Allergic bronchopulmonary aspergillosis due to Aspergillus oryzae.
A 19-year-old female student with allergic bronchopulmonary aspergillosis (ABPA) due to Aspergillus oryzae is reported. This organism was used for fermentation starter to make soybean paste in her father's workshop adjacent to the home where she lived. ABPA might be considered an occupational disease in certain situations.


Smoking in inflammatory bowel disease and the irritable bowel syndrome.
The smoking habits of 145 patients with irritable bowel syndrome (IBS) were compared with those of 63 patients with ulcerative colitis and 25 patients with Crohn's disease. Patients with IBS and ulcerative colitis smoked significantly less than those with Crohn's disease. There was no significant difference in the smoking prevalence between ulcerative colitis and IBS patients. There were significantly more ex-smokers in the ulcerative colitis group and two-thirds of these patients developed their colitis within a year of stopping smoking. It is suggested that any protective role postulated for smoking in the pathogenesis of ulcerative colitis should also be considered for IBS.


Delayed diagnosis of cervical spondylotic myelopathy by primary care physicians.
A retrospective study analyzing medical files of patients who had undergone surgical management for cervical spondylotic myelopathy (CSM) at a single tertiary hospital was performed to determine the time needed by community care physicians to reach a diagnosis of CSM in patients presenting with typical myelopathic signs and symptoms, and to establish the reasons for the delayed diagnosis when present. Previous studies have documented that early diagnosis and surgical treatment of CSM may improve patients' neurological as well as general outcome. However, patients complaining of symptoms compatible with CSM may undergo lengthy medical investigations and treatments by community-based physicians before a correct diagnosis is made. The authors have found no published data on the process and time frame involved in attaining a diagnosis of CSM in the community setting. The medical records of 42 patients were retrospectively reviewed for demographic data, symptoms, time to diagnosis, physician specialty, number of visits involved in the diagnostic process, and neurological status prior to surgery. The mean time delay from initiation of symptoms to diagnosis of CSM was 2.2 ± 2.3 years. The majority of symptomatic patients (90.4%) initially presented to a family practitioner (69%) or an orthopedic surgeon (21.4%), with fewer patients (9.6%) referring to other disciplines (for example, the emergency department) for initial care. In contrast, the diagnosis of CSM was most often made by neurosurgeons (38.1%) and neurologists (28.6%), and less frequently by orthopedic surgeons (19%) or family physicians (4.8%). The diagnosis of CSM in the community is frequently delayed, leading to late referral for surgery. A higher index of suspicion for this debilitating entity is required from family practitioners and community-based orthopedic surgeons to prevent neurological sequelae.


Sunitinib-induced thyrotoxicosis followed by persistent hypothyroidism with shrinkage of thyroid volume.
Sunitinib, a tyrosine kinase inhibitor, has been approved for the treatment of cancers, such as advanced renal cell carcinoma (RCC). On the other hand, sunitinib treatment is known to induce thyroid dysfunction in a substantial proportion of patients treated for advanced RCC; in fact, hypothyroidism is a frequent complication. However, little is known about sunitinib-induced thyrotoxicosis and destructive thyroiditis. Here, we report a patient with RCC who developed transient overt thyrotoxicosis followed by hypothyroidism due to sunitinib treatment. A 58-year-old woman, who had been treated with chronic thyroiditis, was diagnosed as having left RCC with bone metastasis to the rib. The patient underwent resection of the left kidney and the bone metastasis lesion. However, 3 months later, bone metastasis to the rib recurred, and sunitinib treatment was started. At 6 weeks of sunitinib therapy, the patient developed transient thyrotoxicosis, followed by persistent hypothyroidism. In the thyrotoxic phase, the patient was diagnosed as having destructive thyroiditis based on an increased thyroglobulin level, a low radioactive iodine uptake, increased free thyroxine level, and suppressed thyroid-stimulating hormone level. The thyroid volume in the hypothyroid phase was 68% of that in the thyrotoxic phase. In conclusion, the present report suggests that sunitinib-induced persistent hypothyroidism may be a consequence of preceding destructive thyroiditis with transient thyrotoxicosis. The decreased volume of the thyroid during the hypothyroid phase indicates irreversible organ damage in the present patient, thereby resulting in persistent hypothyroidism. Thus, periodic surveillance of thyroid function is mandatory during sunitinib therapy.


Virally encoded interleukin-6 facilitates KSHV replication in monocytes and induction of dysfunctional macrophages.
Kaposi's sarcoma-associated herpesvirus (KSHV) is an oncogenic double-stranded DNA virus and the etiologic agent of Kaposi's sarcoma and hyperinflammatory lymphoproliferative disorders. Understanding the mechanism by which KSHV increases the infected cell population is crucial for curing KSHV-associated diseases. Using scRNA-seq, we demonstrate that KSHV preferentially infects CD14+ monocytes, sustains viral lytic replication through the viral interleukin-6 (vIL-6), which activates STAT1 and 3, and induces an inflammatory gene expression program. To study the role of vIL-6 in monocytes upon KSHV infection, we generated recombinant KSHV with premature stop codon (vIL-6(-)) and its revertant viruses (vIL-6(+)). Infection of the recombinant viruses shows that both vIL-6(+) and vIL-6(-) KSHV infection induced indistinguishable host anti-viral response with STAT1 and 3 activations in monocytes; however, vIL-6(+), but not vIL-6(-), KSHV infection promoted the proliferation and differentiation of KSHV-infected monocytes into macrophages. The macrophages derived from vIL-6(+) KSHV infection showed a distinct transcriptional profile of elevated IFN-pathway activation with immune suppression and were compromised in T-cell stimulation function compared to those from vIL-6(-) KSHV infection or uninfected control. Notably, a viral nuclear long noncoding RNA (PAN RNA), which is required for sustaining KSHV gene expression, was substantially reduced in infected primary monocytes upon vIL-6(-) KSHV infection. These results highlight the critical role of vIL-6 in sustaining KSHV transcription in primary monocytes. Our findings also imply a clever strategy in which KSHV utilizes vIL-6 to secure its viral pool by expanding infected monocytes via differentiating into longer-lived dysfunctional macrophages. This mechanism may facilitate KSHV to escape from host immune surveillance and to support a lifelong infection.


A remark on the Conway-Norton conjecture about the "Monster" simple group.
By the method of second quantization we construct an infinite-dimensional graded module for the centralizer of an involution of the Fischer-Griess "Monster" simple group F(1) so that the Thompson series are those conjectured by Conway and Norton. As a consequence we obtain some identities and congruences relating modular functions j and eta. We are hopeful that this representation can be extended to the whole group F(1), proving all the conjectures by Conway and Norton in their recent paper [Conway, J. H. & Norton, S. P. (1979) Bull. London Math. Soc. 11, 308-339].


IL23R gene variants in relation to IL17A levels and clinical phenotype in patients with ankylosing spondylitis.
IL23 receptor (IL23R) binding by IL23 is required for the maturation of CD4+ cells into Th17 cells and subsequent generation of IL17A and TNF. As IL23R variations contribute to AS susceptibility, we investigated the effect of IL23R variants on cytokine levels and disease measures in an AS cohort. This was a cross-sectional study of AS patients (n = 334, 90% B27+, age 45 years). IL23R genotyping for three non-synonymous single-nucleotide polymorphisms (rs11209026, protective allele A; rs10489629, protective allele A; and rs11209032, risk allele A) was done by Taqman RT-PCR. IL23, IL17A, TNF and IL6 concentrations were determined by sandwich ELISA. Genotypic associations were analysed with non-parametric methods. Twenty-two AS patients (6.6%) carried the protective rs11209026 A allele, whereas 206 (61.7%) carried the rs11209032A risk allele (P = 0.03). Two patients homozygous for rs11209026A had late onset, no co-morbidity and undetectable cytokine levels. IL23R genotypes and five common haplotypes were unrelated with age at onset, BASFI or co-morbidity (all P >0.2). There was no overall difference in the concentration of IL17A (184 vs 233 pg/ml, P > 0.2) or IL23 (276 vs 262 pg/ml, P > 0.4) between AS patients and controls, but a global haplotype association (P = 0.01) was observed for IL23 concentrations. Homozygosity for rs11209026A is rare in AS patients, but may ameliorate the clinical presentation. IL17A and IL23 levels are similar in controls and AS patients. IL23R variants influence IL23 levels but not IL17A levels in AS patients, suggesting that IL23R impacts more on cell types other than Th17 cells.


Acquaintance molestation and youth-serving organizations.
This article is based not only on the research literature but also on the extensive field experience of the authors in consulting with investigators, attorneys, and organizations on the prevention, investigation, prosecution, and civil litigation of molestation of children within or in connection with youth-serving organizations. Acquaintance molesters have often pursued careers or sought out paid or volunteer work with organizations through which they can meet children. To address the problem of such offenders, it is necessary for youth-serving organizations to recognize the diversity of sexual activity, the phenomena of "nice-guy" offenders and compliant child victims, and the grooming/seduction process, each of which is reviewed here. The four most important protection practices for organizations are screening; management, and supervision; response to suspicions, allegations, and complaints; and prevention and awareness programs. The authors recommend general approaches to each of these and describe the reasons many organizations resist implementing available preventive measures.


Design and characterization of a scaffold for anterior cruciate ligament engineering.
Advances in biomedical engineering have led to an understanding of the human body's capacity for anterior cruciate ligament (ACL) healing if provided the correct impetus--a long-term bioresorbable scaffold that anticipates the defect site's requirements. Tissue engineering an ACL requires a scaffold that can meet multiple and often conflicting mechanical and biological design requirements. The design and characterization of a hydrophilic silk scaffold is presented as an example of the preclinical testing required to fully characterize a scaffold for ACL reconstruction. We hypothesize that by providing a structural scaffold which anticipates ACL repair mechanisms, an "engineered" autologous ligament with excellent functional integrity can be developed by the body itself. Mechanical, biological, and patient-clinician testing demonstrate that the hydrophilic silk scaffold is a mechanically robust, biocompatible, long-term bioresorbable ACL scaffold with demonstrated safety that can be implanted in accordance with standard surgical procedures.


Oncological efficacy and safety of nephron-sparing surgery for selected patients with locally advanced renal cell carcinoma.
To evaluate perioperative complication rates, recurrence-free and cancer-specific survival (CSS) in a large group of matched patients who had nephron-sparing surgery (NSS) or radical nephrectomy (RN) for pT2-T3bN0M0 renal cell carcinoma (RCC). With approval from the institutional review board, the institutional nephrectomy database of 3470 patients treated at the authors' institution from 1990 to 2006 was searched for patients who had NSS or RN for unilateral, sporadic, pathological T2-T3bN0M0 RCC. Patients with non-metastatic, node-negative RCC and a follow-up of >/=6 months were included in the analysis. In all, 601 patients treated with RN (567) or NSS (34) for pT2-T3bN0M0 RCC and a mean (median, range) follow-up of 43.4 (31.8, 6.1-172.6) and 62.1 (37.5, 7.0-192.0) months, respectively, met the study inclusion criteria. Disease recurred in four of 34 (12%) patients treated with NSS and in 164/567 (28.9%) managed with RN at a median of 24.2 and 13.2 months, respectively. There were no local recurrences among patients treated with NSS. On multivariate Cox proportional-hazards regression analysis, when adjusted for the effects of stage, grade, size and tumour histology, procedure type (NSS vs RN) was not an independent predictor of disease recurrence or RCC-specific death. Patients treated with NSS had a higher procedure-related complication rate, but similar estimated intraoperative blood loss, transfusion rate, equal duration of surgical procedure and hospital stay compared with patients managed with RN. In highly selected patients with locally advanced RCC, NSS is safe and provides oncological outcomes equivalent to patients managed with RN.


Is there a correlation between antibiotic use and the severity or post-infection conditions of COVID-19 and other viral infections?
Antibiotics are one of the most frequently prescribed medications in modern medicine; besides treating bacterial infections, they may often be utilized for prophylactic purposes, including during select viral infections. It has been shown that 74.9% of COVID-19 patients received antibiotics as a part of their treatment regimen during the pandemic. However, studies suggest that the actual incidence of bacterial coinfection was relatively uncommon with a mere 3.5% of overall cases reported. A recent study revealed that antibiotic administration would not improve disease progression or shorten the length of hospitalization in COVID-19 patients; additionally, some antibiotics, such as linezolid, promote the production of free radicals that might be responsible for exacerbated clinical symptoms during and post-infection. Notably, antibiotic use disturbs the normal gut microbiome, and this interference impedes antiviral immune response enhancing severity and susceptibility to a list of viral infections. Thus, resultant augmented severity of these infections may be a consequence of higher susceptibility to respiratory viral co-infection.


Novel strategies for the treatment of migraine attacks via the CGRP, serotonin, dopamine, PAC1, and NMDA receptors.
Migraine is a common, paroxysmal, and disabling primary headache with a high personal and socioeconomic impact. It involves ∼ 16% of the general population. During the years, a number of hypotheses have been put forward concerning the exact pathomechanism, but the final solution is still undiscovered. Although the origin is enigmatic, parallel therapeutic efforts have been developed. Current attack therapy does not meet the expectations of the patients or the doctors. This article, based on a PubMed search, reviews the novel pharmacological possibilities that influence the peripheral and central sensitization involved in the disease. In order to overcome the therapeutic insufficiency, a calcitonin gene-related peptide receptor antagonist without the side-effect of liver transaminase elevation is required. Another therapeutic option is to develop a neurally acting antimigraine agent, such as a serotonin-1F receptor agonist, with low adverse central nervous system events. Development of a potent dopamine receptor antagonist is necessary to diminish the premonitory symptoms of migraine. A further option is to decrease the headache intensity with a pituitary adenylate cyclase-activating polypeptide type 1 receptor blocker which can cross the blood-brain barrier. Finally, synthetic kynurenine analogues are required to block the pain transmission in the activated trigeminal system.


Sarcopenia Is Predictive of 1-Year Mortality After Acetabular Fractures in Elderly Patients.
To determine whether sarcopenia is an independent predictor of mortality in geriatric acetabular fractures. Retrospective cohort. American College of Surgeons Level I trauma center. One hundred and forty-six patients over the age 60 with acetabular fractures treated at our institution over a 12-year period. The primary outcome was 1-year mortality, collected using the Social Security Death Index. We used the psoas:lumbar vertebral index (PLVI), calculated using the cross-sectional area of the L4 vertebral body and the left and right psoas muscles, to assess for sarcopenia. Using a multivariate logistic regression model, we found that low PLVI was associated with increased 1-year mortality (P = 0.046) when controlling for age, gender, Charlson Comorbidity Index, Injury Severity Score (ISS), smoking status, and associated pelvic ring injury. Increasing age and ISS also showed a relationship with 1-year mortality in this cohort (P < 0.001, P < 0.001, respectively). We defined sarcopenia as those patients in the lowest quartile of PLVI. The mortality rate of this cohort was 32.4%, compared with 11.0% in patients without sarcopenia (odds ratio 4.04; 95% confidence interval 1.62-10.1). Age >75 years, ISS >14, and sarcopenia had 1-year mortality rates of 37.1%, 30.9%, and 32.4%, respectively. In patients with all 3 factors, the mortality rate was 90%. Sarcopenia is an independent risk factor for 1-year mortality in elderly patients with acetabular fractures. This study highlights the importance of objective measures to assess frailty in elderly patients who have sustained fractures about the hip and pelvis. Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.


A novel intrahepatic arterial chemotherapy after radical resection for advanced hepatocellular carcinoma.
Advanced hepatocellular carcinoma (HCC) with portal vein invasion and/or intrahepatic metastasis has an unfavorable prognosis even after radical hepatic resection. The aim of this study was to evaluate the effectiveness of a novel postoperative adjuvant chemotherapy given through the hepatic artery and based on biochemical modulation using cisplatin (CDDP) and 5-fluorouracil (5-FU). Fifteen patients with advanced HCC with portal vein invasion into the main trunk and/or intrahepatic metastases of more than 3 segments were included in this study. After radical hepatic resection, the patients were divided to two groups: the adjuvant chemotherapy group (n=7) given the novel arterial infusion regimen with CDDP and 5-FU, and the control group (n=8) given no adjuvant chemotherapy. Three-year survival rate of the adjuvant chemotherapy group tended to be significantly longer compared to that for the control group (p < 0.05). Most of the tumor recurrence was in the remnant liver, 5 cases in both of the groups. Significant difference of the recurrence patterns was recognized, rather than difference of the disease-free survival rate between the two groups. All of the intrahepatic recurrences are multiple in the control group, but in the adjuvant chemotherapy group, 2 cases of the recurrences showed a localized tumor surgically resected. It is noteworthy that the occurrence of multiple recurrence was significantly later in the adjuvant chemotherapy group compared to the control group (18.9 months vs. 6.5 months; p<0.05). Our data suggest that this novel adjuvant chemotherapy can improve the postoperative prognosis of patients with the advanced HCC.


Gibberellin Signaling Is Required for Far-Red Light-Induced Shoot Elongation in Pinus tabuliformis Seedlings.
Gibberellin (GA) is known to play an important role in low red/far-red (R:FR) light ratio-mediated hypocotyl and petiole elongation in Arabidopsis (Arabidopsis thaliana). However, the regulatory relationship between low R:FR and GAs remains unclear, especially in gymnosperms. To increase our understanding of the molecular basis of low R:FR-mediated shoot elongation in pines and to determine whether there is an association between low R:FR and GAs action, we explored the morphological and transcriptomic changes triggered by low R:FR, GAs, and paclobutrazol (PAC), a GAs biosynthesis inhibitor, in Pinus tabuliformis seedlings. Transcriptome profiles revealed that low R:FR conditions and GAs have a common set of transcriptional targets in P. tabuliformis We provide evidence that the effect of low R:FR on shoot elongation in P. tabuliformis is at least partially modulated by GAs accumulation, which can be largely attenuated by PAC. GAs are also involved in the cross talk between different phytohormones in the low R:FR response. A GA biosynthesis gene, encoding ent-kaurenoic acid oxidase (KAO), was strongly stimulated by low R:FR without being affected by GAs feedback regulation or the photoperiod. We show that GA signaling is required for low R:FR-induced shoot elongation in P tabuliformis seedlings, and that there are different regulatory targets for low R:FR-mediated GA biosynthesis between conifers and angiosperms.


Inhibition of the Mr 70,000 S6 kinase pathway by rapamycin results in chromosome malsegregation in yeast and mammalian cells.
The antifungal and immunosuppressive drug rapamycin arrests the cell cycle in G1-phase in both yeast and mammalian cells. In mammalian cells, rapamycin selectively inhibits phosphorylation and activation of p70 S6 kinase (p70(S6K)), a protein involved in the translation of a subset of mRNAs, without affecting other known kinases. We now report that rapamycin causes chromosome malsegregation in mammalian and yeast cells. Chromosome malsegregation was determined by metaphase chromosome analysis of human lymphocytes and lymphoblasts, detection of CREST-positive micronuclei in human lymphoblasts and Chinese hamster embryonic fibroblast (CHEF) cells, and selection of doubly prototrophic cells in a specially constructed yeast strain. The number of ana-telophases with displaced chromosomes and interphase and mitotic cells with an irregular number of centrosomes was also determined in CHEF cells. In quiescent mammalian cells (human lymphocytes and CHEF cells) induced with growth factor to re-enter the cell cycle, rapamycin was effective when cells were exposed at the time of p70(S6K) activation. In yeast, rapamycin was more effective when treatment was started in G1- than in G2-synchronized cells. Cells from ataxia telangiectasia (A-T) patients are characterized by chromosome instability and have recently been found to be resistant to the growth-inhibiting effect of rapamycin. We found that an A-T lymphoblastoid cell line was also resistant to the induction of chromosome malsegregation by rapamycin, but the level of spontaneous aneuploidy was higher than in normal cells. In yeast, the induction of chromosome malsegregation was dependent on the presence of a wild-type TUB2 gene, encoding the beta-subunit of tubulin. The finding that rapamycin acts in different cell types and organisms suggests that the drug affects a conserved step important for proper segregation of chromosomes. One or more proteins required for chromosome segregation could be under the control of the rapamycin-sensitive pathway.


Lesions associated with Halocercus brasiliensis Lins de Almeida, 1933 in the lungs of dolphins stranded in the Northeast of Brazil.
The parasitic fauna of cetaceans is an important tool for ecological studies, including analyses on the causes of death. Halocercus brasiliensis is a nematode frequently found in the bronchi and bronchioles of some cetaceans, and it is commonly associated with focal inflammation of the respiratory tract leading to bacterial pneumonia and septicemia and, sometimes, to death. The objective of this study was to report infections by H. brasiliensis in the respiratory tract of Delphinidae stranded on the northern seaside of Bahia, Sergipe, and south of Alagoas, all states in the northeast region of Brazil. A total of 30 individuals, 1 Feresa attenuate (pygmy killer whale), 9 Stenella clymene (Clymene dolphin), and 20 Sotalia guianensis (Guiana dolphin) were studied. In 16 of them, the presence of H. brasiliensis was observed with a mean intensity of 3.5 ± 0.6 (range 1-9) in the hosts. Macroscopically, parasitic calcified nodules, lung congestion, edema, and emphysema were observed. Histopathological examination showed interstitial and granulomatous pneumonia with multifocal infiltrates, discrete to moderate edema, congestion, diffuse hemorrhage, and foci of calcification. We conclude that parasitic pneumonia in the sampled individuals may have directly contributed to stranding and death of the animals.


Antibiotic-induced change of bacterial communities associated with the copepod Nitocra spinipes.
Environmental pressures, such as physical factors, diet and contaminants may affect interactions between microbial symbionts and their multicellular hosts. Despite obvious relevance, effects of antimicrobial contaminants on host-symbiont relations in non-target aquatic organisms are largely unknown. We show that exposure to antibiotics had negative effects on survival and juvenile development of the copepod Nitocra spinipes and caused significant alterations in copepod-associated bacterial communities. The significant positive correlations between indices of copepod development and bacterial diversity indicate that disruption of the microflora was likely to be an important factor behind retarded juvenile development in the experimental animals. Moreover, as evidenced by ribotype distribution in the bacterial clone libraries, the exposure to antibiotics caused a shift in dominance from Betaproteobacteria to Cardinium bacteria; the latter have been shown to cause reproductive manipulations in various terrestrial arthropods. Thus, in addition to providing evidence that the antibiotic-induced perturbation of the microbial community associates with reductions in fitness-related traits of the host, this study is the first record of a copepod serving as a host for endosymbiotic Cardinium. Taken together, our results suggest that (1) antimicrobial substances and possibly other stressors can affect micobiome and symbiont-mediated interactions in copepods and other hosts, and (2) Cardinium endosymbionts may occur in other copepods and affect reproduction of their hosts.


Cloning and functional characterization of the oxidative squalene cyclase gene in the deep-sea holothurian Chiridota sp.
Saponins derived from holothurians have high potential medicinal value. However, the de novo synthesis of the derivatization of triterpenes is still unclear. Oxidative squalene cyclase (OSC) can catalyze 2,3-Oxidosqualene into diverse products that serve as important precursors for triterpene synthesis. However, the function of theOSCgene in Chiridotasp. hasnot been elucidated. In this study, an OSCgenederived from the deep-sea holothurianChiridota sp. was cloned and characterized functionally in a yeast system. The open reading frame of the OSC gene was 2086 bp, which encoded 695 amino acids. The Chiridota sp. OSC gene has a similarity of 66.89 % to the OSC of other holothurian species and 63.51 % to that of Acanthaster planci. The phylogenetic tree showed that the echinozoan OSCsclustered together, and then they formeda sister group to fungi and plant homologs. Chiridota sp. OSC catalyzed 2,3-Oxidosqualene into parkeol.Under high pressure, the relative enzymatic activity and stability of cyclase inChiridota sp. was higher than that in the shallow-sea holothurianStichopus horrens. The newly cloned OSC of Chiridota sp.provideskey information for the interpretation of the saponin synthesis pathway in deep-sea holothurians.


Perfusion Imaging in Autoimmune Encephalitis.
Encephalitis is characterized by inflammation of brain tissue and has various infectious and noninfectious causes. CSF analysis and MRI usually reveal inflammatory changes although sometimes brain imaging may be normal. Autoimmune encephalitis is caused by antibodies against neuronal synaptic receptors, surface proteins, or intracellular proteins. In this case report, we present a 65-year-old female who presented with a fall and altered mental status. Workup for infectious etiologies was negative and MRI of the brain displayed focal restricted diffusion with corresponding T2-FLAIR hyperintensity involving gray matter structures, making the diagnosis unclear. CT perfusion of the brain demonstrated increased cerebral blood volume and cerebral blood flow in the left parietooccipital gray matter, with corresponding normal mean transit time. Following treatment failure with acyclovir, antibiotics, and steroids, the patient was found to be positive for GAD65 antibodies and diagnosed with autoimmune encephalitis. Symptoms markedly improved with plasmapheresis. Autoimmune encephalitis rarely causes restricted diffusion and this is the first case report to describe corresponding hyperperfusion on CT perfusion study.


Membrane-bound and exosomal metastasis-associated C4.4A promotes migration by associating with the α(6)β(4) integrin and MT1-MMP.
Metastasis-associated C4.4A, which becomes upregulated during wound healing and, in some tumors, during tumor progression, is known to be frequently associated with hypoxia. With the function of C4.4A still unknown, we explored the impact of hypoxia on C4.4A expression and functional activity. Metastatic rat and human tumor lines upregulate C4.4A expression when cultured in the presence of CoCl(2). Although hypoxia-inducible factor 1α (HIF-1α) becomes upregulated concomitantly, HIF-1α did not induce C4.4A transcription. Instead, hypoxia-induced C4.4A up-regulation promoted in vivo and in vitro wound healing, where increased migration on the C4.4A ligands laminin-111 and -332 was observed after a transient period of pronounced binding. Increased migration was accompanied by C4.4A associating with α(6)β(4), MT1-MMP1, and TACE and by laminin fragmentation. Hypoxia also promoted the release of C4.4A in exosomes and TACE-mediated C4.4A shedding. The association of C4.4A with α(6)β(4) and MT1-MMP1 was maintained in exosomes and exosomal α(6)β(4)- and MT1-MMP1-associated C4.4A but not shed C4.4A sufficient for laminin degradation. Hypoxia-induced recruitment of α(6)β(4) toward raft-located C4.4A, MT1-MMP, and TACE allows for a shift from adhesion to motility, which is supported by laminin degradation. These findings provide the first explanation for the C4.4A contribution to wound healing and metastasis.


Ecological risk assessment of a contaminated stream using multi-level integrated biomarker response in Carassius auratus.
The goal of this study was to evaluate the adverse effects of wastewater effluents on freshwater crucian carp, Carassius auratus, inhabiting Sincheon stream using the integrated biomarker response (IBR) at the genotoxic (micronucleus [MN] test), oxidative stress (activity of catalase [CAT] and glutathione S-transferase [GST], and level of lipid peroxidation [LPO]), histopathological (degree of tissue changes [DTC]), and physiological (condition factor [CF] and liver somatic index [LSI]) levels. The CF and LSI were significantly (p < 0.05) enhanced in fish from downstream sites (DS1 and DS2) as compared to that of upstream (US) fish samples. Moreover, a significant increase in morphometric indices (DTC) was observed in C. auratus collected from downstream sites (p < 0.05) and histopathological responses showed the degree of pathogenicity in the order of liver > kidney > gills. The activities of CAT, GST, and LPO in fish from the DS1 and DS2 sites were notably increased in gills, liver, and kidney compared to that of fish from the US site. Additionally, the MN test level in C. auratus from the DS1 and DS2 were significantly increased (p < 0.05) when compared with that of the US site. Considering the higher bioaccumulation of Cd, Co, Cr, Mn, Ni, and Pb in gills, liver, and kidney of C. auratus collected from downstream sites compared to that of the upstream site (p < 0.05), the observed toxicity was likely attributable to metal accumulation. The multi-level IBR index was higher at the DS1 site (15.08) than at the DS2 (1.02) and the reference US (0.00) sites. Therefore, these findings demonstrated that wastewater effluent discharge induces significant DNA damage, oxidative stress, and tissue injuries in C. auratus and suggested that the multi-level IBR approach should be used to quantify these effects on fish in streams and rivers.


p53-mediated repression of DNA methyltransferase 1 expression by specific DNA binding.
Cytosine methylation patterns in genomic DNA are significantly altered in cancer, and de novo CpG island methylation has been implicated in tumor suppressor gene silencing. Here we demonstrate a mechanistic link between the p53 tumor suppressor gene and control of epigenetic regulation by genomic methylation. Deletion of p53in HCT116 human colon carcinoma cells and primary mouse astrocytes resulted in a 6-fold increase of DNA cytosine methyltransferase 1 (Dnmt1) mRNA and protein, suggesting relief of p53-mediated Dnmt1repression. A p53 consensus binding site in exon 1 of the human Dnmt1gene bound recombinant p53 in vitro and endogenous p53 in vivo in the absence of stimuli that activate p53, implying that p53 controls Dnmt1transcription through direct DNA binding. Interestingly, ionizing radiation or etoposide, both of which stabilize and activate p53, diminished p53 binding in chromatin immunoprecipitation assays, concomitant with a 5-fold increase in Dnmt1 levels. Our findings suggest that activation of p53 reduces binding and relieves transcriptional repression of the Dnmt1gene, whereas loss of p53, a frequent, early event in tumorigenesis, may significantly contribute to aberrant genomic methylation.


Assessing the burden of injuries: competing measures.
This paper compares the different types of injury burden measures in common use and examines criteria that may be useful to consider when selecting between alternative measures. A review was conducted of relevant literature relating to burden of injury measures, important characteristics of data information systems and ethical frameworks for normative analysis in the health sector. Four broad types of burden of injury measures can be distinguished: mortality-related indices; morbidity-related indices; composite measures combining mortality and morbidity; and monetary costs. Each type of measure uses its own construct of injury burden. For example, mortality data defines the injury burden as comprising only fatalities whereas comprehensive costs attempt to capture the total wellbeing lost through injury. Different measures of the burden of injury present differential rankings of the causes and intent of injury, thus the question arises as to what criteria should be used in selecting the best measure. Each measure of the burden of injury has merits and limitations. In selecting between injury measures, consideration should be given to the nature of the policy question, the construct of injury burden that each measure assesses, the availability of data for the measure and its quality and the ethical values inherent in each measure. Measures of the burden of injury play a useful role in positioning injury as a major public health problem and in policy work relating to injury prevention and control. No single measure of the burden of injury is ideal and several measures can be used together if necessary to provide different perspectives on an injury problem.


Developing and testing an instrument to assess aquaticity in humans.
We developed and validated an aquaticity assessment test (AAT) for the evaluation of human physical adequacy in the water. Forty-six volunteers (25M/21F; 20 ± 8 years) participated and performed 10 easy-to-administer and practical aquatic tasks. Group A was formed by 36 elite athletes (M/F 20/16, 24.7 ± 10yrs) from two sports categories depending on their affinity to the water environment: terrestrial (wrestling, cycling, dancing) and aquatic (swimming, synchronized swimming, free diving) sports. Group B was formed by 10 non-athlete participants (5M/5F, 14.4 ± 1.4yrs) and was assessed by two independent evaluators. Participants in Group A performed the aquatic tasks once to develop the final AAT items and cutoffs. Participants in Group B performed the aquatic tasks twice on different days to assess repeatability. Factor analysis recommended all 10 aquatic tasks to be included in the final AAT, resulting in scores ranging from 9.5 to 49.5. The AAT scores were statistically different between the terrestrial and the aquatic sports' participants (p < 0.001). The duration of the test was 25 min from the time of water entry. Receiver operating characteristics curve analyses demonstrated that the cutoffs for low and high aquaticity levels in this sample were ≤23.7 and ≥43.3, respectively. Reliability analyses demonstrated that the aquaticity scores obtained on different days and by different examiners highly correlated (p < 0.001) and were not significantly different (p > 0.05). The AAT appears to be a valid and reliable tool for the evaluation of human physical adequacy in the water. It is an easy and user-friendly test which can be performed in any swimming pool without a need for highly trained staff and specialized equipment, however more research needs to be done in order to be applied in other population group.


Disappearance of the Hexatic Phase in a Binary Mixture of Hard Disks.
Recent studies of melting in hard disks have confirmed the existence of a hexatic phase occurring in a narrow window of density which is separated from the isotropic liquid phase by a first-order transition, and from the solid phase by a continuous transition. However, little is known concerning the melting scenario in mixtures of hard disks. Here we employ tailored Monte Carlo simulations to elucidate the phase behavior of a system of large (l) and small (s) disks with diameter ratio σ_{l}/σ_{s}=1.4. We find that as small disks are introduced to a system of large ones, the stability window of the hexatic phase shrinks progressively until the line of continuous transitions terminates at an end point beyond which melting becomes a first-order liquid-solid transition. This occurs at surprisingly low concentrations of the small disks, c≲1%, emphasizing the fragility of the hexatic phase. We speculate that the change to the melting scenario is a consequence of strong fractionation effects, the nature of which we elucidate.


Stress and deformation characteristics of sea ice in a high-resolution, anisotropic sea ice model.
The drift and deformation of sea ice floating on the polar oceans is caused by the applied wind and ocean currents. Over ocean basin length scales the internal stresses and boundary conditions of the sea ice pack result in observable deformation patterns. Cracks and leads can be observed in satellite images and within the velocity fields generated from floe tracking. In a climate sea ice model the deformation of sea ice over ocean basin length scales is modelled using a rheology that represents the relationship between stresses and deformation within the sea ice cover. Here we investigate the link between emergent deformation characteristics and the underlying internal sea ice stresses using the Los Alamos numerical sea ice climate model. We have developed an idealized square domain, focusing on the role of sea ice rheologies in producing deformation at spatial resolutions of up to 500 m. We use the elastic anisotropic plastic (EAP) and elastic viscous plastic (EVP) rheologies, comparing their stability, with the EAP rheology producing sharper deformation features than EVP at all space and time resolutions. Sea ice within the domain is forced by idealized winds, allowing for the emergence of five distinct deformation types. Two for a low confinement ratio: convergent and expansive stresses. Two about a critical confinement ratio: isotropic and anisotropic conditions. One for a high confinement ratio and isotropic sea ice. Using the EAP rheology and through the modification of initial conditions and forcing, we show the emergence of the power law of strain rate, in accordance with observations.This article is part of the theme issue 'Modelling of sea-ice phenomena'.


Racial Discrimination and Alcohol Problems: Examining Interactions with Genetic Risk and Impulsivity among African American Young Adults.
Experiences of racial discrimination have been shown to increase risk for alcohol problems. Some individuals may be particularly vulnerable to the negative effects of racial discrimination. However, little research has examined interaction effects between racial discrimination and individual characteristics, such as genetic predispositions and personality, in relation to alcohol outcomes. This study examined whether genetic risk and dimensions of impulsivity moderate the association between racial discrimination and alcohol problems among African American young adults (n = 383, Mage = 20.65, SD = 2.28; 81% female). Participants completed online surveys and provided a saliva sample for genotyping. Results from multiple regression analyses indicated that both blatant and subtle forms of racial discrimination (i.e., experience of racist events and racial microaggressions) were associated with more alcohol problems. Racial microaggressions interacted with dimensions of impulsivity in relation to alcohol problems, such that racial microaggressions were associated with more alcohol problems when negative urgency was high or when sensation seeking was low. There was no significant interaction between alcohol use disorder genome-wide polygenic score and experience of racist events or racial microaggression in relation to alcohol problems, which may partly reflect low power due in part to limited representation of African-Americans in genetic research. The findings highlight the need to increase the representation of African Americans in genetically-informed research in order to better characterize genetic risk and understand gene-environment interaction in this understudied population, as well as the importance of examining impulsivity as a multidimensional construct that interacts with racial discrimination in relation to alcohol outcomes.


Genetic ancestry affects the phenotype of normogonadotropic anovulatory (WHOII) subfertility.
Normogonadotropic (World Health Organization category II) anovulation is the most frequent cause of reduced fertility. Anovulation is associated with endocrine changes, i.e. hyperandrogenism, obesity, and insulin resistance. However, the phenotype is notoriously heterogeneous, depending on population characteristics and diagnostic criteria. Our objective was to study the phenotype of normogonadotropic anovulatory women among various ethnic subgroups that coexist in an urban community (The Netherlands). Moreover, we studied whether genetic ancestry testing can be used to identify bio-geographic ancestry and predict the phenotype of individual patients. A standardized clinical and endocrine examination was performed in 1517 normogonadotropic anovulatory women. Bio-geographic ancestry was ascertained by questionnaire and genetic testing (637 cases), using a set of 10 previously validated ancestry informative markers. Subgroups constituted individuals from northwestern European (n = 774), Mediterranean European (north of Sahara and Middle East, n = 220), African (n = 111), Southeast Asian (n = 53), and Hindustani (n = 83) origin. Phenotypic differences included fasting insulin levels, androgen levels, and the frequency of hyperandrogenism (ranging from 76% in Mediterranean-European women to 41% in northwestern European women). Genetic ancestry testing was able to identify population structure on a continental level, i.e. European, African and Southeast Asian descent. We did not observe improved informativeness when genotype data were added to the prediction model. Population differences add to the phenotype of normogonadotropic anovulation and need to be taken into account when evaluating the individual patient. Although effective on a continental level, the present set of ancestry markers was not sufficiently effective to describe all ethnic variation in the phenotype of anovulatory subfertility.


Kinetic approach to relativistic dissipation.
Despite a long record of intense effort, the basic mechanisms by which dissipation emerges from the microscopic dynamics of a relativistic fluid still elude complete understanding. In particular, several details must still be finalized in the pathway from kinetic theory to hydrodynamics mainly in the derivation of the values of the transport coefficients. In this paper, we approach the problem by matching data from lattice-kinetic simulations with analytical predictions. Our numerical results provide neat evidence in favor of the Chapman-Enskog [The Mathematical Theory of Non-Uniform Gases, 3rd ed. (Cambridge University Press, Cambridge, U.K., 1970)] procedure as suggested by recent theoretical analyses along with qualitative hints at the basic reasons why the Chapman-Enskog expansion might be better suited than Grad's method [Commun. Pure Appl. Math. 2, 331 (1949)0010-364010.1002/cpa.3160020403] to capture the emergence of dissipative effects in relativistic fluids.


Evaluation of the efficacy and safety of amustaline/glutathione pathogen-reduced RBCs in complex cardiac surgery: the Red Cell Pathogen Inactivation (ReCePI) study-protocol for a phase 3, randomized, controlled trial.
Red blood cell (RBC) transfusion is a critical supportive therapy in cardiovascular surgery (CVS). Donor selection and testing have reduced the risk of transfusion-transmitted infections; however, risks remain from bacteria, emerging viruses, pathogens for which testing is not performed and from residual donor leukocytes. Amustaline (S-303)/glutathione (GSH) treatment pathogen reduction technology is designed to inactivate a broad spectrum of infectious agents and leukocytes in RBC concentrates. The ReCePI study is a Phase 3 clinical trial designed to evaluate the efficacy and safety of pathogen-reduced RBCs transfused for acute anemia in CVS compared to conventional RBCs, and to assess the clinical significance of treatment-emergent RBC antibodies. ReCePI is a prospective, multicenter, randomized, double-blinded, active-controlled, parallel-design, non-inferiority study. Eligible subjects will be randomized up to 7 days before surgery to receive either leukoreduced Test (pathogen reduced) or Control (conventional) RBCs from surgery up to day 7 post-surgery. The primary efficacy endpoint is the proportion of patients transfused with at least one study transfusion with an acute kidney injury (AKI) diagnosis defined as any increased serum creatinine (sCr) level ≥ 0.3 mg/dL (or 26.5 µmol/L) from pre-surgery baseline within 48 ± 4 h of the end of surgery. The primary safety endpoints are the proportion of patients with any treatment-emergent adverse events (TEAEs) related to study RBC transfusion through 28 days, and the proportion of patients with treatment-emergent antibodies with confirmed specificity to pathogen-reduced RBCs through 75 days after the last study transfusion. With ≥ 292 evaluable, transfused patients (> 146 per arm), the study has 80% power to demonstrate non-inferiority, defined as a Test group AKI incidence increase of no more than 50% of the Control group rate, assuming a Control incidence of 30%. RBCs are transfused to prevent tissue hypoxia caused by surgery-induced bleeding and anemia. AKI is a sensitive indicator of renal hypoxia and a novel endpoint for assessing RBC efficacy. The ReCePI study is intended to demonstrate the non-inferiority of pathogen-reduced RBCs to conventional RBCs in the support of renal tissue oxygenation due to acute anemia and to characterize the incidence of treatment-related antibodies to RBCs.


Ectopic pregnancy; risk factors and comparison of intervention success rates in tubal ectopic pregnancy.
The assessment of ectopic pregnancy, its risk factors and comparison of the treatment modalities. MATERIAL AND DESIGN: Between January 2002 and July 2009, 254 ectopic pregnancies were reviewed retrospectively at the Department of Obstetrics and Gynecology, Ege University. Complaints of patients, localizations of ectopic pregnancy and comparison of patients, whether they had medical therapy or surgery, were evaluated. Metotrexate (50 mg/m2 IM) was used in hemodinamically stable patients (hCG concentrations of patients varied between 450 IU/1 and 3660 IU/1). Patients with fetal cardiac activity and serum hCG concentrations higher than 5000 UI1, were treated surgically. Serum hCG concentrations were measured until the hormone was undetectable (< 1 IU/1). Tubal ectopic pregnancy consisted of 95% of ectopic pregnancies in this trial. The most frequently seen symptom was abdominopelvic pain (77%). Ectopic pregnancy occurred in patients including those with a history of pelvic surgery (12%), previous ectopic pregnancy (6%), usage of intrauterine devices (6%), history of infertility (5.5%) and history of pelvic inflamatory disease (4%). While hemodynamically stable, 83 patients were given single dose methotrexate (50 mg/m2), and 165 patients were treated surgically. Totally 93 salpingectomies and 54 salpingostomies were performed. Of 83 patients administered single dose methotrexate, 69 were successfully treated with one course, six patients needed a second course and surgical intervention was performed in eight patients. On the other hand, of patients that underwent surgery, seven of the salpingostomy group needed methotrexate for persistent trophoblasts and three of this group were reoperated. The tube was preserved in 49 patients in the salpingostomy group (90.7%) versus 75 (92.8%) in the methotexate group (p: 0.916). When undetectable hCG levels following initial therapy were considered, no significant difference was found between the two treatment groups (p: 0.804). In selected patients with low serum hCG concentrations systemic methotrexate is a good alternative. Early diagnosis of ectopic pregnancy improves medical therapy. Although salpingectomy solves the problem definitely, comprehensive studies are required concerning future fertility of salpingectomy patients compared with salpingostomy patients.


Magnetic resonance imaging and intraoperative frozen sectioning for the evaluation of risk factors associated with lymph node metastasis in endometrial cancer.
To analyze the accuracy of magnetic resonance imaging (MRI) and intraoperative frozen sectioning (IFS) for predicting the low- and high-risk patients and risk factors associated with lymph node (LN) metastasis in patients with surgically staged endometrial cancer. The medical records of 175 patients with endometrial cancer who underwent comprehensive surgical staging including pelvic and para-aortic LN dissection between January 2008 and July 2011 were retrospectively analyzed. Results of MRI and IFS of the uterus for the evaluation of risk factors were correlated with final pathology. Our results showed a high specificity and negative predictive value of MRI and IFS for the evaluation of myometrial invasion and cervical stromal invasion. Of the 41 patients identified as low risk by both MRI and IFS, none had pelvic or para-aortic LN metastases in the final pathology. The results indicate that MRI and IFS may be useful for the evaluation of risk factors associated with LN metastasis in patients with endometrial cancer. Magnetic resonance imaging and IFS can be used to accurately identify low-risk patients who do not need comprehensive surgical staging and may prevent unnecessary lymphadenectomy.


Inhibition of GATA2 restrains cell proliferation and enhances apoptosis and chemotherapy mediated apoptosis in human GATA2 overexpressing AML cells.
GATA2, a zinc finger transcription factor predominantly expressed in hematopoietic cells, acts as an essential regulator of hematopoietic stem cell generation, survival and functionality. Loss and gain of GATA2 expression has been implicated in myelodysplastic syndrome and acute myeloid leukemia (AML) yet the precise biological impact of GATA2 expression on human AML cell fate decisions remains ambiguous. Herein, we performed large-scale bioinformatics that demonstrated relatively frequent GATA2 overexpression in AML patients as well as select human AML (or AML-like) cell lines. By using shRNAi to target GATA2 in these AML cell lines, and an AML cell line expressing normal levels of GATA2, we found that inhibition of GATA2 caused attenuated cell proliferation and enhanced apoptosis exclusively in AML cell lines that overexpress GATA2. We proceeded to pharmacologically inhibit GATA2 in concert with AML chemotherapeutics and found this augmented cell killing in AML cell lines that overexpress GATA2, but not in an AML cell line expressing normal levels of GATA2. These data indicate that inhibition of GATA2 enhances chemotherapy-mediated apoptosis in human AML cells overexpressing GATA2. Thus, we define novel insights into the oncogenic role of GATA2 in human AML cells and suggest the potential utilization of transient GATA2 therapeutic targeting in AML.


Contribution of glucose tolerance and plasma insulin levels to the relationships between body fat distribution and plasma lipoprotein levels in women.
Numerous interrelated metabolic and morphological variables such as plasma insulin levels, glucose tolerance and abdominal obesity are associated with changes in plasma lipoprotein levels. The present study was undertaken to differentiate, using a multivariate approach, the respective contributions of plasma glucose and insulin levels, obesity and regional adipose tissue distribution to the variance in plasma lipoproteins. The study group was composed of 69 healthy premenopausal women (age 35.4 +/- 5.0 years (mean +/- s.d.); percent body fat 40.7 +/- 10.1). Indices of carbohydrate metabolism showed significant univariate correlations with triglyceride (TG) and/or cholesterol (CHOL) content of plasma VLDL, LDL and HDL (P less than 0.05). Multivariate analyses indicated that the explained variance in plasma VLDL-TG (R2 x 100 = 44 percent, P less than 0.05) and LDL-apoprotein (apo) B levels (R2 x 100 = 33.1 percent, P less than 0.08) was entirely accounted for by indices of carbohydrate metabolism and body fat distribution, whereas total body fatness added no significant contribution to these models. Multivariate analyses also revealed that the best possible regression model to predict the variation in plasma HDL2-CHOL levels only included computed tomography-derived deep abdominal adipose tissue area (P less than 0.0001). All other variables were unable to further improve the explained variance in plasma HDL2-CHOL levels. In partial correlation analyses, indices of carbohydrate metabolism and the waist-to-hip circumference ratio (WHR) remained significantly correlated with plasma VLDL-TG and LDL-apo B levels after adjustment of VLDL-TG and LDL-apo B for either insulin and glucose levels, or for the WHR (P less than 0.08). After correcting for deep abdominal fat accumulation, no significant correlation was observed between indices of carbohydrate metabolism and plasma HDL2-CHOL levels whereas deep abdominal fat showed significant correlations with HDL2-CHOL levels (P less than 0.05) after correction for indices of carbohydrate metabolism. These results suggest that both disturbances in glucose-insulin homeostasis and abdominal obesity are significantly associated with changes in plasma VLDL-TG and LDL-apo B levels and that these associations are partly independent from each other. These results also indicate that mechanisms other than disturbances in glucose homeostasis and hyperinsulinemia are responsible for the association between the level of deep abdominal fat and plasma HDL2-CHOL levels.


Nucleolin identified by comparative mass‑spectra analysis is a potential marker for invasive progression of hepatocellular carcinoma.
At present, the diagnosis and prognosis of hepatocellular carcinoma (HCC) metastasis remains poor. Recently, a number of proteins associated with the metastasis and invasion of HCC were identified; however, the effective markers require further elucidation. In the current study, a nucleolin expression was observed in MHCC97L and HCCLM9 HCC cell lines, with low and high metastatic potentials respectively, using comparative proteomics. The data indicated that nucleolin expression in the nucleus was significantly higher in HCCLM9 cells, and it primarily influenced the migration of HCC cells in vitro. Thus, to the best of our knowledge this is the first study to hypothesize that nucleolin may be a novel marker for HCC invasive progression.


RBRVS as a financial assessment tool.
The relative value service units that underlie the Health Care Financing Administration's resource-based relative value scale (RBRVS) fee schedule can provide an alternative basis for evaluating many financial aspects of a physician practice.


Role of mouse CYP2E1 in the O-hydroxylation of p-nitrophenol: comparison of activities in hepatic microsomes from Cyp2e1(-/-) and wild-type mice.
Enzymatic activities are routinely used to identify the contribution of individual forms of cytochrome P450 in a particular biotransformation. p-Nitrophenol O-hydroxylation (PNPH) has been widely used as a measure of CYP2E1 catalytic activity. However, rat and human forms of CYP3A have also been shown to catalyze this activity. In mice, the contributions of CYP3A and CYP2E1 to PNPH activity are not known. Here we used hepatic microsomes from Cyp2e1(-/-) and wild-type mice to investigate the contributions of constitutively expressed and alcohol-induced murine CYP2E1 and CYP3A to PNPH activity. In liver microsomes from untreated mice, PNPH activity was much greater in wild-type mice compared with Cyp2e1(-/-) mice, suggesting a major role for CYP2E1 in catalyzing PNPH activity. Hepatic PNPH activities were not significantly different in microsomes from male and female mice, although the microsomes from females have dramatically higher levels of CYP3A. Treatment with a combination of ethanol and isopentanol resulted in induction of CYP3A proteins in wild-type and Cyp2e1(-/-) mice, as well as CYP2E1 protein in wild-type mice. The alcohol treatment increased PNPH activities in hepatic microsomes from wild-type mice but not from Cyp2e1(-/-) mice. Our findings suggest that in untreated and alcohol-treated mice, PNPH activity may be used as a specific probe for CYP2E1 and that constitutively expressed and alcohol-induced forms of mouse CYP3A have little to no role in catalyzing PNPH activity.


Accent trumps race in guiding children's social preferences.
A series of experiments investigated the effect of speakers' language, accent, and race on children's social preferences. When presented with photographs and voice recordings of novel children, 5-year-old children chose to be friends with native speakers of their native language rather than foreign-language or foreign-accented speakers. These preferences were not exclusively due to the intelligibility of the speech, as children found the accented speech to be comprehensible, and did not make social distinctions between foreign-accented and foreign-language speakers. Finally, children chose same-race children as friends when the target children were silent, but they chose other-race children with a native accent when accent was pitted against race. A control experiment provided evidence that children's privileging of accent over race was not due to the relative familiarity of each dimension. The results, discussed in an evolutionary framework, suggest that children preferentially evaluate others along dimensions that distinguished social groups in prehistoric human societies.


Inferring experimental procedures from text-based representations of chemical reactions.
The experimental execution of chemical reactions is a context-dependent and time-consuming process, often solved using the experience collected over multiple decades of laboratory work or searching similar, already executed, experimental protocols. Although data-driven schemes, such as retrosynthetic models, are becoming established technologies in synthetic organic chemistry, the conversion of proposed synthetic routes to experimental procedures remains a burden on the shoulder of domain experts. In this work, we present data-driven models for predicting the entire sequence of synthesis steps starting from a textual representation of a chemical equation, for application in batch organic chemistry. We generated a data set of 693,517 chemical equations and associated action sequences by extracting and processing experimental procedure text from patents, using state-of-the-art natural language models. We used the attained data set to train three different models: a nearest-neighbor model based on recently-introduced reaction fingerprints, and two deep-learning sequence-to-sequence models based on the Transformer and BART architectures. An analysis by a trained chemist revealed that the predicted action sequences are adequate for execution without human intervention in more than 50% of the cases.


Comparison of muscle-sparing thoracotomy and thoracoscopic ligation for the treatment of patent ductus arteriosus.
We reviewed our experience with the treatment of patent ductus arteriosus (PDA), and compared two therapeutic techniques; muscle-sparing thoracotomy (MST) and thoracoscopic PDA ligation (TPDAL). We reviewed the clinical records and operative reports of 19 nonnewborn patients who were treated at our institution for PDA. Eleven patients underwent TPDAL and eight patients MST. The TPDAL patients underwent thoracoscopic clipping (ligation) of the PDA, whereas the MST group had a complete division of the ductus. A two-tailed Student's t test was used to calculate the 95% confidence intervals for length of operation, number of doses of intravenous narcotics and hospital stay. Costs were also compared. All patients underwent diagnostic echocardiography in the evaluation of an asymptomatic murmur. Both groups were similar in age (average, 4 years) and gender. All procedures were performed electively. Two thoracoscopic attempts were aborted, one for bleeding and the other for inadequate clip size. The length of the procedure averaged 1.3 hours +/- 0.330 SD for TPDAL versus 1.4 hours +/- 0.335 SD for MST. Five of the nine successful TPDAL patients were admitted to the Pediatric Intensive Care Unit (PICU) with an average length of stay of 20 hours, and two of eight MST patients stayed in the PICU for average of 18 hours. All patients were extubated after the procedure. Chest tubes were placed in two TPDAL patients and three MST patients. However, two patients who underwent TPDAL required tube thoracostomy for persistent postoperative pneumothorax. Average number of intravenous narcotics administered for the TPDAL was 1.2 doses per patient and for MST, 1.75 doses per patient. Mean hospital stay for TPDAL was 1.33 +/- 0.71 SD days and for MST 1.8 +/- 0.83 SD days. Ninety-five percent (95%) confidence intervals for the difference in means demonstrated no difference between the two groups for length of operation, hospital stay, or number of doses of intravenous narcotics administered. The authors were unable to identify any benefit to thoracoscopic patent ductus arteriosus ligation versus muscle-sparing thoracotomy in terms of hospital stay, length of operation, or morbidity. Additionally, with MST there is a complete division of the PDA theoretically decreasing the risk of recurrence in comparison with clip ligation.


Reducing drug related deaths: a pre-implementation assessment of knowledge, barriers and enablers for naloxone distribution through general practice.
The Scottish Naloxone Programme aims to reduce Scotland's high number of drug-related deaths (DRDs) caused by opiate overdose. It is currently implemented through specialist drug services but General Practitioners (GPs) are likely to have contact with drug using patients and their families and are therefore in an ideal position to direct them to naloxone schemes, or provide it themselves. This research gathered baseline data on GP's knowledge of and willingness to be involved in DRD prevention, including naloxone administration, prior to the implementation of primary care based delivery. Mixed methods were used comprising a quantitative, postal survey and qualitative telephone interviews. A questionnaire was sent to 500 GPs across Scotland. An initial mailing was followed by a reminder. A shortened questionnaire containing seven key questions was posted as a final reminder. Telephone interviews were conducted with 17 GPs covering a range of demographic characteristics and drug user experience. A response rate of 55% (240/439) was achieved. There was some awareness of the naloxone programme but little involvement (3.3%), 9% currently provided routine overdose prevention, there was little involvement in displaying overdose prevention information (<20%). Knowledge of DRD risk was mixed. There was tentative willingness to be involved in naloxone prescribing with half of respondents willing to provide this to drug users or friends/family. However half were uncertain GP based naloxone provision was essential to reduce DRDs.Factors enabling naloxone distribution were: evidence of effectiveness, appropriate training, and adding to the local formulary. Interviewees had limited awareness of what naloxone distribution in primary care may involve and considered naloxone supply as a specialist service rather than a core GP role. Wider attitudinal barriers to involvement with this group were expressed. There was poor awareness of the Scottish National Naloxone Programme in participants. Results indicated GPs did not currently feel sufficiently skilled or knowledgeable to be involved in naloxone provision. Appropriate training was identified as a key requirement.


Supplementing media with NAD+ precursors enhances the in vitro maturation of porcine oocytes.
In vitro maturation (IVM) is an important reproductive technology used to produce embryos in vitro. However, the developmental potential of oocytes sourced for IVM is markedly lower than those matured in vivo. Previously, NAD+-elevating treatments have improved oocyte quality and embryo development in cattle and mice, suggesting that NAD+ is important during oocyte maturation. The aim of this study was to examine the effects of nicotinic acid (NA), nicotinamide (NAM) and nicotinamide mononucleotide (NMN) on oocyte maturation and subsequent embryo development. Porcine oocytes from small antral follicles were matured for 44 h in a defined maturation medium supplemented with NA, NAM and resveratrol or NMN. Mature oocytes were artificially activated and presumptive zygotes cultured for 7 days. Additionally, oocytes were matured without treatment then cultured for 7 days with NMN. Supplementing the IVM medium with NA improved maturation and blastocyst formation while NAM supplementation improved cleavage rates compared with untreated controls. Supplementing the IVM or embryo culture media with NMN had no effect on maturation or embryo development. The results show that supplementing the maturation medium with NA and NAM improved maturation and developmental potential of porcine oocytes.


Innervation of extraocular pulley smooth muscle in monkeys and humans.
Soft pulleys stabilize paths and determine pulling directions of the extraocular muscles (EOMs). This study was conducted to characterize innervation of smooth muscles (SMs) supporting these pulleys. Cadaveric human and monkey orbits were step and serially sectioned for histochemical and immunohistochemical staining. Before perfusion, the superior cervical ganglia of one monkey had been injected with the anterograde tracer Phaseolus vulgaris leukoagglutinin (PHA-L). Immunoperoxidase staining to human SM alpha-actin confirmed pulley SM. Monoclonal and polyclonal antibodies were used to demonstrate PHA-L, tyrosine hydroxylase, dopamine beta-hydroxylase, phenylethanolamine-N-methyltransferase, neuronal nitric oxide synthase (NOS), and synaptophysin. The NADPH-diaphorase reaction was also used as a marker for NOS and the acetylcholinesterase (AChE) reaction for acetylcholine. Pulleys, consisting of collagen and elastin sleeves supported by connective tissue containing SM, were observed around rectus muscles of humans and monkeys. The human and monkey SM was richly innervated. Axons terminating in motor end plates within SM bundles were immunoreactive to PHA-L, tyrosine hydroxylase, and dopamine beta-hydroxylase, but not phenylethanolamine-N-methyltransferase, indicating innervation of pulley SM from the superior cervical ganglion by projections using norepinephrine. Smaller axons and motor end plates were also demonstrated in SM, using NADPH-diaphorase and NOS immunoreactivity, indicating nitroxidergic innervation, and using AchE, indicating cholinergic parasympathetic innervation. The pterygopalatine and, to a lesser extent, the ciliary ganglia, but not the Edinger-Westphal nucleus, contained cells immunoreactive to NOS, suggesting that nitroxidergic innervation to pulley SM is mainly from the pterygopalatine ganglion. The SM suspensions of human and monkey EOM pulleys are similar and receive rich innervation involving multiple neurotransmitters. These complex projections suggest excitatory and inhibitory control of EOM pulley SM, and support their dynamic role in ocular motility.


Hyperhomocysteinemia in renal diseases.
Homocysteine is a sulfurated amino acid used for the synthesis of methionine. The last decade's researches proved that hyperhomocysteinemia is an independent risk factor for atherosclerotic vascular disease. The vascular injury induced by several mechanisms of hyperhomocysteinemia is the hallmark of homocysteine's atherogenic properties. Hyperhomocysteinemia is present in 85% of the patients with chronic renal failure (cardiovascular diseases are the main cause of mortality) and persists after initiating dialysis or after renal transplantation. Although folic therapy or folinic acid therapy reduce homocysteine levels with 20-40% in hemodialysis patients, the effects on cardiovascular morbidity have yet to be proven in future studies.


Coxsackievirus preferentially replicates and induces cytopathic effects in undifferentiated neural progenitor cells.
Enteroviruses, including coxsackieviruses, exhibit significant tropism for the central nervous system, and these viruses are commonly associated with viral meningitis and encephalitis. Previously, we described the ability of coxsackievirus B3 (CVB3) to infect proliferating neuronal progenitor cells located in the neonatal subventricular zone and persist in the adult murine central nervous system (CNS). Here, we demonstrate that cultured murine neurospheres, which comprise neural stem cells and their progeny at different stages of development, were highly susceptible to CVB3 infection. Neurospheres, or neural progenitor and stem cells (NPSCs), isolated from neonatal C57BL/6 mice, supported high levels of infectious virus production and high viral protein expression levels following infection with a recombinant CVB3 expressing enhanced green fluorescent protein (eGFP) protein. Similarly, NPSCs isolated from neonatal actin-promoter-GFP transgenic mice (actin-GFP NPSCs) were highly susceptible to infection with a recombinant CVB3 expressing DsRed (Discosoma sp. red fluorescent protein). Both nestin-positive and NG2(+) progenitor cells within neurospheres were shown to preferentially express high levels of viral protein as soon as 24 h postinfection (p.i.). By day 3 p.i., viral protein expression and viral titers increased dramatically in NPSCs with resultant cytopathic effects (CPE) and eventual cell death. In contrast, reduced viral replication, lower levels of CPE, and diminished viral protein expression levels were observed in NPSCs differentiated for 5 or 16 days in the presence of fetal bovine serum (FBS). Despite the presence of CPE and high levels of cell death following early CVB3 infection, surviving neurospheres were readily observed and continued to express detectable levels of viral protein as long as 37 days after initial infection. Also, CVB3 infection of actin-GFP NPSCs increased the percentage of cells expressing neuronal class III β-tubulin following their differentiation in the presence of FBS. These results suggest that neural stem cells may be preferentially targeted by CVB3 and that neurogenic regions of the CNS may support persistent viral replication in the surviving host. In addition, normal progenitor cell differentiation may be altered in the host following infection.


The effectiveness of metformin ovulation induction treatment in patients with PCOS: a systematic review and meta-analysis.
To evaluate of metformin effectiveness of ovulation induction treatment in polycystic ovary syndrome (PCOS) women. Eight databases and nine related journals were searched for randomized controlled trails (RCTs) on the comparison between metformin and clomiphene citrate used for PCOS women. Meta analysis was performed after quality assessment. Ovulation rate in metformin group compared with clomiphene citrate group was lower with a significant difference [OR = 0.48 (0.26-0.87), p = 0.01]; no significant difference was found for pregnancy rate [OR = 0.94 (0.26-3.43)], miscarriage rate [OR = 0.63 (0.06-6.47)] between two groups. Compared with the combination of metformin and clomiphene citrate group, pregnancy rate in metformin group was significantly lower [Peto OR = 1.56 (1.16-2.08), p = 0.003], but there was no significant difference in the two groups about ovulation rate [OR = 1.52 (0.95-2.45)], miscarriage rate [Peto OR = 1.40 (0.79-2.48)]. Compared with clomiphene citrate, metformin used for ovulation induction treatment in PCOS women, can promote ovulation induction and pregnancy rate, the effect of the combination treatment is better than that of a single drug use.


Genotype and rhizobium inoculation modulate the assembly of soybean rhizobacterial communities.
Rhizosphere bacterial communities are vital for plants, yet the composition of rhizobacterial communities and the complex interactions between roots and microbiota, or between microbiota, are largely unknown. In this study, we investigated the structure and composition of rhizobacterial communities in two soybean cultivars and their recombinant inbred lines contrasting in nodulation through 16S rRNA amplicon sequencing in two years of field trials. Our results demonstrate that soybean plants are able to select microbes from bulk soils at the taxonomic and functional level. Soybean genotype significantly influenced the structure of rhizobacterial communities and resulted in dramatically different co-occurrence networks of rhizobacterial communities between different genotypes of soybean plants. Furthermore, the introduction of exogenous rhizobia through inoculation altered soybean rhizobacterial communities in genotype-dependent manner. Rhizobium inoculation not only stimulated the proliferation of potential beneficial microbes but also increased connections in rhizobacterial networks and changed the hub microbes, all of which led to the association of distinctive bacterial communities. Taken together, we demonstrated that the assembly of soybean rhizobacterial communities was determined by both genotype and the introduction of exogenous rhizobia. These findings bolster the feasibility of root microbiome engineering through inoculation of specific microbial constituents.


POSTOPERATIVE HYPOCALCEMIA FOLLOWING PARATHYROIDECTOMY FOR GIANT PARATHYROID ADENOMA.
Giant parathyroid adenomas (GPAs) are a rare type of parathyroid adenoma (PA) weighing >2 to 3 g. The objective of this manuscript is to report a case of giant parathyroid adenoma and highlight the risk of postoperative hypocalcemia. We describe the presentation and work-up of a woman with GPA confirmed with histopathology as well as management of postoperative hypocalcemia. A 66-year-old Caucasian female with chronic fatigue was found to have elevated calcium levels at 13.7 mg/dL (normal, 8.9 to 10.2 mg/dL) and elevated parathyroid hormone levels at 1,240 pg/mL (normal, 12 to 72 pg/mL). Contrast enhanced computed tomography scan of the neck showed a 5.6 cm heterogeneous mass posterior to the right thyroid. The patient underwent right parathyroidectomy and histopathology confirmed the diagnosis of a giant parathyroid adenoma (GPA) weighing 28.7 g. Postoperatively, the patient developed hypocalcemia secondary to hungry bone syndrome and was treated aggressively with intravenous calcium supplementation. At 4 weeks postoperatively, she had normal calcium levels without any calcium supplementation. GPAs are a rare variant of PA, and could be a distinct clinical entity with features different from both PA and parathyroid carcinoma. We further postulate that the risk of postoperative hypocalcemia secondary to hungry bone syndrome could be higher among patients with GPA compared to patients with PA. These hypotheses needs to be validated with further studies.


Modeling injury severity of crashes involving golf carts: A case study of The Villages, Florida.
Crashes involving golf carts (GCs) have been on an increasing trend in recent years, particularly in the United States. This study focuses on analyzing GC crashes in the Florida community known as The Villages, one of the largest GC-oriented communities in the nation and worldwide. The objective was to evaluate the injury severity of crashes involving GCs in a retirement community where GCs are a common mode of transportation. The ordinal logistic regression (OLR) and Decision Tree Ensemble (DTE) models were used to analyze the injury severity of 616 GC-related crashes. Models' accuracy parameters were used to check their reliability. The analysis revealed that GC crash severity is influenced by various factors. Factors found to be significant by the OLR model in determining injury severity include ejection of one or more occupants from the GC, the extent of damage to the GC, GC speed prior to the crash, roadway characteristics (including divided roadways, traffic control devices, paved shoulders, and T-intersections), and roll-over incidents. The OLR model demonstrated an overall accuracy of approximately 71% in predicting injury severity. The DTE model performed better, with an overall accuracy of 78%. The OLR model's findings were supported by the DTE model, which identified estimated GC speed, occupant(s) ejection from the GC, estimated GC vehicle damage, intersection type, and type of shoulder as the most important factors influencing GC crash severity. Understanding these factors is vital for transportation agencies to develop effective strategies to reduce the severity of GC crashes, ensuring the safety of GC users. This study provides recommendations to transportation agencies on measures to improve the safety of GCs.


The comparison between the novel technique and conventional method in the catheter ablation of premature ventricular contractions originating from the free wall of tricuspid annulus.
This study aimed to assess the safety and effectiveness of a novel technique for catheter ablation in patients with premature ventricular contraction (PVC) from the free wall of tricuspid annulus (TV). We hypothesized that the novel technique is more efficacious than the traditional approach. We retrospectively investigated 59 consecutive patients with PVC originating from the free wall of TV between January 2013 and November 2021. The patients were divided into two groups: the reversed S-curve technique group (RST, n = 26) and the reversed C-curve technique group (RCT, n = 33). The RST under the support of a steerable sheath was used in RST group, while the RCT under the support of a nonsteerable sheath was used in the RCT group. Systematic mapping and radiofrequency ablation were preferentially performed under the valve in all patients. Compared to the RCT group, total procedural time and fluoroscopic exposure time were significantly shorter in RST group. Two patients experienced cardiac tamponade in the RCT group, while no complications were observed in RST group (p = .498). The success rate was significantly higher in RST group compared to RCT group (81.9% vs. 100%, p = .029). Three patients in RCT group failed to ablate during the operation but were successfully ablated using the novel method. During regular follow-up, no patients in the RST group had a recurrence, while three patients in the RCT group did (p = .274). It suggests that the reserved S-curve technique, supported by a steerable sheath, is a feasible and effective method for ablating PVC originating from the free wall of TV.


Antibiotic resistance as a stress response: complete sequencing of a large number of chromosomal loci in Staphylococcus aureus strain COL that impact on the expression of resistance to methicillin.
Tn551 inactivation has identified several determinants--fem or auxiliary genes--that, in addition to the mecA gene, are also critical for the expression of high-level and homogeneous resistance to methicillin. Genetic and/or biochemical analysis has shown that of the nearly dozen aux mutations described so far most are in genes involved in cell wall synthesis (murE, pbp2, glmM, glnR, femA/B, llm, etc.) or in complex regulatory functions (sigmaB), suggesting that optimal expression of resistance may involve the cooperative functioning of a number of genes in cell wall metabolism as well as stress response. The exact mechanism of these functions is not known. In an attempt to explore this unusual aspect of methicillin resistance more fully, a Tn551 transposon library, constructed in the background of the highly and homogeneously methicillin-resistant Staphylococcus aureus strain COL, was screened for all independent insertional mutants in which the level of methicillin resistance of the parental strain (MIC, 1,600 microg/ml) was reduced by at least 15-fold and up to 500-fold. We now describe the sequencing of 21 Tn551-inactivated genes and their vicinities in 23 new auxiliary mutants that have been studied before. Using the inverted polymerase chain reaction (IPCR), we amplified fragments corresponding to the right and left junction of the Tn551 insertions, which were then sequenced by primer walking. The two largest groups of these new auxiliary genes encoded either proteins of unknown functions (6 genes) or showed homology with genes encoding proteins involved with putative sensory/regulatory activities (7 genes: protein kinases, ABC transporters, and a catabolite control protein). Sequencing upstream and downstream allowed the identification of a number of additional open reading frames, some of which may also include functions relevant for the expression of antibiotic resistance.


Nasal histology and nickel concentration in plasma and urine after improvements in the work environment at a nickel refinery in Norway.
Nasal histology and nickel concentration in the plasma and urine of nickel workers were reexamined after 4 a for an evaluation of the effect of improvements in the refining process and work conditions. Ninety-eight (31%) nickel workers who were part of a previous study were reexamined. In addition, 33 of the original 38 workers with nasal epithelial dysplasia were studied for possible regression of the histological changes. Reduction in the atmospheric content of nickel and improved hygienic conditions lowered the concentration of nickel in plasma and urine by approximately 50%. The mean histological score and frequency of dysplasia was virtually the same in the two investigations, 12 and 13%, respectively. Nasal biopsies are of limited diagnostic value in the examination of individual cases. However, the method seems to be of value in identifying and monitoring groups of persons with increased risk of developing nasal carcinoma.


Beyond Botox: Contemporary Management of Nonflaccid Facial Palsy.
Many transient facial nerve insults, including Bell's palsy, Ramsay Hunt syndrome, Lyme-associated facial paralysis, and temporal bone fractures, ultimately lead to nonflaccid facial palsy (NFFP). NFFP is associated with significant functional, aesthetic, psychological, and social impairments. However, algorithms for comprehensive management of this entity are not well developed and are rapidly evolving. Herein, we present our current approach to NFFP, with the goal of providing a framework that may be applied to this complex patient population.


Patient Perspectives of Dignity, Autonomy and Control at the End of Life: Systematic Review and Meta-Ethnography.
Research in the end-of-life context has explored the sense of dignity experienced by patients with advanced disease, examining the factors associated with it. Whereas certain perspectives regard dignity as an intrinsic quality, independent of external factors, in the clinical setting it is generally equated with the person's sense of autonomy and control, and it appears to be related to patients' quality of life. This study aims to explore the relationship between perceived dignity, autonomy and sense of control in patients at the end of life. We conducted a systematic review and meta-ethnography using reciprocal translation and line-of-argument synthesis. The search strategy used MeSH terms in combination with free-text searching of the Pubmed, Web of Science, CINAHL, PsycINFO and Cochrane databases, from their inception until 2015. This identified 186 articles, after excluding duplicates. The inclusion criterion was primary qualitative studies in which dignity, autonomy and control at the end of life were explored. Studies were evaluated using the CASP guidelines. Twenty-one studies recording the experiences of 400 participants were identified. Three themes emerged: a) dignity mediated by the loss of functionality, linked to the loss of control; b) dignity as identity; and c) autonomy as a determining factor of perceived dignity, understood as the desire for control over the dying process and the desire for self-determination. We propose an explanatory model which highlights that those patients with an intrinsic sense of dignity maintained a positive view of themselves in the face of their illness. This synthesis illustrates how dignity and autonomy are intertwined and can be perceived as a multidimensional concept, one that is close to the notion of personal identity. The ability to regard dignity as an intrinsic quality has a positive impact on patients, and the design of care strategies should take this into account.


Legacy contaminant trends in the Great lakes uncovered by the wildlife environmental quality index.
Since the 1970s, wildlife managers have prioritized the recovery of Great Lakes ecosystems from contamination by Persistent Organic Pollutants (POPs). Monitoring and quantifying the region's recovery is challenged by the diversity of legacy contaminants in the environment and the lack of benchmarks for their potential biological effects. We address this gap by introducing the Wildlife Environmental Quality Index (WEQI) based on prior water and sediment quality indices. The tool summarizes, in a single score, the exposure of wildlife to harmful levels of multiple contaminants - with harmful levels set by published guidelines for protecting piscivorous wildlife from biological impacts. We applied the new index to a combined Canadian and American dataset of Herring Gull (Larus argentatus) egg data to elucidate trends in wildlife for eight legacy industrial pollutants and insecticides in the Great Lakes. Environmental quality of the Great Lakes region (as indexed by WEQI) improved by 18% between 2002 and 2017. Improvement came from reductions in both the scope of contamination (the number of guideline-exceeding contaminants) and its amplitude (the average size of guideline exceedances) at bird colonies. But recovery was unequal among lakes, with Lake Erie showing no improvement at one extreme. Weakly- or non-recovering lakes (Erie, Ontario, Huron) were marked by inconsistent improvement in scope and amplitude, likely due to ongoing loading, sediment resuspension and other stressors reported elsewhere. Fast-recovering lakes (Superior and Michigan), meanwhile, improved in both scope and amplitude. Contrasting trends and contaminant profiles (e.g., exceedances of PCBs versus DDTs) highlight the importance of lake-specific management for equalizing recoveries. Lower environmental quality at American and Canadian colonies, particularly in Lake Huron, further suggest uneven success in - and opportunities for - the binational management of wildlife exposure to legacy contaminants.


The ENIGI (European Network for the Investigation of Gender Incongruence) Study: Overview of Acquired Endocrine Knowledge and Future Perspectives.
Literature on the efficacy and safety of gender-affirming hormonal treatment (GAHT) in transgender people is limited. For this reason, in 2010 the European Network for the Investigation of Gender Incongruence (ENIGI) study was born. The aim of this review is to summarize evidence emerging from this prospective multicentric study and to identify future perspectives. GAHT was effective in inducing desired body changes in both trans AMAB and AFAB people (assigned male and female at birth, respectively). Evidence from the ENIGI study confirmed the overall safety of GAHT in the short/mid-term. In trans AMAB people, an increase in prolactin levels was demonstrated, whereas the most common side effects in trans AFAB people were acne development, erythrocytosis, and unfavorable changes in lipid profile. The main future perspectives should include the evaluation of the efficacy and safety of non-standardized hormonal treatment in non-binary trans people. Furthermore, long-term safety data on mortality rates, oncological risk, and cardiovascular, cerebrovascular and thromboembolic events are lacking. With this aim, we decided to extend the observation of the ENIGI study to 10 years in order to study all these aspects in depth and to answer these questions.


[Neuroprotective effects of paeonol in a cell model of Parkinson disease].
To investigate the effects of paeonol on neuron cell model of Parkinson disease (PD). The cell model of Parkinson disease was induced by treatment of 1-Methyl-4-phenylpyridinium (MPP+) in PC12 cells, the PD model cells were treated with 1 μmol/L, 3 μmol/L or 9 μmol/L paeonol for 24h, respectively. Cell viability and LDH leakage were detected by MTT and lactate dehydrogenase (LDH) assay; the apoptosis of PC12 cells was assessed by Hoechst 33258 staining and flow cytometry; reactive oxygen species (ROS) production was detected by DCFH-DA method; and the ratio of Bax/Bcl-2 and activation of caspase-3 were determined by Western blotting. MPP+ treatment significantly reduced cell viability, increased LDH leakage, enhanced the proportion of apoptotic cells and ROS production. In addition, MPP+ treatment dramatically increased the Bax/Bcl-2 ratio, and the activation of caspase-3. Compared to PD model group, paeonol treatment significantly enhanced cell viability, decreased LDH leakage, inhibited the proportion of apoptotic cells and ROS production, reduced the Bax/Bcl-2 ratio and the activated caspase-3 protein. Paeonol can prevent PC12 cells from apoptosis induced by MPP+, and the mechanism may be associated with the down-regulation of ROS production, Bax/Bcl-2 ratio and Caspase-3 activation.


Structural and dynamical properties of hydrogen fluoride in aqueous solution: an ab initio quantum mechanical charge field molecular dynamics simulation.
The novel ab initio quantum mechanical charge field (QMCF) molecular dynamics simulation at the Hartree-Fock level has been employed to investigate hydration structure and dynamics of hydrogen fluoride in aqueous solution. The average H-F bond length of 0.93 A obtained from the QMCF MD simulation is in good agreement with the experimental data. The HHF...Ow distance of 1.62 A was evaluated for the first hydration shell, and 2.00 A was observed for the FHF...Hw distance. The stability of hydrogen bonding is more pronounced in the hydrogen site of hydrogen fluoride, with a single water molecule in this part of the first hydration shell. A wide range of coordination numbers between 3 and 9 with an average value of 5.6 was obtained for the fluorine site. The force constants of 819.1 and 5.9 N/m were obtained for the HHF-FHF and HHF...Ow interactions, respectively, proving the stability of the nondissociated form of hydrogen fluoride in aqueous solution. The mean residence times of 2.1 and 2.5 ps were determined for ligand exchange processes in the neighborhood of fluorine and hydrogen atoms of hydrogen fluoride, respectively, indicating a weak structure-making effect of hydrogen fluoride in water. The corresponding H-bond lifetimes attribute this effect to the H atom site of HF.


Actinomycosis of urachal remnants.
A case of actinomycosis of the urachus is described. A 25-year-old woman presented with a midline mass below the umbilicus. The differential diagnosis included an inflammatory or a neoplastic lesion. Diagnosis was made by histologic examination, after complete excision of the tumour. Post-operative penicillin was given and the patient's recovery was uneventful. A review of the literature is presented with special reference to the pathogenesis and treatment.


Does current evidence support the use of intraoperative cell salvage in reducing the need for blood transfusion in caesarean section?
An important cause of maternal morbidity and direct maternal death is obstetric haemorrhage at caesarean section. Concerns regarding allogeneic blood safety, limited blood supplies and rising health costs have collectively generated enthusiasm for the utility of methods intended to reduce the use of allogeneic blood transfusion in cases of haemorrhage at caesarean section. This can be achieved by intraoperative cell salvage (IOCS). The aim of this review is to summarize and examine the evidence for the efficacy of IOCS during caesarean section, in women at risk of haemorrhage, in reducing the need for allogeneic blood transfusion. The majority of the evidence currently available is from case reports and case series. Although this evidence appears to support the use of IOCS in obstetrics, strong clinical evidence or economic effectiveness from clinical trials are essential to support the routine practice of IOCS in obstetrics. Current evidence is limited to reported case series and two small controlled studies. Overall, IOCS may reduce the need for allogeneic blood transfusions during caesarean section. Future large randomized trials are required to assess effectiveness, cost effectiveness and safety. The results of the current ongoing SALVO (A randomised controlled trial of intra-operative cell salvage during caesarean section in women at risk of haemorrhage) trial will shed light on these aspects.


Clinical significance of sIL2R, sCD23, sICAM-1, IL6 and sCD 14 serum levels in B-cell chronic lymphocytic leukemia.
The aim of the study was to establish the role exerted by some soluble factors in B-CLL disease mechanisms. Serum levels of sIL2R, sCD23, sICAM-1, IL6 and sCD14 were detected in 47 B-CLL patients. Thirty-seven out of the 47 cases were in advanced/progressive stage, while the remaining 10 patients were defined as smouldering B-CLL. Twenty normal controls provided the reference values. Serum samples of 24 out 37 advanced/progressive cases were measured before and six months after the start of chemotherapy. The advanced/progressive patients showed significantly higher levels of sIL2R, sICAM-1 and sCD23 as compared to normal subjects. Furthermore, sIL2R, sICAM-1 and IL6 values were significantly higher in advanced/progressive B-CLL than in smouldering B-CLL patients. A statistically significant difference was found between smouldering B-CLL and controls for sCD14 only. sIL2R and sICAM-1 levels directly correlated with total tumor mass (TTM) score, sCD23 with both TTM score and lymphocytosis, and sCD14 with IgG serum values. sIL2R and sCD23 levels lowered significantly after chemotherapy, but only sCD23 and TTM variations after chemotherapy were closely correlated. sCD23 may be considered the only indicator of tumor mass, while the other soluble factors can be released through different mechanisms. In particular, sICAM-1 seems to correlate with the ability of the tumor to spread, while the sCD14 increase could indicate a role for this soluble factor in preventing infections in B-CLL patients.


Distribution of Tn551 insertion sites responsible for auxotrophy on the Staphylococcus aureus chromosome.
A method was devised to efficiently select isolates of Staphylococcus aureus 8325 in which Tn551, a transposon originating on the pI258 plasmid responsible for erythromycin resistance (Emr), had translocated to the host chromosome. This method consisted of selecting for Emr at 43 degrees C with a strain in which the pI258 plasmid was unable to replicate at 43 degrees C because of a temperature-sensitive plasmid mutation. By selecting isolates that were Emr at 43 degrees C and auxotrophic for nutrients not required by the parent strain. Tn551-induced auxotrophic mutants were readily isolated. The incidence of auxotrophic classes was not random; 80% of the isolates in one experiment were Trp-, whereas only a single example of each of some of the other classes was isolated. Among the Trp- mutants, the distribution of trp genes affected and the frequency of precise excision of Tn551 from individual sites varied. When analyzed by transformation, the Tn551-induced ala, his, ilv, lys, rib, thrA, thrB, and trp mutations were shown to occupy sites previously defined by nitrosoguanidine-induced mutations. Tn551-induced mutagenesis provided three previously unrecognized classes of auxotrophs (tyr, met, and thrC), and the Tn551 integration sites resulting in these mutations have been identified. In addition, a chromosomal region (uraB) was identified by Tn551 mutagenesis that is distinct from uraA (previously defined by chemical mutagenesis). Some Tn551-induced mutations (most notably pur) could not be linked to the known linkage groups of the chromosome by transformation. With the exception of two pur mutations, all of the Tn551-induced auxotrophic mutational sites cotransformed at unity with Tn551 and, in cases in which they were selected, prototrophic transformants were always Ems. Thus, the Tn551 and auxotrophic sites are identical.