double-blind design was used: group I (n = 30) received bupivacaine 0.5% (pH, 5.5) 3 mg/kg, while group II (n = 30) received alkalinized bupivacaine 0.5% (pH, 7.05-7.15) 3 mg/kg. Onset and regression of sensory blockade were determined by pinprick in the C4-T2 skin dermatomes, while motor blockade was assessed using a scheme of proximal to distal muscle group paralysis. Time to onset of sensory blockade (group I, 4.0 +/- 1.2 min; group II, 3.6 +/- 0.9 min) and time to peak sensory effect (group I, 17.7 +/- 1.8 min; group II, 16.3 +/- 1.8 min) did not differ significantly between the groups. Similarly, no difference in time to onset of motor blockade (group I, 6.9 +/- 1.7 min; group II, 6.3 +/- 1.5 min) or time to peak motor effect (group I, 18.1 +/- 1.9 min; group II, 15.1 +/- 1.9 min) was observed. Regression of postoperative sensory and motor blockade was similar in both groups. It is concluded that alkalinization of bupivacaine 0.5% solutions does not confer any added clinical advantage in subclavian perivascular brachial plexus blockade when compared with commercially available bupivacaine.


Mapping the conformational epitope of a therapeutic monoclonal antibody against HBsAg by in vivo selection of HBV escape variants.
Hepatitis B immunoglobulin (HBIG) has been routinely applied in the liver transplantation setting to block HBV reinfection of grafts. However, new monoclonal anti-HBV surface antibodies have been developed to replace HBIG. The epitopes of such monoclonal antibodies may affect the emergence of escape variants and deserve study. The conformational epitope of sLenvervimab, a surrogate form of Lenvervimab, which is a monoclonal anti-HBsAg antibody currently under phase 3 trial, was investigated by selecting escape mutants from a human liver chimeric mouse. HBV-infected chimeric mice treated with sLenvervimab monotherapy showed an initial decline in circulating HBsAg levels, followed by a quick rebound in 1 month. Sequencing of circulating or liver HBV DNA revealed emerging variants, with replacement of amino acid E164 or T140, two residues widely separated in HBsAg. E164 HBV variants strongly resisted sLenvervimab neutralization in cell culture infection, and the T140 variant moderately resisted sLenvervimab neutralization. Natural HBV variants with amino-acid replacements adjacent to E164 were constructed and examined for sLenvervimab neutralization effects. Variants with K160 replacement also resisted neutralization. These data revealed the conformational epitope of sLenvervimab. Selection of antibody-escape HBV variants in human chimeric mice works efficiently. Analysis of such emerging variants helps to identify anchor amino-acid residues of the conformational epitope that are difficult to discover by conventional approaches.


Invasive beta-haemolytic streptococcal infections, Finland, 2006 to 2020: increase in Lancefield group C/G infections.
BackgroundInvasive infections with beta-haemolytic streptococci of Lancefield groups A (iGAS), B (iGBS) and C/G (iGCGS) are a major cause of morbidity and mortality worldwide.AimWe studied incidence trends of invasive beta-haemolytic streptococcal infections in Finland, focusing on iGCGS.MethodsWe conducted a retrospective register-based study. Cases were defined as isolations from blood and/or cerebrospinal fluid and retrieved from the National Infectious Disease Register where all invasive cases are mandatorily notified.ResultsBetween 2006 and 2020, the mean annual incidence was 4.1 per 100,000 for iGAS (range: 2.1-6.7), 5.2 for iGBS (4.0-6.3) and 10.1 for iGCGS (5.4-17.6). The incidence displayed an increasing trend for all groups, albeit for iGBS only for individuals 45 years and older. The increase was particularly sharp for iGCGS (8% annual relative increase). The incidence rate was higher in males for iGCGS (adjusted incidence rate ratio (IRR) = 1.6; 95% confidence interval (CI): 1.5-1.8) and iGAS (adjusted IRR = 1.3; 95% CI: 1.1-1.4); for iGBS, the association with sex was age-dependent. In adults, iGCGS incidence increased significantly with age. Recurrency was seen for iGCGS and secondarily iGBS, but not for iGAS. Infections with iGCGS and iGBS peaked in July and August.ConclusionsThe incidence of invasive beta-haemolytic streptococcal infections in Finland has been rising since 2006, especially for iGCGS and among the elderly population. However, national surveillance still focuses on iGAS and iGBS, and European Union-wide surveillance is lacking. We recommend that surveillance of iGCGS be enhanced, including systematic collection and typing of isolates, to guide infection prevention strategies.


Regularly alternating L,D-peptides. III. Hexacyclic peptides from valine or phenylalanine.
In the present paper we describe the single-crystal x-ray analyses of two cyclic hexapeptides containing an equal number of alternating L,D-residues as putative analogues of the metal binding compounds, enniatin and beauvericine. Both the molecules of c(L-Val-D-Val)3 and C(L-Phe-D-Phe)3 retain in the solid state the center of symmetry and crystallize with six and eight trifluoroacetic acid molecules, respectively. The peptides are strongly hydrogen bonded to the solvent molecules. We estimate, on the basis of the molecular geometry and spatial arrangement of the peptide carbonyl groups and in comparison with other metal binding cyclic peptides, the ability of these molecules to interact with metal ions as 1:1 complexes.


Obstetric management of a woman's first delivery and the implications for pelvic floor surgery in later life.
To determine the influence of intrapartum care during a first delivery on the risk of pelvic floor surgery in later life. Nested case-control study with record linkage of a historical cohort and a current morbidity database. Hospital births in Dundee 1952-1966. The 7556 primiparous women from the Walker cohort. The cases (n= 352) were women who delivered a first singleton baby at term (> or =37 weeks) and subsequently had pelvic floor surgery. Controls (n= 1403) were women who delivered their first baby during the same time period and did not undergo surgery. Univariate and multivariate logistic regression analyses were performed taking account of demographic, anthropometric and obstetric factors. Pelvic floor surgery. Caesarean section was associated with a reduced risk of pelvic floor surgery compared with spontaneous vaginal delivery (odds ratio 0.16, 95% CI 0.05-0.55). Forceps delivery and infant birthweight >4.0 kg were not identified as significant risk factors (OR 0.94, 95% CI 0.71, 1.25, and OR 0.94, 95% CI 0.50, 1.75, respectively). Episiotomy and prolonged labour (>12 hours) may be associated risk factors but were of borderline significance (OR 1.46, 95% CI 0.99, 2.10, and OR 1.51, 95% CI 1.00, 2.27). Caesarean section in a first pregnancy appears to protect against pelvic floor surgery in later life.


Bioinformatic Analysis Reveals the Distinct Role of 5'UTR-Specific m6A RNA Modification in Mice Developing Cerebral Cortices.
N6-methyladenosine (m6A) abundantly exists in the cerebral cortex and is emerging as an essential factor in cortical development and function. As the m6A-binding site appears to be dynamically methylated in different RNA regions at the temporal-specific developing stage, it is of value to distinguish the unique character of region- and temporal-specific m6A. Herein, we analyzed the status of temporal-specific m6A within RNA 5' untranslated region (5'UTR) using m6A-methylated sequencing data and transcriptomic sequencing data from 12.5- to 13-day embryonic cerebral cortices and 14-day postnatal ones. We identified sorts of RNAs that are uniquely m6A-methylated in the 5'UTR and sorted them into specific neurological processes. Compared with 3'UTR-m6A-methylated RNAs, 5'UTR-m6A-methylated RNAs showed unique functions and mechanisms in regulating cortical development, especially through the pathway of mRNA transport and surveillance. Moreover, the 5'UTR-specific m6A was associated with neurological disorders as well. The FoxO signaling pathway was then focused by these pathogenic 5'UTR-m6A-methylated RNAs and explored to be involved in the determination of neurological disorders. Additionally, the 5'UTR-m6A modification patterns and transcriptional patterns play independent but cohesive roles in the developing cortices. Our study emphasizes the importance of 5'UTR-specific m6A in the developing cortex and provides an informative reference for future studies of 5'UTR-specific m6A in normal cortical development and neurological disorders.


Investigating factors associated with success of breastfeeding in first-time mothers undergoing epidural analgesia: a prospective cohort study.
We investigated the possible risk factors that could influence the likelihood of breastfeeding at 5 to 9 weeks postpartum with our primary aim being to analyse the associations between psychological vulnerabilities, such as peripartum depression and anxiety, and continued breastfeeding. Our secondary aim was to investigate other non-psychological factors' influence on continued breastfeeding. A prospective cohort study was conducted in KK Women's and Children's Hospital in Singapore. Healthy nulliparous parturients at ≥36 weeks gestation with a singleton fetus who received epidural analgesia were recruited. Demographic and anaesthetic data were obtained. Self-reported psychological and pain determinants such as anxiety (State-Trait Anxiety Inventory), depression (Edinburgh Postnatal Depression Scale), stress (Perceived Stress Scale), pain susceptibility (Pain Catastrophizing Scale) and pain perception (McGill Pain Questionnaire) were also recorded at baseline. A phone interview was then performed at 5 to 9 weeks postpartum to obtain information on breastfeeding status. 329 participants were included into this study, of which 263 (79.9%) of them were still breastfeeding at 5 weeks postpartum. Multivariate logistic regression analysis showed that a higher State-Trait Anxiety Inventory score (Adjusted Odds Ratio [AOR] 0.97; 95% Confidence Interval [CI] 0.94, 1.00) at baseline, higher intrapartum blood loss (AOR 0.76; 95% CI 0.61, 0.93), and occurrence of fetal anomalies (AOR 0.15; 95% CI 0.03, 0.72) were associated with reduced likelihood of breastfeeding at 5 to 9 weeks postpartum. Indians (AOR 0.56; 95% CI 0.20, 1.53), Malays (AOR 0.30; 95% CI 0.14, 0.62) and other ethnicities (AOR 0.36; 95% CI 0.16, 0.83) were less likely to continue breastfeeding compared to Chinese participants. On the other hand, receiving any support services on breastfeeding during the participants' hospital stay was 3.3 times more likely (AOR 3.30; 95% CI 1.21, 9.02) to increase the likelihood of breastfeeding at 5 to 9 weeks postpartum. We identified 5 independent association factors that could have significant influences on breastfeeding at 5 to 9 weeks postpartum. Healthcare providers could utilize this risk stratification to identify parturients likely to have poorer breastfeeding outcomes and undertake interventions that may help safeguard optimization of breastfeeding outcomes and parturient care. Clinicaltrials.gov NCT02278601. Registered 26 October 2014.


New developments on the role of NMDA receptors in Alzheimer's disease.
Since the initial findings that NMDA receptors play important roles in cellular models of learning as well as neurotoxicity, abnormal function of this receptor has been considered a potential mechanism in the pathophysiology underlying Alzheimer's disease. Treatment of Alzheimer's disease with an NMDA receptor antagonist began several years ago, with some limited success. More recent mechanistic studies have examined the role of NMDA receptors in the synaptic effects of beta amyloid (Aβ).


MRI findings and pathological features in early-stage glioblastoma.
Magnetic resonance imaging (MRI) is an important diagnostic tool for glioblastoma, with almost all cases showing characteristic imaging findings such as a heterogeneous-ring enhanced pattern associated with significant edema. However, MRI findings for early-stage glioblastoma are less clear. In this study, a retrospective review of MRI findings in five patients showed slight T2WI signal changes on initial scans that developed into typical imaging findings of a ring-like or heterogeneously enhanced bulky tumor within 6 months. The diagnoses based on initial MRI were low grade glioma in three cases, venous thrombosis in one case, and uncertain in one case. Four cases were treated with gross total resection, while one case underwent biopsy. Immunohistochemical examinations showed that two cases were p53-positive, and that all cases were IDH1 R132H-negative and had overexpression of EGFR. FISH analysis showed that all cases were 1p19q LOH-negative. De novo glioblastoma was the final diagnosis in all cases. Our results show that initial MRI findings in early-stage glioblastoma of small ill-defined T2WI hyperintense lesions with poor contrast develop to bulky mass lesions with typical findings for glioblastoma in as short a period as 2.5 months. The early MRI findings are difficult to distinguish from those for non-neoplastic conditions, including ischemic, degenerative or demyelinating processes. Thus, there is a need for proactive diagnosis of glioblastoma using short-interval MRI scans over several weeks, other imaging modalities, and biopsy or resection, particularly given the extremely poor prognosis of this disease.


The relation between schizotypy and early attention to rejecting interactions: The influence of neuroticism.
Schizotypy relates to rejection sensitivity (anxiety reflecting an expectancy of social exclusion) and neuroticism (excessive evaluation of negative emotions). Positive schizotypy (e.g., perceptual aberrations and odd beliefs) and negative schizotypy (e.g., social and physical anhedonia) could relate to altered attention to rejection because of neuroticism. Forty-one healthy individuals were assessed on positive and negative schizotypy and neuroticism, and event-related potentials during rejecting, accepting and neutral scenes. Participants were categorised into high, moderate and low neuroticism groups. Using temporo-spatial principal components analyses, P200 (peak latency = 290 ms) and P300 amplitudes (peak latency = 390 ms) were measured, reflecting mobilisation of attention and early attention, respectively. Scalp-level and cortical source analysis revealed elevated fronto-parietal N300/P300 amplitude and P200-related dorsal anterior cingulate current density during rejection than acceptance/neutral scenes. Positive schizotypy related inversely to parietal P200 amplitude during rejection. Negative schizotypy related positively to P200 middle occipital current density. Negative schizotypy related positively to parietal P300, where the association was stronger in high and moderate, than low, neuroticism groups. Positive and negative schizotypy relate divergently to attention to rejection. Positive schizotypy attenuates, but negative schizotypy increases rejection-related mobilisation of attention. Negative schizotypy increases early attention to rejection partly due to elevated neuroticism.


Agent-based modeling insights into the optimal distribution of the Fresh Fruit and Vegetable Program.
The Fresh Fruit and Vegetable Program (FFVP) program provides a free fresh fruit or vegetable snack to children in low-income schools between two and five times a week. This is an important nationwide program, but current funding levels are insufficient to reach all eligible schools. Thus, there is a need to develop insight on contextual factors that may impact the effectiveness of FFVP in facilitating the development of childhood food preferences. An agent-based model of preference formation is used to understand how exposure to FFVP in early elementary school may affect preferences for healthy food by 6th grade. Preferences are modeled using the temporal difference learning algorithm used by Hammond et al. (2012). This model simulates habit formation in the context of food by modeling preference formation in terms of positive or negative feedback about the food most recently consumed. The model is designed to provide insights into how different patterns of exposure to FFVP affect preferences, and how living in a food desert changes the effect of FFVP. We use data on 35,981 students from Arkansas elementary schools (from 2008 to 2016) and information about the commercial food environment in Arkansas communities to populate the model. We find that early FFVP exposure is more beneficial than late exposure conditional on the number of years exposed. We also find that FFVP is more beneficial for children who grow up in environments lacking healthy food.


Normal substantia nigra patients treated with levodopa - Clinical, therapeutic and pathological observations.
Definite diagnosis of idiopathic Parkinson's disease is based on histological findings of marked substantia nigra neuronal loss and Lewy body inclusions. Almost all cases with clinical diagnosis of idiopathic Parkinson's disease are treated with levodopa. Because there is no biological marker for the diagnosis, erroneous clinical diagnosis and treatment of such cases with levodopa are well known. There is very limited literature on levodopa treated cases that had normal substantia nigra at autopsy. Patients seen at Movement Disorders Clinic Saskatchewan are offered autopsy at no cost to the family/estate of the patient. Autopsy studies are performed by certified neuropathologists. Notation on the status of substantia nigra is made in every autopsied case. Between 1968 and 2014, 21 cases treated with levodopa had normal substantia nigra at autopsy. Eleven patients continued levodopa until death and 9 received the drug for four years or longer. No objective motor symptom benefit, dyskinesia or motor response fluctuations on levodopa were observed in any case. The most common final diagnosis was essential tremor. Individuals with normal substantia nigra do not benefit from levodopa and do not manifest motor response fluctuations or dyskinesia. Long-term use of levodopa is not toxic to normal human substantia nigra.


Pimitespib: First Approval.
Pimitespib (Jeselhy®) is an oral small molecule inhibitor of the α and β isoforms of heat shock protein 90 (HSP90). HSP90α and HSP90β regulate the stability and activity of a number of proteins that are crucial for tumour development. Pimitespib is being developed by Taiho Pharmaceutical for the treatment of solid tumours, including gastrointestinal stromal tumour (GIST), and in June 2022 it received its first approval in Japan for GIST that has progressed after chemotherapy. Pimitespib is undergoing phase I development for the treatment of solid tumours in the EU and the USA. This article summarizes the milestones in the development of pimitespib leading to this first approval for GIST that has progressed after chemotherapy.


Accuracy and safety of robot-assisted cortical bone trajectory screw placement: a comparison of robot-assisted technique with fluoroscopy-assisted approach.
To compare the safety and accuracy of cortical bone trajectory screw placement between the robot-assisted and fluoroscopy-assisted approaches. This retrospective study was conducted between November 2018 and June 2020, including 81 patients who underwent cortical bone trajectory (CBT) surgery for degenerative lumbar spine disease. CBT was performed by the same team of experienced surgeons. The patients were randomly divided into two groups-the fluoroscopy-assisted group (FA, 44 patients) and the robot-assisted group (RA, 37 patients). Robots for orthopedic surgery were used in the robot-assisted group, whereas conventional fluoroscopy-guided screw placement was used in the fluoroscopy-assisted group. The accuracy of screw placement and rate of superior facet joint violation were assessed using postoperative computed tomography (CT). The time of single screw placement, intraoperative blood loss, and radiation exposure to the surgical team were also recorded. The χ2 test and Student's t-test were used to analyze the significance of the variables (P < 0.05). A total of 376 screws were inserted in 81 patients, including 172 screws in the robot-assisted group and 204 pedicle screws in the fluoroscopy-assisted group. Screw placement accuracy was higher in the RA group (160, 93%) than in the FA group (169, 83%) (P = 0.003). The RA group had a lower violation of the superior facet joint than the FA group. The number of screws reaching grade 0 in the RA group (58, 78%) was more than that in the FA group (56, 64%) (P = 0.041). Screw placement time was longer in the FA group (7.25 ± 0.84 min) than in the RA group (5.58 ± 1.22 min, P < 0.001). The FA group had more intraoperative bleeding (273.41 ± 118.20 ml) than the RA group (248.65 ± 97.53 ml, P = 0.313). The radiation time of the FA group (0.43 ± 0.07 min) was longer than the RA group (0.37 ± 0.10 min, P = 0.001). Furthermore, the overall learning curve tended to decrease. Robot-assisted screw placement improves screw placement accuracy, shortens screw placement time, effectively improves surgical safety and efficiency, and reduces radiation exposure to the surgical team. In addition, the learning curve of robot-assisted screw placement is smooth and easy to operate.


Perceived stress, family impact, and changes in physical and social daily life activities of children with chronic somatic conditions during the COVID-19 pandemic.
The COVID-19 pandemic has inevitably affected children and their families. This study examines the impact of the COVID-19 measures in children with chronic somatic conditions (CSC) and their parents and compares them with a Dutch general population sample. We included a sample of children with CSC (0-18 years, n = 326) and compared them with children (8-18 years, n = 1,287) from the Dutch general population. Perceived stress, coping, social interaction with friends and family, physical activity, eating behavior, family support, parenting perception, and financial situation were assessed once with the self-reported and parent-reported COVID-19 child check questionnaire, between November 2020 and May 2021. Comparisons between the two samples were made by using t-tests and chi square tests. The proportion of children who reported being less physically active and having less social interaction with friends since the COVID-19 pandemic was higher in children with CSC than in children from the general population. Children with CSC and their parents experienced less stress than children and parents from the general population. Moreover, parents of children with CSC aged 0-7 years and parents of children aged 8-18 years from the general population experienced less support and more financial deterioration than parents of children with CSC aged 8-18 years. In the parents from the general population only, this deteriorated financial situation was associated with more stress, worse family interaction and parenting perception, and less received support. The impact of COVID-19 on children with CSC and their parents differed from those in the general population. Addressing the collateral damage of COVID-19 measures in children and their families may give direction to policy and potentially prevent lifelong impact.


Effects of infinite occurrence of hybrid impulses with quasi-synchronization of parameter mismatched neural networks.
This article is deeply concerned with the effects of hybrid impulses on quasi-synchronization of neural networks with mixed time-varying delays and parameter mismatches. Hybrid impulses allow synchronizing as well as desynchronizing impulses in one impulsive sequence, so their infinite time occurrence with the system may destroy the synchronization process. Therefore, the effective hybrid impulsive controller has been designed to deal with the difficulties in achieving the quasi-synchronization under the effects of hybrid impulses, which occur all the time, but their density of occurrence gradually decrease. In addition, the new concepts of average impulsive interval and average impulsive gain have been applied to cope with the simultaneous existence of synchronizing and desynchronizing impulses. Based on the Lyapunov method together with the extended comparison principle and the formula of variation of parameters for mixed time-varying delayed impulsive system, the delay-dependent sufficient criteria of quasi-synchronization have been derived for two separate cases, viz., Ta<∞ and Ta=∞. Finally, the efficiency of the theoretical results has been illustrated by providing two numerical examples.


Cytochalasin D-mediated hyperinduction of the substrate-associated 52-kilodalton protein p52 in rat kidney fibroblasts.
Regulation of certain differentiated and housekeeping functions in cultured mammalian cells is significantly influenced by cell shape. The shape-modulating agent cytochalasin D (CD) was used, therefore, to elucidate potential cytoarchitectural influences affecting synthesis of a major 52 kDa secreted/substrate-associated protein (p52) of normal rat kidney (NRK) fibroblasts. Biosynthetic labeling experiments indicated that treatment of NRK cells with CD increased, by 10-18-fold, the medium content of an Mr 52,000 protein. Two-dimensional gel electrophoresis and peptide fragment mapping confirmed that the 52 kDa protein produced in abundance as a consequence of CD treatment was identical to p52 constitutively expressed by NRK cells. A lower mw protein (p50; Mr 50,000) was also resolved which, based on pl microheterogeneity, protease fragmentation profile, and sensitivity to tunicamycin, could be identified as a less-glycosylated form of p52. p50 and p52 were both detected in the matrix and medium compartments of NRK and NRK/CD cells. The matrix p52 content of CD-induced and uninduced cells, however, was significantly greater (by 200-500-fold) than the corresponding medium levels. This differential compartmentalization, the time course of p52 accumulation in the matrix of NRK/CD cells compared to its appearance in the medium, and the kinetics of p52 pulse-chase from the matrix collectively indicated that the matrix is the initial site of p52 deposition. Low levels of CD (1 microM) produced extensive disruptions of cellular microfilaments but did not result in an overall cell shape change nor a hyperinduction of p52. Morphologic rounding (seen in 10-100 microM CD) coincided with augmented p52 production. Transition from a flat to a round phenotype in NRK cells, or at least the generation of sufficient microfilament fragmentation to compromise cell-substrate adhesivity, appears to be an essential aspect of CD-mediated p52 hyperinduction.


The complete mitochondrial genome of Tylonycteris fulvida (Chiroptera: Vespertilionidae) in South China.
The complete mitochondrial genome of Tylonycteris fulvida (Peters, 1872) was obtained using high-throughput sequencing technology. The genome is a circular molecule of 16,621 bp length, containing 13 protein-coding genes, 2 rRNA genes, 22 tRNA genes, and a control region. A phylogenetic tree of 13 protein-coding genes was constructed using IQ-TREE. Our result suggests that T. fulvida cluster within Chiroptera and Fereuungulata. The complete mitochondrial genome sequence of T. fulvida will be helpful for future taxonomic and phylogenetic studies on Chiroptera.


Stabilization of rat liver lysosomes by new anti-inflammatory steroids in vitro.
Steroid acid esters, synthesized by modifying the 17-ketol side chain of prednisolone, were tested for their in vitro ability to stabilize heavy mitochondrial lysosomes prepared from rat liver. Membrane stabilization was determined by assessing capability of steroids to decrease extrusion of the marker enzymes (acid phosphatase, beta-glucuronidase and aryl sulfatase) from lysosomes incubated in hypo-osmotic sucrose-Tris acetate buffer. Results indicated that prednisolone (1) significantly inhibited the lysosomal release of acid phosphatase as did the new anti-inflammatory steroid, methyl 20-dihydroprednisolonate. Methyl prednisolonate exhibited weak membrane stabilization capacities and 20-dihydroprednisolonic acid, a metabolic product of methyl 20-dihydroprednisolonate, showed virtually no membrane stabilization.


Off-pump coronary surgery may reduce stroke, respiratory failure, and mortality in octogenarians.
Octogenarians are a challenging group of patients referred for cardiac surgery. The aim of this study is to assess early outcomes of coronary artery bypass grafting (CABG) performed in the elderly population. We performed a meta-analysis of all published observational studies comparing early results of conventional CABG surgery and off-pump CABG surgery in patients aged 80 years or older. The outcomes of interest were mortality, stroke, respiratory failure, renal failure, incidence of support with intraaortic balloon pump, and incidence of postoperative atrial fibrillation. The random effects model was used. Fourteen studies were analyzed. The total number of included subjects was 4,991, of whom 3,113 underwent conventional CABG surgery (62.4%), and 1,878 (37.6%) underwent off-pump CABG surgery. The rates of mortality, stroke, and respiratory failure were significantly higher in the conventional CABG surgery group. These results confirm that off-pump CABG surgery remains a valuable option of surgical myocardial revascularization, and may optimize the outcome in senior patients.


Vaccination with a DNA vaccine encoding CD317-targeting HBs antigen elicits enhanced immunity in mice.
Conventional hepatitis B virus (HBV) vaccines fail to induce protective antibody titers in 5-10% of immune-competent vaccines. Therefore, safe and effective HBV vaccines are still clinically needed. In this study, we developed a plasmid DNA vaccine encoding CD317 single-chain fragment variable (α317scFv) linked with the hepatitis B surface antigen (HBsAg) and detected the humoral and cellular immune responses elicited by this vaccine in BALB/c mice. Vaccination with this fusion DNA vaccine in BALB/c mice induced more robust antiviral T cell and antibody immunity against HBsAg. Compared with mice vaccinated with control vaccine encoding HBsAg, the level of serum-circulating anti-HBsAg antibody (HBsAb) was nearly double in fusion DNA-vaccinated mice. More interesting, splenic lymphocytes isolated from fusion DNA-vaccinated mice showed more potent proliferation and IFN-γ production after being re-stimulated with recombinant HBsAg in vitro. And not only that, the cytotoxicity of fusion DNA vaccine-sensitized splenocytes was ∼3-fold higher than that of controls. Taken together, our results reveal that the fusion DNA vaccine can induce more effective immunological protection against HBV, and is a promising candidate for preventing HBV infection.


Intraocular Teratoid Medulloepithelioma Presenting With a Completely Rhabdomyosarcomatous Distant Metastasis.
Medulloepithelioma is the second most common primary neuroepithelial tumor of the eye. The full range of its morphologic expressions and appearances in metastases have not been fully explored. A patient in her 50s with glaucoma for decades had undergone multiple filtering surgical procedures, including the placement of a glaucoma drainage device. A paraspinal mass was discovered, and tumor and bone marrow biopsies disclosed rhabdomyosarcoma. This led to the discovery of a multicystic intraocular tumor. A metastatic rhabdomyosarcoma to the eye was considered unlikely because, to our knowledge, this event had never been reported. An enucleation was performed, and an intraocular tumor composed almost entirely of rhabdomyoblasts (desmin- and myogenin-positive) was discovered along with rare clusters of persistent neuroepithelial cells. To our knowledge, this is the first case of a medulloepithelioma in which teratoid rhabdomyoblasts effaced all but trace amounts of neuroepithelium and generated a distant metastasis entirely composed of rhabdomyoblasts. The prolonged history and filtering procedures probably led to these 2 phenomena.


Simplifying soft tissue closure of the large meningomyelocele defect: a technical note.
The surgical management of large neural tube defects not amenable to primary closure poses a significant challenge. As a result, large residual skin defects often prompt excessively aggressive primary closure, complicated skin incisions, or flap advancements. However, our experience with the purse-string closure of a large meningomyelocele skin defect demonstrates that this technique can effectively provide coverage of very large meningomyelocele defects with minimal residual deformity. Here, we discuss the successful coverage of a large 5 x 5 cm meningomyelocele skin wound via staged purse-string closure spaced 2 weeks apart.


A method for sample size calculation via E-value in the planning of observational studies.
Confounding adjustment plays a key role in designing observational studies such as cross-sectional studies, case-control studies, and cohort studies. In this article, we propose a simple method for sample size calculation in observational research in the presence of confounding. The method is motivated by the notion of E-value, using some bounding factor to quantify the impact of confounders on the effect size. The method can be applied to calculate the needed sample size in observational research when the outcome variable is binary, continuous, or time-to-event. The method can be implemented straightforwardly using existing commercial software such as the PASS software. We demonstrate the performance of the proposed method through numerical examples, simulation studies, and a real application, which show that the proposed method is conservative in providing a slightly bigger sample size than what it needs to achieve a given power.


A Randomised Controlled Trial to Reduce Sedentary Time in Young Adults at Risk of Type 2 Diabetes Mellitus: Project STAND (Sedentary Time ANd Diabetes).
Type 2 diabetes mellitus (T2DM), a serious and prevalent chronic disease, is traditionally associated with older age. However, due to the rising rates of obesity and sedentary lifestyles, it is increasingly being diagnosed in the younger population. Sedentary (sitting) behaviour has been shown to be associated with greater risk of cardio-metabolic health outcomes, including T2DM. Little is known about effective interventions to reduce sedentary behaviour in younger adults at risk of T2DM. We aimed to investigate, through a randomised controlled trial (RCT) design, whether a group-based structured education workshop focused on sitting reduction, with self-monitoring, reduced sitting time. Adults aged 18-40 years who were either overweight (with an additional risk factor for T2DM) or obese were recruited for the Sedentary Time ANd Diabetes (STAND) RCT. The intervention programme comprised of a 3-hour group-based structured education workshop, use of a self-monitoring tool, and follow-up motivational phone call. Data were collected at three time points: baseline, 3 and 12 months after baseline. The primary outcome measure was accelerometer-assessed sedentary behaviour after 12 months. Secondary outcomes included other objective (activPAL) and self-reported measures of sedentary behaviour and physical activity, and biochemical, anthropometric, and psycho-social variables. 187 individuals (69% female; mean age 33 years; mean BMI 35 kg/m2) were randomised to intervention and control groups. 12 month data, when analysed using intention-to-treat analysis (ITT) and per-protocol analyses, showed no significant difference in the primary outcome variable, nor in the majority of the secondary outcome measures. A structured education intervention designed to reduce sitting in young adults at risk of T2DM was not successful in changing behaviour at 12 months. Lack of change may be due to the brief nature of such an intervention and lack of focus on environmental change. Moreover, some participants reported a focus on physical activity rather than reductions in sitting per se. The habitual nature of sedentary behaviour means that behaviour change is challenging. Controlled-Trials.com ISRCTN08434554.