Metabolomics approach revealed robust changes in amino acid and biogenic amine signatures in patients with schizophrenia in the early course of the disease.
The primary objective of this study was to evaluate how schizophrenia (SCH) spectrum disorders and applied antipsychotic (AP) treatment affect serum level of amino acids (AAs) and biogenic amines (BAs) in the early course of the disorder. We measured 21 different AAs and 10 BAs in a sample of antipsychotic (AP)-naïve first-episode psychosis (FEP) patients (n = 52) at baseline, after 0.6-year as well as after 5.1-year treatment compared to control subjects (CSs, n = 37). Serum levels of metabolites were determined with AbsoluteIDQ p180 kit using flow injection analysis tandem mass spectrometry and liquid chromatography technique. Elevated level of taurine and reduced level of proline and alpha-aminoadipic acid (alpha-AAA) were established as metabolites with significant change in AP-naïve FEP patients compared to CSs. The following 0.6-year treatment restored these alterations. However, further continuous 5.1-year AP treatment changed the metabolic profile substantially. Significantly elevated levels of asparagine, glutamine, methionine, ornithine and taurine, alongside with decreased levels of aspartate, glutamate and alpha-AAA were observed in the patient group compared to CSs. These biomolecule profile alterations provide further insights into the pathophysiology of SCH spectrum disorders and broaden our understanding of the impact of AP treatment in the early stages of the disease.


Three-dimensional evaluation of important surgical landmarks of the face during aging.
One surgical objective is creating an aesthetically satisfying outcome. The morbidity increases with age. Standard values for areas of the face, which are frequently surgically treated, are needed for the surgeon. 240 Caucasians aged 21-65 were divided into six subgroups by gender and age. They were scanned by a three-dimensional (3D) scanner. Distances and angles in faces between landmarks were evaluated. During aging, the relation of the eye's width to the eye's height became significantly smaller (M: p=0.001, F: p≤0.0001). The outer contour of the nose became significantly sharper with increasing age (M: p=0.001, F: p=0.0021). Seen from caudal, the nose formed an isosceles triangle with the base between the left and right alar curvature and the base had an average length of 31.35mm±2.97mm. The leg of this triangle had an average length of 33.67mm±2.09mm. The nose got longer and wider during aging; the age-dependent changes between the different groups of males (p≤0.0001) and the difference between females and males were significant (p≤0.0001). The thickness of the nasal wings remained the same size during a lifetime. Females had significantly greater heights for both lips (p≤0.0001, p=0.027). In males and females, the heights decreased with increasing age. This study provided a database of measurements of parts of the face, especially those parts that can underlie various surgical treatments.


A novel Family V uracil DNA glycosylase from Sulfolobus islandicus REY15A.
Uracil DNA glycosylase (UDG) can excise uracil from DNA, thus playing an essential role in counteracting mutations. The genome of the hyperthermophilic crenarchaeon Sulfolobus islandicus REY15A encodes one putative Family V UDG (Sis-UDGV). Herein, we provide evidence that Sis-UDGV is a bi-functional glycosylase that can not only excise uracil from DNA, but cleave the generated apurinic/apyrimidinic (AP) site, which differs from other reported mono-functional Family V UDG homologs. Intriguingly, the enzyme can cleave DNA containing an AP site, thus suggesting that it might be involved in AP site repair. Biochemical data demonstrate that Sis-UDGV displays maximum activity for uracil removal at 45 °C ∼ 65 oC and at pH 8.0 ∼ 9.0. Furthermore, Sis-UDGV displays a substrate preference for uracil-containing ssDNA over uracil-containing dsDNA, but has no activity and weak activity for excising hypoxanthine from ssDNA and dsDNA, respectively. Importantly, we dissected the roles of seven conserved residues in Sis-UDGV by mutational analyses, demonstrating that residues D91, E117, E128, H167 and R192 are essential for catalysis. To our knowledge, it is the first report on the novel Family V UDG from Archaea with bi-functionality that harbors glycosylase/AP lyase activity.


Effectiveness of enhanced recovery after surgery protocol in open gynecologic oncology surgery: A randomized controlled trial.
To examine the effectiveness of applying the recommended enhanced recovery after surgery (ERAS) protocol compared with our usual care in women with gynecologic malignancy undergoing elective laparotomy. From June 2020 to May 2021, 93 women with gynecologic cancers (cervix, endometrium, and ovary) undergoing elective laparotomy at our institution were randomly assigned into an intervention group (ERAS protocol, 46 women) or control group (usual care, 47 women). For the intervention group, each woman was brought through the pre-specified ERAS protocol starting from preoperative counseling to postoperative management. For the control group, participants underwent routine standard care. The primary outcomes were length of hospital stay and postoperative pain. The intervention group demonstrated shorter hospital stay by 20 h (47.48 h vs 67.17 h, P = 0.02) with lower postoperative pain score at postoperative day 0 (1.58 vs 4.00, P < 0.01) and day 1 (1.00 vs 2.67, P < 0.01) while having decreased opioid consumption (P < 0.01). The intervention group also had faster recovery of gastrointestinal function. Overall, good compliance to most of the ERAS pathway domains was obtained. The ERAS protocol demonstrates benefits on shortening hospital stay, reducing pain, and bowel function recovery without increasing complications in our population. The present study was registered at clinicaltrials.gov (NCT04201626) on December 3, 2019. Initial participant enrollment began on June 1, 2020. Access through URL of the registration site: https://clinicaltrials.gov/ct2/show/NCT04201626?cond=ERAS&cntry=TH&draw=2&rank=3.


The SEEL motif and members of the MYB-related REVEILLE transcription factor family are important for the expression of LORELEI in the synergid cells of the Arabidopsis female gametophyte.
Synergid cells in the micropylar end of the female gametophyte are required for critical cell-cell signaling interactions between the pollen tube and the ovule that precede double fertilization and seed formation in flowering plants. LORELEI (LRE) encodes a putative GPI-anchored protein that is expressed primarily in the synergid cells, and together with FERONIA, a receptor-like kinase, it controls pollen tube reception by the receptive synergid cell. Still, how LRE expression is controlled in synergid cells remains poorly characterized. We identified candidate cis-regulatory elements enriched in LRE and other synergid cell-expressed genes. One of the candidate motifs ('TAATATCT') in the LRE promoter was an uncharacterized variant of the Evening Element motif that we named as the Short Evening Element-like (SEEL) motif. Deletion or point mutations in the SEEL motif of the LRE promoter resulted in decreased reporter expression in synergid cells, demonstrating that the SEEL motif is important for expression of LRE in synergid cells. Additionally, we found that LRE expression is decreased in the loss of function mutants of REVEILLE (RVE) transcription factors, which are clock genes known to bind the SEEL and other closely related motifs. We propose that RVE transcription factors regulate LRE expression in synergid cells by binding to the SEEL motif in the LRE promoter. Identification of cis-regulatory elements and transcription factors involved in the expression of LRE will serve as a foundation to characterize the gene regulatory networks in synergid cells.


Quality of Life in Adults with Neurofibromatosis 1 in Brazil.
Neurofibromatosis type 1 (NF1) is a neurocutaneous genetic disorder that can be associated with severe complications, and it may shorten patients' lifespan and affect their quality of life negatively. This study aimed to examine quality of life constructs among adults with NF1 in Brazil. It is an exploratory, descriptive and cross-sectional study consisting of two stages, involving thirteen adult patients with NF1. The first stage was developed using a quantitative methodology, namely the WHOQOL-100 questionnaire; responses for the 13 patients were compared to a matched control group. The second stage comprised clinical-qualitative research whereby participants took part in a semi-structured interview; these data were analyzed using the categorical thematic analysis technique. There were no statistically significant differences in the questionnaire domains between the NF1 patients and the control subjects. Eighteen main themes were extracted from the interviews, showing interference of the NF1 visibility principally in psychological aspects and social relationships. Patients mentioned curiosity about NF1 and confusion about the distinctions between NF1 and contagious diseases, which lead to prejudice. They were concerned about the future and how the disease would develop in themselves and their offspring, and emphasized difficulties acquiring proper healthcare. These findings may help in planning healthcare for Brazilian NF1 patients and improving their quality of life.


Practical and theoretical considerations concerning the genetics of the Rett syndrome.
The Rett syndrome is exclusively found in girls. Considerable interest has been focused on a possible genetic background. The evidence for such an etiology is not conclusive and the findings in support of such a hypothesis are given. The few twin data and family data together with the chromosomal investigation indicate an X-linked inheritance. The recurrence risk in a family with one Rett girl is about 0.3%. Prenatal diagnosis is not recommended for the time being, as the only diagnosis, possible is prenatal sexing and most girls are healthy as the recurrence risk is low.


RGD-FasL induces apoptosis of pituitary adenoma cells.
This study was to investigate the cytotoxic effects on pituitary adenoma cell lines GH3/MMQ/AtT20 induced by RGD-FasL and the underlying mechanism. Fas/DcR3 mRNAs were detected by RT-PCR and their surface expressions were measured by flow cytometry. Cytotoxicity exerted by RGD-FasL on tumor cells was measured with MTT assay and the induced apoptosis was determined by agarose gel electrophoresis. The cell cycle and apoptosis was assessed by flow cytometry with PI staining. The expressions of caspase8/9/3, Bcl-2, RANKL and JNK2 were detected by Western blotting. Approximately 13.7% of GH3 cells, 25.5% of MMQ cells, 22.2% of AtT20 cells express Fas, while 23.9% of GH3 cells, 24.1% of MMQ cells, 4.6% of AtT20 cells express DcR3. The cytotoxic effects of FasL/RGD-FasL on tumor cells were all taken in a dose-dependent manner. Cell lines MMQ/AtT20 showed the same sensitivity to RGD-FasL as to FasL, while cell line GH3 was less sensitive to RGD-FasL. The cell cycle analysis indicated that RGD-FasL could inhibit cells in G0/G1 phase and G2/M phase. In MMQ and AtT20 cells treated with RGD-FasL, the AI was not significantly different from that treated with FasL, while in GH3 cells treated with RGD-FasL, the AI was lower than that treated with FasL. The expressions of caspase-8/9/3, RANKL and JNK2 were increased while that of Bcl-2 was decreased after treatment with RGD-FasL, suggesting that RGD-FasL induces apoptosis through caspase activation. We concluded that RGD-FasL could possibly be considered as a novel therapeutical candidate for the treatment of pituitary adenomas.


Development of a proficiency testing program for molecular diagnosis of influenza viruses.
The Molecular Virology Proficiency Testing Program at the Wadsworth Center began the assembly and distribution of influenza virus panels to US public health labs (PHLs) in 2008. The program was created to assist PHLs in assessing their performance and in meeting CLIA regulations for mandated proficiency testing (PT). To design and distribute proficiency testing panels containing influenza A virus subtypes H1N1 and H3N2, and influenza B; when H1N1pdm09 emerged it also was incorporated into the panels. A secondary objective was to determine the best matrix for long term storage of the molecular PT samples. Viruses were quantitated using TCID(50) and quantitative real-time RT-PCR. Reference laboratories were enlisted to verify viral identity in the panels and to help determine viral titers to be used in the PT panels sent to PHLs. Of the 29 laboratories that participated the first year, 27 were able to correctly identify all of the virus types in the panel. Fifty-one PHLs participated in the program the second year when pandemic H1N1 was added, and 45 were able to correctly detect, type and subtype all of the viruses in the panel. In the program's third year, 60 laboratories participated; 58 correctly detected and subtyped all of the viruses in the panel. Annual surveys of assay techniques showed that the PHLs had shifted their extraction methods and PCR-thermocycler instrumentation to meet FDA-approved methods. The degradation study revealed that frozen viral stocks were stable for at least 30months, thus allowing ample time to prepare and pre-test panels.


Effects of arginine supplementation on the humoral and innate immune response of older people.
To evaluate whether oral supplementation with arginine affects the humoral and innate immune response after vaccination against Streptococcus pneumoniae in a group of people aged 60 y and older, free-living in the community. A randomized controlled trial with one supplemented group and one control group. Older persons living in the community. A total of 29 adults aged 60 y and older. The older people were randomized into two groups, one with arginine supplementation (15 g/day) for 4 weeks after pneumococcal vaccine. The control group received only the vaccine. Anthropometric measurements and immune system function parameters: neutrophil chemotaxis and phagocytosis, natural killer cell activity, determination of serum pneumococcal polysaccharide antibodies and serum C3 and C4. Neutrophil phagocytosis and the serum concentration of complement (C3 and C4) did not differ between groups. IgG antibodies against pneumococcal polysaccharide serotypes 1, 5 and 6B increased in both groups. The following parameters increased in the arginine-supplemented group compared to the nonsupplemented group: neutrophil chemotaxis (34 vs 19 units of migration, P = 0.002), natural killer cell cytotoxicity (23.3 vs 13.4 10 M/Ul 40%, P = 0.011) and IgG against antigen 5 (12.3 vs 6.2 mug/ml, P = 0.044). This study suggests that, after the pneumococcal vaccine, the intake of arginine increased neutrophil chemotaxis, natural killer cytotoxicity and serum concentration of IgG against antigen 5 in older people. These results suggest that arginine supplementation may enhance the immune response elicited by the pneumococcal vaccine in older people. Supported in part by CAPES and FAEPA.


Medical service use and financial charges among opioid users at a public hospital.
We examined the prevalence of drug use related infectious complications among opioid using or dependent individuals and service charges associated with medical care received over a 2-year period at a public hospital. A computerized medical record review was used to identify 3147 individuals with diagnoses related to opioid use or dependence. Forty-nine percent of these patients were treated for bacterial infections and 30% presented for treatment of medical problems arising from the effects of the drugs themselves (e.g. drug withdrawal, overdoses, and drug-induced psychiatric symptoms). Mean charges were $13393 for these patients, nearly 2.5 times the average per patient charges for non-opioid using patients during the study period. Patients with diagnoses related to opioid use or dependence comprised 2% of the total patient population for this period, yet accounted for 5% of total charges. Homeless patients were less likely to have used ambulatory services and were more likely than non-homeless patients to have used emergency and inpatient services. Early detection of patients with opioid use or dependence problems, coupled with effective strategies to engage them in ambulatory preventive services, could allow interventions to reduce morbidity and associated charges in this patient population. The findings suggest that health care providers and policy makers consider policies that promote ambulatory care use among opioid users seeking medical care through the public health care system.


Rehabilitation of women with gynaecological cancer: the association between adult attachment, post-traumatic stress disorder and depression.
We hypothesised that being diagnosed with gynaecological cancer influences adult attachment and occurrence of depression and post-traumatic stress disorder (PTSD). The main aim of the study was to assess changes in the attachment dimensions, PTSD and depression from baseline to 5-month post-treatment. Further, we evaluated the association between attachment avoidance/anxiety dimensions and PTSD/depression among women newly diagnosed with ovarian, endometrial, or cervical cancer. Consecutive Danish-speaking women aged 20 to 75 years and treated surgically for primary gynaecological cancer were eligible. All patients were offered a rehabilitation programme consisting of two face-to-face sessions and two phone calls carried out by a nurse. Patients were asked to complete the Revised Adult Attachment Scale, the Harvard Trauma Questionnaire and the Major Depression Inventory at baseline and at 5-month follow-up. In all, 151 women consent to participate in the sessions where 51 fulfilled Revised Adult Attachment Scale questionnaire and contribute with socio-demographic data. We found significant positive changes within the attachment anxiety dimension among women with ovarian cancer, a significant reduction of PTSD among endometrial cancer patients and insignificant changes in depression among all cancer types. The attachment anxiety dimension significantly increased the odds for PTSD and depression. Depression and PTSD were prevalent among ovarian and cervical cancer patients. The adjustment of rehabilitation according to patients' attachment anxiety dimension contains possibilities for indirect impact on PTSD and depression symptoms. Copyright © 2015 John Wiley & Sons, Ltd.


White matter measures are near normal in controlled HIV infection except in those with cognitive impairment and longer HIV duration.
The objective of the current study was to quantify the degree of white matter (WM) abnormalities in chronic and virally suppressed HIV-infected (HIV+) persons while carefully taking into account demographic and disease factors. Diffusion tensor imaging (DTI) was conducted in 40 HIV- and 82 HIV+ men with comparable demographics and life style factors. The HIV+ sample was clinically stable with successful viral control. Diffusion was measured across 32 non-colinear directions with a b-value of 1000 s/mm2; fractional anisotropy (FA) and mean diffusivity (MD) maps were quantified with Itrack IDL. Using the ENIGMA DTI protocol, FA and MD values were extracted for each participant and in 11 skeleton regions of interest (SROI) from standard labels in the JHU ICBM-81 atlas covering major striato-frontal and parietal tracks. We found no major differences in FA and MD values across the 11 SROI between study groups. Within the HIV+ sample, we found that a higher CNS penetrating antiretroviral treatment, higher current CD4+ T cell count, and immune recovery from the nadir CD4+ T cell count were associated with increased FA and decreased MD (p < 0.05-0.006), while HIV duration, symptomatic, and asymptomatic cognitive impairment were associated with decreased FA and increased MD (p < 0.01-0.004). Stability of HIV treatment and antiretroviral CNS penetration efficiency in addition to current and historical immune recovery were related to higher FA and lower MD (p = 0.04-p < 0.01). In conclusion, WM DTI measures are near normal except for patients with neurocognitive impairment and longer HIV disease duration.


Physiological and pathological oscillatory networks in the human motor system.
Human brain functions are heavily contingent on neural interactions both at the single neuron and the neural population or system level. Accumulating evidence from neurophysiological studies strongly suggests that coupling of oscillatory neural activity provides an important mechanism to establish neural interactions. With the availability of whole-head magnetoencephalography (MEG) macroscopic oscillatory activity can be measured non-invasively from the human brain with high temporal and spatial resolution. To localise, quantify and map oscillatory activity and interactions onto individual brain anatomy we have developed the 'dynamic imaging of coherent sources' (DICS) method which allows to identify and analyse cerebral oscillatory networks from MEG recordings. Using this approach we have characterized physiological and pathological oscillatory networks in the human sensorimotor system. Coherent 8 Hz oscillations emerge from a cerebello-thalamo-premotor-motor cortical network and exert an 8 Hz oscillatory drive on the spinal motor neurons which can be observed as a physiological tremulousness of the movement termed movement discontinuities. This network represents the neurophysiological substrate of a discrete mode of motor control. In parkinsonian resting tremor we have identified an extensive cerebral network consisting of primary motor and lateral premotor cortex, supplementary motor cortex, thalamus/basal ganglia, posterior parietal cortex and secondary somatosensory cortex, which are entrained in the tremor or twice the tremor rhythm. This low frequency entrapment of motor areas likely plays an important role in the pathophysiology of parkinsonian motor symptoms. Finally, studies on patients with postural tremor in hepatic encephalopathy revealed that this type of tremor results from a pathologically slow thalamocortical and cortico-muscular coupling during isometric hold tasks. In conclusion, the analysis of oscillatory cerebral networks provides new insights into physiological mechanisms of motor control and pathophysiological mechanisms of tremor disorders.


[Characteristics of methyl-specific PCR-test of glutathione-S-transferase P1 gene in plasm DNA and cellular urinary precipitate for differential diagnosis of prostatic adenoma and adenocarcinoma].
The study was made of possibilities of methyl-specific PCR-test of glutathione-S-transferase P1 (GSTP1) gene in differential diagnosis of prostatic cancer: sensitivity of the test, comparison of reagents of Russian and foreign production. Blood plasm and cellur urinary precipitate DNA was investigated in patients with prostatic adenocarcinoma. The results show that the above test with domestic reagents is rather perspective for differential diagnosis.


Tumor growth retardation, cure, and induction of antitumor immunity in B16 melanoma-bearing mice by low electric field-enhanced chemotherapy.
The exposure of cells in vitro to trains of low voltage-pulsed electric fields in the range of 20-100 V/cm was previously shown to induce an efficient uptake of macromolecules with molecular weight in the range of M(r) 300-2,000,000 via an endocytic-like process. This study examines the antitumor effectiveness of treatment based on similar exposure of solid tumors in mice to low electric fields (LEFs) in the presence of chemotherapeutic agents. LEF was applied to approximately 5 mm in diameter (60-70 mm(3)) s.c. B16-F10.9 melanoma tumors by percutaneously placed electrodes after intratumoral injection of either cis-platinum(II) diamminedichloride, Taxol, 5-fluorouracil, or bleomycin. Significant eradication of primary tumors, prolongation of survival, and complete cure of some of the C57Bl/6 mice from both primary tumors and metastases were achieved using this technique with cis-platinum(II) diamminedichloride, bleomycin, and Taxol (13.5, 8, and 26% cure rate, respectively). Mice cured by LEF-enhanced chemotherapy and challenged with a tumorigenic dose of B16-F10.9 cells lived significantly longer than first time inoculated ones, and 23.5% of the challenged mice did not develop tumors at all. Spleen cells from the cured mice that were inoculated together with B16-F10.9 cells inhibited the primary tumor growth in intact mice. Histological analysis of tumor sections of LEF-enhanced chemotherapy-treated mice revealed multiple necrotic areas, apoptosis, and massive infiltrates of T lymphocytes and macrophages. Low voltage electrochemotherapy with Taxol was shown to be more effective than surgical removal of the tumor with Taxol. These findings indicate that LEF-enhanced chemotherapy is an effective treatment of animals bearing metastatic melanoma.


Effects of water temperature and flavoring on voluntary dehydration in men.
Effects of water temperature and flavoring on fluid consumption and body weight losses were studied in fourteen unacclimatized men (21-33 years) during 6 hr of treadmill exercise (4.8 km.hr-1, 5% grade for 30 min.hr-1) in a hot environment. Subjects consumed each of four beverages (15 degrees C water, 40 degrees C water, 15 degrees C flavored water, and 40 degrees C flavored water) on four nonconsecutive days. We identified two groups of individuals by body weight (BW) loss during the cool water trial: drinkers (D) who lost less than 2% initial BW (0.80 +/- 0.15%) and reluctant drinkers (RD) who lost more than 2% (2.53 +/- 0.12%). Although sweat losses were not different between the two groups, D consumed 31% more cool water than RD and experienced 68% less BW loss. Compared to the warm water trial, 6 hr consumption of cool water was significantly increased in both D (59%) and RD (141%) and BW loss was dramatically reduced in both groups. Flavoring significantly enhanced warm water consumption and reduced BW loss in RD only. Reduced consumption of warm water increased rectal temperature, heart rate and plasma osmolality in both groups. The results of this study indicate that either flavoring or cooling warm water will enhance fluid intake and reduce body weight deficits in men reluctant to drink.


Exposure to acid-suppressing drugs during pregnancy and the risk of asthma in childhood: an observational cohort study.
Some research has suggested a potential link between prenatal exposure to proton pump inhibitors (PPIs) or H2 -receptor antagonists (H2 RAs) and the development of childhood asthma. To quantify the relative risk of asthma in children who experienced pre-natal exposure to PPIs and/or H2 RAs, adjusting for potential confounders. In this observational cohort study (NCT01787435), women aged 18-45 years with completed pregnancies between January 1996 and December 2010 were identified from The Health Improvement Network in the United Kingdom, and were linked to infants. Hazard ratios (HRs) were estimated using Cox proportional hazard models. Our analysis identified 2371 prenatally exposed and 7745 unexposed infants. The incidence of asthma (per 1000 person-years) was 19.52 in the unexposed cohort, 23.88 in the PPI cohort and 32.16 in the H2 RA cohort. After adjusting for maternal healthcare utilisation during the year before pregnancy, the HR for asthma in infants whose mothers received prescriptions at any time during pregnancy was 1.12 (95% confidence interval: 0.88-1.44) for PPIs and 1.43 (1.20-1.70) for H2 RAs, when compared with unexposed infants. With further adjustment for maternal comorbidities and other medications, the HR for asthma was 1.03 (0.76-1.40) for PPIs and 1.32 (1.05-1.64) for H2 RAs. Our analysis showed no association between prenatal exposure to PPIs and asthma in childhood after adjusting for confounders. The association found for H2 RAs may be explained largely by underlying environmental or genetic factors, as suggested by reductions in hazard ratio estimates following adjustment for maternal comorbidities.


Is signet-ring cell carcinoma a specific entity among gastric cancers?
The prognosis and chemoresistance of signet-ring cell (SRC) gastric adenocarcinoma have been reported and debated, and the utility of perioperative chemotherapy for such a tumor has been questioned . This study was performed to assess the impact of the SRC type on survival following resection of gastric adenocarcinoma, and to assess whether the prognostic factors (including perioperative chemotherapy) for non-SRC adenocarcinoma differed from those for SRC adenocarcinoma. 1799 cases of adenocarcinoma that were consecutively treated from 1997 to 2010 in 19 French centers by subtotal or total gastrectomy were included in a retrospective study. A D2 lymphadenectomy was performed for antropyloric tumors, and a modified D2 for upper tumors. SRC adenocarcinoma was diagnosed based on the presence of isolated carcinoma cells containing mucin. A total gastrectomy was performed in 979 (54.4 %) patients. SRC adenocarcinoma was diagnosed in 899 (50 %) patients. Patients with an SRC tumor were more frequently female, younger, and malnourished, had lower ASA scores, and had larger tumors than non-SRC patients. Median survival in patients with non-SRC carcinoma was 51 months, as compared to 26 months in patients with SRC carcinoma (p < 0.001). At multivariate analysis, SRC type remained an independent adverse prognostic factor (HR = 1.182). Factors that were prognostic in the SRC subgroup but not in the non-SRC subgroup were age >60 years, linitis, and involvement of adjacent organs. In contrast to non-SRC tumors, pre- and postoperative chemotherapy did not significantly impact on survival following resection of SRC adenocarcinoma. In comparison to non-SRC adenocarcinoma, the SRC type has a worse prognosis, different prognostic factors, and is only poorly sensitive to perioperative chemotherapy. Non-SRC and SRC adenocarcinomas should be considered different entities in future therapeutic trials.


Inhibition of nitric oxide formation and superoxide generation during reduction of LY83583 by neuronal nitric oxide synthase.
6-Anilino-5,8-quinolinedione (LY83583) has been widely used as an agent to reduce levels of nitric oxide (NO)-dependent cGMP in tissues. We report here that suppression of NO formation and production of superoxide during enzymatic reduction of LY83583 by neuronal NO synthase appeared to be potentially involved in the pharmacological action caused by LY83583. LY83583 suppressed neuronal NO synthase activity of 20,000 x g rat cerebellar supernatant preparation in a concentration-dependent manner (IC50 value = 12.9 microM). A kinetic study revealed that LY83583 is a competitive inhibitor with respect to NADPH, with a Ki value of 2.57 microM. With purified neuronal NO synthase it was found that LY83583 was a potent inhibitor of NO formation by the enzyme and served as efficient substrate for reduction with a specific activity of 173 nmol of NADPH oxidized per mg of protein per minute. The reductase activity was stimulated about 19.8-fold by addition of CaCl2/calmodulin, indicating that the presence of CaCl2/calmodulin is essential to express maximal activity of LY83583 reduction. Although LY83583 was a good substrate for both NADPH-cytochrome P450 reductase (P450 reductase) and DT-diaphorase, these flavin enzymes-catalyzed reductions of LY83583 were less than the neuronal NO synthase-mediated reduction in the presence of CaCl2/calmodulin. Enzymatic generation of superoxide during reduction of LY83583 by neuronal NO synthase, P450 reductase or DT-diaphorase was confirmed by electron spin resonance (ESR) experiments. Thus the present results indicate that a benzoquinone derivative LY83583 appears to interact with the P450 reductase domain on neuronal NO synthase, resulting in inhibition of NO formation and superoxide generation, which is involved in suppression of intracellular cGMP content.


Alkaloids of Peganum harmala: Anticancer Biomarkers with Promising Outcomes.
Cancer is a serious and growing global health issue worldwide. In the cancerous cells, the normal cell cycle has been disrupted via a series of irreversible changes. Recently, the investigations on herbal medicine and clarifying the phytochemicals potential in treat cancer has been increased. The combination of phytochemicals with conventional cancer treatment approaches can improve outcomes via advancing cell death, restraining cell proliferation and invasion, sensitizing cancerous cells, and promoting the immune system. Therefore, phytochemicals can be introduced as relevant complementary medicaments in cancer therapy. Peganum harmala L. (Zygophyllaceae) as a valuable medicinal herb, possesses various alkaloid ingredient. Pointing to the importance of new avenues for cancer management and P. harmala convincing effect in this field, this review strived to collect a frame to epitome possible scopes to develop novel medicines in cancer treatment. Keywords "Peganum harmala" and cancer, or chemotherapy, or anti-neoplasm were searched through the "Scopus" database up to 29th of February 2020. Papers linking to agriculture, chemistry, environmental, and genetics sciences were omitted and, papers centered on cancer were selected. In the current study, 42 related papers to cancer treatment and 22 papers on alkaloid bioactive components are collected from 72 papers. The β-carboline alkaloids derived from P. harmala, especially harmine, demonstrate notable anticancer properties by targeting apoptosis, autophagy, abnormal cell proliferation, angiogenesis, metastasis, and cytotoxicity. Based on the collected information, P. harmala holds significant anticancer activity. Considering the mechanism of the various anticancer drugs and their acting similarity to P. harmala, the alkaloids derived from this herb, particularly harmine, can introduce as a novel anticancer medicine solely or in adjuvant cancer therapy.


Genotype-phenotype correlation in 667 Chinese families with spinocerebellar ataxia type 3.
Due to diverse symptoms of spinocerebellar ataxia type 3 (SCA3) and the high prevalence of SCA3 in China, a more in-depth study of Chinese SCA3 patients in a large cohort is well merited. During the last 10 years, 730 patients and 133 premanifest individuals from 667 SCA3 families genetically confirmed to have SCA3 were enrolled from three leading academic hospitals in China. The clinical profile and genotype-phenotype correlation were analyzed. A quadratic equation best explained the relationship between the logarithmically transformed age at onset (AAO) and expanded CAG repeats (expCAGs) (r2 = 0.634, p < 0.001). The expCAG and AAO in Asian populations and western populations were compared with the Chinese population. SCA3 individuals had shorter normal CAG repeats (norCAGs) than healthy controls (Mann-Whitney, p < 0.0001). Most (92.1%) SCA3 patients had gait-ataxia onset. Their AAO and expCAGs were not significantly different from SCA3 patients with non-gait-ataxia onset. Limb ataxia and pyramidal impairment occurred less in patients with disease duration >10 years. Intriguingly, onset after parturition happened in 10 female patients with the AAO of 26.7 ± 4.3 years and the expCAG of 77.4 ± 1.4 repeats. Five out of 12 patients with subtype V and larger expCAGs (78.8 ± 4.8 repeats) suffered from spastic gait initially, and 10 out of 12 showed no limb ataxia. Nystagmus happened most frequently (10.5%) in premanifest individuals. We demonstrated the genotype-phenotype correlation in the largest cohort of SCA3 individuals to date, and interestingly found some new phenomena in Chinese SCA3 individuals.


Radiotherapy for malignant fistula to other tract.
Radiotherapy was applied to 14 esophageal carcinomas with respiratory tract fistulas using various treatment regimens. Closure of the fistulas was observed in four cases after irradiation at a daily dose of 1.5 Gy. The period of closure was transient in two cases but long-term in the other two. One long-term closure case underwent low-dose rate telecobalt therapy (LDRT)(1 Gy per hour, 7 Gy per day; a total dose of 28 Gy) as a boost. His cancer has been well controlled and he is still alive without recurrence at 74 months after fistula formation.


Genotypic monoclonality in immunophenotypically polyclonal orbital lymphoid tumors. A model of tumor progression in the lymphoid system. The 1986 Wendell Hughes lecture.
Molecular genetic (genotypic) analysis elucidates gene rearrangements within lymphocytes that are responsible for either immunoglobulin production in B-lymphocytes or the expression of cell-surface antigen recognition receptors in T-lymphocytes. Molecular genetic analysis is far more sensitive than immunophenotypic methods for the detection of small clones of lymphocytes because as few as 2 to 5% of cells in an infiltrate can be discovered to possess the same rearranged DNA sequences with genetic probes. In truly polyclonal proliferations, each lymphocyte reorganizes its immunoglobulin or T-antigen receptor genes in a unique manner, resulting in an almost infinite number of combinations of genetic rearrangement and the absence of any new hybridizing bands upon Southern blotting. In monoclonal proliferations, a new, homogeneous, nongermline band is identified on Southern blotting because a sufficiently large number of lymphocytes exhibit an identical genetic rearrangement. In a group of five orbital lymphoid tumors that appeared to be benign reactive hyperplasias by light microscopy and that were polyclonal by immunophenotypic methods, three were found by molecular genetic analysis to harbor small clones of B-lymphocytes with new rearrangement bands on Southern blotting. No clonal abnormalities of T-lymphocytes were found in these five lesions, despite the fact that they were the preponderant cells in the tumors. These observations suggest that "reactive lymphoid hyperplasia" of the orbit may be an unstable lesion, owing to a T-cell immunoregulatory imbalance, with the potential for developing clonal expansions of B-lymphocytes that nonetheless usually remain localized to the orbit.


Responding to a fire at a pediatric hospital.
Disaster preparedness in health care organizations facilitates a formalized response to major incidents or disasters. This article reviews a man-made disaster, a fire at a large pediatric hospital. How the fire started, patient evacuation, redirecting services, timing of events, key players, geographic factors, communications, and recovery and restoration of care are discussed. Lessons learned and Information on disaster preparedness also are presented.


The effect of fusarium toxin contaminated maize on performance and health of female weaning piglets.
The influence of increasing amounts of zearalenone and de-oxynivalenol in diets for prepubertal pigs was investigated on 100 female piglets fed diets with increasing concentrations of ZON and DON (0.01mg ZON and 0.2mg DON/kg to 0.42mg ZON and 3.9mg DON/kg). Concentrations of 0.06mg ZON and 0.8mg DON per kg diet caused a significant decrease of serum concentrations of GLDH and FSH as well as vulva swelling. The uterus weight of the piglets receiving 0.42mg ZON and 3.9mg DON/kg was increased by almost 100% compared to the control. Furthermore, this group showed significantly decreased performance, serum protein concentration and zervix swelling. Further studies are needed to scrutinize the adverse effects of ZON and DON in diets for prepubertal female piglets, especially on future reproduction performance.


Nectar production rates of Asclepias quadrifolia: causes and consequences of individual variation.
The causes and reproductive consequences of individual variation in nectar production rates within a population of Asclepias quadrifolia were investigated. Two parameters were correlated with nectar production rate per flower: the root weight of the plant and the number of flowers in the inflorescence (umbel). Nectar production increased with increasing root weight but levelled off after a root size of about 3 g was reached. Nectar production decreased with increasing umbel size, but only for umbels that were greater than average size. A total of 57% of the variance in individual nectar production could be explained by these two variables with root weight accounting for 67% of the explained variance. Root weight is a good indicator of a plant's energetic status, indicating the importance of available energy in determining quantity of nectar produced. About 30% of the energy devoted to flowering is utilized in nectar production. Nectar production was significantly correlated with the male component of reproductive fitness, pollinaria removal, but not with the female component, pollinia insertion. Since pod production is limited by resource availability rather than the number of pollinia insertions, nectar production in A. quadrifolia is most closely associated with the maximization of the male function.


The production of a "universal developer" for the immunological detection of human IgG and its application in immunodiagnostics.
This study describes the development of a biospecific monoclonal antibody capable of the simultaneous recognition of horseradish peroxidase (HRP) and human IgG. This antibody, coded McC2, has been applied in a novel manner as a universal developing reagent for the detection of human IgG. McC2 cross-reacts with all human IgG subtypes and was found to recognise an epitope on the Fc portion of human IgG. McC2 does not cross-react with human IgM or IgA. This bi-specific antibody belongs to the mouse IgG1 subclass. McC2 was used for the detection of human IgG in a simple one step enzyme-linked immunosorbent assay (ELISA). Use of this bi-specific antibody in this assay resulted in an excellent signal to noise ratio with background in negative control wells virtually nonexistent. McC2 was also applied in a clinical diagnostic test for the detection of auto anti-nuclear antibodies in patient sera. McC2 was substituted, in a blind study, for a HRP-conjugated second antibody supplied with the test kit. All sera were tested both with the kit's second antibody and McC2. When using McC2, we obtained no false positive results whereas five false positives were obtained when using the kit's second antibody. However, one false negative result was obtained with the use of McC2 as a developing reagent while none were noted with the use of the kit's second antibody.(ABSTRACT TRUNCATED AT 250 WORDS)


Adoption of Korean children by New York area couples: a preliminary study.
This paper reports on the first segment of a longitudinal study of the effects of transracial and transcultural transplantation into American families.


Neuropathophysiological significance of the c.1449T>C/p.(Tyr64Cys) mutation in the CDC42 gene responsible for Takenouchi-Kosaki syndrome.
Takenouchi-Kosaki syndrome (TKS) is an autosomal dominant congenital syndrome, of which pathogenesis is not well understood. Recently, a heterozygous mutation c.1449T > C/p.(Tyr64Cys) in the CDC42 gene, encoding a Rho family small GTPase, has been demonstrated to contribute to the TKS clinical features, including developmental delay with intellectual disability (ID). However, specific molecular mechanisms underlying the neuronal pathophysiology of TKS remain largely unknown. In this study, biochemical analyses revealed that the mutation moderately activates Cdc42. In utero electroporation-based acute expression of Cdc42-Y64C in ventricular zone progenitor cells in embryonic mice cerebral cortex resulted in migration defects and cluster formation of excitatory neurons. Expression the mutant in primary cultured hippocampal neurons caused impaired axon elongation. These data suggest that the c.1449T > C/p.(Tyr64Cys) mutation causes altered CDC42 function and results in defects in neuronal morphology and migration during brain development, which is likely to be responsible for pathophysiology of psychomotor delay and ID in TKS.


Association Between Race/Ethnicity and Severity of Illness in Pediatric Cardiomyopathy and Myocarditis.
Previous reports demonstrate racial/ethnic differences in survival for children hospitalized with cardiomyopathy and myocarditis. The impact of illness severity, a potential mechanism for disparities, has not been explored. Using the Virtual Pediatric Systems (VPS, LLC), we identified patients ≤ 18 years old admitted to the intensive care unit (ICU) for cardiomyopathy/myocarditis. Multivariate regression models were used to evaluate the association between race/ethnicity and Pediatric Risk of Mortality (PRISM 3). Multivariate logistic and competing risk regression was used to examine the relationship between race/ethnicity and mortality, CPR, and ECMO. Black patients had higher PRISM 3 scores on first admission (𝛽 = 2.02, 95% CI: 0.15, 3.90). There was no difference in survival across race/ethnicity over multiple hospitalizations. Black patients were less likely to receive a heart transplant (SHR = 0.65, 95% CI: 0.45-0.92). Black and unreported race/ethnicity had higher odds of CPR on first admission (OR = 1.64, 95% CI: 1.01-2.45; OR = 2.12, 95% CI: 1.11-4.08, respectively). Black patients have higher severity of illness on first admission to the ICU, which may reflect differences in access to care. Black patients are less likely to receive a heart transplant. Additionally, Black patients and those with unreported race/ethnicity had higher odds of CPR, which was not mediated by severity of illness, suggesting variations in care may persist after admission.


Change in alpha-ketoglutarate dehydrogenase cooperative properties due to dihydrolipoate and NADH.
Reducing 2 SH-groups of KGD by dihydrolipoate leads to cooperativity in substrate binding. Cooperative properties of KGD in the KGD complex are modulated by NADH. Physiological significance of these observations is discussed.


Right up there: hemispatial and hand asymmetries of altitudinal pseudoneglect.
Pseudoneglect is a normal left sided spatial bias observed with attempted bisections of horizontal lines and a normal upward bias observed with attempted bisections of vertical lines. Horizontal pseudoneglect has been attributed to right hemispheric dominance for the allocation of attention. The goal of this study was to test the hypothesis that the upward bias in vertical line bisection may also relate to right hemispheric dominance for the allocation of attention and/or action-intention. Twenty right handed healthy adults were asked to bisect vertical lines presented in the midsagittal plane (center space) and in sagittal planes to the left and right of the midsagittal plane (left and right hemispace) when using a pen held in either the right or left hand. Vertical line bisections were biased upward in all three sagittal planes and higher in left than right hemispace. However, bisections made with the left hand were lower than those made with the right hand. Whereas these results suggest a left hemispace-right hemispheric visuospatial attentional upward bias and a relative left hemispheric-right hand upward action-intentional bias, further studies are needed to document this intentional versus attentional bias and to understand the brain mechanisms that produce these biases.


Mammographic changes after fat transfer to the breast compared with changes after breast reduction: a blinded study.
: One issue in the adoption of autologous fat transfer to the breast is concern over mammographic changes that may obscure cancer detection. The authors compared mammographic changes following fat grafting to the breast with changes seen after breast reduction. : Twenty-seven women who had normal preoperative mammograms were treated with fat grafting to the breast, including admixing of autologous adipose stem cells with the fat graft, for cosmetic augmentation. Repeated mammograms were performed 12 months after surgery. As a control group, postsurgical mammograms from 23 reduction mammaplasty patients were compared. Eight academic breast imaging radiologists reviewed each mammogram in a blinded fashion. Outcomes analysis accounting for individual radiologist's tendencies was performed using generalized estimating equations. : The average volume of fat injected per patient was 526.5 cc. Fifty mammograms (27 lipotransfer, 23 breast reduction) were assessed. Differences in interpretation among individual radiologists were consistently observed (p < 0.10). Differences in abnormality rates were nonsignificant for oil cysts, benign calcifications, and calcifications warranting biopsy. Scarring (p < 0.001) and masses requiring biopsy (p < 0.001) were more common in the reduction cohort. Breast Imaging Reporting and Data System scores were higher after breast reduction (p < 0.001). Significant differences in the recommended follow-up time were also seen (p < 0.01). : Compared with reduction mammaplasty, a widely accepted procedure, fat grafting to the breast produces fewer radiographic abnormalities with a more favorable Breast Imaging Reporting and Data System score and less aggressive follow-up recommendations by breast radiologists. : Therapeutic, III.


A model of jejunoileal in vivo neural isolation of the entire jejunoileum: transplantation and the effects on intestinal motility.
The effects of intestinal transplantation on enteric physiology have not been well studied. Our aim was to determine the effect of jejunoileal transplantation on patterns of small intestinal motility. To avoid confounding effects of immune rejection or immunosuppression, we developed a model of autotransplantation in which all tissue connections to the entire jejunoileum were transected at the base of the mesentery except for the superior mesenteric artery and vein which were stripped meticulously of investing adventitia. After 3 weeks, motility was studied in eight dogs with intestinal electrodes during fasting, after meals of 50 and 500 g of liver, and during intravenous infusions of pentagastrin and cholecystokinin. During fasting, the characteristic inter-digestive migrating motor complex (MMC) was present in both the innervated duodenum and the "autotransplanted" jejunoileum; however, temporal coordination between the two regions was abolished. Feeding 50 g of liver abolished the MMC in the duodenum, but not in the jejunoileum; in contrast, 500 g of liver interrupted the MMC in both regions. Exogenous pentagastrin and cholecystokinin inhibited the MMC for the duration of the infusions. These findings suggest that extrinsic nerves and/or intrinsic (enteric) myoneural continuity do not initiate fasting motor patterns in the jejunoileum but do regulate the temporal coordination of motor patterns between segments of small intestine. Postprandial inhibition of the MMC is only in part mediated by neural factors. After transplantation, motility is abnormal; the overall effects on enteric physiology remain unknown.


The Hyperproliferation Mechanism of Cholesteatoma Based on Proteomics: SNCA Promotes Autophagy-Mediated Cell Proliferation Through the PI3K/AKT/CyclinD1 Signaling Pathway.
Cholesteatoma is a chronic inflammatory ear disease with abnormal keratinized epithelium proliferation and tissue damage. However, the mechanism of keratinized epithelium hyperproliferation in cholesteatoma remains unknown. Hence, our study sought to shed light on mechanisms affecting the pathology and development of cholesteatoma, which could help develop adjunctive treatments. To investigate molecular changes in cholesteatoma pathogenesis, we analyzed clinical cholesteatoma specimens and paired ear canal skin with mass spectrometry-based proteomics and bioinformatics. From our screen, alpha-synuclein (SNCA) was overexpressed in middle ear cholesteatoma and might be a key hub protein associated with inflammation, proliferation, and autophagy in cholesteatoma. SNCA was more sensitive to lipopolysaccharide-induced inflammation, and autophagy marker increase was accompanied by autophagy activation in middle ear cholesteatoma tissues. Overexpression of SNCA activated autophagy and promoted cell proliferation and migration, especially under lipopolysaccharide inflammatory stimulation. Moreover, inhibiting autophagy impaired SNCA-mediated keratinocyte proliferation and corresponded with inhibition of the PI3K/AKT/CyclinD1 pathways. Also, 740Y-P, a PI3K activator reversed the suppression of autophagy and PI3K signaling by siATG5 in SNCA-overexpressing cells, which restored proliferative activity. Besides, knockdown of SNCA in RHEK-1 and HaCaT cells or knockdown of PI3K in RHEK-1 and HaCaT cells overexpressing SNCA both resulted in attenuated cell proliferation. Our studies indicated that SNCA overexpression in cholesteatoma might maintain the proliferative ability of cholesteatoma keratinocytes by promoting autophagy under inflammatory conditions. This suggests that dual inhibition of SNCA and autophagy may be a promising new target for treating cholesteatoma.


Police seizure of drugs without arrest among people who use drugs in Vancouver, Canada, before provincial 'decriminalization' of simple possession: a cohort study.
Several jurisdictions in Canada have recently considered decriminalizing possession of illicit drugs for personal use (henceforth, simple possession) as part of their responses to the ongoing drug toxicity/overdose crisis. In this context, we sought to examine an early implementation case of a de facto depenalization policy of simple possession offences in Vancouver, Canada, that was enacted in 2006. Specifically, we characterized experiences of people who use drugs (PWUD) whose drugs were discretionally seized by police without arrest. Data were derived from three prospective cohorts of community-recruited PWUD in Vancouver over 16 months in 2019-2021. We conducted multivariable generalized estimating equations analyses to determine the prevalence of and factors associated with drug seizure. Sub-analyses used data collected in 2009-2012 and examined the trends over time. Among 995 participants who were interviewed in 2019-2021, 63 (6.3%) had their drugs seized by police at least once in the past 6 months. In multivariable analyses, factors significantly associated with drug seizure included: homelessness (adjusted odds ratio [AOR]: 1.98; 95% confidence interval [CI] 1.09-3.61), working in the unregulated drug market (AOR: 4.93; 95% CI 2.87-8.49), and naloxone administration (AOR: 2.15; 95% CI 1.23-3.76). In 2009-2012, 67.8% reported having obtained new drugs immediately after having their drugs seized by police. Odds of drug seizure were not significantly different between the two time periods (2019-2021 vs. 2009-2012) (AOR: 0.93; 95% CI: 0.64-1.35). Despite the depenalization policy, the Vancouver Police Department has continued to seize illicit drugs from PWUD, even in cases where no arrest occurred. This policing practice may create health and safety risks for PWUD as it forces PWUD to increase the engagement with the unregulated illicit drug market. Our findings support calls for abolishing this often-undocumented discretionary policing practice that may exacerbate ongoing health inequities and interfere with peer-based overdose prevention efforts.


Comparison of the erbium-yttrium aluminum garnet and carbon dioxide lasers for in vitro bone and cartilage ablation.
The in vitro bone- and cartilage-ablation characteristics of the solid-state erbium:yttrium aluminum garnet laser were compared to those of the carbon dioxide laser. Ablations of fresh, frozen cadaver septal cartilage and maxillary sinus bone were performed using total energies between 1 and 6 J. Specimens were studied using hematoxylin and eosin stain and digitized, computer-assisted measurements of 35-mm photographs. Erbium-yttrium aluminum garnet-ablated bone averaged 5 microns of adjacent tissue thermal injury, compared with 67 microns with carbon dioxide-ablated bone. Erbium-yttrium aluminum garnet-ablated cartilage averaged 2 microns of adjacent tissue thermal injury, compared with 21 microns with the carbon dioxide-ablated cartilage. The tissue-ablation characteristics of the erbium-yttrium aluminum garnet laser are promising for future otolaryngologic applications.


Structural basis for the selective inhibition of human 3beta-hydroxysteroid dehydrogenase 1 in human breast tumor MCF-7 cells.
Human 3beta-hydroxysteroid dehydrogenase/isomerase type 1 (3beta-HSD1) is a critical enzyme in the conversion of DHEA to estradiol in breast tumors and may be a target enzyme for inhibition in the treatment of breast cancer in postmenopausal women. Human 3beta-HSD2 participates in the production of cortisol and aldosterone in the human adrenal gland in this population. In our recombinant human breast tumor MCF-7 Tet-off cells that express either 3beta-HSD1 or 3beta-HSD2, trilostane and epostane inhibit the DHEA-induced proliferation of MCF-7 3beta-HSD1 cells with 12- to 16-fold lower IC(50) values compared to the MCF-7 3beta-HSD2 cells. The compounds also competitively inhibit purified human 3beta-HSD1 with 12- to 16-fold lower K(i) values compared to the noncompetitive K(i) values measured for human 3beta-HSD2. Using our structural model of 3beta-HSD1, trilostane or 17beta-acetoxy-trilostane was docked in the active site of 3beta-HSD1, and Arg195 in 3beta-HSD1 or Pro195 in 3beta-HSD2 was identified as a potentially critical residue (one of 23 non-identical residues in the two isoenzymes). The P195R mutant of 3beta-HSD2 were created, expressed and purified. Kinetic analyses of enzyme inhibition suggest that the high affinity, competitive inhibition of 3beta-HSD1 by trilostane and epostane may be related to the presence of Arg195 in 3beta-HSD1 vs. Pro195 in 3beta-HSD2.


Clinical Presentation of Chiari-like Malformation in 2 Persian Cats.
Two Persian breed cats, 10 and 5 years of age, were presented separately for difficulty prehending food as well as behavioral abnormalities including interanimal aggression and restlessness, pacing, or compulsive overgrooming. Both cats would regularly rest their head and neck in an extended position. Neurologic examination demonstrated calvarial and craniocervical junction pain in both and an L4-S3 myelopathy in one. Brain MRI of both cases, and CT and necropsy in 1 case, demonstrated ventriculomegaly and caudal fossa crowding, cerebellar indentation, and foramen magnum herniation consistent with Chiari-like malformation. No syringomyelia was present in either cat. The 2 cats were treated with anti-inflammatory doses of prednisolone with little to no clinical response, but experienced improvement with pregabalin and omeprazole. The 2 cats' clinical signs were consequently attributed to neuropathic and posture-related pain secondary to Chiari-like malformation. Persian breed cats may have a predisposition to Chiari-like malformation, which may not be solely a morphometric variant, and symptomatic cats may present with manifestations of neuropathic pain different from the classic signs reported in dogs.


Hepatitis B virus deoxyribonucleic acid in serum during hepatitis B e antigen clearance in corticosteroid-treated severe chronic active hepatitis B.
The relationship between hepatitis B virus deoxyribonucleic acid in serum and histologic activity was determined in 11 patients with corticosteroid-treated severe chronic active hepatitis B who underwent clearance of hepatitis B e antigen. All patients cleared hepatitis B virus deoxyribonucleic acid from the serum, and clearance preceded the loss of hepatitis B e antigen by 9-49 mo (mean 24 +/- 4 mo). Seropositivity for hepatitis B virus deoxyribonucleic acid was always associated with histologic features of chronic active hepatitis. Resolution of histologic activity followed the loss of hepatitis B virus deoxyribonucleic acid from the serum and it preceded clearance of hepatitis B e antigen in all patients. A transient elevation of serum aspartate aminotransferase activity occurred in 5 patients at the time that absence of hepatitis B virus deoxyribonucleic acid in serum was first demonstrated, and it was followed by resolution of histologic activity. The serum level of hepatitis B virus deoxyribonucleic acid slowly decreased or remained unchanged in all but 1 patient during long-term corticosteroid therapy. We conclude that hepatitis B virus deoxyribonucleic acid in serum is associated with histologic activity in corticosteroid-treated patients with severe chronic active hepatitis B. Disappearance of hepatitis B virus deoxyribonucleic acid from the serum precedes the loss of histologic activity and clearance of hepatitis B e antigen. Serum hepatitis B virus deoxyribonucleic acid levels usually do not increase during long-term corticosteroid therapy.


Safety and tolerability of nintedanib in patients with progressive fibrosing interstitial lung diseases: data from the randomized controlled INBUILD trial.
In the INBUILD trial in patients with progressive fibrosing interstitial lung diseases (ILDs), nintedanib reduced the rate of decline in forced vital capacity compared with placebo, with side-effects that were manageable for most patients. We used data from the INBUILD trial to characterize further the safety and tolerability of nintedanib. Patients with fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), who had experienced progression of ILD within the 24 months before screening despite management deemed appropriate in clinical practice, were randomized to receive nintedanib 150 mg twice daily or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg twice daily. We assessed adverse events and dose adjustments over the whole trial. A total of 332 patients received nintedanib and 331 received placebo. Median exposure to trial drug was 17.4 months in both treatment groups. Adverse events led to treatment discontinuation in 22.0% of patients treated with nintedanib and 14.5% of patients who received placebo. The most frequent adverse event was diarrhea, reported in 72.3% of patients in the nintedanib group and 25.7% of patients in the placebo group. Diarrhea led to treatment discontinuation in 6.3% of patients in the nintedanib group and 0.3% of the placebo group. In the nintedanib and placebo groups, respectively, 48.2% and 15.7% of patients had ≥ 1 dose reduction and/or treatment interruption. Serious adverse events were reported in 44.3% of patients in the nintedanib group and 49.5% of patients in the placebo group. The adverse event profile of nintedanib was generally consistent across subgroups based on age, sex, race and weight, but nausea, vomiting and dose reductions were more common among female than male patients. The adverse event profile of nintedanib in patients with progressive fibrosing ILDs other than IPF is consistent with its established safety and tolerability profile in patients with IPF and characterized mainly by gastrointestinal events, particularly diarrhea. Management of adverse events using symptomatic therapies and dose adjustment is important to minimize the impact of adverse events and help patients remain on therapy. Trial registration Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178 A video abstract summarizing the key results presented in this manuscript is available at: https://www.globalmedcomms.com/respiratory/cottin/INBUILDsafety .


A dual-mode of electrochemical-colorimetric biosensing platform for kanamycin detection based on self-sacrifice beacon and magnetic separation technique.
In this work, iron-based metal organic frameworks (Fe-MOF) are used as a self-sacrifice beacon to produce Prussian blue (PB). Then, a dual-mode electrochemical-colorimetric biosensing platform for kanamycin (KAN) detection is established considering the prominent redox activity and blue color of PB. CoFe2O4 magnetic nanobeads (CoFe2O4 MBs) are employed for immobilization and separation of the signal beacon in the complex matrix, and the combination between CoFe2O4 MBs and magnetic electrodes simplifies the electrochemical testing process. The linear range of the electrochemical mode is 0.1 nM-1.0 μM with a detection limit of 39 pM, and that of the colorimetric mode is 10 nM-2.0 μM with a detection limit of 3.6 nM. Furthermore, the dual-mode strategy shows satisfactory specificity and enhanced applicability for KAN detection in real samples. Compared with known dual-mode determination methods, the proposed design employs the same reaction to produce two signal output modes, thus eliminating the effect of different reactive pathways on the outcome and in turn promoting greater accuracy.


Virtual patient simulation for learning and assessment: Superior results in comparison with regular course exams.
Our study aimed to observe the differences in assessment results between virtual patient simulation (VPS) and regular course exams in an Internal Medicine course for undergraduate medical students. Four cohorts of students (n = 216) used: a VPS or lectures for learning (terms 1 and 2); VPS and lectures or only lectures (term 3); and a paired set-up with both VPS and lectures (term 4). The assessment results, measured with both a VPS-based exam and a paper-based exam, were compared. A scoring rubric (0-6), developed and validated for the purpose of the trial, was applied to both types of assessment. Mean score differences of the results were compared for the four cohorts. Both VPS and regular examination results were significantly higher in the VPS group compared to regular exam group (p < 0.001) in terms 1, 2 and 3. The paired mean difference in term 4 was 0.66 (95% confidence interval (CI) 0.50, 0.83; p < 0.001) for haematology and 0.57 (95% CI 0.45, 0.69; p < 0.001) for cardiology. Our findings suggest that using VPS both for learning and for assessment supports learning. VPS are better than traditional assessment methods when the virtual application is used for both learning and evaluation.


Sustained axial loading lengthens arteries in organ culture.
Although it has been recognized for many years that arteries in vivo exist under significant axial strain, studies of the adaptation of arteries to elevated axial strain have only recently been conducted. To determine the effects of sustained elevation of axial loading on arterial structure and function, axial stresses of 250 kPa or greater were applied to porcine common carotid arteries maintained in a perfusion organ culture system for 7 days at physiologic pressure and flow conditions. Our results demonstrated that axial stretch could lead to an increase in unloaded length that was proportional to the axial stretch ratio (stretched length divided by unloaded length) when the axial stretch ratio was above a threshold value of 2.14. Below this threshold, no significant length change occurred. Above this threshold, a significant increase in unloaded length (13 +/- 7%,) and the number of smooth muscle cell nuclei (20 +/- 7%) was observed. Permanent length change was associated with a significant decrease in axial stiffness, and the maximum elongation achieved was limited by rupture of the arterial wall. All tested arteries demonstrated good viability and strong vasomotor responses. These results show that arteries in organ culture can elongate under sustained axial loading.


Zero-liquid discharge technologies for desulfurization wastewater: A review.
Zero-Liquid Discharge (ZLD) has received a lot of attention due to water scarcity and pollution. This article reviews the treatment of desulfurization wastewater in pretreatment, concentration and solidification with the trend of zero-liquid discharge in China. We summarize the advantages, disadvantages, performance, benefits and other characteristics of different ZLD technologies. Membrane-based technology is an effective means of recycling wastewater in ZLD systems. Therefore, we focus on the application of bipolar membrane electrodialysis (BMED) in desulfurization wastewater and high-salt wastewater treatment, discussing its limitations and solutions. In addition, several Chinese ZLD cases and economic analysis are introduced. It is believed that ZLD will become a new trend in desulfurization wastewater treatment in the future. Therefore, exploring new materials and technologies with low cost and high efficiency is the focus of future work.


Association between subjective cognitive complaints, balance impairment and disability among middle-aged and older adults: Evidence from a population-based cohort study.
To quantify the association between subjective cognitive complaints and balance impairment in relation to the occurrence of disability. In total, 6885 adults aged ≥45 who participated in the China Health and Retirement Longitudinal Study (CHARLS) were followed for 7 years. Subjective cognitive complaints were evaluated by self-reported memory problems. Balance impairment was tested by side-by-side stand, semi-tandem stand and full tandem stand. Disability was measured by activities of daily living (ADL) and instrumental activities of daily living (IADL). Multivariate logistic regression models were applied to test the joint effect between baseline subjective cognitive complaints and balance impairment on disability. The multiplicative interaction was examined. A joint effect of experiencing both subjective cognitive complaints and balance impairment was identified, showing a 1.63-fold higher risk of ADL and IADL disability than those experienced by neither of the two (odds ratio = 1.63, 95% confidence interval: 1.36-1.95). There was evidence of multiplicative interaction (P = 0.004). Among middle-aged and older people, the coexistence of subjective cognitive complaints and balance impairment may lead to a higher disability risk, which is much higher than the simple sum of the two individual effects. Future interventions are required to target these symptoms simultaneously to reduce the risks of disability. Geriatr Gerontol Int 2022; 22: 1025-1031.


[The comprehensively oriented complex rehabilitation of laryngectomized patients].
We report 14 patients who took part in a specially designed comprehensive rehabilitation programme for the laryngectomee. Our results clearly indicate that it is only possible to carry out such a project successfully if there is intensive communication between all participants in the programme, including the patient and his/her partner.


Secretion of E,E-farnesol and biofilm formation in eight different Candida species.
Production of E,E-farnesol (FOH) and biofilm formation were studied under various conditions in 56 strains of eight Candida spp. FOH production differed significantly not only between Candida spp. but within Candida albicans strains as well. FOH concentrations and biofilm formation were the highest for C. albicans.


Self-reported behavior patterns of patients attending a sexually transmitted disease clinic.
Records of the sexually transmitted disease (STD) clinic visits of 12,728 patients in Columbus, Ohio were analyzed to better understand the behavior patterns of these patients. Among heterosexual men, a greater proportion of Blacks than Whites reported a previous history of urethritis. After controlling for previous STD among heterosexual men with discharge or dysuria, we found that Black men sought treatment sooner and were more likely to curtail sexual activity than White men after becoming symptomatic with gonorrhea or nongonococcal urethritis.


Anion dependence of the contractions of skinned cardiac cells.
Cardiac muscle fragments with disrupted sarcolemmas were prepared by homogenization of mouse ventricles. The rate of spontaneous contractions was increased when a solution containing isobutyrate as the main anion was substituted with a solution rich in chloride. At low calcium concentrations preparations which were quiescent in the isobutyrate solution responded to the chloride with a strong single contraction.


Effect of arginine and glucagon on perifused purified beta cells.
The secretory response of purified beta cells was studied employing a newly developed microperifusion technique. In control experiments, initial high insulin release up to 50 minutes followed by a steady state basal level was observed up to five hours. The changes in hydrodynamic pressure of perifusion produced small, statistically non-significant fluctuations in the insulin release in succeeding two samples of effluent. Pulse stimulation of the purified beta cells with arginine 10 mM and 20 mM produced a biphasic secretory response. The total insulin secretion with arginine (1, 5, 10, or 20 mM) was concentration dependent. Glucagon (1, 5, 10, or 20 nM) produced concentration dependent stimulation of insulin secretion. The results of these studies indicate that the secretory responses of the purified beta cells could be studied employing the microperifusion technique described in this report. The purified beta cells respond to arginine and glucagon with increased insulin secretion as observed in microperifusion and static incubation studies (1, 2).


Effects of three Commercial Mouth Rinses on the Cultured Fibroblasts: An in Vitro Study.
An ideal antimicrobial agent should have minimal cytotoxic effect to host cells. The aim of this study was to determine the cytotoxic effect of three commercial mouthwashes (Chlorhexidine, Persica and Irsha) on the cultured fibroblasts. For determining the cytotoxic effect of Irsha, Chlorhexidine and Persica, uninfected cells were grown in the absence and presence of various concentration (2,4,8,16,32,64,128) of these mouth washes for 1, 2, 3 and 4 days. In this study, three mouth washes show cytotoxic effect on the cultured cells, at commercially available concentration and even diluted and Irsha was found to be the most toxic one. Cytotoxicity of three mouthwashes was reduced with decreasing concentration.


Computer-aided optimal design for flexible cable in aerospace products based on dynamic analogy modeling.
Due to large, complex deformations, the accurate design of cables has become a major problem in the manufacturing of aerospace products. The current design method often leads to large products, uncertain centroids, and poor reliability. To solve these problems, a computer-aided optimal design method for flexible cables was proposed based on dynamic analogy modeling. A nonlinear optimization model was established by combining Cosserat theory and the minimum potential energy principle. The total deformation energy was considered as the optimization object, and Euler parameters were used as control variables to describe the cable geometric shape. Considering the length and bending radius requirements, the normalized form of the cable constraints was expressed by the cross-section position and orientation matrix. An efficient method to solve this problem using finite element discretization and the primitive dual interior point method was proposed. A digital wiring module was developed based on an open source geometry kernel system, and a cable geometry test bench was built. To verify our model, a satellite wiring simulation example was implemented using the module, SolidWorks, and the test bench. Our method achieved the optimal design for the cable length and geometric shape. A theoretical and technical foundation for effectively solving the problem of large cable manufacturing errors and realizing the lightweight design of aerospace products was outlined.


Transition from school to adult life for physically disabled young people.
The transition process for young physically disabled people (n = 87) was studied in three districts to determine how it varied between schools, and how it was perceived by the disabled and their carers. The experiences of the young people were compared with guidelines for good practice based on relevant legislation. Results showed that young disabled people experienced a poor handover to adult services if they had no "statement of special educational need" or if they went to further education college. Young people with cerebral palsy or complex multiple problems fared less well than those with spina bifida or juvenile chronic arthritis. There are several deficiencies in the legislation. Physically disabled young people should receive a transition review regardless of whether they have a "statement". The range of severity and type of disorders among the young physically disabled argues for a range of services--the category is too broad to be useful for research, service planning, and provision.


Evaluation of the serum-free medium MDSS2 for the production of poliovirus on vero cells in bioreactors.
The serum-free medium MDSS2 (Merten et al., 1994), was used for cultivating Vero cells as well as for producing poliovirus (Sabin type 1) in static and in perfused micro-carrier cultures. At slightly different growth rates of 0.0120/h and 0.0106/h, respectively, static cultures in serum-containing (SCM) and serum-free (SFM) medium produced titers of (106.75) and 10(6.67) TCID50 per 50 µl; signifying a specific productivity of 0.89 and 1.07 TCID50/c.Serum-free bioreactor cultures of Vero cells on DEAE-dextran microcarriers at 6.25 g/l produced cell densities of about 1.5×10(6)c/ml. After infection with virus (multiplicity of infection (MOI) 0.1-0.3) titers of about 6.3×10(8) TCID50/ml were obtained, signifying an average specific productivity of 7.1 TCID50/c.h. Although these values were 4 and 2 fold, respectively, higher than in classical resum-based production processes (Montagnon et al. Dev. biol. Stand. 1981, 47, 55), a reference culture, for which cell growth was done in SCM and only virus production was done in SFM, produced 2×10(9) TCID/ml with an average specific virus production rate of 18.9 TCID50/c.h. The differences between the fully serum-free and our reference process were mainly due to physiological differences of cells grown in SCM and SFM and also due to strongly modified consumption kinetics after virus infection leading to limitations of one or several essential medium compounds, like glucose and amino acids. Avoiding these limitations by increasing the residual concentration of glucose, glutamine, histidine, and SH-amino acids, led to specific virus production rates (of about 17.9 TCID59/c.h.) comparable to those found in the reference virus production process. The optimisation of the production of the poliovirus (Sabin 1) will be described with respect to the modification of the medium composition.


High sensitive and selective HPTLC method assisted by digital image processing for simultaneous determination of catecholamines and related drugs.
A highly sensitive and selective thin layer chromatographic (TLC) method was developed for simultaneous determination of catecholamines and their related drugs using a new detection method and digital image processing of chromatographic plates. For the quantitative evaluation of the investigated compounds, the chromatographic separation was followed by spraying the plate with 0.02% solution of 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) in ethanol. The BioDit Thin Layer Chromatography (TLC) Scanner device and advanced specific software (ImageDecipher-TLC, Sorbfil TLC Videodensitometer and JustTLC) were used for the detection and quantification of chromatographic spots. For an accurate determination, the RGB colored images of the bright-white spots detected against a purple background were inverted and processed after their conversion into green scale. The results showed a strongly linear correlation between area (R(2)>0.99) and volume (R(2)>0.99) of spots and concentration of investigated compounds in all cases. The limit of detection (LOD) and the limit of quantification (LOQ) were below 49.3 ng/spot and 69.6 ng/spot respectively in all cases. The evaluation of the method was performed using different pharmaceutical samples spiked with the investigated amines and validated with respect to accuracy and precision.


A reassessment of primary thyroid lymphoma: high-grade MALT-type lymphoma as a distinct subtype of diffuse large B-cell lymphoma.
Primary lymphoma of the thyroid gland (PTL) is a relatively rare disease. During an 18-year period, 53 cases of primary non-Hodgkin's lymphoma involving this extranodal site were seen at our institutions. The aims of this study were to evaluate the spectrum of PTLs using current lymphoma classification concepts and immunocytochemical markers, determine whether features of MALT-type lymphoma were evident in PTL, and if there was any clinical significance of such a finding. The cases were retrospectively studied clinically, histologically and immunohistochemically. The tumours were classified according to the Revised European-American Lymphoma Classification of lymphoid malignancies (REAL classification). Thirty-eight patients were females, 15 were males and mean age at diagnosis was 66.3 years (range 38-90). Three cases were low-grade marginal zone lymphomas (low-grade MALT-type lymphomas). There were 45 diffuse large B-cell lymphomas (DLBCL) of which there were 27 DLBCL-NOS and 18 high-grade MALT-type lymphomas. Within the diffuse large B-cell lymphoma (DLBCL) category, cases were subdivided into those without (DLBCL-NOS) and those with features of 'high-grade' MALT-type lymphoma based on presence of a low-grade component or large cell lymphoepithelial lesions (HG MALT-type lymphoma). In addition there were three follicle centre lymphomas, one anaplastic large cell lymphoma and one peripheral T-cell lymphoma. Twenty cases were stage IE, 18 stage IIE, and four stage IV. All patients with low-grade MALT-type lymphoma are alive without disease. The 5-year survivals for DLBCL-NOS and HG MALT-type lymphoma were 75% and 25%, respectively. Univariate analysis (log rank) among the DLBCLs showed stage (P < 0.001) and subtype (P = 0.005) were associated with survival. Stage was associated with type of DLBCL, 65% of DLBCL-NOS being stage IE compared to 20% of HG MALT-type lymphomas. We conclude that primary thyroid lymphomas occur most commonly in elderly women and are frequently present in clinical stage IE and IIE. Low-grade MALT-type lymphomas are relatively uncommon but appear to have a favourable prognosis. DLBCL is the most common lymphoma and features of MALT can be seen in over one-third of cases. As a group, HG MALT-type lymphomas had a worse outcome than DLBCL-NOS, primarily due to higher clinical stage at diagnosis. These two subtypes of DLBCL appear to be distinct clinical and histological entities.


Nonlocal grazing in patterned ecosystems.
Many ecosystems exhibit gapped, labyrinthine, striped or spotted patterns. Important examples are vegetation patterns in drylands: these patterns are viewed as precursors of a catastrophic transition to a degraded state. A possible source of degradation is overgrazing, but many current spatially extended models include grazing in a local linear way. In this article nonlocal grazing responses are derived, taking into account (1) how many consumers there are (demographic response) (2) where they are (aggregative response) and (3) how much they forage (functional response). Different assumptions lead to different grazing responses, the type of grazing has a large influence on how ecosystems adapt to changing environmental conditions. In dryland simulations the different types of grazing are shown to alter the desertification process driven by decreasing rainfall. A sufficiently strong aggregative response leads to the suppression of vegetation patterns, nuancing their role as generic early warning signals.


Potential Competitive Dynamics of Acoustic Ecology.
The top predators in coastal marine ecosystems, such as whales, dolphins, seabirds, and large predatory fishes (including sharks), may compete with each other to exploit food aggregations. Finding these patchy food sources and being first to a food patch could provide a significant competitive advantage. Our hypothesis is that food patches have specific sound signatures that marine predators could detect and that acoustic sources and animal sensory capabilities may contribute to competition dynamics. Preliminary analysis shows that diving gannets have a distinct spectral signature between 80 and 200 Hz, which falls within the hearing sensitivity of large pelagic fishes. Therefore, we suggest that diving birds may contribute to the sound signatures of food aggregations, linking competition dynamics both above and below the water surface.


Modulation of transfected gene expression mediated by changes in chromatin structure.
We examined the molecular basis of modulation of transfected herpes simplex virus (HSV) thymidine kinase (tk) gene in mouse fibroblasts. We observed that one tk+ cell line is capable of reversion to a tk- phenotype, and rereverts to a tk+ phenotype at high frequencies (5%). The revertants lacked tk enzyme activity and tk-specific transcripts. We detected no differences in the organization of foreign DNA or in the CpG methylation patterns in the revertants and rerevertants. We probed the chromatin structure of the revertants and rerevertants, and found the tk sequences in the rerevertants to be more highly sensitive to digestion with DNAase I than the corresponding revertant cells. We conclude that the high frequency switching of gene expression we observed is mediated by changes in chromatin structure, and that this may reflect the behavior of the host sequences at the site of foreign DNA integration.


Optimization of the arginase activity assay micromethod for macrophages and sera.
We optimized the spectrophotometric micromethod for the determination of arginase activity based on the Corraliza et al. modification of Schimke's method. Arginase activity in sera from patients suffering from human African trypanosomiasis, in macrophage lysates from trypanosome-infected mice, and in purified bovine liver arginase was compared using the conventional and optimized micromethods. The sensitivity of both micromethods was comparable. However, our optimized method has the following advantages: it uses small sample volumes (6 µl per assay vs. 50 µl) and reagent volumes (200 µl vs. 400 µl), it can be carried out in a single microplate well, thereby minimizing handling, and it requires fewer materials and utilizes readily available equipment. Our optimized method proved to be applicable and well suited for small-volume samples and resource-poor laboratories.


Regulation of blood-brain barrier integrity by microglia in health and disease: A therapeutic opportunity.
The blood-brain barrier (BBB) is a critical regulator of CNS homeostasis. It possesses physical and biochemical characteristics (i.e. tight junction protein complexes, transporters) that are necessary for the BBB to perform this physiological role. Microvascular endothelial cells require support from astrocytes, pericytes, microglia, neurons, and constituents of the extracellular matrix. This intricate relationship implies the existence of a neurovascular unit (NVU). NVU cellular components can be activated in disease and contribute to dynamic remodeling of the BBB. This is especially true of microglia, the resident immune cells of the brain, which polarize into distinct proinflammatory (M1) or anti-inflammatory (M2) phenotypes. Current data indicate that M1 pro-inflammatory microglia contribute to BBB dysfunction and vascular "leak", while M2 anti-inflammatory microglia play a protective role at the BBB. Understanding biological mechanisms involved in microglia activation provides a unique opportunity to develop novel treatment approaches for neurological diseases. In this review, we highlight characteristics of M1 proinflammatory and M2 anti-inflammatory microglia and describe how these distinct phenotypes modulate BBB physiology. Additionally, we outline the role of other NVU cell types in regulating microglial activation and highlight how microglia can be targeted for treatment of disease with a focus on ischemic stroke and Alzheimer's disease.


Prognostic value of CD56 in patients with acute myeloid leukemia: a meta-analysis.
Extensive studies have investigated the prognostic value of CD56 for patients with acute myeloid leukemia (AML), but the results remained inconclusive. The aim of this meta-analysis is to resolve this controversial issue. A systematic search of PubMed, Embase, Cochrane Library, and CBM was performed to identify studies that assessed the prognostic value of CD56 in AML patients. Pooled hazard ratios (HRs) with 95 % confidence intervals (CIs) for overall survival (OS) and disease-free survival (DFS) and pooled odds ratio (OR) with 95 % CIs for complete remission rate (CRR) and relapse rate (RR) were calculated. Totally, 32 studies with 4074 patients were included. For AML with t(8;21) translocation, CD56 overexpression was associated with shorter OS (HR 2.22; 95 % CI 1.30-3.78) and DFS (HR 2.63; 95 % CI 1.10-6.29) and increased RR (OR 3.29; 95 % CI 1.67-6.48), but did not affect CRR (OR 0.94; 95 % CI 0.49-1.80). For AML with t(15;17) translocation, CD56 overexpression was associated with shorter OS (HR 2.43; 95 % CI 1.66-3.57) and DFS (HR 4.27; 95 % CI 1.15-15.78), increased RR (OR 3.11; 95 % CI 2.01-4.81), and decreased CRR (OR 0.42; 95 % CI 0.25-0.72). For AML as a whole, CD56 overexpression was associated with shorter OS (HR 1.74; 95 % CI 1.38-2.19) and DFS (HR 2.38; 95 % CI 1.87-3.02), increased RR (OR 5.19; 95 % CI 2.84-9.48), and decreased CRR (OR 0.62; 95 % CI 0.41-0.96). This meta-analysis indicated that CD56 overexpression may be an adverse prognostic factor for AML.


Inhibitory effects of psychotropic drugs on mexiletine metabolism in human liver microsomes: prediction of in vivo drug interactions.
Mexiletine, an anti-arrhythmic agent, is used for the control of ventricular arrhythmias and for neuropathic pain from cancer or diabetes mellitus. It is sometimes used together with psychotropic drugs in patients with depression, schizophrenia or sleep disorder. It is metabolized mainly by cytochrome P450 (CYP) 2 D 6 and, to a minor extent, by CYP1A2. To predict possible drug interactions between mexiletine and psychotropic drugs, the inhibitory effects of 14 psychotropic drugs (phenytoin, carbamazepine, fluvoxamine, paroxetine, fluoxetine, citalopram, sertraline, imipramine, desipramine, haloperidol, thioridazine, olanzapine, etizolam, and quazepam) on mexiletine metabolism in human liver microsomes were determined. Fluoxetine (Ki=0.6+/- 0.1 microM), sertraline (Ki=7.6+/- 0.8 microM) and desipramine (Ki=3.2+/- 0.5 microM) competitively inhibited the mexiletine p-hydroxylation in human liver microsomes. Thioridazine (Kis=0.5+/- 0.2 microM; Kii =3.6+/-1.6 microM) and paroxetine (Kis=1.7+/- 0.7 microM; Kii=3.6+/- 0.9 microM) exhibited a mixed-type inhibition (competitive and non-competitive) toward mexiletine p-hydroxylation in human liver microsomes. The changes of the in vivo clearance of mexiletine by the psychotropic drugs were predicted by 1+(I/Ki) using the in vitro Ki and unbound inhibitor concentrations in liver. The values were calculated as 2.4 for paroxetine, 5.5 for fluoxetine, 1.1 for sertraline, 2.8 for desipramine and 2.2 for thioridazine. In addition, paroxetine exhibited a mechanism-based inactivation with Ki=0.7 microM and Kinact=0.15 min(-1). The present study predicted the possibility of drug interactions between mexiletine and paroxetine, fluoxetine, desipramine, and thioridazine in clinical use.


Auxiliary subunits of Shaker-type potassium channels.
Voltage-gated potassium channels are important determinants of membrane excitability. This family of ion channels is composed of several classes of proteins, including the pore-forming Kvalpha subunits and the recently identified auxiliary Kvbeta subunits. A combination of a large number of genes that encode various alpha subunits and beta subunits and the selective formation of alpha-alpha and alpha-beta heteromultimeric channels provides rich molecular diversity that allows for regulated functional heterogeneity in both excitable tissues and nonexcitable tissues. Because the Kvbeta subunits can either upregulate or downregulate potassium currents, depending on the specific subunit combination, it is essential to understand their function at the molecular level. Furthermore, targeted changes of the Kvbeta expression or disruption of certain alpha-beta interactions could serve as a molecular basis for designing drugs and therapy to regulate excitability clinically.


Effect of Implant Thread Geometry on Secondary Stability, Bone Density, and Bone-to-Implant Contact: A Biomechanical and Histological Analysis.
This study evaluated the effect of 2 different thread designs on secondary stability (micromotion) and osseointegration rate in dense and cancellous bones. Forty large threaded and 40 small threaded implants (Cortex) were placed in low- (iliac crest) and high-density (mandible) bone of sheep. Two months later, micromobility tests and histological analysis were performed to measure secondary stability, osseointegration (bone-to-implant contact percentage [%BIC]), and bone density (bone volume percentage [%BV]). The value of actual micromotion of implant is introduced as a new parameter to evaluate secondary stability. Large threaded implants showed significantly higher %BIC and %BV than small threaded implants in low-density bone and statistically higher secondary stability in cancellous and cortical bones. Implants in dense bone reach higher secondary stability than those in cancellous bone, despite the lower %BIC. Implant geometry and bone density play a key role in secondary stability. Large thread design improves bone anchorage mechanically and histologically as compared with small threaded implants.


Eating avoidance disorder and Wernicke-Korsakoff syndrome following gastric bypass: an under-diagnosed association.
Wernicke-Korsakoff syndrome (WKS) and disordered eating behavior have been reported separately after bariatric surgery. We report a patient who following a bariatric operation developed WKS associated with a disturbed eating behavior without vomiting. This morbidly obese man developed an intense fear of gaining weight in the postoperative period and engaged in an extreme form of "food avoidance behavior". 2 months postoperatively after severe weight loss, he was hospitalized with disorientation and an amnesic syndrome. He was discharged 2 months later with stable weight and regular eating habits. Despite this, at the last follow-up visit 2 years postoperatively, he still had a residual partial amnesic syndrome. The surgical team must be aware of peculiar forms of pathological eating that may appear after bariatric surgery; the emergence of an eating avoidance disorder may be associated with the development of WKS.


Neuromuscular Electrical Stimulation Preserves Leg Lean Mass in Geriatric Patients.
This study aimed to examine changes in lean mass during hospitalization in geriatric patients and the effect of muscle activation by neuromuscular electrical stimulation. Thirteen patients (69-94 yr) at a geriatric ward completed tests at hospital admission (days 2-3) and discharge (days 8-10). One leg received daily stimulation of the knee extensors, whereas the other leg served as a control leg. Lean mass was evaluated by dual-energy x-ray absorptiometry scans and muscle thickness by ultrasound scans. Muscle biopsies were collected from both legs at admission and discharge in nine patients and analyzed for fiber size, satellite cell number, and activation and expression of genes associated with muscle protein synthesis and breakdown, connective tissue, and cellular stress. The relative decline in leg lean mass and midthigh region lean mass was larger in the control (-2.8% ± 1.5%) versus the stimulated leg (-0.5% ± 1.4%, P < 0.05). Although there were no changes in fiber size or satellite cell number, the mRNA data revealed that, compared with control, the stimulation resulted in a downregulation of myostatin (P < 0.05) and a similar trend for MAFbx (P = 0.099), together with an upregulation of Collagen I (P < 0.001), TenascinC (P < 0.001), CD68 (P < 0.01), and Ki67 (P < 0.05) mRNA. These findings demonstrate a moderate decline in leg lean mass during a hospital stay in geriatric patients, whereas leg lean mass was preserved with daily neuromuscular electrical muscle activation. At the cellular level, the stimulation had a clear influence on suppression of atrophy signaling pathways in parallel with a stimulation of connective tissue and cellular remodeling processes.


Understanding Ballistic Injuries.
Understanding the pathophysiology of a disease allows physicians to make a diagnosis, alter its natural course, and develop and implement appropriate preventative and management strategies. With ballistic injuries, an understanding of how the mechanism of injury translates to the injuries observed makes it possible to make sense of what can, at times be a complex imaging appearance and mitigate against the long-term complications of gunshot wounds. In this article, the authors describe the different types of ballistic projectiles, their mechanism of injury as well as the injury patterns they cause. In addition, both lead arthropathy and MR imaging safety in patients with retained ballistic debris are discussed.


Diurnal Cortisol Slope and Nighttime Blood Pressure: A Study in European Americans and African Americans.
African Americans (AAs) have higher nighttime blood pressure (BP) than European Americans (EAs). Stress has been suggested to play a role in this difference, but the mechanism is not well-understood. Flatter diurnal cortisol slope (DCS) is a well-known biological marker of stress. The objectives of this study were to: 1) examine ethnic differences in DCS; 2) evaluate the association between DCS and nighttime BP; and 3) determine the extent to which ethnic differences in nighttime BP can be explained by ethnic differences in DCS. A total of 510 participants (age range: 14-35 years; 49.6% AAs, 54.5% females) provided four salivary cortisol samples at bedtime, wakeup, 30-minutes post-wakeup, and 60-minutes post-wakeup. Additionally, participants wore an ambulatory BP monitor for 24 hours. DCS was calculated as the average of the three morning samples minus the bedtime measurement. After adjustment for age, sex, BMI, and smoking, AAs had blunted DCS (P=.018) and higher nighttime systolic BP (SBP) and diastolic BP (DBP) (Ps<.001) compared with EAs. The DCS was inversely related to nighttime SBP and this relationship did not depend on ethnicity. The ethnic difference of nighttime SBP was significantly attenuated upon addition of DCS to the model. Mediation test showed that 9.5% of ethnic difference in nighttime SBP could be explained by DCS (P=.039). This study confirms ethnic differences in DCS and nighttime BP and further demonstrates that the ethnic differences in DCS can, at least partially, explain the ethnic differences found in nighttime BP.