A multi-sample approach increases the accuracy of transcript assembly.
Transcript assembly from RNA-seq reads is a critical step in gene expression and subsequent functional analyses. Here we present PsiCLASS, an accurate and efficient transcript assembler based on an approach that simultaneously analyzes multiple RNA-seq samples. PsiCLASS combines mixture statistical models for exonic feature selection across multiple samples with splice graph based dynamic programming algorithms and a weighted voting scheme for transcript selection. PsiCLASS achieves significantly better sensitivity-precision tradeoff, and renders precision up to 2-3 fold higher than the StringTie system and Scallop plus TACO, the two best current approaches. PsiCLASS is efficient and scalable, assembling 667 GEUVADIS samples in 9 h, and has robust accuracy with large numbers of samples.


Comparative evaluation of Tell-Show-Do technique and its modifications in managing anxious pediatric dental patients among 4-8 years of age.
Dentistry has made a remarkable progress in techniques, materials and technologies, however the anxiety of the child related to dental treatment still remains constant. Tell Show Do is the most common technique behaviour management of the child in the dental clinic since many years. Recently, many modifications of Tell Show Do technique have been researched and most of them provided an enhanced potential for the conventional technique research but were always individually compared to conventional technique. To evaluate the effectiveness of Tell Show Do technique in comparison with its 4 modifications Tell Play Do, Tell Play Do with Smart Phone Dentist Game, Tell Show Play Doh, Ask Tell Ask among 4-8 years old children during restorative treatment. 150 children aged 4-8 years were randomly selected divided into 5 groups comprising of 30 patients each. Evaluation of anxiety was done using Physiologic-Pulse Rate, Facial Image Scale and Venham's Anxiety Scale. Except for Ask Tell Ask Group the anxiety level of the subjects decreased in all groups according to physiologic readings and facial image score. Anxiety Score decreased preoperatively to postoperatively in all groups except for Tell Play Do and Ask Tell Ask group according to venhams anxiety scale. Although Tell Show Do technique is most widely accepted and modified technique, due to changing scenarios of today's children Tell Play Do, Tell Play Do with Smart Phone Dentist Game and Tell Show Play Doh are also showing encouraging results.


The heterogeneity of target recognition by lymphokine-activated killer precursor cells.
Lymphokine-activated killer (LAK) cells were generated from peripheral blood lymphocytes (PBL) that were depleted of mature cytotoxic natural killer (NK) cells. PBL NK activity was abolished by pretreatment of effector cells with the toxic lysosomotropic agent L-leucine methyl ester (LME) or by depletion of effector cells by K562 monolayer absorption (MA). Both treatments markedly reduced the proportion of cells expressing NK-associated markers such as CD 16 (Leu 11b, B73.1), Leu 7, and NKH-1 (Leu 19), whereas these treatments had minimal effects on cells expressing T cell markers (CD 3, CD 4, and CD 8). LME and MA also drastically decreased the proportion of K562 target-binding lymphocytes. LAK activity against NK-sensitive and NK-resistant targets can be generated from the NK cell-depleted PBL by incubation with interleukin-2. Peak LAK activity generated from MA-treated PBL was later than the peak of LAK activity generated from either untreated or LME-treated PBL. Although MA of PBL on NK-resistant S4 sarcoma targets had little effect on NK activity, LAK activity against both K562 and S4 targets was reduced. These results suggest that there are at least three LAK precursor subpopulations in PBL: mature NK cells that can bind and kill K562 targets (LME-sensitive and MA-sensitive); "pre-NK" cells that can bind but cannot kill (LME-resistant and MA-sensitive); and non-NK cells that cannot bind and cannot kill K562 targets (MA-resistant).


Long-term outcome and survival with laparoscopy-assisted pylorus-preserving gastrectomy for early gastric cancer.
Laparoscopically assisted pylorus-preserving gastrectomy (LAPPG) is introduced as a function-preserving operation with minimal invasion for early gastric cancer (EGC). This study aimed to investigate the long-term outcome and survival with LAPPG. From January 2005 to July 2008, 188 patients with EGC underwent LAPPG. The surgical and long-term outcomes and survival were assessed retrospectively. The accuracy of the preoperative EGC diagnosis was 92.6%. The median follow-up period was 38 months (range, 2-63 months). Two patients experienced gallstones, and three patients experienced a second primary EGC. One patient with T3N0 gastric cancer died of peritoneal metastasis, and four patients died of other causes. The overall 3-year survival rate was 97.8%, and the disease-specific 3-year survival rate was 99.3%. The LAPPG procedure is safe in terms of satisfactory long-term outcome and survival for patients with EGC in the middle third of the stomach.


Efficacy of famotidine 20 mg twice a day versus 40 mg twice a day in the treatment of erosive or ulcerative reflux esophagitis.
Two different doses of famotidine (20 mg twice a day versus 40 mg twice a day) were evaluated in a double-blind, randomized multicenter study in 474 symptomatic patients with erosive ulcerative reflux esophagitis. A total of 238 patients were treated with famotidine 20 mg and 236 patients with 40 mg at breakfast and dinner-time. Relief of symptoms was significant in all patients after six and 12 weeks and not different in both treatment groups. Overall endoscopic healing was significantly better in the famotidine 40 mg twice a day group compared with 20 mg twice a day at week 6 (58% versus 43%; P < 0.05) and at week 12 (76% versus 67%; P < 0.05). Extending treatment to 24 weeks with 40 mg of famotidine twice a day in those patients not healed after 12 weeks did not result in further symptom relief or in significantly better overall healing. The differences in efficacy of these two doses were more pronounced with increasing severity of esophagitis. Analyzed by grade of esophagitis at entrance, healing was significantly better with famotidine 40 mg twice a day at week 6 for grade II, at week 12 for grades III and IV, and at week 24 for grade IV esophagitis. The results show that in the treatment of erosive/ulcerative reflux patients famotidine 40 mg twice a day is more effective and achieves faster healing than famotidine 20 mg twice a day.


Plastic responses of larval mass and alkaline phosphatase to cadmium in the gypsy moth larvae.
Biochemical analyses can point to toxicant presence before its effects can be detected at higher organizational levels. We investigated responses of larval mass and alkaline phosphatase (ALP) to different cadmium treatments in 4th instar gypsy moth larvae from 20 full-sib families. Changes in trait values and trait plasticities as well as their variation were monitored after acute and chronic exposure or recovery from two cadmium concentrations (Cd(1)=10microg and Cd(2)=30microg Cd/g dry food). Larval mass only decreased, without returning to the control level at recovery stage following chronic cadmium challenge. Acute stress did not change trait value but increased genetic variance of larval mass. Significant ALP activity changes, sensitivity of isozyme patterns (Mr of 60, 64, and 85kDa) and increased variation in ALP plasticity during acute exposure to cadmium point to its possible aplication as an exposure biomarker.


[Prevention and care for obese children and adolescents in Germany: quality and eficiencies of programs and interventions].
The Hamburg University Hospital (UKE), together with the German Federal Centre for Health Education (BZgA), conducted a nationwide screening of obesity-related care. The screening was composed of two stages: Firstly, a short questionnaire of 150 items was developed and validated by experts. It comprised 14 summary criteria, derived from obesity care guidelines. The most important aspects of the providers' services were surveyed. This resulted in a description of intervention quality in 492 institutions or programs on a national level, controlled for representativity, and analyses of quality in specific institutional types. Secondly, a sample of 38 interventions was selected, using cluster analysis, and assessed in depth by means of the quality assurance system QIP (Quality in Prevention), extended to include obesity-related criteria from medical guidelines. The main results of the survey were as follows: Only 51.4 % of the guideline-based quality criteria were met by an average program. The costs of the various programs differed vastly but predicted the intervention quality only to a moderate degree. Two thirds of the programs were offered by outpatient care institutions. The screening documented that there was a lack of setting-related projects. On the basis of the findings, a registration system for projects and programs, based upon evidence-based quality criteria, is proposed. Furthermore, outpatient services and projects should be strengthened, and setting-based interventions should be developed, enhanced by a national strategy of obesity prevention on several policy levels, according to WHO recommendations.


Ethnic differences in dentofacial relationships of Turkish and Saudi young adults with normal occlusions and well-balanced faces.
The aims of the present study were (1) to determine ethnic differences in craniofacial dimensions between Turkish and Saudi populations and (2) to identify possible gender differences between males and females, based on a sample of untreated young adult subjects with normal occlusions and well-balanced faces. In total, 163 cephalometric radiographs were traced and evaluated to compare untreated adults of Turkish and Saudi ethnicity. The Turkish group comprised 86 subjects; 45 females and 41 males. The Saudi group comprised 77 subjects; 39 females and 38 males. For statistical evaluation, an independent-samples t-test was performed. The Turkish sample had a more retrognathic maxilla and mandible (p < 0.001 for SNA and SNB) and a more vertical direction of facial development (p < 0.001), with Turkish males having more retrusive lips (p < 0.001). Distinctive ethnic differences were found in craniofacial structures between Turkish and Saudi young adults. It is appropriate to consider these aesthetic differences when a Turkish or a Saudi patient is being evaluated during routine diagnosis and treatment planning.


Pulmonary surfactant inhibits LPS-induced nitric oxide production by alveolar macrophages.
The objectives of this investigation were 1) to report that pulmonary surfactant inhibits lipopolysaccharide (LPS)-induced nitric oxide (. NO) production by rat alveolar macrophages, 2) to study possible mechanisms for this effect, and 3) to determine which surfactant component(s) is responsible. NO produced by the cells in response to LPS is due to an inducible. NO synthase (iNOS). Surfactant inhibits LPS-induced. NO formation in a concentration-dependent manner;. NO production is inhibited by approximately 50 and approximately 75% at surfactant levels of 100 and 200 microg phospholipid/ml, respectively. The inhibition is not due to surfactant interference with the interaction of LPS with the cells or to disruption of the formation of iNOS mRNA. Also, surfactant does not seem to reduce. NO formation by directly affecting iNOS activity or by acting as an antioxidant or radical scavenger. However, in the presence of surfactant, there is an approximately 80% reduction in the amount of LPS-induced iNOS protein in the cells. LPS-induced. NO production is inhibited by Survanta, a surfactant preparation used in replacement therapy, as well as by natural surfactant. NO formation is not affected by the major lipid components of surfactant or by two surfactant-associated proteins, surfactant protein (SP) A or SP-C. However, the hydrophobic SP-B inhibits. NO formation in a concentration-dependent manner;. NO production is inhibited by approximately 50 and approximately 90% at SP-B levels of 1-2 and 10 microgram/ml, respectively. These results show that lung surfactant inhibits LPS-induced. NO production by alveolar macrophages, that the effect is due to a reduction in iNOS protein levels, and that the surfactant component responsible for the reduction is SP-B.


Cerebral Venous Thrombosis After Unintentional Dural Puncture: Raising awareness for an uncommon cause of postpartum headache.
Headache is a common symptom in the postpartum period, which can have a varied aetiology. Although rare, cerebral venous thrombosis can be a fatal complication in the parturient. Dural puncture is considered as one of the risk factors for cerebral venous thrombosis and the proposed mechanism pathogenesis can be explained by the components of Virchow's triad: stasis of the blood, hypercoagulability, and endothelial damage. Headache is usually the most frequent symptom and can mimic those of postdural puncture headache, which can delay the diagnosis. We will report a case of an 18-year-old woman that develops a postpartum headache after an accidental dural puncture during epidural catheter placement for labour analgesia. Our patient was initially managed for postdural puncture headache, but later the character changed, which made us look for a differential diagnosis. After a multidisciplinary approach, neuroimaging confirmed the diagnosis of cerebral venous thrombosis. This case report emphasises the importance of a careful differential diagnosis of postpartum headache particularly if the headache persists or changes its character. Brain imaging and multidisciplinary evaluation can lead to prompt diagnosis and initiation of appropriate treatment.


The Effect of Glutathione Deficit During Early Postnatal Brain Development on the Prepulse Inhibition and Monoamine Levels in Brain Structures of Adult Sprague-Dawley Rats.
Recent studies suggest that impaired glutathione synthesis and distorted dopaminergic transmission are important factors in the pathophysiology of schizophrenia. In the present study, on the postnatal days p5-p16, male pups were treated with the inhibitor of glutathione synthesis, L-buthionine-(S,R)- sulfoximine (BSO, 3.8 or 7.6 mmol/kg), and the dopamine uptake inhibitor, GBR 12,909 (5 mg/kg) alone or in combination, and prepulse inhibition of the acoustic startle response (PPI) was evaluated in adult 90-day-old rats. Moreover, the monoamine levels in the cortex and hippocampus of 16-day-old rats or 91-day-old rats were measured. The present results showed that administration of BSO at 3.8 mmol/kg led to a decreasing tendency in PPI for all tested prepulse intensities. In contrast, a combined treatment with BSO in both studied doses and GBR 12,909 did not induce significant deficits in PPI. Moreover, the results of biochemical studies indicated that treatment with BSO or GBR 12,909 alone induced a weak increase in the activity of dopaminergic, serotonergic, and noradrenergic systems in the frontal cortex and hippocampus of 16-day-old rats and 91-day-old rats. However, the combined administration of both substances allowed for maintaining the normal activity of monoaminergic systems in the rat brain. The most significant changes in the functioning of monoaminergic systems were observed in the frontal cortex of 16-day-old rats. Therefore, it seems that the frontal cortex of rat puppies is most sensitive to glutathione deficiencies resulting in increased oxidative stress in neurons. As a result, it can lead to cognitive and memory impairment.


Personalized prediction of optimal water intake in adult population by blended use of machine learning and clinical data.
Growing evidence suggests that sustained concentrated urine contributes to chronic metabolic and kidney diseases. Recent results indicate that a daily urinary concentration of 500 mOsm/kg reflects optimal hydration. This study aims at providing personalized advice for daily water intake considering personal intrinsic (age, sex, height, weight) and extrinsic (food and fluid intakes) characteristics to achieve a target urine osmolality (UOsm) of 500 mOsm/kg using machine learning and optimization algorithms. Data from clinical trials on hydration (four randomized and three non-randomized trials) were analyzed. Several machine learning methods were tested to predict UOsm. The predictive performance of the developed algorithm was evaluated against current dietary guidelines. Features linked to urine production and fluid consumption were listed among the most important features with relative importance values ranging from 0.10 to 0.95. XGBoost appeared the most performing approach (Mean Absolute Error (MAE) = 124.99) to predict UOsm. The developed algorithm exhibited the highest overall correct classification rate (85.5%) versus that of dietary guidelines (77.8%). This machine learning application provides personalized advice for daily water intake to achieve optimal hydration and may be considered as a primary prevention tool to counteract the increased incidence of chronic metabolic and kidney diseases.


Do antihypertensive medications have an effect on dental implants? A systematic review.
The purpose of this systematic review was to compare the clinical outcomes of dental implants in users of antihypertensive medication with those of nonusers. This systematic review followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and was registered in the International Prospective Register of Systematic Reviews under the number CRD42022319336. The electronic databases Medline (PubMed) and Central Cochrane were searched for relevant scientific literature published in English through May 2022. The focused question was, "Do patients taking antihypertensive medications have a similar impact on the clinical outcome and survival of dental implants compared with nonusers?". A total of 49 articles were found, of which 3 articles were finally selected for a qualitative synthesis. The three studies included 959 patients. In all three studies, the commonly used medication was renin-angiotensin system (RAS) inhibitors. Two studies mentioned implant survival rate, which was 99.4% in antihypertensive medication users and 96.1% in the nonusers. One study found a higher implant stability quotient (ISQ) in patients taking antihypertensive medication (75.7 ± 5.9) compared with patients not taking antihypertensive medication (73.7 ± 8.1). The limited available evidence showed that patient taking antihypertensive medications had comparable success rate and implant stability to patients not taking medications. The studies included patients taking different antihypertensive medications, so a drug-specific conclusion regarding the clinical outcome of dental implants is not possible. Further studies are needed, including patients taking certain antihypertensive medications, to determine their effects on dental implants.


Immunohistochemical localization of the inositol 1,4,5-trisphosphate receptor in the human nervous system.
A monoclonal antibody raised against the mouse cerebellar inositol trisphosphate receptor was used to study the immunohistochemical localization of this protein in the human central nervous system. As in the brain of rodents, strong immunoreactivity was found in dendrites, axon and cell bodies of Purkinje cells, as well as in nerve endings in the cerebellar and vestibular nuclei. Cerebellar efferent fibres were the only positive structures demonstrated in the brainstem and no immunostaining could be detected in the spinal cord or dorsal root ganglia. By contrast, numerous immunoreactive neurons were present in several telencephalic and diencephalic structures, including the brain cortex, hippocampus, basal ganglia, basal forebrain, amygdala and thalamus. Immunostaining of these brain neurons was weaker than that found in Purkinje cells and was evident in cell bodies and dendrites. Thus, the human brain contains a molecule cross-reacting with the mouse inositol trisphosphate receptor protein that is expressed in a pattern similar to that found in rodents. These findings can be of great importance for understanding the function of this protein in normal brain and its modifications in neuropathological disorders.


Morphological identification and molecular characterization of economically important ticks (Acari: Ixodidae) from North and North-Western Egypt.
Ticks represent a major source of growing economic and public health concern, especially in the tropics and sub-tropics. Towards evidencing ticks' invasion in the North and North-Western parts of Egypt, the present study aimed to investigate the morpho-molecular aspects of those ectoparasites using stereomicroscopy, scanning electron microscopy (SEM) and sequencing of the mitochondrial 16S ribosomal DNA gene (rDNA) and nuclear second internal transcribed spacer (ITS2). Our analysis confirmed the presence and well-distribution of Rhipicephalus sanguineus s.l. infesting dogs and sheep (Alexandria governorate), Rhipicephalus annulatus infesting cattle (Beheira governorate), and Hyalomma dromedarii infesting camels (Marsa Matruh governorate) from North/North-Western Egypt. 16S rDNA and ITS2 sequences of the ticks were amplified using universal and gene-specific sets of primers, sequenced and analyzed. Lengths of amplified 16S rDNA sequences in all examined tick species were found to be similar in size (approximately 460 bp); however, they differed in base pair constitutions, whereas ITS2 lengths were 1,500 bp, 1,550 bp, and 1,800 bp for Rh. annulatus, Rh. sanguineus s.l., and Hy. dromedarii, respectively. Phylogenetically, based on the 16S rDNA results, Rh. sanguineus s.l. ticks clustered with the southeastern Europe lineage from Romania and Greece, Rh. annulatus ticks were similar to Turkish populations, and Hy. dromedarii were close to the isolates from Tunisia. Similarly, based on ITS2 sequences, Rh. sanguineus s.l. from dogs were showing 99% similarity to Nigerian populations; however, those collected from sheep were closer to Iranian populations with 4.1% nucleotide divergence between the two populations of different hosts. Rh. annulatus ticks were identical to a population from Romania, whereas Hy. dromedarii was close by 99.7% similarity to a population from Kenya. This is the first study reporting nucleotide sequences of 16S rDNA and ITS2 in integration with morphological identification of ticks from this part of Egypt.


Impact of Coronavirus Disease 2019 on Hospital Admissions, Health Status, and Behavioral Changes of Patients with COPD.
Patients with chronic obstructive pulmonary disease (COPD) have an increased risk of acquiring severe coronavirus disease 2019 (COVID-19), which is why self-isolation was recommended. However, long periods of social isolation, accompanied by limited access to health care systems, might influence the outcome of patients with severe COPD negatively. Data from COPD and pneumonia patients at Charité-Universitätsmedizin Berlin and the volume of endoscopic lung volume reduction (ELVR) surgeries from the German Lung Emphysema Registry (Lungenemphysem Register e.V.) were analyzed from pre-pandemic (2012 to 2019) to the pandemic period (2020 and 2021). In addition, 52 patients with COPD Global initiative for chronic Obstructive Lung Disease (GOLD) stage 4 status included in the lung emphysema registry received questionnaires during lockdowns from June 2020 to April 2021. Admissions and ventilation therapies administered to COPD patients significantly decreased during the COVID-19 pandemic. Likewise, there was a reduction in ELVR treatments and follow-ups registered in German emphysema centers. Mortality was slightly higher among patients hospitalized with COPD during the pandemic. Increasing proportions of COPD patients with GOLD stage 3 and GOLD stage 4 status reported behavioral changes and subjective feelings of increasing COPD symptoms the longer the lockdown lasted. However, COPD symptom questionnaires revealed stable COPD symptoms over the pandemic time period. This study reveals reduced COPD admissions and elective treatment procedures of COPD patients during the pandemic, but a slight increase in mortality among patients hospitalized with COPD, irrespective of COVID-19. Correspondingly, patients with severe COPD reported subjective deterioration of their health status, probably caused by their very strict compliance with lockdown measures.


Oncogenic transformation of human benign prostate hyperplasia with chronic cadmium exposure.
Experimentally, it has been proved that cadmium served as an effective carcinogen and able to induce tumors in rodents in a dose-specific manner. However, systemic evaluation of cadmium exposure for the transformation of prostatic hyperplasia into prostate cancer (PCa) is still unclear. In the present study, an attempt has been made to establish cadmium-induced human prostate carcinogenesis using an in vitro model of BPH cells. Wide range of cadmium concentrations, i.e., 1 nM, 10 nM, 100 nM and 1μM, were chronically exposed to the human BPH cells for transformation into PCa and monitored using cell and molecular biology approaches. After eight weeks of exposure, the cells showed subtle morphological changes and shifts of cell cycle in the G2M phase. Significant increase in expression of prostatic genes AR, PSA, ER-β, and 5αR with increased nuclear localization of AR and pluripotency markers Cmyc, Klf4 indicated the carcinogenic effect of Cd. Further, the BPH cells exposed to Cd showed a substantial increase in the secretion of MMP-2 and MMP-9, influencing migratory potential of the cells along with decreased expression of the p63 protein which further strengthen the progression towards carcinogenesis and aggressive tumor studies. Data from the present study state that Cd exhibited marked invasiveness in BPH cells. These observations established a connecting link of BPH towards PCa pathogenesis. Further, the study will also help in investigating the intricate pathways involved in cancer progression.


Rapid detection and quantification of triacylglycerol by HPLC-ELSD in Chlamydomonas reinhardtii and Chlorella strains.
Triacylglycerol (TAG) analysis and quantification are commonly performed by first obtaining a purified TAG fraction from a total neutral lipid extract using thin-layer chromatography (TLC), and then analyzing the fatty acid composition of the purified TAG fraction by gas chromatography (GC). This process is time-consuming, labor intensive and is not suitable for analysis of small sample sizes or large numbers. A rapid and efficient method for monitoring oil accumulation in algae using high performance liquid chromatography for separation of all lipid classes combined with detection by evaporative light scattering (HPLC-ELSD) was developed and compared to the conventional TLC/GC method. TAG accumulation in two Chlamydomonas reinhardtii (21 gr and CC503) and three Chlorella strains (UTEX 1230, CS01 and UTEX 2229) grown under conditions of nitrogen depletion was measured. The TAG levels were found to be 3-6 % DW (Chlamydomonas strains) and 7-12 % DW (Chlorella strains) respectively by both HPLC-ELSD and TLC/GC methods. HPLC-ELSD resolved the major lipid classes such as carotenoids, TAG, diacylglycerol (DAG), free fatty acids, phospholipids, and galactolipids in a 15-min run. Quantitation of TAG content was based on comparison to calibration curves of trihexadecanoin (16:0 TAG) and trioctadecadienoin (18:2 TAG) and showed linearity from 0.2 to 10 μg. Algal TAG levels >0.5 μg/g DW were detectable by this method. Furthermore TAG content in Chlorella kessleri UTEX 2229 could be detected. TAG as well as DAG and TAG content were estimated at 1.6 % DW by HPLC-ELSD, while it was undetectable by TLC/GC method.


A phase I/II study of decitabine in combination with panitumumab in patients with wild-type (wt) KRAS metastatic colorectal cancer.
KRAS mutations are predictive of lack of response to monoclonal antibodies (mAb) against EGFR in metastatic colorectal cancer (mCRC). Most wild-type KRAS patients, however, are also resistant. Retrospective data suggest that EGFR silencing play a role in resistance to therapy. We conducted a study to evaluate the safety and efficacy of decitabine (a hypomethylating agent) in combination with panitumumab (mAb against EGFR) in mCRC patients. 20 patients with wild-type KRAS mCRC were included in this phase I/II study. Patients were treated with decitabine at 45 mg/m(2) IV over 2 h on day 1 and 15 and panitumumab 6 mg/kg IV over 1 h on day 8 and 22 every 28 days. Blood samples were collected at baseline, day 8, 15 and 22. Quantitative polymerase chain reaction was used to measure promoter-specific methylation in peripheral-blood cells (PBMCs). The most common adverse events were grade 1-2 (rash and hypomagnesemia); 3 (16 %) patients had grade III-IV neutropenia including one patient with neutropenic fever. Two of 20 patients (10 %) had a partial response. Both had previously received cetuximab. Ten patients had stable disease (3 of them longer than 16 weeks). Decreased methylation of the MAGE promoter was not evidenced in PBMCs. The combination of decitabine and panitumumab was well tolerated and showed activity in wild-type KRAS mCRC patients previously treated with cetuximab. Target modulation in surrogate tissues was not achieved and tumor biopsies were not available. Future studies evaluating hypomethylating agents in combination with EGFR mAb in patients with mCRC are warranted.


Dynamic changes of apoptosis and expression of Bcl-2 family members in the posthatch hippocampus of Bengalese finches.
The hippocampus of songbirds plays an important role in spatial memory, and probably in song learning. Although prolonged neuronal generation and apoptosis are thought to be closely correlated with memory function, natural changes of the number of neurons and in apoptosis in the hippocampus of songbirds have not been fully investigated during development and in the adult. In the current study, we examined developmental changes in the volume and the number of neurons and apoptotic cells in the hippocampus of songbirds (Lonchura striata) from posthatch day (P5) to adulthood. Apoptotic cells were determined by Nissl staining and immunohistochemistry for cleaved caspase-3, a key apoptotic caspase executioner. The expression levels of Bcl-2 family member mRNA and protein, including Bcl-2, Bcl-xL and Bax, were also investigated. Our results indicated that: (1) the hippocampus volume significantly increased from P5 to P60, although the number of neurons remained stable in all studied stages; (2) the number of apoptotic cells was highest at P45, based either on the Nissl staining or on the immunohistochemistry for caspase-3; (3) Bcl-2 mRNA expression was high from P5 to adulthood, while Bax mRNA declined abruptly from P5 to adulthood, and Bcl-x mRNA was high after P45. Bcl-2 protein was only detected at P5 and P15, while detection of Bcl-xL and Bax proteins paralleled levels of mRNA expression. Our study provides detailed changes of apoptosis in the posthatch songbird hippocampus, suggesting an important role for caspase-3 and Bcl-2 family members in hippocampus apoptosis.


Differences in protonation of ubiquinone and menaquinone in fumarate reductase from Escherichia coli.
Escherichia coli quinol-fumarate reductase operates with both natural quinones, ubiquinone (UQ) and menaquinone (MQ), at a single quinone binding site. We have utilized a combination of mutagenesis, kinetic, EPR, and Fourier transform infrared methods to study the role of two residues, Lys-B228 and Glu-C29, at the quinol-fumarate reductase quinone binding site in reactions with MQ and UQ. The data demonstrate that Lys-B228 provides a strong hydrogen bond to MQ and is essential for reactions with both quinone types. Substitution of Glu-C29 with Leu and Phe caused a dramatic decrease in enzymatic reactions with MQ in agreement with previous studies, however, the succinate-UQ reductase reaction remains unaffected. Elimination of a negative charge in Glu-C29 mutant enzymes resulted in significantly increased stabilization of both UQ-* and MQ-* semiquinones. The data presented here suggest similar hydrogen bonding of the C1 carbonyl of both MQ and UQ, whereas there is different hydrogen bonding for their C4 carbonyls. The differences are shown by a single point mutation of Glu-C29, which transforms the enzyme from one that is predominantly a menaquinol-fumarate reductase to one that is essentially only functional as a succinate-ubiquinone reductase. These findings represent an example of how enzymes that are designed to accommodate either UQ or MQ at a single Q binding site may nevertheless develop sufficient plasticity at the binding pocket to react differently with MQ and UQ.


Comparative Study of the Levels of IL-1β, IL-4, IL-8, TNFα, and IFNγ in Stable Course and Exacerbation of Chronic Obstructive Pulmonary Disease of Varying Severity.
In patients with chronic obstructive pulmonary disease, the levels of cytokines IL-1β, IL-4, IL-8, TNFα, and IFNγ depended on the degree of bronchial obstruction and severity and period of the disease. The maximum levels of IL-4, IL-8, and TNFα were observed in severe chronic obstructive pulmonary disease during exacerbation. The highest concentration of IL-1β and IFNγ were recorded during activation of inflammation in patients with moderate bronchial obstruction. The revealed correlations between the tested cytokines and spirometry parameters make it possible to consider the levels of these proteins as quantitative markers of systemic inflammation progression.


Culturability and concentration of indoor and outdoor airborne fungi in six single-family homes.
In this study, the culturability of indoor and outdoor airborne fungi was determined through long-term sampling (24-h) using a Button Personal Inhalable Aerosol Sampler. The air samples were collected during three seasons in six Cincinnati area homes that were free from moisture damage or visible mold. Cultivation and total microscopic enumeration methods were employed for the sample analysis. The geometric means of indoor and outdoor culturable fungal concentrations were 88 and 102 colony-forming units (CFU) m(-3), respectively, with a geometric mean of the I/O ratio equal to 0.66. Overall, 26 genera of culturable fungi were recovered from the indoor and outdoor samples. For total fungal spores, the indoor and outdoor geometric means were 211 and 605 spores m(-3), respectively, with a geometric mean of I/O ratio equal to 0.32. The identification revealed 37 fungal genera from indoor and outdoor samples based on the total spore analysis. Indoor and outdoor concentrations of culturable and total fungal spores showed significant correlations (r = 0.655, p<0.0001 and r = 0.633, p<0.0001, respectively). The indoor and outdoor median viabilities of fungi were 55% and 25%, respectively, which indicates that indoor environment provides more favorable survival conditions for the aerosolized fungi. Among the seasons, the highest indoor and outdoor culturability of fungi was observed in the fall. Cladosporium had a highest median value of culturability (38% and 33% for indoor and outdoor, respectively) followed by Aspergillus/Penicillium (9% and 2%) among predominant genera of fungi. Increased culturability of fungi inside the homes may have important implications because of the potential increase in the release of allergens from viable spores and pathogenicity of viable fungi on immunocompromised individuals.


The role of Notch signaling in bone development and disease.
During the last decade a considerable amount of data have been accumulated regarding the role of intracellular signaling pathways in the pathogenesis of human diseases. One of these, Notch signaling, well known for its significance in cellular development and tissue morphogenesis, has been increasingly recognized as a crucial participant in the pathogenetic mechanisms underlying certain skeletal disorders. A better understanding of the biology and regulation of this multifaceted pathway is considered an important step towards clarification of the pathogenesis of various skeletal diseases and the development of novel targets for therapeutic purposes.


Selection during cefepime treatment of a new cephalosporinase variant with extended-spectrum resistance to cefepime in an Enterobacter aerogenes clinical isolate.
Enterobacter aerogenes resistant to cefepime (MIC, 32 microg/ml) was isolated from a patient treated with cefepime for an infection caused by a strain of E. aerogenes overproducing its AmpC beta-lactamase (MIC of cefepime, 0.5 microg/ml). The AmpC beta-lactamase of the resistant strain had an L-293-P amino acid substitution and a high k(cat)/K(m) ratio for cefepime. Both of these modifications were necessary for resistance to cefepime.


The novel HLA-B*55:131 allele, identified by Sanger dideoxy nucleotide sequencing in a Chinese individual.
HLA-B*55:131 differs from HLA-B*55:02:01:01 by one nucleotide in exon 4.


Parent abuse by adolescents with first-episode psychosis in Egypt.
To determine the rate of parent abuse in a sample of Egyptian adolescents with first-episode psychosis (FEP) and to identify the association between parent abuse and a number of sociodemographic and clinical factors of interest in these patients. As yet, the abuse of parents by their children, especially mentally ill children, in contrast to child abuse, has remained a research taboo. In a cross-sectional study in Zagazig (Egypt), a sample of 150 adolescent outpatients (82 boys; 68 girls), presenting with FEP, was assessed for the occurrence of parent abuse using both interview and questionnaire methods (Abused Parent Questionnaire, APQ). Univariate analyses were used to compare parent abusers and nonabusers along a number of sociodemographic and clinical variables. Variables that were associated with parent abuse were entered into a multivariate logistic regression analysis model. We found that 61 patients (40.7%) perpetrated abuse against parents, mostly mothers (55/61; 90.2%). Five significant risk factors for parent abuse were identified by multivariate analysis. These were parent's female gender (95% CI = 7.82-45.56), patient's male gender (95% CI = 3.15-37.14), Childhood Trauma Questionnaire - Short Form total score (95% CI = 1.48-14.91), Positive and Negative Syndrome Scale positive subscale score (95% CI = 1.26-9.59), and duration of untreated psychosis (95% CI = 1.01-4.72). The study indicates that parent abuse, particularly mother abuse, in untreated adolescents with FEP is an issue calling for increased awareness of the problem. The findings may have important implications for parental psychoeducation and support, and earlier access to treatment.


Determination of the interconversion energy barrier of three novel pentahelicene derivative enantiomers by dynamic high resolution liquid chromatography.
Dynamic high resolution liquid chromatography (DHPLC) was used to determine the kinetic and thermodynamic activation parameters of interconversion of three novel pentahelicene derivatives {3,5-bis(trifluoromethyl)benzo[i]pentahelicene, naphtho[1,2-i]pentahelicene and 4-methoxybenzo[i]pentahelicene}. DHPLC was performed on a chiral isopropyl - carbamate cyclofructan 6 (LARIHC CF6-P) column under normal phase conditions. Variation of the column temperature and flow rate was used to study the interconversion process. A computer assisted deconvolution method was employed to determine the individual peak areas and the retention times required for the calculation of apparent enantiomerization energy barriers, enthalphy and entropy of the interconvertion of above defined pentahelicene derivative enantiomers. An ab initio quantum chemistry method was used to estimate theoretical kinetic and thermodynamic interconversion parameters and to evaluate experimental data of these three novel pentahelicene derivative enantiomers.


Surgical treatment for dermatofibrosarcoma protuberans: the Dartmouth experience and literature review.
Dermatofibrosarcoma protuberans (DFSP) is an invasive soft tissue tumor with asymmetric pattern of growth and propensity for recurrences, thus warranting systematic treatment planning at onset. We conducted a retrospective analysis of 25 patients with DFSP that received either wide excision, modified wide excision (with horizontal processing), Mohs micrographic surgery (MMS), or combination surgery. Follow-up ranged from 15-133 months, with a median of 68 months. Fourteen patients were treated with wide excision, 4 with modified wide excision, 6 with MMS followed by modified wide excision, and 1 with MMS. No recurrences were reported. Patients with lesions arising from "cosmetically sensitive" areas (head and neck) most often underwent MMS or modified wide excision. Our study supports that all 4 surgical treatment methods were successful in achieving recurrence-free survival, but emphasis on presurgical planning and patient selection for each surgical approach is key to allow for the least complicated repair while maximizing tissue preservation.


Evaluating the Effectiveness of Suicide Prevention Gatekeeper Trainings as Part of an American Indian/Alaska Native Youth Suicide Prevention Program.
According to the Centers for Disease Control suicide rates in 2022 for American Indian/Alaska Native youth are 2.5 times higher than the national average. An Urban Indian Health Organization's response to this crisis was to provide community and State-wide Gatekeeper trainings between 2012 and 2019 to teach trainees (N = 810) to respond appropriately to youth at-risk of suicide. We report data on pre-, post-, and six-month follow-up surveys with trainees. Data were analyzed using generalized linear models repeated measures to test within-subject, and between-subject mean score changes on suicide prevention-related measures "knowledge," "ask directly," "respond," "comfort," and "preparedness." Results indicated improved capacity to be prepared to address suicide in the short term and that having a graduate degree enhanced baseline suicide prevention knowledge. Over time those with less education benefited the most and better retained content. Future Trainings should engage young people and those with less education to realize the largest benefit.


Publisher Correction: High-sensitivity and high-specificity biomechanical imaging by stimulated Brillouin scattering microscopy.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


High expression of a neutral endo-β-glucanase gene from Humicola insolens in Trichoderma reesei.
The neutral endo-β-glucanase gene cel5A from Humicola insolens was cloned and connected with the cellobiohydrolase 1 promoter from Trichoderma reesei to construct a recombinant plasmid pCB-hEG with the hygromycin B resistance marker. The plasmid was introduced into conidia of T. reesei using the Agrobacterium tumefaciens mediated transformation method. Eight transformants were obtained on screening plates with sodium carboxymethyl cellulose as the sole carbon source. Stable integration of the cel5A gene into the chromosomal DNA of T. reesei was confirmed by PCR. An obvious protein band (approximately 52 kDa) was detected by SDS-PAGE from fermentation broth, which showed that the cel5A gene in recombinant T. reesei successfully fulfilled efficient expression and extracellular secretion. After 96 h shaking-flask fermentation, the endo-β-glucanase activity at pH 6.5 from recombinant T. reesei reached 3,068 U/ml, which was 11 times higher than that of the host strain. In a 2 m³ fermenter, the endo-β-glucanase activity could be further increased to 8,012 U/ml after 96 h fermentation. The results showed a good prospect for application of neutral endo-β-glucanase in the textile industry.


No benefits of ultrafractionation in two head-and-neck cancer cell lines with different inherent radiosensitivity.
To assess if ultrafractionation is applicable in the context of an unknown hyperradiosensitivity (HRS) status, we studied the survival and repair capacity of two tumor cell lines after irradiation with two different dose/fractionation schedules that can be used in a clinical setting. Squamous cell carcinoma cell lines SCC-3 (radioresistant) and SCC-6 (radiosensitive) were used. Survival was studied by clonogenic assay after multiple fractions of 0.5 Gy (2 fractions/day, 6-h interval) and 2 Gy (1 fraction/day) for a total dose of 8 Gy of gamma-rays. The capacity to repair single-strand and double-strand breaks (SSB, DSB) was assessed by comet assay. The messenger RNA (mRNA) levels of DNA-dependent protein kinase (PK) components were analyzed by RNase protection and real-time polymerase chain reaction (PCR). In both cell lines, no apparent difference was noted between the two fractionation protocols. In particular for SCC-3, the mean surviving fraction tended to be lower after 2 Gy than after 0.5 Gy fractions. In SCC-3 and SCC-6 no significant difference was observed in the repair capacity of SSB and DSB after exposure to single doses of 0.5 Gy or 2 Gy. After exposure to the same single doses, the mRNA levels of DNA-PK catalytic subunit (PKcs), Ku 70, and Ku 80 were similar. Our data do not support the concept of ultrafractionation, at least when using fractions of 0.5 Gy in the cell lines studied. This suggests that methods for testing HRS status in individual tumors need to be developed before the relevance of ultrafractionation can be investigated in the clinic.


Comparison between screw fixation and plate fixation via sinus tarsi approach for displaced intra-articular calcaneal fractures: a systematic review and meta-analysis.
Optimal surgical fixation for displaced intra-articular calcaneal fractures (DIACF) remains a subject of debate, particularly regarding the superiority between screw fixation and plate fixation via the sinus tarsi approach (STA). This review aims to determine the preferred treatment for DIACF and compare the outcomes of minimally invasive surgery options. Our study involved thorough searches across multiple electronic databases, including PubMed, Cochrane, Embase, and Web of Science, to identify all relevant publications on distal intra-articular fractures of the calcaneus (DIACFs) that were fixed using cannulated screws or plates via STA. Through a comprehensive meta-analysis, we evaluated several outcomes, including post-operative function, radiological measurements, and complications. A total of 728 patients from 7 studies met the inclusion criteria. Among them, 435 patients underwent screw fixation via STA, and 373 patients underwent plate fixation via STA. The study found no statistically significant differences between the screw fixation and the plate fixation via sinus tarsi approach (STA) in terms of AOFAS scores, Bohler's angle, Gissane's angle, sural nerve injury, secondary subtalar arthrodesis and reoperation. Compared with screw fixation, plate fixation via STA can reduce reduction loss of Bohler's angle (WMD = - 1.64, 95% CI = [- 2.96, - 0.31], P = 0.06, I2 = 59%), lower the incidence of fixation failure (OR = 0.32, 95% CI = [0.13, 0.81], P = 0.78, I2 = 0%), and decrease intra-articular step-off (WMD = - 0.52, 95% CI = [- 0.87, - 0.17], P = 0.66, I2 = 0%). Plate fixation demonstrates superior capability in restoring calcaneal width, maintaining Bohler's angle, and minimizing intra-articular step-off, thereby maintaining better reduction of the subtalar articular surface. In addition, plate fixation exhibits the modest complication rate and a low incidence of fixation failure. Therefore, we recommend the use of plate fixation through the STA, especially for complex and comminuted intra-articular calcaneal fractures.


Goals of surgery and assessment tools for elderly patients referred for cardiac and noncardiac surgery.
Surgery in elderly patients is associated with the risk of death, complications, functional decline and disability. Prior to surgery, therefore, an assessment of the health-related priorities, a realistic evaluation of the surgical risks, and individualized optimization of the procedural pathway to follow are mandatory.


Examining Health Literacy in Taiwanese Smoking Cessation Populations: A Multidimensional Evaluation of Sociodemographic Factors and Domain-Specific Competencies.
Cigarette smoking is a serious global health issue. Limited studies previously analyzed health literacy components in patients undergoing smoking cessation interventions. This study focuses on individuals enrolled in smoking cessation services and investigates the distribution of health literacy in three domains (health care, disease prevention, and health promotion) and four abilities (access, understand, appraise, and apply health information). The study also explores the correlation between background factors (age, BMI, etc.) and health literacy, as well as the differences in health literacy levels among different background variables (gender, etc.). 228 individuals completed the health literacy questionnaire. Descriptive statistical analysis, Pearson Correlation, and a Chi-Squared Test were employed to investigate the various health literacy levels and background variables. 68% had excellent or sufficient health literacy. A total of 32% were considered problematic or to have inadequate health literacy. Of the three domains of health literacy, participants performed better in the healthcare domain. More than one-third were problematic in accessing and appraising information. this paper, being the pilot study in providing an analysis of health literacy components in individuals undergoing smoking cessation, could serve as a useful reference for devising interventions for different population groups in trying to maximize successful cessation rates.


Autoradiography of [14C]paraquat or [14C]diquat in frogs and mice: accumulation in neuromelanin.
The herbicide paraquat has been suggested as a causative agent for Parkinson's disease because of its structural similarity to a metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which may induce a parkinsonism-like condition. MPTP as well as its metabolite 1-methyl-4-phenylpyridine have melanin affinity, and the parkinsonism-inducing potency of MPTP is much stronger in species with melanin in the nerve cells. Autoradiography of [3H]MPTP in experimental animals has shown accumulation in melanin-containing tissues, including pigmented neurons. In the present whole body autoradiographic study accumulation and retention was seen in neuromelanin in frogs after i.p. injection of [14C]paraquat or [14C]diquat. By means of whole body autoradiography of [14C]diquat in mice (a species with no or very limited amounts of neuromelanin) a low, relatively uniformly distributed level of radioactivity was observed in brain tissue. Accumulation of toxic chemical compounds, such as paraquat, in neuromelanin may ultimately cause lesions in the pigmented nerve cells, leading to Parkinson's disease.


[The Saxon test for objective assessment of xerostomia. A contribution to the diagnosis of Sjögren's syndrome].
In 100 patients with rheumatoid arthritis and in a control group of 100 test persons with healthy joints who were exactly equal concerning age and sex with the help of a simple method (back-weighing of a sponge after defined retention time in the oral cavity) the secretion of the saliva was measured. According to the test variant in 9-10 patients and 0-1 controls, respectively, pathologic values were found. In comparison to other symptoms which are characteristic for the presence of a Sjogren syndrome, an average sensitivity and high specifity could be ascribed to the test for the evidence of a functional disturbance of the salivary glands.


Isotope scanning of brain tumors in children.
A total of 31 brain tumors (21 verified histologically, 10 by clinical and neuroradiologic methods) in children aged from 7 months to 13 years were investigated by scintigraphy with 99mTc as a radioactive isotope tracer. There were 16 supratentorial and 15 infratentorial tumors. The supratentorial tumors were detected in 88%, and the infratentorial in 13%, of case by brain isotope scanning. The advantages and disadvantages of the method are discussed.


Combined interaction of antiherpes substances and interferon beta on the multiplication of herpes simplex virus.
The inhibition of herpes simplex virus type 1 (strain McIntyre) by two anti-herpes substances applied in combination was studied by means of a CPE inhibition method In Vero cell microcultures. The following substances were studied: AraA monophosphate, thymine arabinoside, ethyldeoxyuridine, acycloguanosine (acyclovir). 3-fluorothymidine, phosphonoformic acid. Most substance pairs showed a moderate degree of synergism. Two additive interactions and one case of antagonism was observed. Human fibroblast interferon, combined with the antiherpes substances, showed an additive interaction with AraAMP, but synergism with the others.


Erratum to "Comparison of Repeated Fluid-Air Exchange and Passive Drainage for Removing Residual Emulsified Silicone Oil Droplets".
[This corrects the article DOI: 10.1155/2020/8184607.].


Comparison of Contrast Enhanced Ultrasound With Contrast Enhanced Computed Tomography for the Diagnosis of Hepatocellular Carcinoma.
The most common primary malignant tumor of liver is hepatocellular carcinoma (HCC). The highest risk of developing HCC is seen in patients of cirrhosis. Ultrasound is used for surveillance in these patients. This study evaluates the role of contrast enhanced ultrasound (CEUS) in the diagnosis of HCC and compares CEUS to contrast enhanced computed tomography (CECT). This prospective study included 22 patients with cirrhosis and suspected to have HCC on the basis of gray scale ultrasound or elevated Alpha-fetoprotein. Multiphasic CECT and CEUS were done. On both CECT and CEUS, arterial phase enhancement patterns of the lesions were classified as heterogeneously hyperenhancing, homogeneously hyperenhancing, isoenhancing or nonenhancing. The enhancement patterns of the lesions in portal venous phase were classified as hyperenhancing, isoenhancing, washout or nonenhancing. Presence or absence of neovascularity and peripheral capsule were also noted. The diagnosis of HCC was made as per American Association for the Study of Liver Diseases (AASLD) guidelines. There was moderate degree of agreement between the two modalities in characterizing the enhancement pattern in arterial phase, as calculated by using kappa test (k = 0.59, P < 0.05). Substantial agreement between them, for demonstrating the neovascularity, was also seen (k = 0.772, P < 0.05). CEUS was found to be superior to CECT in demonstrating portal venous phase wash out and peripheral capsule. Only fair agreement was seen between them, with kappa value for portal venous washout being k = 0.38 (P < 0.05) and for peripheral capsule being k = 0.328 (P < 0.05). CEUS is comparable to CECT in demonstrating the arterial phase enhancement pattern of HCC and the neovascularity. CEUS was found to be better than CECT in demonstrating the portal venous phase washout and peripheral capsule.


Unregulated exposure of the ribosomal M-site caused by NAC depletion results in delivery of non-secretory polypeptides to the Sec61 complex.
Nascent polypeptide associated complex (NAC) interacts with nascent polypeptides emerging from ribosomes. Both signal recognition particle (SRP) and NAC work together to ensure specificity in co-translational targeting by competing for binding to the ribosomal membrane attachment site. While SRP selects signal-containing ribosomes for targeting, NAC prevents targeting of signal peptide-less nascent chains to the endoplasmic reticulum membrane. Here we show that the ribosome binding that occurs in NAC's absence delivers signalless nascent chains to the Sec61 complex, underscoring the danger of unregulated exposure of the ribosomal M-site. Recently, the idea that NAC prevents ribosome binding has been challenged. By carefully examining the physiologic NAC concentration in a variety of tissues from different species we here demonstrate that the discrepancy resulted from subphysiologic NAC concentrations.


Isolation and genetic characterization of canine distemper virus in domestic dogs from central and northern provinces in Vietnam.
Canine distemper virus (CDV) is a pathogen causing fatal disease in a wide range of carnivores. Sequence analysis of CDV strains has been classified into several geographically-related lineages, and the evolution and emergence of these strains are not fully yet investigated. In this study, the complete H gene sequences of 15 CDV strains isolated on Vero DST cell culture from clinical samples of vaccinated domestic dogs in Vietnam were investigated. Fifteen CDV isolates belonging to Asia-1 CDV variants were predominant antigenic type circulated in Central and Northern Vietnam with notable differences regarding the region and some genetic variation, and the most closely related Asia-1 variants lineage reported in Vietnam, China, Taiwan, and Japan. All identified CDV isolates clustered into 2 novel clades Asia-1-C1 and Asia-1-C2. The major amino acid mutation variants of Vietnamese Asia-1 CDV strains were found at sites 51, 157, 159, 160, 171, 178, 186, 235, 245, 277, 288, 313, 324, 330, 337, 345, 358, 359, 365, 383, 446, 475, 517, 530, 584, 598 which include N-glycosylation sites and neutralizing epitope regions in H gene. The results of the virus neutralization titer (VNT) assay showed that the dogs vaccinated with commercial vaccines had significantly low VNT (4.89 and 12.8) against field CDV isolate strains (VNUA NA04, HN18, and NB05) isolated in northern and central Vietnam, respectively. These data may suggest the need for further research in CDV monitoring and development of preventative measures against CDV in Vietnam.


Invited commentary on: Proposals for massive expansion of psychological therapies would be counterproductive across society.
Will an expansion of access to cognitive-behavioural therapy lead to greater happiness? Summerfield and Veale debate this question by focusing on the nature of mental distress and the best evidence for ameliorating it. Stimulating though it is, their debate left me wondering about the wider philosophical and ethical implications behind our rush to therapy.


TNFalpha inhibits skeletal myogenesis through a PW1-dependent pathway by recruitment of caspase pathways.
Cachexia is associated with poor prognosis in patients with chronic disease. Tumor necrosis factor-alpha (TNFalpha) plays a pivotal role in mediating cachexia and has been demonstrated to inhibit skeletal muscle differentiation in vitro. It has been proposed that TNFalpha-mediated activation of NFkappaB leads to down regulation of MyoD, however the mechanisms underlying TNFalpha effects on skeletal muscle remain poorly understood. We report here a novel pathway by which TNFalpha inhibits muscle differentiation through activation of caspases in the absence of apoptosis. TNFalpha-mediated caspase activation and block of differentiation are dependent upon the expression of PW1, but occur independently of NFkappaB activation. PW1 has been implicated previously in p53-mediated cell death and can induce bax translocation to the mitochondria. We show that bax-deficient myoblasts do not activate caspases and differentiate in the presence of TNFalpha, highlighting a role for bax-dependent caspase activation in mediating TNFalpha effects. Taken together, our data reveal that TNFalpha inhibits myogenesis by recruiting components of apoptotic pathways through PW1.


[Follow-up of testicular germ cell tumors-historical aspects and current recommendations].
Systematic follow-up examinations of patients cured of testicular cancer first gained attention by caregivers in the 1980s only after the management of the disease had significantly been improved by the introduction of cisplatin-based chemotherapy and almost synchronously, by the implementation of computerized tomography (CT) and serum tumor markers. Follow-up involves three aims: early diagnosis of recurrence, detection of treatment-related toxicity, and detection of secondary diseases. As the clinical presentation of testicular cancer is very heterogeneous, there is no uniform follow-up for the disease. Instead, risk-adapted follow-up schedules are required. Since the release of the German AWMF S3 guideline for the management of testicular cancer in 2019, high level evidence has accumulated for the noninferiority of magnetic resonance imaging (MRI) to CT with regard to abdominal imaging. Therefore, it is appropriate to modify the recommendations for follow-up given in the 2019 issue of the S3 guidelines. The modifications recommended herein relate to three issues: (1) Only three risk groups (instead of formerly four) are identified, i.e., seminoma (all stages); nonseminoma clinical stage 1b (i.e., pT2, with lymphovascular invasion) on surveillance; nonseminoma all other stages. All patients cured from poor risk disease or from relapses require individual follow-up schedules not included in the recommendations tabulated herein. (2) CT and abdominal sonography are replaced by MRI. (3) Chest X‑ray imaging during follow-up of seminoma patients is no longer recommended.


Involvement of insulin-like growth factor-1 and its binding proteins in proliferation and differentiation of murine bone marrow-derived macrophage precursors.
Insulin-like growth factor 1 (IGF-1) and its binding proteins (IGFBPs) are involved in proliferation and differentiation of many cell types. In the present study, the involvement of IGF-1 and IGFBPs in proliferation and differentiation of murine bone marrow-derived macrophages (BMDM) was investigated. L929-conditioned media (LCM) containing abundant macrophage colony-stimulating factor CSF-1 were used to stimulate BMDM development from their bone marrow precursors. The alteration of IGF-1 and IGFBPs during LCM-induced BMDM proliferation and differentiation was first studied. The cells were cultured in RPMI complete media containing 20% LCM for different time periods and then incubated in serum-free media for 24 h. The supernatants were collected for Western ligand blotting and immunoblotting analyses, and the cell pellets for Northern blotting analyses. The mRNA level of IGF-1 increased in a time-dependent manner. An increase of IGFBP-4 accumulation in the conditioned media was also observed during this process. However the mRNA expression of IGFBP-4 remained constant, indicating a posttranscriptional regulation of IGFBP-4 secretion and/or stability. The effects of exogenous recombinant human IGF-1 (rhIGF-1) on BMDM proliferation and differentiation were further studied. Two IGF-1 analogs (long R3 IGF-1 and des [1-3] IGF-1) were also used in parallel with regular IGF-1 to indicate the involvement of IGFBPs in BMDM development. Cells were cultured in complete media containing 20% LCM for different time periods, and then incubated in serum-free media in the presence of rhIGF-1 or its analogs for 24 h. These three forms of IGF-1 all potentiated the proliferation of freshly isolated BMDM precursors (d 0). rhIGF-1 and long R3 IGF-1, but not des (1-3) IGF-1, continued to stimulate the cell proliferation on d 1. The effects of these three forms of IGF-1 on BMDM differentiation were investigated using mannose receptor expression as a marker. Long R3 IGF-1 and des (1-3) IGF-1, but not rhIGF-1, enhanced BMDM differentiation on d 4. The different effects of rhIGF-1 and its analogs on BMDM differentiation suggest that the accumulation of IGFBP-4 in BMDM development might have an inhibitory effect on IGF-1 actions by sequestering free IGF-1.


The effect of celecoxib on the development of diethylnitrosamine-induced liver tumors in rats.
Hepatocellular carcinoma is one of the most commonly diagnosed malignant tumors in the world, and it typically has a poor prognosis. Extensive studies have examined the effects of non-steroidal anti-inflammatory drugs selective to COX-2 on the chemoprevention of various tumors. The objective of this study is to observe the effect of celecoxib on the development of liver tumors in rats. Hepatocellular carcinoma was induced in a group of 75 rats with the carcinogen diethylnitrosamine. The animals were divided into 5 groups. Three groups received various doses of celecoxib, one group received indomethacin, and a control group received no non-steroidal selective anti inflammatory drugs. The experimental model was considered to be successful because 78% of the rats in the control group developed liver tumors. The number of neoplastic lesions was similar among the celecoxib, indomethacin and control groups, although the nodule diameter of the lesions was smaller in the celecoxib group. Better results were observed in animals that received celecoxib at doses of 6 and 9 mg/kg/ day; 4 rats in these groups did not show any neoplastic histological lesions, and a greater proportion of the nodules in the other animals in these groups were benign than in the groups that did not use celecoxib. These results suggest that celecoxib may play a role in modifying the natural history of hepatocellular carcinoma development.


Variation of dark focus of accommodation with laser speckle exposure duration.
Dark focus of accommodation (DFA) was measured in 10 subjects using a computer-aided He-Ne Badal laser optometer having high temporal and amplitude resolution. Accommodative responses were tracked during 5 min sessions for 10 speckle exposure durations ranging from 100 to 1000 ms. DFA-speckle exposure functions fell into four distinct groups. This identifies the laser speckle exposure time as a possible contaminant in measures of DFA made by laser optometers if individual variability across exposure times is ignored. Group averaging of accommodative responses for laser exposure times obfuscates the reported individual variability.


Genetic variation in the progesterone receptor gene and susceptibility to recurrent pregnancy loss: a case-control study.
To investigate the association of progesterone receptor (PGR) gene variants with susceptibility to recurrent pregnancy loss (RPL). Retrospective case-control study. Outpatient obstetrics and gynaecology clinics. Women with RPL (396), defined as three or more consecutive miscarriages of unknown aetiology, and 361 women used as controls. PGR genotyping was performed by the allelic exclusion method (real-time polymerase chain reaction). PGR single nucleotide polymorphisms (SNPs) and the distribution of their alleles, genotypes and haplotypes. Higher minor allele frequencies (MAFs) for rs590688, rs10895068, and rs1942836 were seen in RPL cases than in controls, which remained significant after controlling for multiple comparisons. Significantly higher frequencies of heterozygous (1/2) rs608995, along with heterozygous (1/2) and homozygous (2/2) rs590688, rs10895068, and rs1942836 genotype carriers, were seen between RPL cases versus controls, respectively, which persisted after controlling for age, body mass index (BMI), and menarche. The increased risk of RPL associated with rs590688 and rs1942836 was dependent on the number of minor alleles, thus suggesting a 'dose-dependent' effect associated with both variants. Varied linkage disequilibrium (LD) was noted between rs590688, rs10895068, rs608995, and rs1942836 PGR variants associated with RPL. Haplotypes with an increased frequency of CGTC and reduced frequency of GGAT were noted in women with RPL, compared with controls, thereby indicating these haplotypes as RPL-susceptible and RPL-protective, respectively. This association persisted after controlling for multiple comparisons, and after adjusting for covariates. We have confirmed a positive association of specific PGR variants (rs590688, rs10895068, and rs1942836) and PGR haplotypes (ATGCCGTC and ATTCGGTC) with an increased risk of RPL, thereby supporting a role for PGR as an RPL candidate locus. Genetic variants in progesterone receptor gene are associated with increased risk of recurrent pregnancy loss.


Urinary Volatile Organic Compound Testing in Fast-Track Patients with Suspected Colorectal Cancer.
Colorectal symptoms are common but only infrequently represent serious pathology, including colorectal cancer (CRC). A large number of invasive tests are presently performed for reassurance. We investigated the feasibility of urinary volatile organic compound (VOC) testing as a potential triage tool in patients fast-tracked for assessment for possible CRC. A prospective, multi-center, observational feasibility study was performed across three sites. Patients referred to NHS fast-track pathways for potential CRC provided a urine sample that underwent Gas Chromatography-Mass Spectrometry (GC-MS), Field Asymmetric Ion Mobility Spectrometry (FAIMS), and Selected Ion Flow Tube Mass Spectrometry (SIFT-MS) analysis. Patients underwent colonoscopy and/or CT colonography and were grouped as either CRC, adenomatous polyp(s), or controls to explore the diagnostic accuracy of VOC output data supported by an artificial neural network (ANN) model. 558 patients participated with 23 (4%) CRC diagnosed. 59% of colonoscopies and 86% of CT colonographies showed no abnormalities. Urinary VOC testing was feasible, acceptable to patients, and applicable within the clinical fast track pathway. GC-MS showed the highest clinical utility for CRC and polyp detection vs. controls (sensitivity = 0.878, specificity = 0.882, AUROC = 0.896) but it is labour intensive. Urinary VOC testing and analysis are feasible within NHS fast-track CRC pathways. Clinically meaningful differences between patients with cancer, polyps, or no pathology were identified suggesting VOC analysis may have future utility as a triage tool.


Suture- or Plug-Based Large-Bore Arteriotomy Closure: A Pilot Randomized Controlled Trial.
This study sought to test the superiority in terms of efficacy and safety of a dedicated plug-based vascular closure device (VCD) during transcatheter aortic valve replacement (TAVR) over a suture-based VCD. Vascular complications after TAVR are relevant and often associated with VCD failure. The MASH (MANTA vs. Suture-based vascular closure after transcatHeter aortic valve replacement) trial is an international, 2-center pilot randomized controlled trial comparing the MANTA VCD (Teleflex, Wayne, Pennsylvania) versus 2 ProGlides (Abbott Vascular, Abbott Park, Illinois). The primary composite endpoint consisted of access site-related major or minor vascular complications at 30-days' follow-up. Secondary endpoints included clinically relevant access site bleeding, time to hemostasis, and modified VCD failure (defined as failure to achieve hemostasis within 5 min or requiring additional endovascular maneuvers such as endovascular stenting, surgical techniques, or additional closure devices). Adverse events were adjudicated by an independent clinical events committee according to the VARC-2 definitions. A total of 210 TAVR patients were included between October 2018 and January 2020. Median age was 81 years, 54% were male, and the median STS score was 2.7%. There was no significant difference in the primary endpoint of access site-related vascular complications between MANTA and ProGlide (10% vs. 4%; p = 0.16). Clinically significant access site bleedings were similar with both closure techniques (9% vs. 6%; p = 0.57). Modified VCD failure occurred less frequently in MANTA versus ProGlide (20% vs. 40%; p < 0.01). Suture-based closure required more often additional closure devices, whereas MANTA numerically needed more covered stents and surgical bailouts. Plug-based large-bore arteriotomy closure was not superior to suture-based closure. Plug-based closure required fewer, but a different kind of bailout maneuvers.


Cancer incidence in patients with schizophrenia and their first-degree relatives - a meta-analysis.
Controversy concerning cancer incidence in schizophrenia exists because of heterogeneous study findings. A meta-analysis was performed on standardized incidence ratios (SIR) of cancer in patients with schizophrenia and first-degree relatives and compared with general population samples. The pooled overall cancer incidence in patients was not significantly increased (SIR = 1.05, CI 0.95-1.15). Lung cancer incidence was slightly increased (SIR = 1.31, CI 1.01-1.71), but was reduced after adjusting for smoking prevalence. The incidence of several cancers unrelated to smoking was reduced in patients. Breast cancer rates were significantly increased in female patients. The pooled overall cancer incidence in siblings (SIR = 0.89, CI 0.84-0.94) and parents (SIR = 0.90, CI 0.88-0.93) was significantly reduced. A meta-regression detected a significant relationship between cancer risk in the general population and relative risk in patients. The meta-analysis aided exploration of inconsistent study findings. There is a discrepancy between cancer risk exposure and cancer incidence in schizophrenia consistent with a protective effect.


Effects of ethanol on axon outgrowth and branching in developing rat cortical neurons.
Humans exposed prenatally to ethanol can exhibit brain abnormalities and cognitive impairment similar to those seen in patients expressing mutant forms of the L1 cell adhesion molecule (L1CAM). The resemblance suggests that L1CAM may be a target for ethanol, and consistent with this idea, ethanol can inhibit L1CAM adhesion in cell lines and L1CAM-mediated outgrowth and signaling in cerebellar granule neurons. However, it is not known whether ethanol inhibits L1CAM function in other neuron types known to require L1CAM for appropriate development. Here we asked whether ethanol alters L1CAM function in neurons of the rat cerebral cortex. We find that ethanol does not alter axonal polarization, L1CAM-dependent axon outgrowth or branching, or L1CAM recycling in axonal growth cones. Thus, ethanol inhibition of L1CAM is highly dependent on neuronal context.


Urinary concentrations of bisphenol A and phthalate metabolites and weight change: a prospective investigation in US women.
Both bisphenol A (BPA) and phthalates are known endocrine-disrupting chemicals for which there is widespread general population exposure. Human exposure occurs through dietary and non-dietary routes. Although animal studies have suggested a potential role of these chemicals in obesity, evidence from human studies is sparse and inconsistent, and prospective evidence is lacking. This study evaluated urinary concentrations of BPA and major phthalate metabolites in relation to prospective weight change. The study population was from the controls in a prospective case-control study of type 2 diabetes in the Nurses' Health Study (NHS) and NHSII. A total of 977 participants provided first-morning-void urine samples in 1996-2002. Urinary concentrations of BPA and nine phthalate metabolites were measured using liquid chromatography-mass spectrometry. Body weights were self-reported at baseline and updated biennially thereafter for 10 years. On average, the women gained 2.09 kg (95% confidence interval (CI), -2.27 to 6.80 kg) during the 10-year follow-up. In multivariate analysis with adjustment of lifestyle and dietary factors, in comparison with women in the lowest quartile of BPA concentration, those in the highest quartile had 0.23 kg per year (95% CI, 0.07-0.38 kg per year) greater weight gain during the 10-year follow-up (P-trend=0.02). Several phthalate metabolites, including phthalic acid, MBzP and monobutyl phthalate, were also associated with faster prospective weight gain in a dose-response fashion (P-trend<0.01), whereas other phthalates metabolites, including MEP and monoethylhexyl phthalate, were not monotonically associated with body weight change. These data suggest urinary concentrations of BPA and certain individual phthalate metabolites that were associated with modestly greater weight gain in a dose-response fashion. These data are consistent with a potential role of BPA and phthalates in obesity, although more prospective data are needed to corroborate these observations.


Subsurface microbial methanotrophic mats in the Black Sea.
A nodule-shaped microbial mat was found subsurface in sediments of a gas seep in the anoxic Black Sea. This mat was dominated by ANME-1 archaea and consumed methane and sulfate simultaneously. We propose that such subsurface mats represent the initial stage of previously investigated microbial reefs.


Contribution to the standardization of the chromatographic conditions for the lipophilicity assessment of neutral and basic drugs.
The chromatographic conditions aiming to a better simulation of n-octanol-water partitioning using a base deactivated silica (BDS) column as stationary phase were investigated for structurally diverse basic and neutral drugs. Extrapolated retention factors log k(w), determined using different methanol fractions as organic modifier, were considered as lipophilicity indices. The effect of n-decylamine and n-octanol as mobile phase additives was examined and the appropriateness of the final retention outcome to reproduce lipophilicity data was evaluated. Moreover, the influence of n-octanol on the linearity of the log k/methanol fraction relationship and on the uniformity of the retention mechanism was investigated. 1:1 correlation between log k(w) values and the logarithm of the distribution coefficient (logD) was established for basic drugs in presence of both n-decylamine and n-octanol as mobile phase additives. However, for neutral drugs n-decylamine proved to be a sufficient and more important factor than n-octanol.


Coexistence of antiferromagnetic and ferromagnetic orders at remanent state in epitaxial multiferroic Bi2FeCrO6 nanostructures.
We report the local electronic and magnetic properties of Bi(2)FeCrO(6) nanostructures by element-specific polarized x-ray techniques. Sizable magnetic ordering in the remanent state is observed at room temperature for both Fe and Cr ions. The Bi(2)FeCrO(6) system offers an example of d(5)-d(3) magnetic superexchange interaction with a magnetic order for both Fe and Cr, which are both formally in the + 3 valence state. The results suggest a coexistence of antiferromagnetic and ferromagnetic superexchange interaction between Fe and Cr spins in the nanostructures at the remanent state and at room temperature.


Hemoglobin Levels, Anemia, and Their Associations with Body Mass Index among Pregnant Women in Hail Maternity Hospital, Saudi Arabia: A Cross-Sectional Study.
The level of association between hemoglobin level/anemia and obesity during pregnancy is not yet fully understood. A cross-sectional study was conducted in Hail Maternity Hospital in northern Saudi Arabia from March to May 2023 to assess the associations between hemoglobin levels, anemia, and obesity among pregnant women. Reproductive history was gathered through a questionnaire. Body mass index (BMI) was calculated/computed from the women's weight and height. Linear and binary regression analyses were performed. A total of 334 pregnant women were enrolled. The median (interquartile range (IQR)) age and parity were 33.2 (27.4-37.8) years and 3 (1-5), respectively. Of the 334 women, 52 (15.6%) were normal weight, while 87 (26.0%) were overweight and 195 (58.4%) were obese. In the multiple linear regression, parity (coefficient = -0.121, p = 0.001) and BMI (coefficient = 0.030, p = 0.006) were negatively associated with the hemoglobin level. Ninety-nine (26.9%) women had anemia. In the multivariate analysis, primiparity (adjusted odds ratio (AOR) = 0.54, 95% confidence interval (CI) = 0.30-0.97), increasing BMI (AOR = 0.93, 95% CI = 0.89-0.97), and obesity (AOR = 0.31, 95% CI = 0.16-0.61) were associated with decreased ORs of anemia. Increasing parity was associated with increased ORs of anemia (AOR = 1.18, 95% CI = 1.05-1.32). Being overweight was not associated with anemia (AOR = 0.56, 95% CI = 0.27-1.16). In the current study, a high hemoglobin level and lower prevalence of anemia were observed among obese pregnant women.


Interactions of six SNPs in APOA1 gene and types of obesity on low HDL-C disease in Xinjiang pastoral area of China.
This study aims to investigate association between six single nucleotide polymorphisms(SNPs) in APOA1 gene and types of obesity with the risk of low level HDL-C in the pastoral area of northwest China. A total of 1267 individuals including 424 patients with low HDL-C disease and 843 health subjects were analyzed based on matched for age, sex. SNPShot technique was used to detect the genotypes of rs670, rs5069, rs5072, rs7116797, rs2070665 and rs1799837 in APOA1 gene. The relationship between above six SNPs and types of obesity with low HDL-C disease was analyzed by binary logistic regression. Carriers with rs670 G allele were more likely to get low HDL-C disease (OR = 1.46, OR95%CI: 1.118-1.915; P = 0.005); The genotypic and allelic frequencies of rs5069, rs5072, rs7116797, rs2070665, rs1799837 revealed no significant differences between cases and controls (P < 0.05); with reference to normal weight, Waist circumference (WC), Waist-to-hip ratio (WHR) individuals, respectively, general obesity measured by BMI had 2.686 times (OR95%CI: 1.695-4.256; P < 0.01), abdominal obesity measured by WC had 1.925 times (OR95%CI: 1.273-2.910; P = 0.002) and abdominal obesity measured by WHR had 1.640 times (OR95%CI: 1.114-2.416; P = 0.012) risk to get low HDL-C disease; APOA1 rs670 interacted with obesity (no matter general obesity or abdominal obesity) on low HDL-C disease. APOA1 gene may be associated with low HDL-C disease in the pastoral area of northwest China; obesity was the risk factor for low HDL-C disease; the low HDL-C disease is influenced by APOA1, obesity, and their interactions.


The Effect of Inter-pulse Interval on TMS Motor Evoked Potentials in Active Muscles.
The time interval between transcranial magnetic stimulation (TMS) pulses affects evoked muscle responses when the targeted muscle is resting. This necessitates using sufficiently long inter-pulse intervals (IPIs). However, there is some evidence that the IPI has no effect on the responses evoked in active muscles. Thus, we tested whether voluntary contraction could remove the effect of the IPI on TMS motor evoked potentials (MEPs). In our study, we delivered sets of 30 TMS pulses with three different IPIs (2, 5, and 10 s) to the left primary motor cortex. These measurements were performed with the resting and active right hand first dorsal interosseous muscle in healthy participants (N = 9 and N = 10). MEP amplitudes were recorded through electromyography. We found that the IPI had no significant effect on the MEP amplitudes in the active muscle (p = 0.36), whereas in the resting muscle, the IPI significantly affected the MEP amplitudes (p < 0.001), decreasing the MEP amplitude of the 2 s IPI. These results show that active muscle contraction removes the effect of the IPI on the MEP amplitude. Therefore, using active muscles in TMS motor mapping enables faster delivery of TMS pulses, reducing measurement time in novel TMS motor mapping studies.


Type 3 membranoproliferative glomerulonephritis: clinicopathologic correlations and long-term follow-up in nine patients.
We studied the renal pathologic findings and results of long-term follow-up (four to 15 years; mean 7.8 years) in nine patients with type 3 membranoproliferative glomerulonephritis (MPGN). We selected these patients because biopsy specimens displayed extensive glomerular, subepithelial, electron-dense deposits, besides other changes characteristic of MPGN. We compared these patients with 14 others with type 1 MPGN similarly followed up for a period of 7.4 years. Patients with type 3 MPGN were older, had hypocomplementemia less often, and enjoyed a slightly better outcome. Although six patients with type 3 MPGN had the nephrotic syndrome, end-stage renal failure developed only in two, whereas it developed in five of the 14 patients with type 1 MPGN.


A review of primary congenital glaucoma in the developing world.
Primary congenital glaucoma is the most common type of infantile glaucoma, yet it remains a relatively rare disease. Treatment is principally surgical, and management lasts a lifetime. In the developing world, delayed diagnosis, limited treatment, and inadequate follow-up lead to a heavier burden on the patient and community. We highlight the epidemiology and genetics of the disease, its current management and prognosis, and the limitations facing both providers and patients in the developing world. Further efforts are necessary to provide effective, timely screening of children and allocate adequate resources to allow health care workers to reduce the rate of avoidable blindness in developing countries.


Inhibition of dopamine and norepinephrine reuptake produces additive effects on energy balance in lean and obese mice.
Although originally developed as an antidepressant, long-term bupropion (BUP) treatment was recently shown to cause 5-8% weight loss over placebo in clinical trials with obese adults. BUP's antidepressant properties probably stem from its ability to increase extracellular brain dopamine (DA) and norepinephrine (NE) levels by inhibiting their reuptake, although the mechanism of BUP-induced weight loss is unknown. Consequently, the acute effects of DA and NE reuptake inhibition on energy homeostasis were determined by measuring food intake and body weight in mice following peripheral (intraperitoneal (i.p.)) administration of either BUP, a selective DA (GBR12783), or a selective NE (nisoxetine (NIS)) reuptake inhibitor. BUP, GBR12783, and NIS all dose-dependently decreased acute food intake in fasted lean mice. The ability of BUP to decrease food intake was independent of its ability to cause a temporary increase in locomotor activity. The inhibitory effects of acute GBR12783 and NIS on short-term food intake were additive. Subchronic (via mini-osmotic pump) administration of GBR12783 and NIS produced a transient nonadditive effect on food intake, but produced an additive reduction in body weight (8-10%). Because obesity can affect catecholaminergic signaling, we determined the effects of i.p. BUP, GBR12783, and NIS on short-term food intake in obese mice. Acute BUP, GBR12783, and NIS dose-dependently reduced acute food intake, and the additive effect of GBR12783 and NIS on acute food intake was preserved in obese mice. These results demonstrate that combined DA and NE reuptake inhibition produces additive effects on energy balance in lean and obese mice on both standard and high-fat diet, providing a foundation for further research on the effects of BUP and similar compounds on energy balance in mice.


Building yeast libraries to dissect terminal degrons with fluorescent timers.
Selective degradation of unnecessary or abnormal proteins by the ubiquitin-proteasome system is an essential part of proteostasis. Ubiquitin ligases recognize substrates of selective protein degradation and modify them with polyubiquitin chains, which mark them for proteasomal degradation. Substrate recognition by ubiquitin ligases often involves degradation signals or degrons, which are typically short linear motifs found in intrinsically disordered regions, e.g., at protein termini. However, specificity in selective protein degradation is generally not well understood, as for most ubiquitin ligases no degrons have been identified thus far. To address this limitation, high-throughput mutagenesis approaches, such as multiplexed protein stability (MPS) profiling, have been developed, enabling systematic surveys of degrons in vivo or allowing to define degron motifs recognized by different ubiquitin ligases. In MPS profiling, thousands of short peptides can be assessed in parallel for their ability to trigger degradation of a fluorescent timer reporter. Here, we describe common types of libraries used to identify and dissect degrons located at protein termini using MPS profiling in budding yeast, and provide protocols for their construction.


Pt nanoparticles under oxidizing conditions - implications of particle size, adsorption sites and oxygen coverage on stability.
Platinum nanoparticles are efficient catalysts for different reactions, such as oxidation of carbon and nitrogen monoxides. Adsorption and interaction of oxygen with the nanoparticle surface, taking place under reaction conditions, determine not only the catalytic efficiency but also the stability of the nanoparticles against oxidation. In this study, platinum nanoparticles in oxygen environment are investigated by systematic screening of initial nanoparticle-oxygen configurations and employing density functional theory and a thermodynamics-based approach. The structures formed at low oxygen coverages are described by adsorption of atomic oxygen on the nanoparticles whereas at high coverages oxide-like species are formed. The relative stability of adsorption configurations at different oxygen coverages, including the phase of fully oxidized nanoparticles, is investigated by constructing p-T phase diagrams for the studied systems.


Cocaine abuse: dermatologic manifestations and therapeutic approaches.
Cocaine affects the cutaneous system and other organ systems. Cocaine use is associated with vasculitides, infectious complications, and numerous dermatologic conditions. It has been associated with formication (ie, tactile hallucinations of insects crawling underneath the skin), which leads to delusions of parasitosis and other psychosis-related dermatologic disorders. When a patient presents to a dermatology clinic with chronic skin lesions, a vague medical history, negative findings from previous evaluations, labile affect, and delusional behavior, drug screening should be performed to identify possible cocaine use.


Investigation of different approaches for exhaled breath and tumor tissue analyses to identify lung cancer biomarkers.
Development of early noninvasive methods for lung cancer diagnosis is among the most promising technologies, especially using exhaled breath as an object of analysis. Simple sample collection combined with easy and quick sample preparation, as well as the long-term stability of the samples, make it an ideal choice for routine analysis. The conditions of exhaled breath analysis by preconcentrating volatile organic compounds (VOCs) in sorbent tubes, two-stage thermal desorption and gas-chromatographic determination with flame-ionization detection have been optimized. These conditions were applied to estimate differences in exhaled breath VOC profiles of lung cancer patients and healthy volunteers. The combination of statistical methods was used to evaluate the ability of VOCs and their ratios to classify lung cancer patients and healthy volunteers. The performance of diagnostic models on the test data set was greater than 90 % for both VOC peak areas and their ratios. Some of the exhaled breath samples were analyzed using gas chromatography coupled with mass spectrometry (GC-MS) to identify VOCs present in exhaled breath at lower concentration levels. To confirm the endogenous origin of VOCs found in exhaled breath, GC-MS analysis of tumor tissues was conducted. Some of the VOCs identified in exhaled breath were found in tumor tissues, but their frequency of occurrence was significantly lower than in the case of exhaled breath.


Perihamate-Peripisiform-Transtriquetrum Axial Ulnar Fracture Dislocation of the Hand With an Associated Perilunate Injury.
Axial fracture-dislocations are rare, high-energy injuries. Although cases of axial fracture-dislocations are reported in the literature, there are few reports of a patient who suffered a combined perilunate injury with an ulnar axial dislocation of the hand. This case report describes the anatomical injury and operative treatment of a patient who suffered this injury and discusses the importance of associated soft tissue management.


Occurrence and transformation of heavy metals during swine waste treatment: A full scale study.
This study tracked the fate of nine detected heavy metals in an industrial swine farm with integrated waste treatment, including anoxic stabilization, fixed-film anaerobic digestion, anoxic-oxic (A/O), and composting. Results show that heavy metals exhibited different transformation behaviors in the treatment streamline with Fe, Zn, Cu and Mn as the most abundant ones in raw swine waste. The overall removal of water-soluble heavy metals averaged at 30 %, 24 % and 42 % by anoxic stabilization, anaerobic digestion and A/O unit, respectively. In particular, anoxic stabilization could effectively remove Cu, Mn and Ni; while A/O unit was highly effective for Fe, Cr and Zn elimination from water-soluble states. As such, the environmental risk of liquid products for agricultural irrigation decreased gradually to the safe pollution level in swine waste treatment. Furthermore, heavy metals in the solid (slurry) phase of these bioprocesses could be immobilized with the passivation rate in the range of 42-70 %. Nevertheless, heavy metals preferably transformed from liquid to biosolids to remain their environmental risks when biosolids were used as organic fertilizer in agriculture, thereby requiring effective strategies to advance their passivation in all bioprocesses, particularly composting as the last treatment unit.


Functional characterisation guides classification of novel BAP1 germline variants.
We have identified six patients harbouring distinct germline BAP1 mutations. In this study, we functionally characterise known BAP1 pathogenic and likely benign germline variants out of these six patients to aid in the evaluation and classification of unknown BAP1 germline variants. We found that pathogenic germline variants tend to encode truncated proteins, show diminished expression of epithelial-mesenchymal transition (EMT) markers, are localised in the cytosol and have reduced deubiquitinase capabilities. We show that these functional assays are useful for BAP1 variant curation and may be added in the American College of Medical Genetics and Genomics (ACMG) criteria for BAP1 variant classification. This will allow clinicians to distinguish between BAP1 pathogenic and likely benign variants reliably and may aid to quickly benchmark newly identified BAP1 germline variants. Classification of novel BAP1 germline variants allows clinicians to inform predisposed patients and relevant family members regarding potential cancer risks, with appropriate clinical interventions implemented if required.


SUMO promotes HDAC-mediated transcriptional repression.
Recently, SUMO modification has been shown to impart repressive properties on several transcriptional regulatory proteins. Indeed, the ETS domain transcription factor Elk-1 is modified by SUMO, and this modification is reversed by ERK MAP kinase pathway activation. This causes a switch from a repressive to activated state. However, the mechanism(s) of SUMO-mediated transcriptional repression is unclear. Here, we have investigated how sumoylation of Elk-1 leads to transcriptional repression. We demonstrate that sumoylation of Elk-1 results in the recruitment of histone deacetylase activity to promoters. In particular, our data point to a key role for HDAC-2. This recruitment leads to decreased histone acetylation and hence transcriptional repression at Elk-1 target genes. Thus, our data demonstrate an important integration point for two protein-modifying pathways in the cell, the SUMO and deacetylation pathways, that combine to promote transcriptional repression.


Improved compliance with a gentamicin prescribing policy after introduction of a monitoring form.
Compliance with our local hospital policy for gentamicin administration and monitoring was found to be inadequate on audit. A gentamicin monitoring form was introduced with the aim of improving staff compliance with the policy thus minimizing the risks of toxicity while ensuring adequate dosing. The initial audit examined the prescribing, administration and monitoring of intravenous gentamicin given to 20 patients. The introduction of a gentamicin monitoring form was prompted by unsatisfactory initial dosing and subsequent monitoring and adjustment of gentamicin doses. Following introduction of the monitoring form, the proportion of appropriate starting doses had increased from 13 out of 20 to 18 out of 20 prescriptions. The timing of initial serum levels was significantly better: 18 timed correctly, compared with 12 in initial audit. Subsequent administration and monitoring appeared more compliant with fewer doses inappropriately omitted and more levels checked appropriately. No improvement was seen in the quality of dose adjustment. In conjunction with the support and advice of the pharmacy and microbiology departments, the use of a gentamicin monitoring form can improve the quality of intravenous gentamicin use in the hospital setting.


Implicative role of epidermal growth factor receptor and its associated signaling partners in the pathogenesis of Alzheimer's disease.
Epidermal growth factor receptor (EGFR) plays a pivotal role in early brain development, although its expression pattern declines in accordance with the maturation of the active nervous system. However, recurrence of EGFR expression in brain cells takes place during neural functioning decline and brain atrophy in order to maintain the homeostatic neuronal pool. As a consequence, neurotoxic lesions such as amyloid beta fragment (Aβ1-42) formed during the alternative splicing of amyloid precursor protein in Alzheimer's disease (AD) elevate the expression of EGFR. This inappropriate peptide deposition on EGFR results in the sustained phosphorylation of the downstream signaling axis, leading to extensive Aβ1-42 production and tau phosphorylation as subsequent pathogenesis. Recent reports convey that the pathophysiology of AD is correlated with EGFR and its associated membrane receptor complex molecules. One such family of molecules is the annexin superfamily, which has synergistic relationships with EGFR and is known for membrane-bound signaling that contributes to a variety of inflammatory responses. Besides, Galectin-3, tissue-type activated plasminogen activator, and many more, which lineate the secretion of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, and IL-18) result in severe neuronal loss. Altogether, we emphasized the perspectives of cellular senescence up-regulated by EGFR and its associated membrane receptor molecules in the pathogenesis of AD as a target for a therapeutical alternative to intervene in AD.