Fully automated AI-based splenic segmentation for predicting survival and estimating the risk of hepatic decompensation in TACE patients with HCC.
Splenic volume (SV) was proposed as a relevant prognostic factor for patients with hepatocellular carcinoma (HCC). We trained a deep-learning algorithm to fully automatically assess SV based on computed tomography (CT) scans. Then, we investigated SV as a prognostic factor for patients with HCC undergoing transarterial chemoembolization (TACE). This retrospective study included 327 treatment-naïve patients with HCC undergoing initial TACE at our tertiary care center between 2010 and 2020. A convolutional neural network was trained and validated on the first 100 consecutive cases for spleen segmentation. Then, we used the algorithm to evaluate SV in all 327 patients. Subsequently, we evaluated correlations between SV and survival as well as the risk of hepatic decompensation during TACE. The algorithm showed Sørensen Dice Scores of 0.96 during both training and validation. In the remaining 227 patients assessed with the algorithm, spleen segmentation was visually approved in 223 patients (98.2%) and failed in four patients (1.8%), which required manual re-assessments. Mean SV was 551 ml. Survival was significantly lower in patients with high SV (10.9 months), compared to low SV (22.0 months, p = 0.001). In contrast, overall survival was not significantly predicted by axial and craniocaudal spleen diameter. Furthermore, patients with a hepatic decompensation after TACE had significantly higher SV (p < 0.001). Automated SV assessments showed superior survival predictions in patients with HCC undergoing TACE compared to two-dimensional spleen size estimates and identified patients at risk of hepatic decompensation. Thus, SV could serve as an automatically available, currently underappreciated imaging biomarker. • Splenic volume is a relevant prognostic factor for prediction of survival in patients with HCC undergoing TACE, and should be preferred over two-dimensional surrogates for splenic size. • Besides overall survival, progression-free survival and hepatic decompensation were significantly associated with splenic volume, making splenic volume a currently underappreciated prognostic factor prior to TACE. • Splenic volume can be fully automatically assessed using deep-learning methods; thus, it is a promising imaging biomarker easily integrable into daily radiological routine.


Prolongation of QTc intervals and risk of death among patients with sickle cell disease.
Unexplained sudden death is common among patients with sickle cell diseases (SCD). QTc prolongation is a risk factor for fatal arrhythmias among adults. This study sought to identify the predictors for QTc prolongation and determine whether QTc prolongation is associated with increased mortality in patients with SCD. We reviewed the electrocardiograms (EKG) and the transthoracic echocardiograms (TTE) of 140 consecutive adults (>18 years) with SCD from October 1996 to January of 2012. QTc prolongation was categorized into three gender-specific categories based on previous publications. Stepwise regression was performed to evaluate QTc interval and mortality as dependent variables. Hemolytic burden as reflected in laboratory evaluation, diastolic, and systolic TTE variables were included in this model. In a stepwise regression analysis, only increased tricuspid regurgitant jet velocity (TRV) (r = 0.483, P = 0.015) had a significant association with QTc interval. Among 49 (35%) patients, the QTc interval was persistently prolonged (PP) (>450 ms in men, >470 ms in women). Twenty-one patients (15%) died over 9 years of follow-up. PP QTc was associated with increased mortality (HR; 8.3 with 95% CI: 2.8-24.6, P < 0.001) compared with normal QTc. In stepwise regression analysis, along with increased TRV (P = 0.005) and acute chest syndrome (P < 0.001), prolonged QTc (P = 0.004) was independently associated with increased mortality. Prolonged QTc among the patients with SCD is an independent risk factor for increased mortality.


Left ventricular dilatation and high-grade ventricular arrhythmias in the first year after myocardial infarction. CATS Investigators. Captopril and Thrombolysis Study.
Progressive left ventricular dilatation is an important determinant of prognosis after myocardial infarction. The association of this process with the occurrence of ventricular arrhythmias is less well established. Of 153 patients with a first anterior myocardial infarction treated with thrombolytic therapy, 34 (22%) had high-grade ventricular arrhythmias (Lown 4A and B) during Holter monitoring after 1 year. Patients with high-grade ventricular arrhythmias had a larger end-systolic volume (38 +/- 12 vs 25 +/- 11 mL/m2; P < .001) at hospital discharge and more left ventricular dilatation (10 +/- 18 vs 1 +/- 9 mL/m2; P = .011) during the follow-up period. Increased end-systolic volume at discharge and subsequent dilatation proved to be independent predictors of high-grade ventricular arrhythmias. Six patients died suddenly during the first 12 months after myocardial infarction. Four of these patients had an enlarged end-systolic volume (> 22 mL/m2) at discharge, and the three patients who died suddenly after 3 months showed a significant increase in end-systolic volume from discharge to 3 months compared to survivors (16 +/- 6 vs 2 +/- 9; P = .008). Left ventricular remodeling after myocardial infarction is an independent predictor of the occurrence of ventricular arrhythmias late after myocardial infarction.


Molecular targets in spinal cord injury.
The spinal cord can be compared to a highway connecting the brain with the different body levels lying underneath, with the axons being the ultimate carriers of the electrical impulse. After spinal cord injury (SCI), many cells are lost because of the injury. To reconstitute function, damaged axons from surviving neurons have to grow through the lesion site to their initial targets. However, the territory they have to traverse has changed: the highway is full of inhibitory signals (myelin and scar components); the pavement itself has become bumpy (demyelination); and specialized cells are recruited to clear the way (inflammatory cells). Thus, actual strategies to treat spinal injuries aim at providing a permissive environment for regenerating axons and boosting the endogenous potential of axons to regenerate while limiting progression of secondary damage. Here we review some of the strategies currently under consideration to treat spinal injuries.


Regulatory role of Wnt signal in the oestradiol synthesis of different size categories of ovarian follicles in buffalo (Bubalus bubalis).
The aim of the present study was to understand the role of Wnt signal in ovarian oestradiol synthesis in various size categories of ovarian follicles. A six-day cell culture system was adopted to test the effect of a Wnt inhibitor i.e. Inhibitor of Wnt response (IWR) on the ovarian granulosa cell oestradiol synthesis and associated genes related to oestradiol synthesis and Wnt signalling (CYP19A1, CCND2, WNT2, FZD6, DVL1, APC, AXIN2, CTNNB1) in buffalo. It was conducted with four groups: Group 1: control, Group 2: control + FSH, Group 3: IWR, Group 4: IWR + FSH. No significant effect of IWR was observed on the ovarian granulosa cell proliferation. No significant difference in the oestradiol levels was found in the spent media harvested after six days of in vitro culture among different groups in small and large-sized ovarian follicles. However, the oestradiol level varied significantly (p < .05) among different treatment groups in medium-sized follicles. The oestradiol level was significantly lower (p < .05) in IWR group compared with the control group and was also significantly lower in IWR + FSH group compared with the FSH group. The Wnt inhibitor had significantly (p < .05) reduced the gene expression of CYP19A1 in large ovarian follicles. Varied effects of IWR-1 and FSH on the expression of other genes were observed. The results indicated that there is a positive role of Wnt signal in oestradiol synthesis in buffalo, but the positive role was more discernible in medium- and large-sized follicles.


Exosomal NAMPT from chronic lymphocytic leukemia cells orchestrate monocyte survival and phenotype under endoplasmic reticulum stress.
Endoplasmic reticulum (ER) stress has been reported to be transmitted from tumor cells to immune cells via exosome and implicated in immune escape. However, the influence of ER stress on monocytes in chronic lymphocytic leukemia (CLL) cells is largely unknown. Here, we observed the expression of ER stress markers (GRP78, ATF6, PERK, IRE1a, and XBP1s) in CLL cells. The increasing mRNA expression of these ER stress response components was positively correlated with more aggressive disease. Exosome from ER stress inducer tunicamycin (TM)-primed CLL cells (ERS-exo) up-regulated the expression of ER stress marker on monocytes, indicating ER stress is transmissible in vitro via exosome. Treatment with ERS-exo promoted the survival of monocytes and induced phenotypic changes with a significantly larger percentage of CD14+ CD16+ monocytes. Finally, we identified exosome-mediated transfer of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) from ER stressed CLL cells into monocytes as a novel mechanism through which ERS-exo regulated monocytes. Exosomal eNAMPT up-regulated nicotinamide adenine dinucleotide (NAD+ ) production which subsequently activated SIRT1-C/EBPβ signaling pathway in monocytes. Our results suggest the role of ER stress in mediating immunological dysfunction in CLL.


Animal usage in vaccine development and production: maximising results while minimizing use.
The Third International Symposium on Advancing Science and Elimination of the Use of Laboratory Animals for Development and Control of Vaccines and Hormones, organized by the National Institute of Public Health and the Environment (RIVM, The Netherlands) under the auspices of the International Association for Biologicals (IABS), was held in Utrecht, The Netherlands, 12-14 November 2001.


Pathogenesis of diffuse intimal thickening (DIT) in non-human primate thoracic aortas.
The pathogenesis of diffuse intimal thickening (DIT) is not well understood. In animals, it is positively correlated with size, and with the exception of the pig, is thought to involve the proximal more than the distal portions of vessels. DIT is often not visible grossly, so that it's study requires extensive microscopic sampling of tissue. Review of previous studies in animals suggests that microscopic sampling may not have been sufficient to determine exactly where DIT occurs throughout the entire length of a vessel. The present study is a longitudinal step-serial section examination of the entire descending thoracic aorta from 12 adult non-human primates of varying size and species and with varying degrees of DIT as determined previously by more limited cross-section techniques. The findings indicate that DIT is not more pronounced in the proximal versus the distal segments of the vessel, and is not correlated with branch orifices. Review of the literature suggests that DIT may not be a single process, but may vary in pathogenesis from vessel to vessel and from species to species.


Glutathione and cellular redox control in epigenetic regulation.
Epigenetics is defined as the mitotically/meiotically heritable changes in gene expression that are not due to changes in the primary DNA sequence. Over recent years, growing evidence has suggested a link between redox metabolism and the control of epigenetic mechanisms. The effect of the redox control, oxidative stress, and glutathione (GSH) on the epigenetic mechanisms occur at different levels affecting DNA methylation, miRNAs expression, and histone post-translational modifications (PTMs). Furthermore, a number of redox PTMs are being described, so enriching the histone code. Pioneer works showed how oxidized GSH inhibits the activity of S-adenosyl methionine synthetase, MAT1A, a key enzyme involved in the synthesis of S-adenosyl methionine (SAM), which is used by DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs). Alteration in NAD /NADH ratio affects the activity of class III histone deacetylases (HDACs) and poly-ADP ribosyltransferases (PARPs). Furthermore, the iron redox state of the catalytic center of key enzymes influences the activity of HDACs and the activity of Tet methylcytosine dioxygenases (DNA demetylases) and JmjC histone demethylases. In this communication, we will show the intricate mechanisms that participate in the redox control of the epigenetic mechanisms. We specially focus our work in the characterization of new PTMs in histones, such as histone carbonylation and glutathionylation. Demonstrating how GSH influences the epigenetic mechanisms beyond a mere regulation of SAM levels. The mechanisms described in this communication place GSH and redox control in the landscape of the epigenetic regulation. The results shown underscore the relevant role that oxidative stress and GSH play as key factors in epigenetics, opening a new window for understating the underlying mechanisms that control cell differentiation, proliferation, development, and disease.


Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV-related steatosis.
HCV and NAFLD are associated with atherosclerosis in general population. The prevalence of atherosclerosis in chronic hepatitis C (CHC) patients is unknown. We hypothesized that HCV per se and HCV-related steatosis could favour atherosclerosis. Thus, in CHC patients we assessed: (a) the prevalence of atherosclerosis; (b) the role of HCV, cardio-metabolic risk factors and hepatic histology. Overall, 803 subjects were enrolled: (A) 326 patients with liver biopsy-proven treatment naive CHC (175 with and 151 without steatosis); (B) 477 age and gender matched controls, including 292 healthy subjects without steatosis (B1) and 185 with NAFLD (B2). Carotid atherosclerosis (CA), assessed by high-resolution B-mode ultrasonography, was categorized as either intima-media thickness (IMT: >1mm) or plaques (≥ 1.5mm). CHC patients had a higher prevalence of CA than controls (53.7% vs 34.3%; p<0.0001). Younger CHC (<50 years) had a higher prevalence of CA than controls (34.0% vs 16.0%; p<0.04). CHC patients without steatosis had a higher prevalence of CA than B1 controls (26.0% vs 14.8%; p<0.02). CHC with steatosis had a higher prevalence of CA than NAFLD patients (77.7% vs 57.8%, p<0.0001). Viral load was associated with serum CRP and fibrinogen levels; steatosis with metabolic syndrome, HOMA-IR, hyperhomocysteinemia and liver fibrosis. Viral load and steatosis were independently associated with CA. Diabetes and metabolic syndrome were associated with plaques. HCV infection is a risk factor for earlier and facilitated occurrence of CA via viral load and steatosis which modulate atherogenic factors such as inflammation and dysmetabolic milieu.


Biliary involvement in familial adenomatosis coli.
Two patients with polypoid bile duct tumors associated with familial adenomatosis coli are presented. A jaundiced man, aged 63, had polypoid masses identified as adenocarcinoma in the common and hepatic ducts. The other patient, a 38-year-old woman undergoing surgery for duodenal adenomas, had a solitary benign adenoma of the distal common duct in addition to duodenal adenocarcinoma. Only one earlier report of bile duct polyps could be found in association with familial adenomatosis. These cases support the view that familial gastrointestinal adenomatosis is a systemic disease, which is not restricted to the colon and rectum.


Computer-aided analysis of chromosomal aberrations occurring in an abnormal human karyotype.
A semi-automatic method for recognition of chromosomal changes is presented: from a coded description of an abnormal chromosome (formulated with the aid of an R-banding technique), a computer program makes simulations to reconstitute this chromosomal image from a group of normal chromosomes. Nine types of aberrations (see text) can thus be recognized and the aggregate structure of a group of abnormal chromosomes occurring in a human karyotype can also be rediscovered.


Cleavage activation and functional comparison of Manduca sexta serine protease homologs SPH1a, SPH1b, SPH4, and SPH101 in conjunction with SPH2.
Phenoloxidase (PO) is a crucial component of the insect immune response against microbial infection. In the tobacco hornworm Manduca sexta, PO is generated from its precursor proPO by prophenoloxidase activating proteases (PAPs) in the presence of two noncatalytic serine protease homologs (SPHs). cDNA cloning and genome analysis indicate that SPH1a (formerly known as SPH1), SPH1b, SPH4, SPH101, and SPH2 contain a clip domain, a linker, and a protease-like domain (PLD). The first 22 residues of the SPH1b, SPH4, and SPH101 PLDs are identical, and differ from SPH1a only at position 4, Thr154 substituted with Asn154 in SPH1a. While the sequence from Edman degradation was used to establish PAP cofactor as a high Mr complex of SPH1a and SPH2, this assignment needed further validation, especially because SPH1b mRNA levels are much higher than SPH1a's and better correlate with SPH2 transcription. Thus, here we determined expression profiles of these SPH genes in different tissues from various developmental stages using highly specific primers. High levels of SPH1b and SPH2 proteins, low SPH4, and no SPH1a or SPH101 were detected in hemolymph from larvae in the feeding, wandering and bar stages, pupae, and adults by targeted LC-MS/MS analysis, based on unique peptides from the trypsin-treated SPHs. We expressed the five proSPHs in baculovirus-infected Sf9 cells for use as standards to identify and quantify their counterparts in plasma samples. Moreover, we tested their cleavage by PAP3 and efficacy of the SPH1a, 1b, 4, and 101 as SPH2 partners in PAP3-mediated proPO activation. PAP3 processed proSPH1b and 101 more readily than proSPH1a and 4; PAP3 activated proPO more efficiently in the presence of SPH2 with SPH101 or SPH1b than with SPH1a or SPH4. These results generally agree with their order of appearance or sequence similarity: SPH101 > SPH1b (98%) > SPH1a (90%) > SPH4 (83%). In other words, likely due to positive selection, products of the newly duplicated genes (SPH1b and SPH101) are more favorable substrates of PAP3 and better SPH2 partners in forming a high Mr cofactor than SPH1a or SPH4 is. Electrophoresis on native gel and immunoblot analysis further indicated that SPH101 or 1b form high Mr complexes more readily than SPH1a or 4 does. In comparison, SPH2 showed a small mobility decrease and then increase on native gel after PAP3 cleavage at the first site. Since the natural cofactor in bar-stage hemolymph is complexes of SPH1 and 2 with an average Mr of 790 kDa, PAP3-activated SPH2 may associate with the higher Mr SPH1b scaffolds to form super-complexes. Their structures and formation in relation to cleavage of SPH1b at different sites await further exploration.


Amyloid angiopathy of the floor of the mouth: a case report and review of the literature.
Amyloidosis is a rare disease characterised by the deposition of insoluble extracellular fibrillar proteins in various tissues of the body. The pattern of manifestation is organ dependent and also on whether the disease is localised or systemic, primary or secondary.Though the disease is usually fatal with a 5-year survival rate of 20%, there is still paucity of literature on this disease entity worldwide. Diagnosis has remained mostly at autopsy.A case of amyloid angiopathy involving the submandibular gland and floor of the mouth with an associated fatal bleed is reported. The purpose of this case report is to reiterate the importance of a high index of suspicion in the approach to the management of head and neck swellings.


Investigation of microplastics release behavior from ozone-exposed plastic pipe materials.
Microplastics (MPs) are detected in drinking water and plastic used during water treatment and distribution is one of the possible sources of MPs. This work aimed to investigate the MPs release behavior from ozone-exposed plastic pipe materials. The changes on physicochemical properties of the plastic materials were analyzed. The carbonyl groups introduction, the oxidation induction time variation, and the surface topography altering were detected after ozone exposure. The MPs release behavior varied between different plastic materials. As the ozone exposure duration of plastic materials prolonged, the released MPs abundance from the materials sharply increased, especially for LDPE, HDPE and PP. PVC was an exception where the released MPs abundance had little changes (p > 0.05). The total released MPs concentration from 20 h-aged samples could be ranked in order as follows: LDPE (656 ± 20 MP L-1) > PP (349 ± 20 MP L-1) > HDPE (337 ± 22 MP L-1) > PVC (63 ± 13 MP L-1). MPs release behavior was more likely to occur for LDPE, which was possibly related to the low oxidation resistance and weak stability of LDPE under ozone exposure. There was a more dominant contribution to MPs abundance increase caused by MPs release from aged plastic pipe materials than secondary MPs generation from original plastic particles. The generated MPs from 20 h-aged LDPE, HDPE, and PP accounted for 88.4%, 82.2%, and 88.3% of the total released MPs, respectively. For ozone-exposed plastic materials, the surface crack propagation and fragmentation posed an entry point for MPs generation. The proportion of generated MPs with polymer composition consistent with pipe materials (PE/PP) increased as the ozone exposure proceeded. Small-sized particles, especially 1-10 μm, were released more predominantly. This study provides an implication that possible MPs release from long-term aged plastic pipe materials under proper conditions could not be ignored.


Splicing and the formation of stable RNA.
To determine whether RNA splicing plays an obligatory role in gene expression, we have constructed a series of SV40-transducing viruses carrying various combinations of splice junctions derived from the viral genome and a mouse globin gene. All of the viruses that retain at least one functional splice junction, derived from either the viral or the mouse genome, encode stable hybrid RNAs. In contrast, a virus from which all the splice junctions have been removed fails to produce any detectable stable RNA. These results suggest that splicing is a prerequisite for stable RNA formation.


Does a pulsed mode offer advantages over a continuous wave mode for excisional biopsies performed using a carbon dioxide laser?
Animal studies of excisional biopsies have shown less thermal damage when a carbon dioxide (CO(2)) laser (10.6 μm) is used in a char-free (CF) mode than in a continuous-wave (CW) mode. The authors' aim was to evaluate and compare clinical and histopathologic findings of excisional biopsies performed with CW and CF CO(2) laser (10.6 μm) modes. This prospective randomized controlled clinical trial included 60 patients with similar fibrous hyperplasias of the buccal plane willing to undergo excisional CO(2) laser biopsy. Patients were randomly allocated to the CW (5 W) or CF (140 Hz, 400 μs, 33 mJ) group. Duration of surgery, intra- and postoperative complications, and the width (micrometers) of the histopathologic collateral thermal damage zone were registered as primary outcome variables. Secondary outcome variables were pain (patients filled in a visual analog scale [VAS]) and analgesic intake (recorded by patients). The study group consisted of 36 women and 24 men with a median age of 50.5 years. Median durations of surgery were 74.5 seconds in the CW group and 83.5 seconds in the CF group. Intraoperative venous bleeding occurred in 16.7% of patients in the CW group and in 13.3% of patients in the CF group. Median areas of histopathologic collateral damage zones were similar in the CW group (166.5 μm) and the CF group (162.5 μm). There was no statistically significant difference between the VAS values of the 2 groups. Analgesic intake was recorded by 16.7% of patients in the CW group and by 6.7% of patients in the CF group (P = .23, not significant). No statistically significant correlation was found between areas of thermal damage zones and postoperative VAS scores. In contrast to previous animal studies, no significant difference was found in the widths of thermal damage zones between the CW and CF groups. The VAS values and analgesic intake were low in the 2 groups. The 2 CO(2) laser modes are appropriate for the excision of intraoral mucosal lesions. A safety border of at least 1 mm is recommended regardless of the laser mode used.


Uncoupling protein 1 knockout aggravates isoproterenol-induced acute myocardial ischemia via AMPK/mTOR/PPARα pathways in rats.
Uncoupling protein 1 (UCP1) was found exclusively in the inner membranes of the mitochondria of brown adipose tissue (BAT). We found that UCP1 was also expressed in heart tissue and significantly upregulated in isoproterenol (ISO)-induced acute myocardial ischemia (AMI) rat model. The present study is to determine the underlying mechanism involved in the UCP1 upregulation in ISO-induced AMI rat model. The Ucp1-/- rats were generated by CRISPR-Cas9 system and presented decreased BAT volume. 2-months old Sprague Dawley (SD) wild-type (WT) and Ucp1-/- rats were treated with ISO intraperitoneally 30 mg/kg once a day for 3 consecutive days to establish AMI model. In saline group, the echocardiographic parameters, serum markers of myocardial injury cardiac troponin I (cTnI), creatine kinase isoenzyme MB (CK-MB), oxidant malondialdehyde (MDA), antioxidant superoxide dismutase (SOD) or fibrosis were comparable between WT and Ucp1-/- rats. ISO treatment induced worse left ventricle (LV) hypertrophy, myocardial fibrosis, increased higher cTnI, CK-MB and MDA and decreased lower SOD level in Ucp1-/- rats compared with that of WT rats. Ucp1-/- rats also presented lower myocardial phosphocreatine (PCr)/ATP-ratio, which demonstrated worse cardiac energy regulation defect. ISO treatment induced the phosphorylation of AMP-activated protein kinase (AMPK) activation, subsequently the phosphorylation of mammalian target of rapamycin (mTOR) inhibition and peroxisome proliferators-activated receptor α (PPARα) activation in WT rats, whereas activation of AMPK/mTOR/PPARα pathways significantly inhibited in Ucp1-/- rats. To sum up, UCP1 knockout aggravated ISO-induced AMI by inhibiting AMPK/mTOR/PPARα pathways in rats. Increasing UCP1 expression in heart tissue may be a cytoprotective therapeutic strategy for AMI.


Clinical features of functional hearing loss with inattention problem in Japanese children.
Functional hearing loss is a condition in which hearing is lost without actual pathology. In children, inattention during pure tone audiometry may be due in part to functional hearing loss. This study examined the issue of inattention as a psychological trait by analyzing the clinical features of functional hearing loss children in Japan. Using the ADHD-Rating Scale IV, 97 functional hearing loss children were screened for inattention (27 boys, 70 girls; mean age 9 years 5 months, range 5-17 years). Those with high levels of inattention (Inattention group) were compared with others (Attention group) for clinical features statistically. Furthermore observed psychological clinical features were described. 36.1% were categorized in the Inattention group, which had more boys, lower in age, and had more physical, developmental, and environmental problems than the Attention group. Two groups had very different psychological feature. In children's functional hearing loss, there exists a group with psychological trait of inattention. Three younger children 5-6 years old with attention problems showed no psychological problems, their FHL was considered to be caused by generalized maturation and development. Nearly all of the rest children showed psychological problems, supporting the notion that FHL in children is psychogenic in nature. Because clinical features in Inattention group children were different from the Attention group significantly, it was concluded that distinguishing the Inattention group as a subtype of functional hearing loss in children would be effective for both diagnosis and treatment. Larger scale studies with many angles needed for the inattention problem in FHL children.


Human skeletal muscle fibre contractile properties and proteomic profile: adaptations to 3 weeks of unilateral lower limb suspension and active recovery.
It is generally assumed that muscle fibres go through atrophy following disuse with a loss of specific force and an increase in unloaded shortening velocity. However, the underlying mechanisms remain to be clarified. Most studies have focused on events taking place during the development of disuse, whereas the subsequent recovery phase, which is equally important, has received little attention. Our findings support the hypotheses that the specific force of muscle fibres decreased following unilateral lower limb suspension (ULLS) and returned to normal after 3 weeks of active recovery as a result of a loss and recovery of myosin and actin content. Furthermore, muscle fibres went through extensive qualitative changes in muscle protein pattern following ULLS, and these were reversed by active recovery. Resistance training was very effective in restoring both muscle mass and qualitative muscle changes, indicating that long-term ULLS did not prevent the positive effect of exercise on human muscle. Following disuse, muscle fibre function goes through adaptations such as a loss of specific force (PO /CSA) and an increase in unloaded shortening velocity, which could be a result of both quantitative changes (i.e. atrophy) and qualitative changes in protein pattern. The underlying mechanisms remain to be clarified. In addition, little is known about the recovery of muscle mass and strength following disuse. In the present study, we report an extensive dataset describing, in detail,the functional and protein content adaptations of skeletal muscle in response to both disuse and re-training. Eight young healthy subjects were subjected to 3 weeks of unilateral lower limb suspension (ULLS), a widely used human model of disuse skeletal muscle atrophy. Needle biopsies samples were taken from the vastus lateralis muscle Pre-ULLS, Post-ULLS and after 3 weeks of recovery during which heavy resistance training was performed. After disuse, cross-sectional area (CSA), PO /CSA and myosin concentration (MC) decreased in both type 1 and 2A skinned muscle fibres. After recovery, CSA and MC returned to levels comparable to those observed before disuse, whereas Po/CSA and unloaded shortening velocity reached a higher level. Myosin heavy chain isoform composition of muscle samples did not differ among the experimental groups. To study the mechanisms underlying such adaptations, a two-dimensional proteomic analysis was performed. ULLS induced a reduction of myofibrillar, metabolic (glycolytic and oxidative) and anti-oxidant defence system protein content. Resistance training was very effective in counteracting ULLS-induced alterations, indicating that long-term ULLS did not prevent the positive effect of exercise on human muscle.


Quantum superposition of target and product states in reactive electron scattering from CF4 revealed through velocity slice imaging.
Exploiting the technique of velocity slice imaging, we have performed a detailed study of reactive electron scattering with CF4. We have measured the electron impact energy dependence of both the angular and kinetic energy distributions of the channels yielding F- and CF3(-) anions. These data provide an unprecedented insight into the quantum superposition of the target state and product channels, respectively, of Td and C3v symmetry, and shed new light on the dissociation dynamics.


A rapid fluorimetric screening method for chlortetracycline, oxytetracycline and tetracycline in pig meat and kidney tissues.
A rapid fluorimetric screening method for chlortetracycline, oxytetracycline and tetracycline in pig meat and kidney tissues is described. After sonication-aided extraction with ethyl acetate, the extract is cleaned and concentrated by means of solid-phase extraction using an aromatic sulphonic acid cation-exchange column. Subsequent screening is carried out by fluorimetry. The detection level is estimated to be about 0.05 mg kg-1 for oxytetracycline, 0.1 mg kg-1 for chlortetracycline and 0.2 mg kg-1 for tetracycline.


Homeostasis of extracellular ATP in uninfected RBCs from a Plasmodium falciparum culture and derived microparticles.
Plasmodium falciparum, a dangerous parasitic agent causing malaria, invades human red blood cells (RBCs), causing hemolysis and microvascular obstruction. These and other pathological processes of malaria patients are due to metabolic and structural changes occurring in uninfected RBCs. In addition, infection activates the production of microparticles (MPs). ATP and byproducts are important extracellular ligands modulating purinergic signaling within the intravascular space. Here, we analyzed the contribution of uninfected RBCs and MPs to the regulation of extracellular ATP (eATP) of RBCs, which depends on the balance between ATP release by specific transporters and eATP hydrolysis by ectonucleotidases. RBCs were cultured with P. falciparum for 24-48 h prior to experiments, from which uninfected RBCs and MPs were purified. On-line luminometry was used to quantify the kinetics of ATP release. Luminometry, colorimetry and radioactive methods were used to assess the rate of eATP hydrolysis by ectonucleotidases. Rates of ATP release and eATP hydrolysis were also evaluated in MPs. Uninfected RBCs challenged by different stimuli displayed a strong and transient activation of ATP release, together with an elevated rate of eATP hydrolysis. MPs contained ATP in their lumen, which was released upon vesicle rupture, and were able to hydrolyze eATP. Results suggest that uninfected RBCs and MPs can act as important determinants of eATP regulation of RBCs during malaria. The comparison of eATP homeostasis in infected RBCs, ui-RBCs, and MPs allowed us to speculate on the impact of P. falciparum infection on intravascular purinergic signaling and the control of the vascular caliber by RBCs.


Associations for subgroups of E-cigarette, cigarette, and cannabis use with asthma in a population sample of California adolescents.
Knowledge about the respiratory health consequences of adolescents' use of tobacco products with cannabis remains limited. We studied whether e-cigarettes, combustible cigarettes, and cannabis were independently associated with asthma in a population-based sample of 150,634 public high school students (10th and 12th graders), drawn in a two-stage design to be representative of the state of California in 2019-2020. Measures were obtained for use of e-cigarettes, combustible cigarettes, and cannabis; motives for use (three substances); method of use (for cannabis); ever being diagnosed with asthma; and having an asthma attack in past 12 months. Cross-classification indicated Nonuse for 64% of the sample; 15% Dual E-cigarette/Cannabis Use; 10% Exclusive Cannabis Use; 5% Exclusive E-cigarette Use; and 5% Triple Use. Multinomial logistic regression with a three-level criterion variable, controlling for age, sex, parental education, race/ethnicity, and three types of household use showed that compared with Nonuse, odds of Lifetime Asthma (vs. Never Had) was elevated for Triple Use (AOR = 1.14, CI 1.06-1.24), Dual E-cigarette/Cannabis Use (1.17, 1.12-1.23), Exclusive Cannabis Use (1.17, 1.11-1.23), and Exclusive E-cigarette Use (1.10, 1.02-1.18). Similar results were noted for Recent Asthma. Among persons who had used cannabis, 88% of the Triple group and 74% of the Dual E-cigarette/Cannabis group reported both smoking and vaping cannabis. Thus, co-occurrence of e-cigarette and cannabis use was a common pattern among adolescents in this study, and subgroups of cannabis and e-cigarette use showed similar associations with asthma. Preventive approaches should highlight the health implications of exclusive or combined e-cigarette and cannabis use.


DOsing Strategy Effectiveness of Diltiazem in Atrial Fibrillation With Rapid Ventricular Response.
To evaluate the dose-dependent comparative safety and effectiveness between weight-based and alternative dosing strategies for diltiazem in atrial fibrillation with rapid ventricular response. This retrospective cohort study included adult patients presenting to the emergency department (ED) with atrial fibrillation with rapid ventricular response who received treatment with intravenous diltiazem. Groups were retrospectively categorized according to the initial dose: low (<0.1875 mg/kg), weight-based (0.1875 to 0.3125 mg/kg), and high (>0.3125 mg/kg). The primary outcome was rate control (heart rate <100 beats/min) within 30 minutes of treatment. Of 345 records, 252 were included. Because of scarcity (N=6), outcomes for the high-dose group were not analyzed. By 30 minutes, the weight-based dosing group had more often achieved rate control (weight-based 55%; low 27%; difference 29% [95% confidence interval (CI) 17% to 40%]). Regression analysis identified the weight-based dosing group (odds ratio 3.63, 95% CI 2.06 to 6.39) and initial heart rate of less than 145 beats/min (odds ratio 2.56, 95% CI 1.46 to 4.51) as variables associated with the primary outcome. The weight-based dosing group less often required rescue therapy (weight-based 6%; low 17%; difference -12% [95% CI -20% to -4%]) relative to the low-dose group. Mortality was higher in the low-dose group than in the weight-based dosing group (low 7%; weight-based 1%; difference 6% [95% CI 1% to 11%]). This study shows dose-dependent hemodynamic effects with diltiazem in patients with atrial fibrillation with rapid ventricular response. Weight-based diltiazem (0.25 mg/kg) was associated with greater rate control with no evidence of increased adverse effects. There was no perceived advantage in using lower, alternative doses.


Community analysis of ammonia and nitrite oxidizers in start-up of aerobic granular sludge reactor.
A lab-scale sequencing batch reactor (SBR) was set-up and the aerobic granular sludge was successfully incubated using anaerobic granular sludge as seed sludge. Nitrogen was partially removed by simultaneous nitrification and denitrification (SND) via nitrite with free ammonia (FA) of about 10 mg/L. The denaturing gradient gel electrophoresis (DGGE) method was used to investigate community structure of alpha-Proteobacteria, beta-Proteobacteria, ammonia oxidizing bacteria (AOB), and Nitrospira populations during start-up. The population sizes of bacteria, AOB and Nitrospira were examined using real-time PCR method. The analysis of community structure and Shannon index showed that stable structure of AOB population was obtained at day 35, while the communities of alpha-Proteobacteria, beta-Proteobacteria, and Nitrospira became stable after day 45. At stable stage, the average cell densities were 1.1 x 10(12), 2.2 x 10(10) and 1.0 x 10(10) cells/L for bacteria, AOB and Nitrospira, respectively. The relationship between characteristics of nitrifying bacteria community and nitrogenous substrate utilization constant was discussed by calculating Pearson correlation. Certain correlation seemed to exist between population size, biodiversity, and degradation constant. And the influence of population size might be greater than that of biodiversity.


Fast and Automated Hyperreflective Foci Segmentation Based on Image Enhancement and Improved 3D U-Net in SD-OCT Volumes with Diabetic Retinopathy.
To design a robust and automated hyperreflective foci (HRF) segmentation framework for spectral-domain optical coherence tomography (SD-OCT) volumes, especially volumes with low HRF-background contrast. HRF in retinal SD-OCT volumes appear with low-contrast characteristics that results in the difficulty of HRF segmentation. Therefore to effectively segment the HRF we proposed a fully automated method for HRF segmentation in SD-OCT volumes with diabetic retinopathy (DR). First, we generated the enhanced SD-OCT images from the denoised SD-OCT images with an enhancement method. Then the enhanced images were cascaded with the denoised images as the two-channel input to the network against the low-contrast HRF. Finally, we replaced the standard convolution with slice-wise dilated convolution in the last layer of the encoder path of 3D U-Net to obtain long-range information. We evaluated our method using two-fold cross-validation on 33 SD-OCT volumes from 27 patients. The average dice similarity coefficient was 70.73%, which was higher than that of the existing methods with significant difference (P < 0.01). Experimental results demonstrated that the proposed method is faster and achieves more reliable segmentation results than the current HRF segmentation algorithms. We expect that this method will contribute to clinical diagnosis and disease surveillance. Our framework for the automated HRF segmentation of SD-OCT volumes may improve the clinical diagnosis of DR.


Effect of guanidine, germine, and steroids in a case of botulism.
A patient with severe type A botulism demonstrated several interesting features. Characteristic electrophysiologic findings are not necessary for the diagnosis. Guanidine hydrochloride provided mild improvement. High doses of steroids and low dose of germine-monoacetate had no effect.


Comparison of two marketed nifedipine modified-release formulations: an exploratory clinical food interaction study.
The objective of this study was to compare the in vitro and in vivo characteristics of 2 nifedipine modified-release tablet formulations for once-daily dosing marketed in the European community, which were expected to be bioequivalent. In vitro dissolution was tested at different pH values prior to the clinical part of the study. Either 1 tablet of a test formulation or of the reference formulation, both containing 30 mg nifedipine, were administered to healthy white male volunteers immediately after a high-fat breakfast in a randomized, open-label, 2-period crossover design. Plasma samples obtained over the subsequent period of 48 hours were analyzed using a validated LC-MS/MS method. Safety profile and tolerability of the study medications were assessed by analysis of adverse events obtained by vital sign measurements, electrocardiography, and clinical laboratory analysis. Twelve volunteers were enrolled (median age, 28.0 years [range, 21-42 years]; mean body mass index, 24.2 kg/m(2) [range, 19.3-27.0 kg/m(2)]). In vitro dissolution experiments revealed a significant pH dependency in drug release from the investigational tablets, while the reference tablets were found to have pH-independent dissolution. After oral administration of both tablet formulations in the fed state, marked differences in rate and extent of bioavailability were observed. Geometric mean of AUC(0-last)(test, 504.21 h x ng/mL; reference, 361.28 h x ng/mL) was significantly higher for the test product, with a point estimate of 140% and a corresponding 90% CI of 121% to 161%. For the comparison of Cmax values, geometric means were: test, 76.46 ng/mL; reference, 19.20 ng/mL, with a point estimate of 398% and a CI of 316% to 503%. Thus, a significant difference in rate and extent of bioavailability was observed between the 2 products. Although both treatments were well tolerated by all volunteers, the test and reference tablets were found to have different pharmacokinetic properties when administered after a high-fat meal.


Reciprocal inhibition of inhibition: a circuit motif for flexible categorization in stimulus selection.
As a precursor to the selection of a stimulus for gaze and attention, a midbrain network categorizes stimuli into "strongest" and "others." The categorization tracks flexibly, in real time, the absolute strength of the strongest stimulus. In this study, we take a first-principles approach to computations that are essential for such categorization. We demonstrate that classical feedforward lateral inhibition cannot produce flexible categorization. However, circuits in which the strength of lateral inhibition varies with the relative strength of competing stimuli categorize successfully. One particular implementation--reciprocal inhibition of feedforward lateral inhibition--is structurally the simplest, and it outperforms others in flexibly categorizing rapidly and reliably. Strong predictions of this anatomically supported circuit model are validated by neural responses measured in the owl midbrain. The results demonstrate the extraordinary power of a remarkably simple, neurally grounded circuit motif in producing flexible categorization, a computation fundamental to attention, perception, and decision making.


Fatty acid specificity of the lysosomal acid cholesterol esterase in intact human arterial smooth muscle cells.
The fatty-acid specificity of the lysosomal cholesterol esterase was examined in cultured human arterial smooth muscle cells. The lysosomal compartment of cultured cells was enriched with cholesteryl esters by incubation of cells with 0.2 mg/ml low-density lipoprotein and 50 microM chloroquine for 24 h. The hydrolysis of cholesteryl esters was subsequently induced by incubating cells in a medium containing 5% lipoprotein-deficient serum without chloroquine. Cellular cholesteryl ester mass was markedly reduced after 23 h in the lipoprotein-deficient serum. Fatty-acid analysis of cholesteryl esters in cells before and after the 23 h incubation with lipoprotein-deficient serum revealed that polyunsaturated cholesteryl esters (linoleate and arachidonate) were preferentially hydrolyzed compared to cholesteryl oleate or saturated cholesteryl esters. An increase in the ratio of cholesteryl oleate to cholesteryl linoleate was observed even when the cellular activity of acyl-CoA:cholesterol acyltransferase was inhibited with Sandoz Compound 58-035. We conclude that, in human arterial smooth muscle cells, the lysosomal acid cholesterol esterase preferentially hydrolyzes polyunsaturated cholesteryl esters.


Validation of an instrument to assess food diversity in women of childbearing age in Medellín, Colombia.
To validate a Food Diversity Questionnaire (CDA, for its name in Spanish) that identifies the prevalence of the risk of deficiency in the intake of eleven micronutrients. The CDA paper form, an online application for data entry and handling, was designed and compared with the 24-h recall (24HR) as a reference method. All data were processed in Personal Computer Software for Intake Distribution Estimation (PC-SIDE) v1 software. A descriptive analysis and comparisons between prevalence, concordance and reproducibility analyses were performed. Medellín, Colombia. Women of childbearing age between 19 and 50 years (n 186) who worked for the Buen Comienzo programme in 2019. When comparing the adjusted 24HR technique and the CDA, there was no significant difference in population-level data at risk of deficiency in any micronutrient intake. However, based on individual-level data of the best linear unbiased predictor, the concordance analyses were weak, and although agreements were high according to the diagnostic performance tests, a good ability to detect deficiency was only observed in a few nutrients: vitamin A 100·0 %, Ca 98·7 %, Fe 92·8 %, folates 91·6 %, and pyridoxine 81·8 %. The CDA validated in this study is useful and faster at evaluating population-level data at risk of deficiency in the intake of Ca, Fe, Zn, thiamine, riboflavin, niacin, pyridoxine, folates, vitamin B12, vitamin C and vitamin A. Based on individual-level data, a good ability to detect deficiencies was observed in the intake of vitamin A, Ca, Fe, folates and pyridoxine.


Appropriate dosing of sugammadex for reversal of rocuronium-/vecuronium-induced muscle relaxation in morbidly obese patients: a meta-analysis of randomized controlled trials.
To conduct a meta-analysis to compare different dosing scalars of sugammadex in a morbidly obese population for reversal of neuromuscular blockade (NMB). PubMed®, ClinicalTrials.gov, Cochrane Central Register of Controlled Trials (CENTRAL) and Google Scholar were searched for relevant randomized controlled trials (RCTs) comparing lower-dose sugammadex using ideal body weight (IBW) or corrected body weight (CBW) as dosing scalars with standard-dose sugammadex based on total body weight (TBW) among morbidly obese people after NMB. Mean difference with SD was used to estimate the results. The analysis included five RCT with a total of 444 morbidly obese patients. The reversal time was significantly longer in patients receiving sugammadex with dosing scalar based on IBW than in patients receiving sugammadex with dosing scalar based on TBW (mean difference 55.77 s, 95% confidence interval [CI] 32.01, 79.53 s), but it was not significantly different between patients receiving sugammadex with dosing scalars based on CBW versus TBW (mean difference 2.28 s, 95% CI -10.34, 14.89 s). Compared with standard-dose sugammadex based on TBW, lower-dose sugammadex based on IBW had 56 s longer reversal time whereas lower-dose sugammadex based on CBW had a comparable reversal time.


Delayed intracerebral hemorrhage after uneventful embolization of brain arteriovenous malformations is related to volume of embolic agent administered: multivariate analysis of 13 predictive factors.
The mechanisms and management of delayed intracerebral hemorrhage (dICH) after treatment of brain arteriovenous malformations (AVMs) are poorly understood and widely debated. Many clinical predictive factors have been theorized for dICH after an otherwise uneventful AVM embolization, but there is an absence of data to discern their significance. To analyze 13 proposed predictive factors and to assess their potential in guiding prevention strategies. One hundred sixty-eight embolization procedures were performed on 67 patients with brain AVMs by a single surgeon. Patients were divided into 2 groups: those with symptomatic dICH and control subjects. Thirteen factors were analyzed: age, sex, race, previous ICH, Spetzler-Martin grade, AVM size, eloquence, embolic volume, embolic agent, percent obliteration, and timing, number, and stage of embolizations. Univariate and multivariate analyses were performed on these factors to determine significance. Six procedures were complicated by dICH; 5 (83%) occurred after the final planned procedure. The volume of embolic agent was significantly higher in the dICH group (4.5 ± 1.0 mL) compared with control subjects (1.7 ± 0.2 mL) in both univariate and multivariate analyses (P < .01), even after controlling for AVM size. AVM size was significant in univariate analysis but not multivariate analysis. There were no statistically significant differences between the groups for any of the other possible predictive factors. High volume of embolic agent administered per procedure is an independent predictive factor for dICH. Limiting the injected volume for each procedure may reduce this poorly understood complication.


Biochemical abnormalities in spinal cord myelin and CNS homogenates in heterozygotes affected by the shiverer mutation.
Myelin was purified from the spinal cords of normal mice and mice heterozygous for the shiverer mutation, and measurements were made of the major myelin proteins and lipids and the specific activities of three myelin-associated enzymes. The myelin purified from the spinal cords of the heterozygotes (shi/+) was deficient by 30-40% in yield and had an apparently unique composition. In particular, when compared with normal mouse spinal cord myelin, there were more high-molecular-weight protein, less myelin basic protein, a higher protein-to-lipid ratio, and higher specific activities of 2',3'-cyclic nucleotide-3'-phosphohydrolase (EC 18.104.22.168) and carbonic anhydrase (EC 22.214.171.124) in the myelin purified from the shi/+ animals. These abnormalities were reflected in the composition of shi/+ whole spinal cord, where the protein-to-lipid ratio was intermediate between the respective values for +/+ and shi/shi spinal cords. Whole brains from shi/+ mice showed deficiencies in galactocerebroside and galactocerebroside sulfate and an increase in total phospholipid, and the lipid composition in the brains of the shi/shi mice was similar to that reported for another dysmyelinating mutant, quaking. The findings provide the first values for the lipids in normal mouse spinal cord myelin and show that heterozygotes are affected by the shiverer mutation. The observations imply that there can be considerable deviation from the normal CNS myelin content and composition without apparent qualitative morphological abnormalities or loss of function and that the amount of myelin basic protein available during myelination may influence the incorporation of other constituents into the myelin membranes.(ABSTRACT TRUNCATED AT 250 WORDS)


[Phycomycoses].
Phycomycoses are opportunistic fungal diseases as far as mucormycosis is concerned, but for basidiobolomycosis and entomophthoromycosis, the adjective 'opportunistic' should be used with caution. Mucormycosis assumes cranial, pulmonary, gastrointestinal, disseminated, cutaneous and focal forms: the infection nearly always develops in a person whose resistance is lowered by a metabolic disorder, a blood dyscrasia, corticosteroid or immunodepressive therapy. It is a frequent complication in leukemia or diabetic acidosis. Basidiobolomycosis and entomophtoromycosis are caused by fungi which belong to the order, Entomophthorales. They are characterized in tissue by broad hyphae which are surrounded by eosinophilic material. These mycoses are treated by potassium iodide.


Clinicopathological features of advanced gastric cancer detected by periodic mass screening.
We have attempted to clarify the clinicopathologic features of advanced gastric cancers that were detected in periodic mass screening by comparing them with those of cancers detected by an initial mass screening. The macroscopic type of the cancers detected by periodic mass screening included Borrmann's type 3 in 47% of cases but was an unclassifiable type because of its resemblance to early cancer in gross appearance in another 47% of cases. The predominant histologic type of the cancers was found to be poorly differentiated adenocarcinoma with scirrhous growth. From these results, advanced gastric cancers that resemble early cancers of the depressed type, in gross morphology, and which are histologically diagnosed as poorly differentiated scirrhous carcinoma, are assumed to be rapidly growing tumors. Therefore, some of the cases that have these characteristics may, in fact, represent early-phase scirrhous carcinoma, diffuse carcinoma classified as Borrmann's type 4, of the stomach.


Safety and effectiveness of istradefylline as add-on therapy to levodopa in patients with Parkinson's disease: Final report of a post-marketing surveillance study in Japan.
Istradefylline is approved in Japan and the US for treatment of Parkinson's disease (PD) in adult patients who experience the wearing-off phenomenon while receiving levodopa; however, safety and efficacy data for real-world clinical use are lacking. We report the final results of a prospective, long-term, post-marketing surveillance study of istradefylline adjunct to levodopa for adults with PD experiencing the wearing-off phenomenon. Patients across 214 study sites initiating treatment with oral istradefylline once-daily 20- or 40-mg were followed-up for 1 year. We collected demographic data, disease and treatment histories, and recorded adverse events and adverse drug reactions (ADRs). The priority survey item was the occurrence of psychiatric ADRs. Effectiveness was evaluated by the physician's global and motor function assessments. Case report forms were collected for 1320 patients, and the safety and effectiveness analysis sets included 1318 and 1284 patients, respectively. The mean age was 71.5 years and 56.2% of patients were women. A total of 274 patients (20.8%) experienced an ADR, 39 patients had a serious ADR, and 7 patients had a fatal ADR that was considered not related to istradefylline. Common ADRs included dyskinesia, hallucination, and visual hallucination. Sixty-five patients (4.9%) experienced a psychiatric ADR. Istradefylline was effective (physician-rated) in 59.8% of patients, and most patients had reduced or unchanged off-time duration, improved or unchanged off-time symptoms, and improved or unchanged motor symptoms. Istradefylline safely and effectively improves motor symptoms in PD patients experiencing the wearing-off phenomenon with levodopa therapy in the real-world setting.


Retinal vasoproliferative tumors in ocular conditions of childhood.
Retinal vasoproliferative tumor (RVPT) is a vascular mass with exudative retinopathy and minimally dilated feeder vessels. This type of tumor can occur as a primary or secondary condition. Our purpose was to describe secondary vasoproliferative tumors from ocular conditions in childhood. The clinical records and fundus photographs of patients with secondary RVPTs were reviewed and a detailed literature search was conducted to identify reported cases of secondary RVPTs. This information was used to compile a list of ocular and nonocular childhood conditions associated with development of RVPTs. The ocular conditions related to vasoproliferative tumors in children include intermediate uveitis, retinitis pigmentosa, ocular toxocariasis, Coats disease, neurofibromatosis, retinal toxoplasmosis, retinopathy of prematurity, familial exudative vitreoretinopathy, and other rare conditions. Several pediatric ocular conditions can ultimately lead to retinal vasoproliferative tumor.


Microscale immunoaffinity SPE and MEKC in fast determination of testosterone in male urine.
Conventional methods for the determination of testosterone in body fluids typically suffer from poor recovery, lack of specificity, complex sample pretreatment, or the need for derivatization. Here, a simple, specific, and fast analysis method for testosterone was developed, with a methodology based on testosterone-specific immunoaffinity SPE (IA-SPE) and subsequent analysis by partial filling MEKC (PF-MEKC). An immunosorbent consisting of a recombinant antitestosterone Fab fragment covalently attached to activated Sepharose was prepared. IA-SPE and PF-MEKC were set up in hyphenated and off-line constructions, and the applicability of the two constructions in analysis of testosterone in male urine was investigated. The results obtained with the hyphenated construction proved to be only indicative of the presence of testosterone. The off-line IA-SPE and PF-MEKC construction, however, was successfully used in the determination of free testosterone in male urine samples after enzymatic hydrolysis of the glucuronide conjugates. Except for the hydrolysis reaction, no sample pretreatment was required. After hydrolysis, the overall analysis time per sample was only 14 min. The off-line IA-SPE and PF-MEKC method proved to be robust, sensitive (LOQ 35 mug/L), and specific, enabling separation of testosterone from four related steroids. Thus, it provides attractive features when compared to traditional methods for determination of testosterone in male urine.


Comparison of reverse torque values of abutment screws with the application of oil-based and water-based antibacterial agents.
Using antibacterial agents to remove the foul odor of the implant cavity and prevent peri-implantitis can affect the detorque values and lead to the loosening of the abutment screw. This study investigated the effects of tetracycline and chlorhexidine gel on detorque values. This in vitro study was carried out on three groups of five implants. Group G1 was the control group, and no material was applied to the implant cavity. In group G2, the implant cavity was first filled with artificial saliva and then with chlorhexidine gel. In group G3, the implant cavity was first filled with artificial saliva and then with tetracycline. The abutments were tightened with 25 N/cm2 and then loosened. Finally, the detorque values were calculated. The highest detorque values were recorded in group G1. Group G3 showed the lowest detorque values. ANOVA showed significant differences in mean detorque values (P<0.05) between the three groups. According to this study, applying antibacterial agents decreased the detorque values and increased the risk of screw loosening. The reduction of detorque values was more pronounced with the oil-based antibacterial agent (tetracycline).


Pediatric renal trauma at a level 1 trauma center in a rural state: A 10-year institutional review and protocol implementation.
Unintentional injury is a leading cause of mortality and morbidity in children. There is no consensus on the ideal, discrete management of pediatric renal trauma (PRT). Therefore, management protocols tend to be institution-specific. This study aimed to characterize PRT at a rural level-1 trauma center and subsequently develop a standardized protocol. A retrospective review of a prospectively maintained database of PRT at a rural level 1 trauma center between 2009 and 2019 was conducted. Injuries were characterized regarding renal trauma grade, associated multi-organ involvement and the need for intervention. The benefit of patient transfer from regional hospitals and length and cost of stay were evaluated. Of 250 patients admitted with renal trauma diagnosis 50 patients <18 years were analyzed. Of those, the majority (32/50, 64%) had low-grade (grade I-III) injuries. Conservative management was successful in all low-grade injuries. Of 18 high-grade PRT, 10 (55.6%) required intervention, one prior to transfer. Among patients with low-grade trauma, 23/32 (72%) were transferred from an outside facility. A total of 13 (26%) patients with isolated low-grade renal trauma were transferred from regional hospitals. All isolated, transferred low-grade renal trauma had diagnostic imaging before transfer and none required invasive intervention. Interventional management of renal injury was associated with a longer median LOS [7 (IQR = 4-16.5) vs 4 (IQR = 2-6) days for conservative management, p = 0.019)] and an increased median total cost of $57,986 vs. $18,042 for conservative management (p = 0.002). The majority of PRT, particularly low-grade, can be managed conservatively. A significant proportion of children with low-grade trauma are unnecessarily transferred to higher level centers. Review of pediatric renal trauma at our institution over a decade has allowed us to develop an institutional protocol which we believe allows for safe and effective patient monitoring. Isolated, low-grade PRT can be managed conservatively at regional hospitals without needing transfer to a level 1 trauma center. Children with high-grade injuries should be closely monitored and are more likely to need invasive intervention. Development of a PRT protocol will help to safely triage this population and identify those who may benefit from transfer to a tertiary care center.


Ultrasound-guided percutaneous tracheostomy in critically ill obese patients.
The purpose of this study was to evaluate the feasibility of ultrasound (US)-guided percutaneous tracheostomy (PCT) and the incidence of complications in critically ill, obese patients. Fifty consecutive patients were included in a prospective study in two surgical and critical care medicine departments. Obesity was defined as a body mass index (BMI) of at least 30 kg/m². The feasibility of PCT and the incidence of complications were compared in obese patients (n = 26) and non-obese patients (n = 24). Results are expressed as the median (25th-75th percentile) or number (percentage). The median BMIs were 34 kg/m² (32-38) in the obese patient group and 25 kg/m² (24-28) in the non-obese group (p < 0.001). The median times for tracheostomy were 10 min (8-14) in non-obese patients and 9 min (5-10) in obese-patients (p = 0.1). The overall complication rate was similar in obese and non-obese patient groups (35% vs. 33%, p = 0.92). Most complications were minor (hypotension, desaturation, tracheal cuff puncture and minor bleeding), with no differences between obese and non-obese groups. Bronchoscopic inspection revealed two cases of granuloma (8%) in obese patients. One non-obese patient developed a peristomal skin infection, which was treated with intravenous antibiotics. Ultrasound-guided PCT was possible in all enrolled patients and there were no surgical conversions or deaths. This study demonstrated that US-guided PCT is feasible in obese patients with a low complication rate. Obesity may not constitute a contra-indication for US-guided PCT. A US examination provides information on cervical anatomy and hence modifies and guides choice of the PCT puncture site. ClinicalTrials.gov: NCT01502657.


Ectopic ACTH syndrome due to pheochromocytoma: case report and review of the literature.
A 51-year-old female was diagnosed preoperatively to have a pheochromocytoma producing ACTH. This diagnosis was based upon her paroxysmal hypertension, hyperpigmentation, and hypokalemia. Elevated levels of serum and urine corticosteroids, plasma ACTH, urinary VMA, and catecholamines fell after a right adrenal pheochromocytoma was removed. Subsequently this tumor was found to have a high content of ACTH. Review of the literature indicates a mortality rate of 57% for this syndrome. Proper preoperative recognition and management can result in total cure.


The Lister steam spray in Aberdeen.
A Lister 'steam spray producer' in the possession of Aberdeen University is described. The introduction of antiseptic surgery to Aberdeen by Alexander Ogston and the subsequent adoption of the spray and its enthusiastic use by him is recounted, with emphasis on the final years of its employment as part of the antiseptic ritual.


The interplay between Mn and Fe in Deinococcus radiodurans triggers cellular protection during paraquat-induced oxidative stress.
The bacterium Deinococcus radiodurans is highly resistant to several stress conditions, such as radiation. According to several reports, manganese plays a crucial role in stress protection, and a high Mn/Fe ratio is essential in this process. However, mobilization of manganese and iron, and the role of DNA-binding-proteins-under-starved-conditions during oxidative-stress remained open questions. We used synchrotron-based X-ray fluorescence imaging at nano-resolution to follow element-relocalization upon stress, and its dependency on the presence of Dps proteins, using dps knockout mutants. We show that manganese, calcium, and phosphorus are mobilized from rich-element regions that resemble electron-dense granules towards the cytosol and the cellular membrane, in a Dps-dependent way. Moreover, iron delocalizes from the septum region to the cytoplasm affecting cell division, specifically in the septum formation. These mechanisms are orchestrated by Dps1 and Dps2, which play a crucial role in metal homeostasis, and are associated with the D. radiodurans tolerance against reactive oxygen species.


A prophylactic TXA administration effectively reduces the risk of intraoperative bleeding during open management of pelvic and acetabular fractures.
This study aimed to evaluate the efficacy of perioperative intravenous TXA in reducing blood loss in pelvic and acetabular fracture patients managed surgically. The study included 306 consecutive patients, divided as: group I, 157 patients who did not receive perioperative infusion of TXA and group II, 149 patients who received perioperative TXA. The perioperative blood test results and complication rates were compared between the two groups. The average perioperative hematocrit was higher during the preoperative period than during the first, second and third postoperative day in both groups. In the estimated blood loss between the two groups, there was a significant difference of 1391 (± 167.49) ml in group I and 725 (± 403.31) ml in group II respectively (p = 0.02). No significant difference was seen in the total of intraoperative transfusion units as well as in the total units of blood transfused. There was a reduced level of postoperative hemoglobin (9.28 ± 17.88 g/dl in group I and 10.06 ± 27.57 g/dl in group II compared to the values obtained in preoperative investigations (10.4 ± 2.37 g/dl in group I and 11.4 ± 2.08 g/dl in group II); with a significant difference in postoperative transfusion rates (p = 0.03). Therefore, the use of TXA effectively reduces the risk of intraoperative bleeding during open management of pelvic and acetabular fractures.


Injectable decellularized nucleus pulposus tissue exhibits neuroinhibitory properties.
Chronic low back pain (LBP) is a leading cause of disability, but treatments for LBP are limited. Degeneration of the intervertebral disc due to loss of neuroinhibitory sulfated glycosaminoglycans (sGAGs) allows nerves from dorsal root ganglia to grow into the core of the disc. Treatment with a decellularized tissue hydrogel that contains sGAGs may inhibit nerve growth and prevent disc-associated LBP. A protocol to decellularize porcine nucleus pulposus (NP) was adapted from previous methods. DNA, sGAG, α-gal antigen, and collagen content were analyzed before and after decellularization. The decellularized tissue was then enzymatically modified to be injectable and form a gel at 37°C. Following this, the mechanical properties, microstructure, cytotoxicity, and neuroinhibitory properties were analyzed. The decellularization process removed 99% of DNA and maintained 74% of sGAGs and 154% of collagen compared to the controls NPs. Rheology demonstrated that regelled NP exhibited properties similar to but slightly lower than collagen-matched controls. Culture of NP cells in the regelled NP demonstrated an increase in metabolic activity and DNA content over 7 days. The collagen content of the regelled NP stayed relatively constant over 7 days. Analysis of the neuroinhibitory properties demonstrated regelled NP significantly inhibited neuronal growth compared to collagen controls. The decellularization process developed here for porcine NP tissue was able to remove the antigenic material while maintaining the sGAG and collagen. This decellularized tissue was then able to be modified into a thermally forming gel that maintained the viability of cells and demonstrated robust neuroinhibitory properties in vitro. This biomaterial holds promise as an NP supplement to prevent nerve growth into the native disc and NP in vivo.


Age adjustment of cancer survival rates: methods, point estimates and standard errors.
We empirically evaluated the performance of a new method for age adjustment of cancer survival compared to traditional age adjustment using data from the Finnish Cancer Registry. We find that both methods provide almost identical results for absolute survival but the new method generally provides more meaningful estimates of relative survival with often a smaller standard error.


Impaired corticostriatal connectivity in impulse control disorders in Parkinson disease.
To compare the striatum's resting-state functional connectivity in patients with Parkinson disease (PD) with and without impulse control disorders (ICDs). Twenty patients with PD and ICDs, 19 patients with PD but no ICDs, and 19 healthy controls underwent fMRI in the resting state. The ventral striatum, dorsal caudate, and anterior and posterior putamen were segmented semiautomatically. For each region of interest, a seed-based connectivity analysis was performed on preprocessed fMRI data mapped on the ipsilateral cortical surface. An additional cortical thickness analysis was used to assess and compare gray matter atrophy in the 3 study subgroups. The presence of an ICD in patients with PD was associated with functional disconnection between the left anterior putamen and both the left inferior temporal gyrus and the left anterior cingulate gyrus, as well as a trend toward a functional disconnection between several motor and associative striatal regions and limbic, associative, and motor cortical regions. Patients without ICDs did not differ from healthy controls in corticostriatal connectivity. The cortical thickness analysis did not reveal any significant differences among the 3 study subgroups. In PD, ICDs are associated with altered connectivity between an associative striatal area (the left anterior putamen) and associative and limbic cortical regions (the left inferior temporal gyrus and the left anterior cingulate gyrus).


Planned cesarean hysterectomy versus modified form of segmental resection in patients with placenta percreta.
The aim of this study was to compare some clinical characteristics of two different management alternatives in pregnants with placental invasion anomalies. We conducted a single-center retrospective study of all patients who delivered with invasive placentation between January 2016 and May 2017. We included only the patients with placental invasion anomaly and planned cesarean section. Fifty-one pregnants met the inclusion criteria. Cesarean hysterectomy was performed in 29 patients and segmental resection in 22. Major intraoperative and postoperative complications were comparable between the two groups. There were significant differences between the groups with regard to gravidity, pre- and post-operative hemoglobin concentrations, number of packed red blood cell transfused, and operation time (p < .05). An initial fertility conserving surgical procedure is an option in patients with extensive invasive placentation with lesser transfusion requirement and shorter operative time compared to cesarean hysterectomy.


Water-soluble luminescent copper nanoclusters as a fluorescent quenching probe for the detection of rutin and quercetin based on the inner filter effect.
In the present study, we proposed a simple, sensitive and selective fluorescence method for the detection of rutin (Rut) and quercetin (Que) based on the inner filter effect (IFE) utilizing water- soluble cysteine-stabilized copper nanoclusters (Cys-CuNCs) as a fluorescent probe. The Cys-CuNCs were successfully synthesized and characterized using UV-visible absorption, emission, Fourier-transform infrared (FT-IR) spectroscopy, fluorescence lifetime, high resolution transmission electron microscopy (HR-TEM) and zeta potential measurements. Cys-CuNCs exhibited bluish-green luminescence under UV light with characteristic emission maxima at 486 nm. Cys-CuNCs was successfully exploited as fluorescent probes for the detection of Rut/Que. The addition of increasing concentrations of Rut/Que led to a gradual decrease in the emission intensity of Cys-CuNCs. The decrease in Cys-CuNC emission intensities were attributed to the strong IFE and static quenching mechanism. The calculated limit of detection values for Rut and Que were as low as 0.021 μM and 0.035 μM, respectively. The Cys-CuNCs sensing probe exhibited excellent selectivity in the presence of other potential interfering compounds. Furthermore, the present method was successfully applied to the analysis of both Rut and Que in biological samples.


Culture-based bacterial detection systems for platelets: the effect of time prior to sampling and duration of incubation required for detection with aerobic culture.
Bacterial contamination of platelet (PLT) products occurs at low concentrations requiring a period of incubation for growth to minimize sampling error. Culture-based detection methods also need sufficient incubation time; together these periods may limit the useful life of PLTs. This study characterizes the impact of sampling and detection times with two commercially available bacteria detection products. Apheresis PLTs inoculated with nine bacterial species at low concentrations were sampled immediately and 24 hours after inoculation. Test results were analyzed after incubation at 16, 20, and 24 hours after sampling with two bacterial detection systems. When sampled immediately after inoculation, two commercially available bacterial detection systems (BacT/ALERT, bioMérieux; and eBDS, Pall Corp.) failed to detect some PLTs inoculated with Staphylococcus epidermidis, Serratia liquefaciens, or Pseudomonas aeruginosa and S. epidermidis, S. liquefaciens, Bacillus cereus, or P. aeruginosa, respectively. The BacT/ALERT was better at 20 hours (p<0.02), but not at 16 or 24 hours for Time 0 sampling. When sampling occurred 24 hours after inoculation, there were no difference between the two systems. Results suggest that for either bacteria detection system, holding PLTs for 24 hours before sampling improves the detection sensitivity for PLTs contaminated with low concentrations of bacteria, and longer incubation periods improve detection.


Cloning and molecular characterization of the first innexin of the phylum annelida-expression of the gene during development.
A novel member of the innexin family (cv-inx) has been isolated from the annelid polychaete worm Chaetopterus variopedatus using a PCR approach on genomic DNA and sequence analysis on genomic DNA clones. The gene is present in a HindIII-HindIII segment of 2250 bp containing an uninterrupted open reading frame of 1196 bp encoding a protein of 399 amino acids. The predicted protein shows the typical structural features of innexins and consensus sites for phosphorylation. Analyses on genomic DNA demonstrate that cv-inx is a single copy gene with no introns in the coding region, exactly corresponding to the cDNA sequence. The gene expression is regulated during development as shown by Northern blots analyses of the RNA and by immunoreaction with antibodies against the protein at several embryonic stages. The finding of an innexin in the phylum Annelida, outside of the Ecdysozoa clade, and its peculiar gene structure suggest the necessity to reconsider the current hypothesis on the origin and evolution of gap junctional proteins.


The evaluation of immune responses to hepatitis B vaccination in diabetic and non-diabetic haemodialysis patients and the use of tetanus toxoid.
The aim of this study was to investigate whether haemodialysis (HD) patients suffering from diabetes mellitus could be considered at risk for the development of the protective antibodies to hepatitis B (HB) vaccination and, to evaluate the effectiveness of tetanus toxoid (TT) administrated 2 days before HB vaccination. Forty-nine HD patients were divided into two groups: group A (19 diabetic patients) and group B (30 non-diabetic patients). A dose of 40 microg recombinant HB vaccine was injected intramuscularly to the patients at 0, 1, 2 and 6 months. After the completion of the course, the patients in group A were found to have a lower protective antibody rates than the patients in group B (57.8% vs 70%) (P > 0.05). After the administration of additional booster doses during 12 months, the protective antibody to hepatitis B surface antigen (HBsAb) levels were detected in 78.9% and 96.6% of the patients in group A and group B, respectively (P > 0.05). The patients not having protective HBsAb levels were administered TT and HB vaccines, and after course, all of them have produced protective HBsAb levels. The present study showed that diabetic patients on HD may carry a greater risk of not seroconverting than non-diabetic ones for antibody response to HB vaccination. The use of TT 2 days before HB vaccination may be a useful and effective method of enhancing the immune response to HB vaccination, especially in the patients with diabetes mellitus on HD.


Efficient information coding and degeneracy in the nervous system.
Efficient information coding (EIC) is a universal biological framework rooted in the fundamental principle that system responses should match their natural stimulus statistics for maximizing environmental information. Quantitatively assessed through information theory, such adaptation to the environment occurs at all biological levels and timescales. The context dependence of environmental stimuli and the need for stable adaptations make EIC a daunting task. We argue that biological complexity is the principal architect that subserves deft execution of stable EIC. Complexity in a system is characterized by several functionally segregated subsystems that show a high degree of functional integration when they interact with each other. Complex biological systems manifest heterogeneities and degeneracy, wherein structurally different subsystems could interact to yield the same functional outcome. We argue that complex systems offer several choices that effectively implement EIC and homeostasis for each of the different contexts encountered by the system.


The role of physiatry in the management of neuromuscular disease.
Patients with neuromuscular disease (NMD) are complex and pose a myriad of clinical problems. Management is best carried out by a team consisting of physicians, physical, occupational, and speech therapists, social workers, vocational counselors, and psychologists, among others. Physiatrists are well-suited to this type of multi-disciplinary care and can play a significant role in the care of these patients.


Prognostic factors for long-term results after condylar head fractures: A comparative study of non-surgical treatment versus open reduction and osteosynthesis.
This longitudinal study compared functional, anatomical, and quality of life (QoL) outcomes after closed reduction (CR) versus open reduction and internal fixation (ORIF) of condylar head fractures (CHFs). The aim was to determine predictability of results and to establish prognostic factors for poor outcomes, thus allowing therapeutic decision making between CR and ORIF. All fractures of the non-surgical group were treated by CR with maxillomandibular fixation (CR-MMF) according to an managed analogically. Morphological and functional results were acquired using axiography and clinical functional diagnostics, as well as MRI in problematic cases. Outcomes were compared with those of a collective of patients treated by ORIF with small fragment screws (SFS), according to a uniform standard. A total of 26 patients with 29 unilateral and bilateral CHFs of the non-surgical group were examined over a period of 28.5 months after completion of therapy and compared with a collective of 54 patients with 73 CHFs treated by ORIF. Statistically significant differences were found between both groups in protrusion and mediotrusion on the fracture side, in favour of ORIF. Significantly more patients in the ORIF group were symptom free in terms of the Helkimo dysfunction index and the RDC TMD compared with conservatively treated patients. Associations between Angle class and Helkimo dysfunction index, and between occlusion or number of teeth and pain after CT, could be confirmed. Given their respective indications, both treatment options demonstrated acceptable results in the majority of cases. However, for therapeutic decision making, it is crucial that the long-term results after CR are significantly less predictable. Our study showed only few positive prognostic factors for a stable functional outcome after CR such as isolated CHFs with stable occlusal conditions in younger patients (<25 years).


Specific inhibition of cell proliferation in the mouse intestine by an aqueous extract of rabbit small intestine.
An aqueous extract was prepared from the mucosa of rabbit small intestine by homogenization and centrifugation at 105,000 g. After precipitation with ammonium sulfate, the 0-50 fraction (F1) and the supernatant (F2) were collected, dialysed against a phosphate buffer and tested on rats in vitro and mice in vivo. The F1 fraction was found to inhibit thymidine incorporation into rat intestinal DNA in vitro, but this effect was not found to be tissue specific (liver, kidney). Two hours after a single injection of F1 (10 mg protein content), the uptake of tritiated thymidine was decreased in jejunal and colonic DNA in mice. This effect was maximal between 2 and 4 hr and totally reversible after 7 hr; this effect was found in neither the kidney nor the testis. A slowing of cellular migration was also noticed in the jejunum and the colon. Conversely, the F2 fraction did not inhibit the synthesis of jejunal and colonic DNA either in vitro or in vivo. Our results suggest that the F1 fraction of the aqueous extract of rabbit small intestine contains one or more substances which may act either on intestinal DNA synthesis or on the GI--S transition of the cellular cycle in the mouse intestine. This reversible and specific intestinal action appears to inhibit cell proliferation and presents several of the characteristics defining a chalone.


Possible abscopal effect after discontinuation of nivolumab in metastatic renal cell carcinoma.
Renal cell carcinoma has been considered radioresistant. Recently, several studies have reported the efficacy of combination therapy using radiotherapy and immune checkpoint inhibitors. In 1999, a 56-year-old woman underwent left nephrectomy (clear cell carcinoma, pT1bN0M0). Seventeen years postoperatively, recurrence in the left lung hilum was observed. Despite administration of three molecular target drugs, all treatments were terminated due to adverse events. Nivolumab was initiated in December 2016. In August 2017, subcutaneous and lung metastases were observed. Moreover in January 2018, right renal metastasis was noted. After 22 cycles of nivolumab treatment, metastasis in the iliac bone was observed, and the patient was subjected to conventional palliative external beam radiation therapy. Five months after radiotherapy, there was significant reduction in multiple metastases. Here, we reported the case presenting with possible abscopal effect. Radiotherapy combined with immune checkpoint inhibitors may induce systemic effects against metastatic renal carcinoma.


Vegetative reproduction as a stabilizing feature of the population dynamics of Yucca glauca.
The life history of Yucca glauca in the Great Plains was the subject of a four year field study. Data were incorporated in a stage transition model (based on rosette size) to explain how populations are maintained in spite of large regional and temporal variation in sexual reproductive success. Rosette size was found to be a good predictor of flowering effort, but a poor predictor of fruit set. Large rosettes that failed to set fruit, however, exhibited an increased capacity for vegetative reproduction. Asexual reproduction contributes to population stability by reducing the variance in annual recruitment, and perhaps by damping oscillations caused by departures from a stable stage distribution.


RadialFirst in CHIP and Cardiogenic Shock.
This article highlights the advantages and disadvantages of transradial arterial (TRA) access for a variety of presentations including acute coronary syndromes; cardiogenic shock; unprotected left main, heavily calcified coronaries; bifurcations; and chronic total occlusions. It includes techniques for overcoming challenges of using TRA access, including spasm and the need for larger bore guides. In addition, the authors review the use of ultrasound for access, percutaneous hemodynamic support via axillary approach, and tips and tricks to performing right heart catheterizations from the antecubital vein.


Psychiatric morbidity in pemphigus and psoriasis: a comparative study from India.
This study was designed to examine the prevalence of psychiatric morbidity and its psychosocial and psychopathological correlates in patients with pemphigus in comparison to those with psoriasis. Patients with pemphigus (n=50), group matched for demography, with those with psoriasis (n=30), and healthy controls (n=30), were subjected to cross-sectional assessment for duration, severity, and impact of dermatological disorder, attitude to appearance, social support, coping strategies, disability, quality of life, and psychiatric morbidity and diagnosis. The pemphigus group recorded the psychiatric morbidity rates at 40% by GHQ-12 and 26% by ICD-10; the ICD-10 diagnoses included adjustment disorder (16%), depressive episode (8%), and acute and transient psychosis (2%). This comorbidity was not very different from that of the psoriasis group at 46.7% by GHQ-12 and 36.7% by ICD-10; the ICD-10 diagnoses including adjustment disorder (13.3%), depressive episode (10.0%), alcohol dependence (6.6%), paranoid schizophrenia (3.3%), and delusional disorder plus severe depressive episode with psychotic symptoms (3.3%). The pemphigus group scored higher on disability, despite the dermatological severity and psychosocial profile being similar. Dermatological severity, psychopathology, and certain psychosocial variables were correlated in the pemphigus group, as also in the psoriasis group. The high psychiatric and psychosocial morbidity in pemphigus and other chronic and severe dermatologic disorders indicates a need for more studies on the psychosocial aspect of these disorders and for sensitization by the dealing physicians with this aspect.


Glucokinase activation leads to an unsustained hypoglycaemic effect with hepatic triglyceride accumulation in db/db mice.
To investigate how subchronic administration of a glucokinase activator (GKA) results in attenuation of the hypoglycaemic effect in the diabetic condition. Six-week-old db/db mice were fed standard chow containing a GKA or the sodium-glucose cotransporter 2 inhibitor ipragliflozin for 1, 6, 14 or 28 days. We performed histological evaluation and gene expression analysis of the pancreatic islets and liver after each treatment and compared the results to those in untreated mice. The unsustained hypoglycaemic effect of GKAs was reproduced in db/db mice in conjunction with significant hepatic fat accumulation. The initial reactions to treatment with the GKA in the liver were upregulation of the gene expression of carbohydrate response element-binding protein beta (Chrebp-b) and downregulation of phosphoenolpyruvate carboxykinase (Pepck) on day 1. Subsequently, the initial changes in Chrebp-b and Pepck disappeared and increases in the expression of genes involved in lipogenesis, including acetyl-CoA carboxylase and fatty acid synthase, were observed. There were no significant changes in the pancreatic β cells nor in hepatic insulin signalling. The GKA showed an unsustained hypoglycaemic effect and promoted hepatic fat accumulation in db/db mice. Dynamic changes in the expression of hepatic genes involved in lipogenesis and gluconeogenesis could affect the unsustained hypoglycaemic effect of the GKA despite no changes in pancreatic β-cell function and mass.


Naringin-induced p21WAF1-mediated G(1)-phase cell cycle arrest via activation of the Ras/Raf/ERK signaling pathway in vascular smooth muscle cells.
The flavonoid naringin has been shown to play a role in preventing the development of cardiovascular disease. However, the exact molecular mechanisms underlying the roles of integrated cell cycle regulation and MAPK signaling pathways in the regulation of naringin-induced inhibition of cell proliferation in vascular smooth muscle cells (VSMCs) remain to be identified. Naringin treatment resulted in significant growth inhibition and G(1)-phase cell cycle arrest mediated by induction of p53-independent p21WAF1 expression; expression of cyclins and CDKs in VSMCs was also down-regulated. In addition, among the pathways examined, blockade of ERK function inhibited naringin-dependent p21WAF1 expression, reversed naringin-mediated inhibition of cell proliferation and decreased cell cycle proteins. Moreover, naringin treatment increased both Ras and Raf activations. Transfection of cells with dominant negative Ras (RasN17) and Raf (RafS621A) mutant genes suppressed naringin-induced ERK activity and p21WAF1 expression. Finally, naringin-induced reduction in cell proliferation and cell cycle protein was abolished in the presence of RasN17 and RafS621A mutant genes. The Ras/Raf/ERK pathway participates in p21WAF1 induction, leading to a decrease in cyclin D1/CDK4 and cyclin E/CDK2 complexes and in naringin-dependent inhibition of cell growth. These novel and unexpected findings provide a theoretical basis for preventive use of flavonoids to the atherosclerosis disease.


Isolation and partial characterization of dinoflagellate U1-U6 small RNAs homologous to rat U small nuclear RNAs.
The dinoflagellates are a group of diverse eukaryotic algae possessing a number of unique cellular properties. Evidence is presented for the presence of six capped small nuclear RNAs in these dinoflagellates. By several criteria such as the (a) presence of trimethylguanosine cap structure in U1 to U5 RNAs, (b) sequence homology between rat and dinoflagellate U2, U5 and U6 RNAs, (c) presence of other post-transcriptional modifications such as sugar and base modifications, and (d) association of Sm antigen with five of these six RNAs, the six RNAs of dinoflagellates appear to be similar to the well characterized U1 to U6 RNAs found in higher eukaryotes. This is the first demonstration of antigenic small nuclear RNA-containing particles in any unicellular organism. These results suggest that the U1 to U6 RNAs and the associated Sm antigen evolved at a very early stage of eukaryotic evolution. With respect to U small nuclear RNAs and their associated proteins, the dinoflagellates appear to exhibit eukaryotic characteristics.


Epidermal growth factor in mouse milk during early lactation: lack of dependency on submandibular glands.
Using a specific and sensitive radioimmunoassay, we found epidermal growth factor (EGF) in mouse milk during early lactation in normal and sialoadenectomized mice. Levels of EGF peaked around the 6th day postpartum and decreased thereafter up to day 12. Sephadex G-50 column chromatography of milk from normal and sialoadenectomized mice showed a single immunoreactive component comigrating with purified 6045 dalton EGF from the mouse submandibular gland. The concentrations of EGF were similar in milk collected from the breast and the stomach of the offspring immediately after feeding. The molecular profiles, concentrations, and ontogeny of EGF in milk of control and sialoadenectomized mice were also similar, suggesting that the submandibular gland is not the major source of EGF in mouse breast milk.


Does orthopedic training compromise the outcome in total hip arthroplasty?
This study compares the outcomes of total hip arthroplasty surgery performed by a consultant with those performed by supervised and unsupervised orthopedic trainees. We reviewed 6 years of patient data from the New Zealand Joint Registry in patients undergoing total hip arthroplasty comparing the outcome measures of revision surgery and Oxford hip score at 6 months with the experience of the primary surgeon. Over the study period 35,415 patients underwent elective total hip arthroplasty; 30,344 performed by a consultant, 2982 by a supervised trainee and 1067 by an unsupervised trainee. There was an overall revision rate of 0.77 per 100 component years. The revision rate was 0.75 (95% confidence interval [CI] 0.68-0.82) for consultants, 0.97 (95% CI, 0.72-1.28) for supervised trainees and 0.70 (95% CI, 0.36-1.22) for unsupervised trainees with no significant differences. There was no significant difference in the reason for revision surgery between the 3 groups. The mean Oxford hip score was higher for consultants at 40.70 compared with 38.95 and 38.27 for supervised and unsupervised trainees respectively. These results are reassuring and indicate orthopedic training does not adversely compromise arthroplasty patient outcomes.


Developmental changes in the modulation of cyclic AMP formation by the metabotropic glutamate receptor agonist 1S,3R-aminocyclopentane-1,3-dicarboxylic acid in brain slices.
Metabotropic glutamate receptors (mGluRs) have been recently described as a family of guanine nucleotide-binding regulatory protein-coupled receptors with multiple signal transduction pathways. At least one of these receptors appears to be negatively coupled to adenylyl cyclase when stably expressed in transfected cells. We have studied how activation of native mGluRs modulates cyclic AMP (cAMP) formation in brain slices prepared from rats at different ages. 1S,3R-1-Aminocyclopentane-1,3-dicarboxylic acid (1S,1R-ACPD), a selective agonist of mGluRs, slightly increased basal cAMP formation but reduced forskolin-stimulated cAMP formation in adult hippocampal slices, in agreement with previous results. The action of 1S,3R-ACPD on basal cAMP formation was not reproduced by the ionotropic receptor agonists N-methyl-D-aspartate, kainate, and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate and was antagonised by L-2-amino-3-phosphonopropionate (L-AP-3). L-AP-3, however, did not prevent but rather mimicked the inhibitory action of 1S,3R-ACPD on forskolin-stimulated cAMP formation. In hippocampal slices from 1-, 8-, or 15-day-old rats, 1S,3R-ACPD increased basal cAMP formation but failed to reduce the action of forskolin. A similar development pattern of modulation was observed in hypothalamic slices with the difference that 1S,3R-ACPD did not stimulate basal cAMP formation in the hypothalamus of adult animals. These results suggest that inhibition of forskolin-stimulated cAMP formation by 1S,3R-ACPD is mediated by a specific mGluR subtype that is preferentially expressed in the adult.