Selective LXXLL peptides antagonize transcriptional activation by the retinoid-related orphan receptor RORgamma.
The retinoid-related orphan receptor gamma (RORgamma) has been shown to function as a positive regulator of transcription in many cell lines. Transcriptional activation by nuclear receptors involves recruitment of co-activators that interact with receptors through their LXXLL motifs (NR box). In this study, we analyze the interaction of RORgamma with the co-activator SRC1 and use a series of LXXLL-containing peptides to probe for changes in the conformation of the co-activator interaction surface of the RORgamma LBD. We demonstrate that the H3-4/H12 co-activator interaction surface of RORgamma displays a selectivity for LXXLL peptides that is distinct from those of other nuclear receptors. LXXLL peptides that interacted with RORgamma efficiently antagonized RORgamma-mediated transcriptional activation. Mutations E502Q and Y500F in H12, and K334A, Q347A, and I348D in H3 and H4 of RORgamma, severely impact the recruitment of LXXLL peptides. The effects of these mutations are consistent with predictions made on the basis of the structure of the RORgamma(LBD) derived through homology modeling. These peptide antagonists provide a useful tool to analyze the conformation changes in the RORgamma(LBD) and to study RORgamma receptor signaling.


Vaccination, information and parental confidence in the digital age in England.
Immunisation programmes have led to substantial reductions in vaccine-preventable infectious diseases globally. A variety of factors have been shown to impact parental confidence and uptake of childhood vaccines, from concerns about vaccine safety to a lack of perceived need. Determinants of vaccine decision making include information, risk perceptions, and modifying factors such as attitude, identity, norms, habit and barriers. With the rise of the internet and social media, there has been a vast increase in information available about vaccines, not all scientifically-based and well-informed. 285 locations in England were randomly selected to survey a nationally representative sample of the English population. 1735 primary care givers of children aged between 2 months and <5 years old from England were randomly selected and surveyed via face-to-face interviews between January and March 2019. A much higher percentage of parents surveyed trust health care workers, the NHS, pharmacists and government for advice about immunisation, in comparison to media, the internet and social media. Most parents use official sources to obtain information on vaccines including parents who use the internet. The small proportion of parents who reported having seen negative information about vaccines were more likely to find it on the internet. Parents who felt they did not have enough information were more likely to have delayed or refused a vaccine for their child. This study showed that for parents of young children in England, vaccination continues to be the social norm but this can rapidly change and clear, consistent messaging from trusted sources continues to be important. Although a proportion do seek vaccine information on the internet, the majority use official sources. Representative attitudinal surveys continue to be key in identifying any emerging threats to parental vaccine confidence.


A water-soluble and biocompatible chitosan-based fluorescent probe for real-time monitoring formaldehyde in living cells and zebrafish.
Formaldehyde (HCHO) is a common environmental toxicant that can harm the human respiratory tract and nervous system when exposed for long period of time. As a carcinogen, HCHO also increases the risk of cancer in humans. HCHO can be produced endogenously in living systems and plays an essential role in physiological and biochemical reactions and pathogenesis. Therefore, monitoring the level of HCHO in vivo and in vitro has become the focus of attention. The designed naphthalene fluorophore was introduced onto modified chitosan to prepare a chitosan-based fluorescent probe (CS-FA) for HCHO detection. Compared to other small-molecule probe analogs for the detection of HCHO, the randomly coiled polymer chain of chitosan enabled CS-FA to "enrich" HCHO using the synergistic binding of hydrazino-naphthalimide recognition sites. Thus, the reaction of the analyte with the recognition site was accelerated, resulting in a faster equilibrium fluorescence response (2-3 min) and high sensitivity. In addition, the introduction of biomass material chitosan also improved the biocompatibility of the probe. Then a series of composite materials (test strips and hydrogel) were prepared based on the probe to expand the application form of the probe.


Spring model of biological attachment pads.
Many animals bear adhesive pads on their limbs to attach to a variety of surfaces. Previous force measurements on pads of the great green bushcricket (Tettigonia viridissima) have shown that the maximum adhesion force depends on the initially applied force [Jiao et al., 2000. J. Exp. Biol. 203 (12), 1887-1895]. We have developed a model that explains this behaviour. The adhesive pad is modelled as a flexible layer that consists of independent linear springs connected to a rigid sphere. Each spring can generate an adhesive contact with the surface by means of the capillary force or due to van der Waals interactions. The model shows a very good agreement with the experiments.


Plerixafor improves the endothelial health balance. The effect of diabetes analysed by polychromatic flow cytometry.
Diabetes damages the endothelium and reduces the availability of bone marrow (BM)-derived endothelial progenitor cells (EPCs). The mobilization of hematopoietic stem cells (HSCs) and EPCs in response to G-CSF is impaired by diabetes, owing to CXCL12 dysregulation. We have previously shown that the CXCR4/CXCL12 disruptor plerixafor rescues HSC and EPC mobilization in diabetes. We herein explored the effects of plerixafor on HSCs, EPCs, and circulating endothelial cells (CECs) in patients with and without diabetes. We re-analysed data gathered in the NCT02056210 trial, wherein patients with (n = 10) and without diabetes (n = 10) received plerixafor to test stem/progenitor cell mobilization. We applied a novel and very specific polychromatic flow cytometry (PFC) approach to identify and quantify HSCs, EPCs, and CECs. We found that 7-AAD(-)Syto16(+)CD34(+)CD45(dim) HSC levels determined by PFC strongly correlated to the traditional enumeration of CD34(+) cells, whereas 7-AAD(-)Syto16(+)CD34(+)CD45(neg)KDR(+) EPCs were unrelated to the traditional enumeration of CD34(+)KDR(+) cells. Using PFC, we confirmed that plerixafor induces rapid mobilization of HSCs and EPCs in both groups, with a marginally significant defect in patients with diabetes. Plerixafor reduced live (7-AAD(-)) and dead (7-AAD(+)) Syto16(+)CD34(bright)CD45(neg)CD146(+) CECs more in patients without than in those with diabetes. The EPC/CEC ratio, a measure of the vascular health balance, was increased by plerixafor, but less prominently in patients with that in those without diabetes. In addition to rescuing defective mobilization associated with diabetes, plerixafor improves the balance between EPCs and CECs, but the latter effect is blunted in patients with diabetes.


Demonstration of a novel gene DEXT3 of Drosophila melanogaster as the essential N-acetylglucosamine transferase in the heparan sulfate biosynthesis: chain initiation and elongation.
Hereditary multiple exostoses gene (EXT) family members encode glycosyltransferases required for heparan sulfate (HS) biosynthesis in humans as well as in Drosophila. In the present study, we identified a novel Drosophila EXT protein with a type II transmembrane topology and demonstrated its glycosyltransferase activities. The truncated soluble form of this new homolog designated DEXT3 transferred N-acetylglucosamine (GlcNAc) through an alpha1,4-linkage not only to N-acetylheparosan oligosaccharides that represent growing HS chains (alpha-GlcNAc transferase II activity) but also to GlcUAbeta1-3Galbeta1-O-C(2)H(4)NHCbz, a synthetic substrate for alpha-GlcNAc transferase I that determines and initiates HS biosynthesis. The results suggest that DEXT3 is the ortholog of human EXTL3 and Caenorhabditis elegans rib-2. Semiquantitative reverse transcriptase-PCR analysis revealed ubiquitous expression of the DEXT3 mRNA. Based on the findings of the present study and those of a recent study where a fly mutant, deficient in the botv gene identical to DEXT3, affected HS proteoglycan-mediated developmental signalings, it is suggested that DEXT3 with the revealed glycosyltransferase activities is critically involved in HS formation in Drosophila. These results suggest the essential roles of DEXT3, its human ortholog EXTL3, and the C. elegans ortholog rib-2 in the biosynthesis of heparan sulfate and heparin, if present, in the respective organisms.


MS-based monitoring of proteolytic decay of synthetic reporter peptides for quality control of plasma and serum specimens.
To determine the preanalytical quality of serum and plasma by monitoring the time-dependent ex vivo decay of a synthetic reporter peptide (RP) with liquid chromatography/mass spectrometry (LC/MS). Serum and plasma specimens were spiked with the RP and proteolytic fragments were monitored with LC/MS at different preanalytical time points ranging from 2 to 24 hours after blood withdrawal. The concentration of fragments changed in a time-dependent manner, and respective peptide profiles were used to classify specimens according to their preanalytical time span. Classification accuracy was high, with values always above 0.89 for areas under receiver operating characteristic curves. This "proteomics degradation clock" can be used to estimate the preanalytical quality of serum and plasma and might have impact on quality control procedures of biobanking repositories.


Autumn vertical distribution of zooplankton in the oxygen minimum zone of the Eastern Tropical North Pacific.
To confirm the Habitat Compression Hypothesis, a cruise to the Eastern Tropical North Pacific (ETNP) took place at the entrance of the Gulf of California, in an area rarely studied at the southern limit of the California Current, where it mixes with waters of the West Mexican Current and the Gulf of California. No significant day-night differences in the vertical distribution (0-500 m depth) of zooplankton were found based on 22 MOCNESS tows and, for the first time, a 48-h cycle of stratified zooplankton sampling. Most zooplankton groups were observed within the upper 100 m, above the oxycline, with oxygen concentrations as low as 45 μmol kg-1. Some California Current-influenced samples showed a slightly different vertical distribution. A ∼50% reduction in the number and abundance of 24 zooplankton groups was recorded within the Oxygen Minimum Zone, from 100 to 500 m depth. Vertical migrator's exceptions include some euphausiid species that migrate into the OMZ during the day. Principal Component Analyses showed that the vertical distribution of zooplankton is limited by oxygen, with a low zooplankton carbon density below ∼100 m depth within the OMZ. The difference between day and night for the upper 0-100 m layer was non-significant (U221 = 57; p = 0.947); however, the data showed great variability. Thus, zooplankton Carbon remains relatively constant, in the upper 100 m, and is available during day and night, in the studied area.


Activity of the de novo engineered antimicrobial peptide WLBU2 against Pseudomonas aeruginosa in human serum and whole blood: implications for systemic applications.
Cationic amphipathic peptides have been extensively investigated as a potential source of new antimicrobials that can complement current antibiotic regimens in the face of emerging drug-resistant bacteria. However, the suppression of antimicrobial activity under certain biologically relevant conditions (e.g., serum and physiological salt concentrations) has hampered efforts to develop safe and effective antimicrobial peptides for clinical use. We have analyzed the activity and selectivity of the human peptide LL37 and the de novo engineered antimicrobial peptide WLBU2 in several biologically relevant conditions. The host-derived synthetic peptide LL37 displayed high activity against Pseudomonas aeruginosa but demonstrated staphylococcus-specific sensitivity to NaCl concentrations varying from 50 to 300 mM. Moreover, LL37 potency was variably suppressed in the presence of 1 to 6 mM Mg(2+) and Ca(2+) ions. In contrast, WLBU2 maintained its activity in NaCl and physiologic serum concentrations of Mg(2+) and Ca(2+). WLBU2 is able to kill P. aeruginosa (10(6) CFU/ml) in human serum, with a minimum bactericidal concentration of <9 microM. Conversely, LL37 is inactive in the presence of human serum. Bacterial killing kinetic assays in serum revealed that WLBU2 achieved complete bacterial killing in 20 min. Consistent with these results was the ability of WLBU2 (15 to 20 microM) to eradicate bacteria from ex vivo samples of whole blood. The selectivity of WLBU2 was further demonstrated by its ability to specifically eliminate P. aeruginosa in coculture with human monocytes or skin fibroblasts without detectable adverse effects to the host cells. Finally, WLBU2 displayed potent efficacy against P. aeruginosa in an intraperitoneal infection model using female Swiss Webster mice. These results establish a potential application of WLBU2 in the treatment of bacterial sepsis.


Experimental tests of the adaptive significance of sexual recombination.
Numerous theories have been proposed to explain the advantages of sexual recombination the exchange of hereditary material between different genomes or homologous chromosomes. Many of these candidate benefits have been evaluated in controlled laboratory experiments, which, collectively, strongly indicate that sexual recombination provides important long-term advantages.


Ancillary Services in Pediatric Departments of USA.
It is well known that prolonged hospitalizations and medical procedures have adverse psychological impact on children. Ancillary services in the pediatric departments help in mitigating stress, improve patient satisfaction, reduce procedural time, and improve the quality of life. This can be translated to measurable outcomes such as less doctor's visits, fewer symptoms, early discharge and fewer medications. Other benefits include conserving staff time and energy, thereby increasing productivity, staff retention and decreasing burnout. As more free-standing children's hospitals emerge, the ancillary services will gain more recognition and popularity to give the best patient care experience.


Does the degree of preoperative gait disturbance remain after tumor resection in patients with intradural extramedullary spinal cord tumors?
Retrospective comparative study. This study aimed to determine whether the degree of preoperative gait disturbance remains following surgical resection in patients with intradural extramedullary spinal cord tumors (IDEMSCTs), and to investigate any factors that may influence poor improvement in postoperative gait disturbance. The single institution in Japan. In total, 78 IDEMSCTs patients who required surgical excision between 2010 and 2019 were included. According to the degree of preoperative gait disturbance using modified McCormick scale (MMCS) grade, they were divided into the Mild and Severe groups. The mean postoperative follow-up period was 50.7 ± 17.9 months. Data on demographic and surgical characteristics were compared between the two groups. There was no significant difference in terms of age at surgery, sex, tumor size, surgical time, estimated blood loss, tumor histopathology, and postoperative follow-up period between the Mild and Severe groups. At the final follow-up, 84.6% of IDEMSCTs patients were able to walk without support. Gait disturbance improved after surgery in most of the patients with preoperative MMCS grades II-IV, but remained in approximately half of patients with preoperative MMCS grade V. Age at surgery was correlated with poor improvement in postoperative gait disturbance in the Severe group. Regardless of the degree of preoperative gait disturbance, it improved after tumor resection in most of the IDEMSCTs patients. However, in the preoperative MMCS grade III-V cases, older age at surgery would be an important factor associated with poor improvement in postoperative gait disturbance.


Planning mass eradication of Helicobacter pylori infection for indigenous Taiwanese peoples to reduce gastric cancer.
The aim of this study is to identify gastric cancer burden in Indigenous Taiwanese peoples and conduct a project to evaluate how to reduce the disparities most effectively in Indigenous communities. First, we quantified the health disparities in gastric cancer in Indigenous peoples using data from the cancer registries during the period of 2006-2014. Second, we identified parameters that might be associated with Helicobacter pylori infection or help identify a good eradication strategy. Gastric cancer incidence (24.4 vs 12.3 per 100 000 person-years) and mortality rates (15.8 vs 6.8 per 100 000 person-years) were higher in Indigenous than in non-Indigenous, with 2.19-fold (95% confidence interval [CI]: 2.06-2.33) and 2.47-fold (2.28-2.67) increased risk, respectively. In Indigenous communities, H. pylori infection was more prevalent in Indigenous than in non-Indigenous (59.4% vs 31.5%, P < 0.01). Regression analyses consistently showed that either the mountain or plain Indigenous had 1.89-fold (95% CI: 1.34-2.66) and 1.73-fold (95% CI: 1.24-2.41) increased risk for H. pylori infection, respectively, as compared with non-Indigenous, adjusting for other baseline characteristics. The high infection rates were similarly seen in young, middle-aged, and older adults. Program eradication rates using clarithromycin-based triple therapy were suboptimal (73.7%, 95% CI: 70.0-77.4%); the habits of smoking (1.70-fold, 95% CI: 1.01-2.39) and betel nut chewing (1.54-fold, 95% CI: 0.93-2.16) were associated with the higher risk of treatment failure. Gastric cancer burden is higher in Indigenous Taiwanese peoples than in their non-Indigenous counterparts. Eliminating the prevalent risk factor of H. pylori infection is a top priority to reduce this health disparity.


Synthetic Triterpenoid RTA-408: Limits Radiation Damage to Normal Tissue.
To assess the efficacy and mechanism of action of a novel approach to mitigate acute and chronic radiation toxicity in a validated animal model. Randomized, prospective study using an in vivo rat model. Experimental animal study utilizing Sprague-Dawley rats divided into three cohorts: 1) radiation + dimethyl sulfoxide (DMSO) (inert vehicle); 2) radiation + RTA-408 (therapeutic drug); and 3) no radiation + DMSO. All animals in the radiation cohorts underwent 40 Gy of radiation with subsequent inferior epigastric axial rotational flap 30 days later in all cohorts with percentage of flap necrosis and vascular density calculated by blinded observers. In a second experiment, an additional three cohorts, underwent serial punch biopsies of the abdominal skin before, during, and after radiation and drug/vehicle control treatment. Transcriptome analysis utilizing gene set enrichment analysis and digital polymerase chain reaction were performed at various time points. The first experiment revealed average flap necrosis of 20% (95% confidence interval [CI] 16-45) in the radiation control group, 3% (95% CI 0-11) in the nonirradiated control, and 3% (95% CI 0.2-10) in the radiation group treated with RTA-408. Vascular density was preserved in the treatment group as compared to the radiated control. Nine rats were included in the second experiment, and transcriptome analyses in the treatment group revealed robust activation of antioxidant pathways with induced expression of genes associated with hypoxia and adipogenesis/angiogenesis. Administration of RTA-408 during radiation treatment in a rat model resulted in transcriptome changes which appear to mitigate the toxic effects of radiation, preserving capillary networks and improving flap survival and tissue healing after subsequent surgery. Foundational Evidence, Animal Research Laryngoscope, 132:1196-1204, 2022.


Heterogeneity of antibodies in Goodpasture syndrome reacting with type IV collagen.
Sera from patients with antiglomerular basement membrane (anti-GBM) antibodies associated with Goodpasture syndrome (GP) or glomerulonephritis were tested by ELISA and electroimmunoblot against whole basement membrane collagen (type IV) isolated from bovine anterior lens capsule (ALC) and bacterial collagenase resistant domains of the collagen molecule, that is, the NC-1 and 7-S domains isolated from either ALC or bovine and human glomerular basement membrane (GBM). Reactivity was high with the NC-1 domain by both the ELISA and the electroimmunoblot techniques. Some of the anti-GBM sera reacted with both the NC-1 and 7-S domains of both human and bovine type IV collagen. At a time when the patients' sera reacted weakly with a collagenase digest of human GBM using a radioimmunoassay, the reactivity with the NC-1 domain was also low, but some of the sera continued to react with the 7-S domain. The data suggest that there may be heterogeneity in the nature of autoantibodies with respect to collagen type IV domain reactivity in the sera of patients with anti-GBM antibody disease.


[Gender inequality and mental health medicalization: Sociocultural determining factors from the analysis of expert perceptions].
To identify the sociocultural roots that explain the higher frequency of diagnoses of depression and/or anxiety and the prescription of psychotropic drugs in women, in order to propose a preliminary explanatory framework for the investigation of gender inequalities in mental health and its medicalization. Qualitative study with a descriptive-interpretive design, through in-depth interviews conducted in January and February 2021. Interviews were held in various cities of the Basque Country, Barcelona and Madrid. 12 experts in gender and mental health from the clinical (Primary Care and Mental Health), academic and associative fields. Intentional sampling, following the snowball technique, until covering the diversity of previously identified profiles and the saturation of the discourse. An analysis of thematic content was carried out starting from a critical-realistic epistemological perspective. The main dimensions to explain gender inequalities in diagnoses of depression or anxiety and prescription of psychoactive drugs were: 1) the material and symbolic subordination of women, 2) the role of «psi» sciences in the pathologization of the feminine identity, 3) the epistemological and androcentric biases of biomedicine, and 4) the active agency of women in medicalization processes. The reduction of gender inequalities in the diagnoses and prescription of psychotropic drugs will require joint intervention at the clinical, community and structural levels that, from a feminist perspective, manage to reverse the socioeconomic, symbolic and epistemic vulnerability of women.


Benzodiazepine augmentation of antipsychotic drugs in schizophrenia: a meta-analysis and Cochrane review of randomized controlled trials.
Applying various psychopharmacological combination and augmentation strategies in schizophrenia is common clinical practice. This meta-analysis evaluated the efficacy of benzodiazepines added to antipsychotics. The Cochrane Schizophrenia Group trial register (until February 2011) and PubMed/Medline (until July 2012) were searched for randomized controlled trials (RCTs) with a minimum duration of one week that compared benzodiazepine augmentation of antipsychotics with a control group receiving antipsychotic monotherapy in schizophrenia and schizophrenia-like psychoses. Study selection and data extraction were conducted independently by at least two authors. The primary outcome was response to treatment. Secondary outcomes were positive and negative schizophrenic symptoms, anxiety symptoms, and dropouts due to any reason, inefficacy of treatment, and adverse events. Pooled risk ratios (RRs) with the 95% confidence intervals (CIs) were calculated using a random-effects model, with number-needed-to-treat/harm (NNT/H) calculations where appropriate. Overall, 16 relevant RCTs with 1045 participants were identified. Benzodiazepine augmentation was not associated with statistically significantly more responders (N=6; n=511; RR 0.97, 95% CI 0.77-1.22). Adjunctive benzodiazepines were well accepted and tolerated according to dropout-rates and adverse effects apart from dizziness (N=3; n=190; RR 2.58, 95% CI 1.08-6.15) and somnolence (N=2; n=118; RR 3.30, 95% CI 1.04-10.40). There is no evidence for antipsychotic efficacy of additional benzodiazepine medication in schizophrenia. Therefore, benzodiazepines should be considered primarily for desired ultra short-term sedation of acutely agitated patients but not for augmentation of antipsychotics in the medium- and long-term pharmacotherapy of schizophrenia and related disorders.


Effect of UVB on alloactivating and antigen-presenting capacity of human epidermal Langerhans cells.
Human epidermal cell suspensions (EC) were obtained by the suction blister technique and enzyme digestion. EC were irradiated in microtitre plates with doses up to 510 mJ/cm2 (2.6 minimal erythemal dose (MED] by means of fluorescent light bulbs emitting a 280-320 nm continuous spectrum with a peak at 310 nm. Purified allogeneic T cells were added to the EC immediately or 24 h after radiation. Irradiated EC were pulsed with purified protein derivative (PPD) for 90 min immediately or 24 h after radiation and then cocultured with purified autologous T cells. PPD-pulsed EC were also irradiated before being cocultured with autologous T cells. Pretreatment of EC suspensions with anti-DR antiserum plus complement abolished both the alloactivating and the antigen-presenting capacity, indicating that the DR-positive Langerhans cells are mainly responsible for these functions. There were no differences in the number of DR-positive cells in EC before or immediately after radiation. A statistically significant and UV-dose-dependent reduction of the alloactivating ability of EC was found both when allogeneic T cells were added immediately and when they were added 24 h after radiation. Likewise, a significant and dose-dependent reduction of the PPD-specific T-cell response was obtained in cultures when using irradiated EC that were PPD-pulsed immediately or 24 h after radiation. EC that were first PPD-pulsed and then irradiated induced a significantly increased T-cell response after low UV doses (1 or 2 MED), whereas higher doses induced a significant reduction of the T-cell responses.


Incidence and prevalence of polymyositis and dermatomyositis in a health management organization in Buenos Aires.
Polymyositis (PM) and dermatomyositis (DM) are infrequent diseases. Data on incidence and prevalence are scarce and conflicting. There are no such data in Latin America and in Argentina in particular. We undertook to examine the incidence and prevalence of PM/DM in the prepaid health maintenance organization (HMO) of our hospital, in the city of Buenos Aires. Members of the HMO between January 1999 and June 2009 were identified from medical records of patients followed up by us at the HMO. Incident cases and prevalence were calculated at the end of the period. During the study period, 146,747 persons contributed a total of 937,902.6 person-years (mean age was 46.6 [SD, 18.4] years, and 59% were female). Ten incident cases were detected, 7 women and 3 men with a global incidence rate (IR) of 1.07 per 100,000 person-years (95% confidence interval [CI], 0.5-1.84). Three subjects had DM with an IR of 0.32 per 100,000 person-years (95% CI, 0.1-0.99), and 7 had PM with an IR of 0.75 per 100,000 person-years (95% CI, 0.35-0.16). On June 1, 2009, 17 prevalent cases were detected, with a mean age of 48.9 (SD, 17.7) years; 76% were female, representing a prevalence of 17.4 per 100,000 persons (95% CI, 10.1-27.8). Among the 17 patients with idiopathic inflammatory myopathy, 10 patients had DM, with a prevalence of 10.22 per 100,000 persons (95% CI, 4.9-18.8), and 7 had PM (prevalence, 7.2 per 100,000 persons [95% CI, 2.9-14.7]). It is difficult to compare studies from different populations and using different ascertainment techniques. These first data from Latin America are in general agreement with many studies.


Genital warts and cervical cancer. IV. A colposcopic index for differentiating subclinical papillomaviral infection from cervical intraepithelial neoplasia.
Five colposcopic signs (thickness, color, contour, vascular atypia, and iodine staining) were graded into three objective categories representing (1) subclinical papillomaviral infection, (2) lower-grade dysplasia, and (3) grade 3 cervical intraepithelial neoplasia. Seventy-two colposcopically different biopsy specimens (25 of subclinical papillomaviral infection and 18 of grade 1, 18 of grade 2, and 11 of grade 3 cervical intraepithelial neoplasia) were collected from 52 women and interpreted by validated, quantitative histologic analysis. Attempts to grade lesions by the prominence of the acetowhitening reaction or the mere presence of aberrant surface capillaries were unsuccessful. In contrast, each of five new colposcopic criteria were significantly correlated with histologic severity. Differences in color, vascular atypia, and iodine staining were more predictive than those of thickness and contour. Combined into a weighted index, these colposcopic features were 96% correct in forecasting approximate histologic findings. Because this method relies upon critical analysis rather than pattern recall, the use of this colposcopic index greatly simplifies the learning of colposcopy.


A bioequivalence study of oral controlled-release morphine using naltrexone blockade.
Twenty-three normal volunteers who received morphine sulphate (MS Contin) with naltrexone completed this randomized, analytically blinded, two-way crossover comparison of the bioavailability of one 200-mg oral controlled-release morphine sulfate tablet with two 100-mg MSC tablets. Morphine effects were blocked by three 100-mg doses of naltrexone. The first dose of naltrexone was given 24 hours before MSC dosing, followed by a second dose at the time of MSC dosing and a third dose 24 hours after MSC administration. Compared with two 100-mg MSC tablets, the 200-mg tablet was 96% bioavailable (90% confidence interval, 88.14-105.74%). The 90% confidence intervals for mean Cmax and AUC0-24 for one 200-mg MSC tablet were within +/- 20% of the Cmax and AUC0-24 of two 100-mg tablets, indicating the two dosage forms are bioequivalent. Single 200-mg doses of MSC given with the naltrexone blockade were generally well tolerated, and adverse effects were similar to those reported for naltrexone alone and for lower doses of morphine without naltrexone. Naltrexone proved safe and effective in blocking the effects of controlled-release morphine, permitting bioequivalence studies of a high dose of morphine in normal volunteers.


Therapeutic options in the management of life-threatening arrhythmias.
These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Homer A. Boushey, MD, Professor of Medicine, and John G. Fitz, MD, Assistant Professor of Medicine, under the direction of Lloyd H. Smith, Jr, MD, Professor of Medicine and Associate Dean in the School of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, School of Medicine, San Francisco, CA 94143.


Infective endocarditis following transcatheter aortic valve replacement: Diagnostic yield of echocardiography and associated echo-Doppler findings.
Studies have suggested the diagnostic yield of echocardiography to be lower in prosthetic valve endocarditis (PVE) after transcatheter aortic valve replacement (TAVR) than reported in surgically-implanted valves but data are limited. We reviewed transthoracic (TTE) and transesophageal (TEE) echo-Doppler findings in 17 patients with PVE (13 definite and 4 possible cases according to modified Duke criteria) after TAVR at Mayo Clinic, Rochester, MN between 2007 and 2016. Median age was 81 years [56; 91] and 5 patients (29%) were female. Median Society of Thoracic Surgery predicted risk of mortality was 8.8%. PVE occurred 197 days [27; 923] after TAVR. Enterococcus faecalis was the most commonly encountered organism (29%). All patients had TEE performed at the time of PVE; TTE was performed in 11 patients. TEE was diagnostic for PVE in 47% of cases and TTE in 18%. TEE was diagnostic in 62% of patients if only definite PVE cases are included. Two patients showed prosthetic obstruction at the time of PVE; obstruction improved with antibiotic therapy in the surviving patient. Standard echocardiography techniques had limited diagnostic performance in patients with TAVR-related PVE. PVE can present as features of TAVR obstruction, thus PVE should also be considered in patients presenting with worsening prosthetic obstruction.


Upregulated PTPN2 induced by inflammatory response or oxidative stress stimulates the progression of thyroid cancer.
PTPN2 is one of the members of the protein Tyrosine Phosphatases (PTPs) family. To explore the promotive effect of upregulated PTPN2 induced by inflammatory response or oxidative stress on the progression of thyroid cancer. PTPN2 level in thyroid cancer tissues and cell lines was detected. Kaplan-Meier method was applied for evaluating the prognostic value of PTPN2 in thyroid cancer patients. After stimulation of inflammatory response (treatment of IFN-γ and TNF-α), or oxidative stress (treatment of H2O2), protein level of PTPN2 in K1 cells was measured by Western blot. Regulatory effects of PTPN2 on EdU-positive staining and Ki-67 positive cell ratio in K1 cells either with H2O2 stimulation or not were determined. PTPN2 was upregulated in thyroid cancer tissues and cell lines. Its level was higher in metastatic thyroid cancer patients than those of non-metastatic ones. High level of PTPN2 predicted worse prognosis of thyroid cancer. Treatment of either IFN-γ or TNF-α upregulated protein level of PTPN2 in K1 cells. Meanwhile, H2O2 stimulation upregulated PTPN2, which was reversed by NAC administration. With the stimulation of increased doses of H2O2, EdU-positive staining and Ki-67 positive cell ratio were dose-dependently elevated. Silence of PTPN2 attenuated proliferative ability and Ki-67 expression in K1 cells either with H2O2 stimulation or not. Inflammatory response or oxidative stress induces upregulation of PTPN2, thus promoting the progression of thyroid cancer.


Minimising the risk of hospital transmission of pulmonary TB.
Pulmonary tuberculosis is a threat to other patients and healthcare workers in hospital settings. Laila King discusses the ways to minimise the risk of transmission.


Corticotropin releasing factor receptor expression in painful human dental pulp.
Our objective was to correlate the presence of symptoms and dental pulp injury with the amount of a subtype of corticotropin releasing factor receptor (CRF-R) in symptomatic and asymptomatic human teeth. We hypothesized that patients diagnosed with irreversible pulpitis have increased levels of CRF-R. Dental history, diagnosis and radiographs were obtained from treatment records following extractions. Teeth were diagnosed as asymptomatic or symptomatic demonstrated by clinical and radiographic evaluation. Tissue sections from tooth pulp were immunoreacted with antibodies directed against CRF receptor 2 (CRF-R2) and neurofilament protein and examined to correlate CRF-R expression with pulpal diagnosis. Our results indicated that symptomatic pulps demonstrated significantly greater expression of CRF-R2. The increased expression was localized on distinct cellular profiles throughout the pulp and was not directly correlated with neurofilament expression. Our findings suggest that the analgesic effects of endogenously produced CRF may be enhanced via upregulation of CRF-R2 expression, and may explain the occurrence of reduced pain symptoms in some patients with irreversible pulpitis. The application of CRF-R agonists may be a feasible strategy in reducing pain associated with irreversible pulpitis.


Anorectal function in the solitary rectal ulcer syndrome.
The anorectal function of nine patients with solitary rectal ulcer syndrome (SRUS) (5 F: 4 M, median age, 27 (range, 19-41 years) and nine control subjects (5 F: 4 M, median age, 47 (35-66) P less than 0.01) has been investigated by a new technique that radiologically visualizes the anorectum during voiding of a semisolid contrast medium, while simultaneously measuring intrarectal pressure and anal sphincter EMG activity. A degree of rectal prolapse was demonstrated in eight of the SRUS patients; six of these lesions were clinically occult. Abnormal failure of the anal sphincter to relax on voiding was present in seven of the SRUS patients. These abnormalities resulted in the SRUS patients requiring a greater increase in intrarectal pressure (median, 100 cm water) to void than the control subjects (median, 65 cm water, P less than 0.01). This combination of high intrarectal pressure and rectal prolapse during staining seems to be the cause of SRUS.


Intraoperative Magnetic Resonance Imaging in Intracranial Glioma Resection: A Single-Center, Retrospective Blinded Volumetric Study.
Intraoperative magnetic resonance imaging (IoMRI) was devised to overcome brain shifts during craniotomies. Yet, the acceptance of IoMRI is limited. To evaluate impact of IoMRI on intracranial glioma resection outcome including overall patient survival. A retrospective review of records was performed on a cohort of 164 consecutive patients who underwent resection surgery for newly diagnosed intracranial gliomas either with or without IoMRI technology performed by 2 neurosurgeons in our center. Patient follow-up was at least 5 years. Extent of resection (EOR) was calculated using pre- and postoperative contrast-enhanced and T2-weighted MR-images. Adjusted analysis was performed to compare gross total resection (GTR), EOR, permanent surgery-associated neurologic deficit, and overall survival between the 2 groups. Overall median EOR was 92.1%, and 97.45% with IoMRI use and 89.9% without IoMRI, with crude (unadjusted) P < 0.005. GTR was achieved in 49.3% of IoMRI cases, versus in only 21.4% of no-IoMRI cases, P < 0.001. GTR achieved was more with the use of IoMRI among gliomas located in both eloquent and noneloquent brain areas, P = 0.017 and <0.001, respectively. Permanent surgery-associated neurologic deficit was not (statistically) more significant with no-IoMRI, P = 0.284 (13.8% vs. 6.7%). In addition, the IoMRI group had better 5-year overall survival, P < 0.001. This study shows that the use of IoMRI was associated with greater rates of EOR and GTR, and better overall 5-year survival in both eloquent brain areas located and non-eloquent brain areas located gliomas, with no increased risk of neurologic complication.


Age-class differences in the pattern of hibernation in yellow-bellied marmots, Marmota flaviventris.
Age-related differences in the patterns of body temperature regulation during hibernation were found in yellow-bellied marmots. The timing of all entrances into and arousals from torpor was determined from continuous records of thermocouples mounted in each animal's nest box. Older marmots spent more time at high body temperatures following periodic arousals from torpor than did juveniles undergoing their first season of hibernation. In addition, older marmots spontaneously terminated their hibernation seasons in the spring, whereas most juveniles continued to hibernate until either they were emaciated from starvation or they were fed. These two patterns of hibernation reflect age- and size-related differences in the degree to which the animals are constrained energetically and the probability that they can successfully reproduce in spring. The patterns also are consistent with age-related differences in the timing of dormancy in nature.


Release of hazardous nanoplastic contaminants due to microplastics fragmentation under shear stress forces.
The presence of nanoplastics in water has become a major environmental concern in the last decade however the knowledge on the origin and formation of these emerging contaminants is lacking due to analytical challenges in detection and quantification techniques. The release of nanoplastics due to the fragmentation of microplastics extracted from a facial scrub and the resulting toxicity on aquatic species are reported here for the first time. The daily use of 4 g of facial scrub could release up to 1011 microplastics of 400 nm in size per litre of wastewater from household drains. Turbulences created by mixing or pumping induced the fragmentation of microplastics into nanoplastics smaller than 10 nm via a crack propagation and failure mechanism, increasing the number of particles in water by one order of magnitude. Compared to microplastics at a fixed concentration number of 6.8 × 108 part./mL, the generated nanoplastics initiated the death of 54% more cells in zebrafish by passive ingestion via skin diffusion which therefore pose a real threat for aquatic living organisms. These results stress the need to reduce the release of nano/microplastics in the aquatic environment to prevent the contamination of all trophic levels.


SARS-CoV-2-specific neuropathology: fact or fiction?
Neurological symptoms and varying levels of central nervous system (CNS) immunopathology have been described in COVID-19. Recent reports have suggested an increased level of innate immune activation associated with CNS border areas, as well as with a compartmentalized cytokine response and a dysregulated, autoreactive cerebrospinal fluid (CSF) immune profile. However, it remains contested whether these changes reflect bystander effects of systemic inflammation or relate to CNS-specific viral infection. We summarize some of the key findings pertaining to this ongoing debate and highlight directions for future investigation.


Effects of sodium salicylate on epithelial cells of the rectal mucosa of the rat: a light and electron microscopic study.
Using a ligation method, rat rectal epithelium was exposed to 2% sodium salicylate, and light and electron microscopic methods were used to assay for: 1) permeability of the epithelium to a marker dye, trypan blue, and 2) damage expressed in terms of disruption of the epithelial surface. Rectal mucosa was exposed to salicylate at pH 4.8, 7.0, and 9.0, and the effects of pretreatment with phlorizin were also studied. Results indicated that 2% sodium salicylate does very little damage to rectal epithelial cells at pH 7.0 while enhancing their permeability to trypan blue, an effect that is reversed upon washing out the sodium salicylate. The major cellular change induced by salicylate was a reduction in the length or distribution of glycocalyx filaments on microvilli of epithelial cells. It was also noted that pretreatment with phlorizin counteracted some of the effects of salicylate treatment.


Chronic Kidney Disease and Third-Generation P2Y12 Inhibitors Use in Patients With Acute Coronary Syndrome: Impact on the Prognosis at 1 Year.
Chronic kidney disease (CKD) is associated with worse clinical outcomes in patients with acute coronary syndrome. However, they are underrepresented in clinical trials. We aimed to investigate differences in prognosis of acute coronary syndrome patients with and without CKD, focusing on the use of novel P2Y12 receptor inhibitors. This multicenter registry involved patients with acute coronary syndrome from 3 tertiary institutions. After excluding anticoagulated patients and patients on antiplatelet monotherapy, 1280 patients remained. During 1 year of follow-up, we recorded all major adverse cardiovascular events (composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke), bleeds (Bleeding Academic Research Consortium classification) and deaths. Of 1280 patients, 325 (25.4%) had CKD; 55.5% of non-CKD patients and 22.7% of CKD patients were prescribed novel P2Y12 inhibitors. During follow-up, CKD patients under novel P2Y12 inhibitors showed a not statistically significant lower mortality and incidence of thrombotic events than clopidogrel-treated ones. In contrast, non-CKD patients taking novel P2Y12 inhibitors had better outcomes in terms of major adverse cardiovascular events (4.72 vs 9.41; P = .006), all-cause mortality (1.32 vs 4.24; P = .006), and severe bleeding events (Bleeding Academic Research Consortium 3-5) (0.94 vs 2.82; P = .030), without differences for any bleeding (8.11 vs 8.47; P = .849). Bleeding risk was not increased by using third-generation P2Y12 inhibitors in either group of patients. In conclusion, the use of third-generation P2Y12 inhibitors among non-CKD patients was associated with better outcomes. CKD patients receiving third-generation P2Y12 inhibitors treatment showed no statistically significant lower mortality and thrombotic events. Bleeding risk was not increased with the use of third-generation P2Y12 inhibitors in either group of patients.


Early results after synchronous carotid stent placement and coronary artery bypass graft in patients with asymptomatic carotid stenosis.
The optimal management of patients with combined carotid and coronary artery disease requiring cardiac surgery is still unknown. Staged carotid endarterectomy and carotid artery stenting (CAS), each followed by coronary artery bypass graft (CABG), are options frequently employed. However, for patients with severe carotid artery disease in urgent need of open cardiac revascularization, staged operations may not be the most appropriate alternative. The aim of this study was to describe our experience using a synchronous CAS-CABG method with minimal interprocedural time. We used this synchronous combination of procedures in patients with combined carotid and coronary artery disease admitted for urgent CABG. Patients with concomitant severe carotid and coronary artery disease scheduled for synchronous CAS and urgent CABG between December 2006 and January 2010 were included in the study. All procedures were performed at a single center: the Cardiovascular Foundation of Colombia, in Floridablanca, Santander, Colombia. The study cohort was characterized according to demographic and clinical characteristics, which included degree of carotid stenosis, presence/absence of preoperative neurological symptoms, and cardiac operative risk profile. All patients underwent CAS under embolic protection devices and then CABG within the next 2 hours. Patients received aspirin pre- and postprocedure but were started on clopidogrel only after CABG. The primary end point of the study was the composite incidence rate of myocardial infarction, stroke, and death 30 days after CAS-CABG. Fifteen patients with concomitant severe carotid and coronary artery disease underwent synchronous CAS-CABG. Most patients (60%) were men, and mean (± standard deviation) age was 65.2 (± 8.4) years. Most patients (93%) were neurologically asymptomatic. The median (interquartile range) ejection fraction and logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) for the cohort were 55% (36%-62%) and 9.7% (4.6%-14.8%), respectively. There were no deaths, major strokes, minor strokes, or myocardial infarctions during the procedure or within 30 days of CAS-CABG. One patient experienced neurological symptoms likely as a result of transient ischemic attack ipsilateral to the CAS procedure. None of the patients required cardiac or carotid reinterventions, and there were no cases of postoperative bleeding requiring reoperation. Synchronous CAS-CABG, when CABG is performed within the 2 hours of the CAS procedure, may be a viable alternative to the more generally accepted staged combination, particularly among patients for whom CABG cannot be postponed. We hope that this strategy will be further evaluated in larger prospective studies and adequately powered randomized clinical trials.


An empirical evaluation of qualitative Hennigian analyses of protein electrophoretic data.
In an empirical evaluation of a qualitative approach to construction of phylogenetic trees from protein-electrophoretic data, we have employed Hennigian cladistic principles to generate molecular trees for water-fowl, rodents, bats, and other phylads. This procedure of tree construction is described in detail. Branching structures of molecular trees produced by three different algorithms were compared against those of "model" classifications previously proposed by other systematists. In each case, the qualitative cladistic trees provided fits to model phylogenies which were strong and as good or better than those resulting from phenetic-clustering or distance-Wagner trees based on manipulation of quantitative values in matrices of genetic distance. The qualitative Hennigian approach has several pragmatic (as well as theoretical) advantages for analyzing routine sets of electrophoretic data: (1) the analyses are simple and can be performed by hand; (2) they provide the researcher with a strong "feel" for the data; (3) additional data (from new loci or species) can readily be added to the tree without need to recalculate distance matrices; and (4) the qualitative output of the analyses explicitly defines character states along all branches of the tree, and hence affords a high degree of testability. However, these advantages are counterbalanced by a number of serious disadvantages which will likely limit the general applicability of this qualitative approach. These drawbacks are also discussed in detail. For a deeper appreciation of electrophoretic-based protein phylogenies, it is suggested that both quantitative phenetic and qualitative cladistic analyses be employed when possible, and that results of the two approaches be contrasted.


Physics informed neural network for charged particles surrounded by conductive boundaries.
Molecular dynamics of charged particles in porous conductive media have received considerable attention in recent years due to their application in cutting-edge technologies such as batteries and supercapacitors. Due to the presence of long-range electrical interactions, induced charges present at the boundary, and the influence of boundary conditions, the simulation of these systems is more challenging than the simulation of typical molecular dynamic systems. Simulating these kinds of systems typically involves using a numerical solver to solve the Poisson equation, which is a very time-consuming procedure. Recently, Physics-Informed Neural Networks (PINNs) have been introduced as an alternative to numerical solutions of PDEs. In this paper, we present a new PINN-based model for predicting the potential of point-charged particles surrounded by conductive walls. As a result of the proposed PINN model, the mean square error is less than [Formula: see text] and [Formula: see text] score is more than [Formula: see text] for the corresponding example simulation. Results have been compared with typical neural networks and random forest as standard machine learning algorithms. The [Formula: see text] score of the random forest model was [Formula: see text], and a standard neural network could not be trained well.


On-demand integrated nano-engager converting cold tumors to hot via increased DNA damage and dual immune checkpoint inhibition.
Cancer immunotherapy has become a promising strategy. However, the effectiveness of immunotherapy is restricted in "cold tumors" characterized with insufficient T cells intratumoral infiltration and failed T cells priming. Herein, an on-demand integrated nano-engager (JOT-Lip) was developed to convert cold tumors to hot via "increased DNA damage and dual immune checkpoint inhibition" strategy. JOT-Lip was engineered by co-loading oxaliplatin (Oxa) and JQ1 into liposomes with T-cell immunoglobulin mucin-3 antibodies (Tim-3 mAb) coupled on the liposomal surface by metalloproteinase-2 (MMP-2)-sensitive linker. JQ1 inhibited DNA repair to increase DNA damage and immunogenic cell death (ICD) of Oxa, thus promoting T cells intratumoral infiltration. In addition, JQ1 inhibited PD-1/PD-L1 pathway, achieving dual immune checkpoint inhibition combining with Tim-3 mAb, thus effectively promoting T cells priming. It is demonstrated that JOT-Lip not only increased DNA damage and promoted the release of damage-associated molecular patterns (DAMPs), but also enhanced T cells intratumoral infiltration and promoted T cell priming, which successfully converted cold tumors to hot and showed significant anti-tumor and anti-metastasis effects. Collectively, our study provides a rational design of an effective combination regimen and an ideal co-delivery system to convert cold tumors to hot, which holds great potential in clinical cancer chemoimmunotherapy.


Demographic, tumour, and treatment characteristics of female patients with breast cancer in Sri Lanka; results from a hospital-based cancer registry.
Although breast cancer is the most common cancer among Sri Lankan women, there is little published data on patient characteristics and treatment in the local context. We aimed to describe disease characteristics and management in a large contemporary cohort of women with breast cancer at the National Cancer Institute of Sri Lanka (NCISL). All women with invasive primary breast cancers diagnosed during 2016-2020 were identified from the NCISL breast cancer registry. The NCISL sees approximately 40% of all cancer patients in Sri Lanka. Cancer stage at diagnosis was defined according to the Tumour, Node, and Metastasis (TNM) staging system and the Estrogen (ER) and progesterone (PR) receptor status was determined based on the results of immunohistochemistry tests. Descriptive statistics were used to describe the study cohort and treatment patterns. Over 5100 patients were diagnosed with breast cancer during the study period at the NCISL. The mean age of the women was 56 (SD 12) years. Common co-morbidities were hypertension (n = 1566, 30%) and diabetes mellitus (n = 1196, 23%). Two thirds (66%) of the cancers were early stage (stage I & II) at diagnosis. ER/PR positivity rate was 72% and HER-2 positivity rate was 22%. Two thirds of the women had undergone mastectomy while 68% had undergone axillary clearance. The rate of chemotherapy delivery was 91% for women with node positive disease while 77% of eligible women (i.e., after wide local excision or with > 3 positive lymph nodes) had received adjuvant radiotherapy. Endocrine therapy was initiated in 88% of eligible women with hormone receptor positive disease while rate of trastuzumab use was 59% among women with HER2 positive breast cancer. High percentage of advanced breast cancer at diagnosis and high prevalence of comorbidities are some of the major challenges faced in the management of breast cancer in Sri Lanka. Given that stage at diagnosis is the most important prognostic factor determining survival, greater efforts are needed to promote early diagnosis of breast cancer. Considerable lapses in the concordance between guideline recommendations and the delivery of cancer care warrants closer assessment and intervention.


Pharmacotherapy considerations in pregnant patients on hemodialysis.
Successful pregnancy rates on dialysis are increasing with the advent of intensive hemodialysis and advances in medical management. Data support the use of intensive hemodialysis in pregnant women with end-stage kidney disease (ESKD). This paper provides an overview of common pharmacotherapeutic changes in management when caring for a pregnant woman receiving intensive hemodialysis. Pregnant patients on peritoneal dialysis were excluded from this analysis due to insufficient data. Topics covered include those related to anemia (iron and erythropoietin stimulating agents), blood pressure agents, monitoring of phosphorus, as well as nutrition and anticoagulation. When patients on hemodialysis become pregnant, medication adjustments are needed regarding antihypertensives, anemia management, and mineral-bone disease management as many agents require dose adjustment, switching agents due to teratogenicity, or cessation due to fetal complications. There are minimal data in this population; however, successful and healthy infants have been delivered in this patient population with the medication changes discussed.


Factors influencing alopecia and hair cortisol in rhesus macaques (Macaca mulatta).
Alopecia can occur in captive non-human primates, but its etiology is poorly understood. The purpose of this study was to assess alopecia and hair cortisol in rhesus monkeys and to identify the potential risk factors. Subjects were 117 rhesus monkeys at two National Primate Research Centers. Photographs and hair samples were obtained during routine physicals. Photographs were analyzed using Image J software to calculate hair loss, and hair samples were assayed for cortisol. Age, days singly housed, and their interactions contributed to the alopecia model for both facilities. Sex and location changes contributed to the hair cortisol model for Facility 1; sedations contributed for Facility 2. Alopecia and hair cortisol were associated at Facility 1. Captive management practices can affect alopecia and hair cortisol. However, there are facility differences in the relationship between alopecia and hair cortisol and in the effect of intrinsic variables and management procedures.


Full-length transcriptome analysis of Misgurnus anguillicaudatus.
Faithful analysis of transcripts represents a critical component of the gene discovery, genomic characterization and annotation process in species without a reference genome. The present study generated 28,001 full-length transcripts of Misgurnus anguillicaudatus using the Pacific Bioscience (PacBio) single-molecule real-time (SMRT) sequencing system. A total of 77,346 consensus isoforms were identified, and 18,991 complete open reading frames (ORFs) detected. In total, 1345 lncRNAs were identified with high-confidence, with additional identification of a number of well-known transcription factors. The present study may facilitate additional exploration of the genomic signatures of M. anguillicaudatus.


Detection of right atrial thrombus in a woman with pulmonary embolism and right heart compromise by bedside echocardiography.
A 59-year-old female with a history of stage IV lung adenocarcinoma presented with worsening shortness of breath and cough over several weeks. She was tachycardic, hypotensive, and tachypneic. Portable chest x-ray suggested bilateral pleural effusions and computed tomography angiography (CTA) revealed bilateral pulmonary emboli (PE) with suspected right heart strain. Upon admission to the medical intensive care unit for treatment of PE, bedside echocardiography was performed to direct management. Indicators of cor pulmonale and right heart strain were apparent including right ventricle dilation, reduced tricuspid systolic excursion, and a deformed left ventricle with "D sign". Most notably, a right atrial thrombus was detected, a finding not initially seen on CTA. Ultimately, prompt detection of the effects on the right ventricle by bedside echocardiography directed the next step in this patient's clinical course without delay.


[Multimodal therapy patients with chronic cervical and lumbar pain. Results of a comparative prospective study].
Multimodal therapy has been established for patients with chronic low back pain, but studies reporting results in patients with chronic neck pain are rare. This prospective clinical study compared the results in 97 patients with chronic cervical pain and 231 patients with chronic lumbar pain after three weeks of multimodal therapy. The following factors were analyzed in both groups at the beginning and after 6 months: ability to work, pain intensity and functional back capacity. Both groups had improved significantly after 6 months in all outcome parameters. Functional back capacity and ability to work at 6 months were not different between the two groups, but pain intensity was significantly lower in patients with low back pain compared to patients with neck pain. Multimodal therapy is also an efficient treatment strategy for patients with chronic cervical pain as has already been shown for patients with chronic lumbar pain.


The adult patient's difficulties with inhalers.
Fifty percent or less of adult patients can be expected to be able to use the conventional metered dose inhaler (MDI) efficiently if the only tuition they receive is the manufacturer's instruction pamphlet and a high proportion of patients should be expected to develop a poor inhalation technique unless their ability to use an MDI is checked regularly. Because of these problems I believe that the future of the conventional MDI is limited. The new generation of inhalation devices have exciting design features and are undoubtedly better than established inhalation systems in that they are as effective and much easier to use. When these new devices are all available for the delivery of bronchodilators and corticosteroids there is no doubt that many patients will benefit. They should be prescribed in preference to the MDI for all patients whose ability to use a conventional pressurized inhaler is not routinely assessed prior to the institution of therapy and at regular intervals thereafter.


Exploring the Evolving Scope of Neoadjuvant Immunotherapy in NSCLC.
While lung cancer remains the leading cause of cancer death worldwide, lung cancer mortality has notably decreased in the past decade. Immunotherapy with immune checkpoint inhibitors have played a noteworthy role in contributing to this improved survival, particularly for patients with non-small cell lung cancer (NSCLC). However, until now the benefits have primarily been seen in patients with advanced or metastatic disease. Several recent early phase and ongoing phase III trials have been assessing whether the treatment benefit of immunotherapy in NSCLC can extend to the neoadjuvant setting for resectable diseases. In this comprehensive narrative review, we evaluate the most recent efficacy and safety data from these studies. We also outline questions that will need to be further examined to legitimate neoadjuvant immunotherapy's role in NSCLC treatment, including the best surrogate marker of response, the incorporation of liquid biopsy for disease monitoring, the ability to be combined with other treatment modalities, the need for further adjuvant therapy, and potential future treatment combinations.


Murine immune response induced by Leishmania major during the implantation of paraffin tablets.
We carried out a model of chronic inflammation using a subcutaneous paraffin tablet in mice experimentally infected with Leishmania major. It was previously reported that the parasite load following paraffin implantation occurred at a peak of 21 days in both BALB/c and C57BL/6 mice. At the present study, we have investigated what cytokines and chemokines are directly related to the parasite load in C57BL/6 mice. All mice were divided in four groups: mice implanted with paraffin tablets; mice experimentally infected with L. major; mice implanted with paraffin tablets and experimentally infected with L. major; and mice submitted only to the surgery were used for the Real-Time Polymerase Chain Reaction (RT-PCR) controls. Fragments of skin tissue and the tissue surrounding the paraffin tablets (inflammatory capsule) were collected for histopathology and RT-PCR studies. By 21 days, a diffuse chronic inflammatory reaction was mainly observed in the deep dermis where macrophages parasitized with Leishmania amastigotes were also found. RT-PCR analysis has shown that BALB/c mice showed strong IL-4 and IL-10 mRNA expression than controls with very little expression of IFN-γ. In contrast, both IFN-γ and IL-10 mRNA was found in higher levels in C57BL/6 animals. Moreover, in C57BL/6 mice the expression of chemokines mRNA of CCL3/MIP-1α was more highly expressed than CCL2/MCP-1. We conclude that the Th1 immune response C57BL/6 did not change to a Th2 response, even though C57BL/6 animals presented higher parasitism than BALB/c mice 21 days after infection and paraffin implantation.


The Prognostic Role of CYP Enzyme in Kidney Transplantation: A Single Centre Experience.
The main goal of immunosuppressive agents is to reach a balance of preserving allograft function while minimizing adverse effects. The purpose of our research is to corroborate the role of CYP3A enzyme in developing individual medication therapy via measuring medicine levels in patients' blood samples. This retrospective analysis studies 15 kidney transplant recipients. We carried out genotyping (CYP3A5, CYP3A4) after isolating DNA and RNA in patient and donor blood samples; we also determined CYP3A4 messenger RNA expression in case of recipients. Tacrolimus blood levels, dosage, and tacrolimus concentration normalized by dose and the body weight (C0/D ratio) were evaluated. In this research, recipients were divided into 2 groups based on their CYP3A5 genotype. Those who carry CYP3A5*1 allele (*1/*1 or *1/*3) are CYP3A5 expressors, whereas those who are homozygous for the nonfunctional CYP3A5*3 allele are CYP3A5 nonexpressors. There were 3 patients with functioning CYP3A5 enzyme (patients with CYP3A5*1/*3 genotype) where increased tacrolimus metabolism was expected. Our data show that C0/D ratio of CYP3A5 nonexpressors was around 3 times higher than of CYP3A5 expressors. Looking at CYP3A4 enzyme, we found 1 patient carried CYP3A4*22/*22 genotype where we expected decreased CYP3A4 expression. It is clear that this patient had adequate therapy medication levels (9.50 μg/L) despite having received very low dosage of tacrolimus (0.03 mg/weight/d). Our results confirmed the importance of determining CYP status of recipients after a transplant because individual differences were observed in tacrolimus treatment that were partly influenced by CYP status of recipients.


Prevalence of and relationship between pulp and renal stones: A radiographic study.
The aim of the present study was to determine the prevalence of and the relationship between pulp and renal in affected patients and in healthy adults. A total of 240 patients participated in the study. Group A consisted of 120 patients who had renal calculi and Group B had 120 randomly selected controls for the study. The periapical radiographs for all patients were evaluated for the presence or absence of the narrowing of dental pulp chambers and pulp canals. The radiographs were also evaluated to determine the presence or absence of pulp stones. The results were compared and analyzed using the Chi-square test (p < 0.001). A total of 164 patients had pulp narrowing and 112 patients had pulp stones, which included 55 controls and 57 renal calculi patients. There was no statistical correlation between pulp narrowing and renal stones (p > 0.001) and also between pulp stones and renal stones (p > 0.001). However, there was no significant correlation between the presence of pulp stones and renal stones, and the incidental findings of pulp stones on periapical radiographs can provide useful information in the early diagnosis of the systemic calcifications.


Sample size determination for quadratic inference functions in longitudinal design with dichotomous outcomes.
Quadratic inference functions (QIF) methodology is an important alternative to the generalized estimating equations (GEE) method in the longitudinal marginal model, as it offers higher estimation efficiency than the GEE when correlation structure is misspecified. The focus of this paper is on sample size determination and power calculation for QIF based on the Wald test in a marginal logistic model with covariates of treatment, time, and treatment-time interaction. We have made three contributions in this paper: (i) we derived formulas of sample size and power for QIF and compared their performance with those given by the GEE; (ii) we proposed an optimal scheme of sample size determination to overcome the difficulty of unknown true correlation matrix in the sense of minimal average risk; and (iii) we studied properties of both QIF and GEE sample size formulas in relation to the number of follow-up visits and found that the QIF gave more robust sample sizes than the GEE. Using numerical examples, we illustrated that without sacrificing statistical power, the QIF design leads to sample size saving and hence lower study cost in comparison with the GEE analysis. We conclude that the QIF analysis is appealing for longitudinal studies.


Tongue reconstruction post partial glossectomy during the COVID-19 pandemic. A case report.
The COVID-19 pandemic has necessitated temporary modifications in the current head and neck oncology treatment paradigm. Till date, no definite treatment for COVID-19 has been discovered. Considering the situation of the global COVID-19 outbreak, methods that minimize patient visits with no compromise in efficacy should be considered. The optimal method for tongue reconstruction has not been determined yet. The artificial bilayer membrane has been used as mucosal substitute in few cases of tongue reconstruction with promising results. We present two cases of tongue reconstruction with acellular dermal matrix post partial glossectomy for tongue carcinoma during the COVID-19 pandemic. Both patients showed good recovery and healing, and no side effects and/or complications were reported. The acellular dermal matrix is not a standard technique for tongue reconstruction but one of the available options. The few reported cases in literature showed promising results in regard of function and healing. We believe the use of acellular dermal matrix can help in preventing the spread of COVID-19 because of the absence of donor morbidity, decreasing post-operative hospital stay and visits.


Small-molecule inhibition of human immunodeficiency virus type 1 replication by targeting the interaction between Vif and ElonginC.
The HIV-1 viral infectivity factor (Vif) protein is essential for viral replication. Vif recruits cellular ElonginB/C-Cullin5 E3 ubiquitin ligase to target the host antiviral protein APOBEC3G (A3G) for proteasomal degradation. In the absence of Vif, A3G is packaged into budding HIV-1 virions and introduces multiple mutations in the newly synthesized minus-strand viral DNA to restrict virus replication. Thus, the A3G-Vif-E3 complex represents an attractive target for development of novel anti-HIV drugs. In this study, we identified a potent small molecular compound (VEC-5) by virtual screening and validated its anti-Vif activity through biochemical analysis. We show that VEC-5 inhibits virus replication only in A3G-positive cells. Treatment with VEC-5 increased cellular A3G levels when Vif was coexpressed and enhanced A3G incorporation into HIV-1 virions to reduce viral infectivity. Coimmunoprecipitation and computational analysis further attributed the anti-Vif activity of VEC-5 to the inhibition of Vif from direct binding to the ElonginC protein. These findings support the notion that suppressing Vif function can liberate A3G to carry out its antiviral activity and demonstrate that regulation of the Vif-ElonginC interaction is a novel target for small-molecule inhibitors of HIV-1.


Transcutaneous bilirubin measurement at the time of hospital discharge in a multiethnic newborn population.
Severe neonatal hyperbilirubinemia continues to occur in healthy newborns. Recent guidelines have supported using transcutaneous devices in estimating bilirubin levels. Previous studies using these devices are limited. Newborns requiring serum bilirubin level measurements before hospital discharge were recruited prospectively. The agreement between a transcutaneous bilirubin (TCB) and total serum bilirubin (TSB) level was assessed. Sensitivity analysis was conducted. A total of 430 infants were enrolled. Correlation between the values was high (Pearson's correlation coefficient 0.83; Lin's concordance coefficient 0.81 [95% CI 0.77 to 0.84]; P<0.001). The mean (± SD) TSB level was 194±60 μmol/L. The TCB measurement tended to overestimate the value (mean difference 12.7), with wide 95% limits of agreement (-52 μmol/L to 77 μmol/L). Sensitivity and specificity analysis of TCB values allowed estimation of clinically important TSB levels. The TCB correlated, but was imprecise in predicting TSB. TCB values can be used at the time of discharge to safely plan care for jaundiced infants if the limits of agreement are considered and clinical judgment is maintained.


Clinical manifestations and bacteriological features of culture-proven Gram-negative bacterial arthritis.
To investigate the clinical manifestations and bacteriological features of culture-proven, Gram-negative bacterial arthritis. This study was conducted at the Chi Mei Medical Center, a 1300-bed teaching hospital located in southern Taiwan. Patients with synovial fluid cultures positive for Gram-negative bacilli (GNB) during the period January 2009 to May 2014 were identified from the hospital's computerized microbiology database. During the study period, a total of 48 patients with culture-confirmed, GNB septic arthritis were identified. In the majority of patients (n = 33, 68.8%), the knee was the most commonly involved joint. The most common causative pathogen was Pseudomonas spp. (n = 16, 33.3%), followed by Escherichia coli (n = 13, 28.1%). Among the 29 clinical isolates of Enterobacteriaceae, eight (27.6%) were resistant to ceftriaxone and six (20.7%) were resistant to cefpirome. Three E. coli isolates and three Klebsiella pneumoniae isolates were extended-spectrum beta-lactamase producers (n = 6, 20.7%). Among the nonfermenting GNB (NFGNB), 21.1% were resistant to ceftazidime, 21.1% were resistant to ciprofloxacin, 26.3% were resistant to piperacillin-tazobactam, and 15.8% were resistant to imipenem. The overall mortality rate was 10.4%, and the significant risk factors for death were concomitant bacteremia [odds ratio (OR): 14.6, 95% confidence interval (CI): 1.9-115.2, p = 0.011] and liver cirrhosis (OR: 20.0, 95% CI: 2.4-169.9, p = 0.006). Approximately 25% of cases of septic arthritis were due to GNB and resistance to commonly used antimicrobial agents was common. Liver cirrhosis and concomitant bacteremia were significant risk factors for death.


Surface expression of Hsp70B' in response to proteasome inhibition in human colon cells.
Hsp70B' was expressed on the surface of HT-29 and CRL-1809 but not SW-480 human colon cell lines in response to proteasome inhibition as detected using flow cytometry. Surface expression was not detected under non-stress conditions nor was heat shock an inducer of surface expression in the three cell lines tested. Phylogenetic analysis indicated that the Hsp70B' protein sequence was most closely related to another major inducible human Hsp70, Hsp72. Hsp70B' appeared to be recently diverged, as homologs for Hsp70B' have not been found in rodents. Hsp72 and Hsp70B' shared 100% amino acid sequence identity in their predicted peptide-binding regions suggesting that they bind the same peptide substrates, perhaps in extracellular antigen presentation. Amino acid sequence differences were concentrated in the lid regions and the C-terminal domains raising the possibility that Hsp72 and Hsp70B' bind different co-chaperones or cell surface receptors.


The relationship between fetal hemoglobin level and glycosylation in sickle cell disease.
Glycosylated hemoglobin (glyco Hb) was determined by affinity chromatography and Hb S1 and Hb F by Bio-Rex 70 chromatography in patients with sickle cell anemia, SC disease, S beta+-thalassemia, and S beta 0-thalassemia. SC and S beta-thalassemia patients had normal levels of glyco Hb whereas SS patients had significantly lower levels. Within each group of patients a direct correlation existed between Hb F and glyco Hb or Hb S1 levels. A similar relationship was noticed when glyco Hb and Hb F levels were compared in red cell populations of various densities (ages). Hb F seems to influence glycosylation through its effect on red cell survival.


Dietary fructose induces a wide range of genes with distinct shift in carbohydrate and lipid metabolism in fed and fasted rat liver.
Dietary fructose has been suspected to contribute to development of metabolic syndrome. However, underlying mechanisms of fructose effects are not well characterized. We investigated metabolic outcomes and hepatic expression of key regulatory genes upon fructose feeding under well defined conditions. Rats were fed a 63% (w/w) glucose or fructose diet for 4 h/day for 2 weeks, and were killed after feeding or 24-hour fasting. Liver glycogen was higher in the fructose-fed rats, indicating robust conversion of fructose to glycogen through gluconeogenesis despite simultaneous induction of genes for de novo lipogenesis and increased liver triglycerides. Fructose feeding increased mRNA of previously unidentified genes involved in macronutrient metabolism including fructokinase, aldolase B, phosphofructokinase-1, fructose-1,6-bisphosphatase and carbohydrate response element binding protein (ChREBP). Activity of glucose-6-phosphate dehydrogenase, a key enzyme for ChREBP activation, remained elevated in both fed and fasted fructose groups. In the fasted liver, the fructose group showed lower non-esterified fatty acids, triglycerides and microsomal triglyceride transfer protein mRNA, suggesting low VLDL synthesis even though plasma VLDL triglycerides were higher. In conclusion, fructose feeding induced a broader range of genes than previously identified with simultaneous increase in glycogen and triglycerides in liver. The induction may be in part mediated by ChREBP.


[Strategy for keeping efficient expression and pharmacodynamics in reducing rAAV gene medicine immune response based on the decrease of vector dosage].
How to reduce immune response is an unprecedented challenge for rAAV gene medicine. Recent studies suggested that lowering dosage of the vector used could reduce immune response caused by rAAV gene medicine. Nevertheless, it would also decrease the transgene expression, leading to failure of gene treatment. It is therefore important to take appropriate steps to maintain high gene expression level and pharmacodynamic, while the dosage of rAAV used is reduced. Here, steps to enhancing gene therapy, such as optimization of the administration, reconstruction of the viral vector and selection of the promoter, are discussed in order to achieve maximum outcome.


Machine learning of spectra-property relationship for imperfect and small chemistry data.
Machine learning (ML) is causing profound changes to chemical research through its powerful statistical and mathematical methodological capabilities. However, the nature of chemistry experiments often sets very high hurdles to collect high-quality data that are deficiency free, contradicting the need of ML to learn from big data. Even worse, the black-box nature of most ML methods requires more abundant data to ensure good transferability. Herein, we combine physics-based spectral descriptors with a symbolic regression method to establish interpretable spectra-property relationship. Using the machine-learned mathematical formulas, we have predicted the adsorption energy and charge transfer of the CO-adsorbed Cu-based MOF systems from their infrared and Raman spectra. The explicit prediction models are robust, allowing them to be transferrable to small and low-quality dataset containing partial errors. Surprisingly, they can be used to identify and clean error data, which are common data scenarios in real experiments. Such robust learning protocol will significantly enhance the applicability of machine-learned spectroscopy for chemical science.


Evidence-Based Nursing Practice in Ghana.
Introduction: The nursing profession in the 21st century requires service delivery in a highly specialized nursing environment with a high degree of professionalism and optimum patient outcome. Evidence-Based Nursing Practice (EBP) may provide a great opportunity for moving nursing care to a level that may involve clinical reasoning to meet demand in the 21st century and beyond, improve patient outcome and cost containment. To investigate evidence-based nursing practice among nurses in Ghana. This is a descriptive cross-sectional survey and data was collected among clinical nurses and nurse educators from both private and public institutions across Ghana. Nurses were included if they have full-time or part-time appointment; were in active service and have a valid Personal Identification Number (PIN) from the Nursing and Midwifery Council of Ghana. About half of the nurses disagreed or were neutral regarding formulation of answerable research questions and 40% do not critically track relevant scientific evidence. Also, more than 30% of the nurses disagreed or were neutral regarding the integration of scientific evidence into practice. Clinical nurses were about 2.1 times more likely to have difficulty determining the applicability of research findings in service delivery compared to nurse educators. The findings suggest EBP uptake and integration is suboptimal in Ghana.


Membrane-dependent signal integration by the Ras activator Son of sevenless.
The kinetics of Ras activation by Son of sevenless (SOS) changes profoundly when Ras is tethered to membranes, instead of being in solution. SOS has two binding sites for Ras, one of which is an allosteric site that is distal to the active site. The activity of the SOS catalytic unit (SOS(cat)) is up to 500-fold higher when Ras is on membranes compared to rates in solution, because the allosteric Ras site anchors SOS(cat) to the membrane. This effect is blocked by the N-terminal segment of SOS, which occludes the allosteric site. We show that SOS responds to the membrane density of Ras molecules, to their state of GTP loading and to the membrane concentration of phosphatidylinositol-4,5-bisphosphate (PIP2), and that the integration of these signals potentiates the release of autoinhibition.


Origin of a 'Southern Hemisphere' geochemical signature in the Arctic upper mantle.
The Gakkel ridge, which extends under the Arctic ice cap for approximately 1,800 km, is the slowest spreading ocean ridge on Earth. Its spreading created the Eurasian basin, which is isolated from the rest of the oceanic mantle by North America, Eurasia and the Lomonosov ridge. The Gakkel ridge thus provides unique opportunities to investigate the composition of the sub-Arctic mantle and mantle heterogeneity and melting at the lower limits of seafloor spreading. The first results of the 2001 Arctic Mid-Ocean Ridge Expedition (ref. 1) divided the Gakkel ridge into three tectonic segments, composed of robust western and eastern volcanic zones separated by a 'sparsely magmatic zone'. On the basis of Sr-Nd-Pb isotope ratios and trace elements in basalts from the spreading axis, we show that the sparsely magmatic zone contains an abrupt mantle compositional boundary. Basalts to the west of the boundary display affinities to the Southern Hemisphere 'Dupal' isotopic province, whereas those to the east-closest to the Eurasian continent and where the spreading rate is slowest-display affinities to 'Northern Hemisphere' ridges. The western zone is the only known spreading ridge outside the Southern Hemisphere that samples a significant upper-mantle region with Dupal-like characteristics. Although the cause of Dupal mantle has been long debated, we show that the source of this signature beneath the western Gakkel ridge was subcontinental lithospheric mantle that delaminated and became integrated into the convecting Arctic asthenosphere. This occurred as North Atlantic mantle propagated north into the Arctic during the separation of Svalbard and Greenland.


Cross-reactivity between coconut and hazelnut proteins in a patient with coconut anaphylaxis.
The medical literature reports few cases of severe allergic reactions to coconut. We encountered a patient with anaphylaxis to coconut and oral symptoms to tree nuts. To identify cross-reactive antibodies between coconut and other tree nuts. We performed commercial radioallergosorbent tests to coconut and various tree nuts using the patient's serum. Skin prick testing was performed to fresh coconut and commercial extracts of coconut, almond, Brazil nut, cashew, pecan, walnut, and hazelnut. Proteins from fresh coconut, commercial coconut extract, and tree nuts were extracted. Immunoblot and inhibition assays were performed to evaluate for cross-reacting IgE antibodies between similar-sized allergens in coconut and hazelnut. Positive skin test results occurred to the coconut and multiple tree nut extracts. In vitro serum specific IgE was present for coconut, hazelnut, Brazil nut, and cashew. Immunoblots demonstrated IgE binding to 35- and 50-kDa protein bands in the coconut and hazelnut extracts. Inhibition assays using coconut demonstrated complete inhibition of hazelnut specific IgE, but inhibition assays using hazelnut showed only partial inhibition of coconut specific IgE. Our study demonstrates the presence of cross-reactive allergens between hazelnut (a tree nut) and coconut (a distantly related palm family member). Because there are many potentially cross-reactive allergens among the tree nuts, we recommend patients with coconut hypersensitivity be investigated for further tree nut allergies.


Effect of isgin (Rheum ribes L.) on biochemical parameters, antioxidant activity and DNA damage in rats with obesity induced with high-calorie diet.
The present study was designed to investigate the effects of Rheum ribes L. plant root extracts on DNA damage, biochemical and antioxidant parameters in rats with experimental obesity induced with a high-calorie diet. The study groups were divided as "normal control(NC)", "obese control(OC)", "obese + Rheum ribes(OR1)(200 mg/kg)" and "obese + Rheum ribes (OR2)(400 mg/kg)". At the end of the application, rats were sacrificed and blood and tissue samples were obtained. According to the results obtained, the marker of DNA damage in tissues of 8-OHdG was determined to be significantly reduced in brain tissue of the OR1 and OR2 groups compared to the NC group. However, fluctuations were identified in the MDA activity, antioxidant defense system elements and serum biomarkers in tissues. In conclusion, Rheum ribes plant root extract ensured improvements in DNA damage in brain tissues and MDA levels and showed positive effects on antioxidant parameter activities in different tissues.


The changes in the binding capacity of testosterone-oestradiol binding globulin (TeBG) following castration and DES-D administration in patients with prostatic carcinoma.
The levels of plasma testosterone, testosterone-oestradiol binding globulin (TeBG) and total serum acid phosphatase (TSAP) following antiandrogenic hormone therapy were investigated in 17 patients with prostatic carcinoma. The low levels of plasma total and free testosterone induced by castration decreased further after diethylstilboestrol diphosphate (DES-D) administration. Plasma TeBG binding capacity after castration was 118.9% of the pre-treatment level and increased to 193.9%, 204.0% and 212.7% at 1, 2 and 3 weeks after DES-D dosing. The in vitro binding of 3H-testosterone to TeBG was not influenced in the presence of DES-D or stilboestrol. Clinical response following the DES-D therapy was associated with a decrease in the levels of TSAP. A significantly inversed correlation was found between the decrease in TSAP and increase in TeBG at completion of DES-D therapy. These results suggest that the high binding capacity of TeBG lowers the biologically active fraction of testosterone and thus may produce clinical effects.


Pilocarpine-induced increases in the activity of 6-phosphofructo-2-kinase and the fructose-2,6-bisphosphate content of rat salivary glands.
The activity of 6-phosphofructo-1-kinase (PFK-1), an important regulatory enzyme of glycolysis, was determined after injection of the sialagogue pilocarpine. The fructose-2,6-bisphosphate content of the glands and 6-phosphofructo-2-kinase (PFK-2) activity were also measured. The increase in PFK-1 activity after pilocarpine treatment was likely to be due to the increase in the content of its potent modulator, fructose-2,6-bisphosphate. This in turn was assumed to be due to the increase in the activity of the active form of PFK-2.


Early patellofemoral cartilage and bone pathology in a rat model of noninvasive anterior cruciate ligament rupture.
Anterior cruciate ligament rupture (ACLR) is a risk factor for the development of post-traumatic osteoarthritis (PTOA). While PTOA in the tibiofemoral joint compartment is well-characterized, very little is known about pathology in the patellofemoral compartment after ACL injury. Here, we evaluated the extent to which ACLR induces early patellofemoral joint damage in a rat model. Adult female Lewis rats were randomized to noninvasive ACLR or Sham. Two weeks post-injury, contrast-enhanced micro-computed tomography (µCT) of femoral and patellar cartilage was performed using 20% v/v ioxaglate. Morphometric parameters of femoral trochlear and patellar cartilage, subchondral bone, and trabecular bone were derived from µCT. Sagittal Safranin-O/Fast-Green-stained histologic sections were graded using the OARSI score in a blinded fashion. Cartilage and bone remodelling consistent with an early PTOA phenotype were observed in both femoral trochleas and patellae. ACLR caused osteophyte formation of the patella and pathology in the superficial zone of articular cartilage, including surface fibrillation, fissures, increased cellularity, and abnormal chondrocyte clustering. There were significant increases in thickness of patellar and trochlear cartilage. Loss of subchondral bone thickness, bone volume fraction, and tissue mineral density, as well as changes to patellar and trochlear trabecular microarchitecture, were indicative of catabolic bone remodelling. Several injury-induced changes, including increased cartilage thickness and trabecular spacing and decreased trabecular number were more severe in the patella compared to the trochlea. The patellofemoral joint develops mild but evident pathology in the early period following ACL rupture, extending the utility of this model to the study of patellofemoral PTOA.


Effect of reserpine on salivary gland radioiodine uptake in thyroid cancer.
Nine patients with thyroid cancer were treated with reserpine in an attempt to reduce radiation exposure to the salivary glands from 100-150 mCi doses of I-131 therapy to thyroid remnants or metastases. Three control patients were not treated with reserpine but did receive 100-150 mCi of I-131. Parotid/background ratios of activity after radioablative doses of I-131 in patients not treated with reserpine were significantly higher than the patients treated with reserpine, and this was also true seven days after the radioablative dose. Combined therapy with reserpine, chewing gum, lemon candies, and hydration is suggested for the prevention of sialadenitis and xerostomia due to large doses of radioiodine.


The incidence and characteristics of bacteremia in cardiac arrest.
Despite improvements in both preventative and post-event care, cardiac arrest still occurs frequently with high morbidity and mortality. Bacteremia is a potential cause or complication of cardiac arrest that has received increasing notoriety in recent years. To identify the incidence of and predictive factors for bacteremia in both inside and outside of hospital cardiac arrest patients. Retrospective, single centered, cohort study conducted at an academic medical center. Patients 18 years of age or older with cardiac arrest and blood cultures drawn within 24 h of the event were included. Two-hundred sixty-three cardiac arrest patients were included, of which forty-three patients (16.3%) were bacteremic. Patients with bacteremia had higher rates of home parenteral nutrition and a history of known infection before cardiac arrest. Bacteremic patients had a higher blood urea nitrogen (30 mg/dL vs. 23, p = 0.02), serum creatinine (2.40 mg/dL vs. 1.70, p = 0.05), and troponin (0.39 ng/mL vs. 0.12, p = 0.03) compared with the non-bacteremic group. There were no differences in duration of mechanical ventilation, hospital length of stay or ICU length of stay. Mortality at 28-days was higher in the bacteremic group (79%) compared to the non-bacteremic group (60.9%, p = 0.02). No factors associated with bacteremia were identified. Bacteremia was observed in 16.3% of patients, with significant differences between the bacteremic and non-bacteremic group regarding home parenteral nutrition and known infection before the event, cardiac arrest characteristics (blood urea nitrogen, serum creatinine, and troponin), and 28-day mortality.


Potent antibacterial and antibiofilm activities of TICbf-14, a peptide with increased stability against trypsin.
The poor stability of peptides against trypsin largely limits their development as potential antibacterial agents. Here, to obtain a peptide with increased trypsin stability and potent antibacterial activity, TICbf-14 derived from the cationic peptide Cbf-14 was designed by the addition of disulfide-bridged hendecapeptide (CWTKSIPPKPC) loop. Subsequently, the trypsin stability and antimicrobial and antibiofilm activities of this peptide were evaluated. The possible mechanisms underlying its mode of action were also clarified. The results showed that TICbf-14 exhibited elevated trypsin inhibitory activity and effectively mitigated lung histopathological damage in bacteria-infected mice by reducing the bacterial counts, further inhibiting the systemic dissemination of bacteria and host inflammation. Additionally, TICbf-14 significantly repressed bacterial swimming motility and notably inhibited biofilm formation. Considering the mode of action, we observed that TICbf-14 exhibited a potent membrane-disruptive mechanism, which was attributable to its destructive effect on ionic bridges between divalent cations and LPS of the bacterial membrane. Overall, TICbf-14, a bifunctional peptide with both antimicrobial and trypsin inhibitory activity, is highly likely to become an ideal candidate for drug development against bacteria.


Prognostic significance of atherogenic index of plasma, atherogenic coefficient and lipoprotein combined index among elderly patients with non-ST-segment elevation myocardial infarction in 1-year follow-up.
Coronary artery disease (CAD) remains a leading cause of death in elderly patients. Recently, novel lipoproteins- Atherogenic Index of Plasma (AIP), Atherogenic Coefficient (AC) and Lipoprotein Combine Index (LCI) have been suggested as CAD risk factors; their clinical usefulness, however, remains unknown. The aim of the study was to assess the predictive value of AIP, AC and LCI concerning incidence of major adverse cardiovascular events (MACE) and all-cause mortality in 1-year follow-up. For the study, 1,083 patients, aged 60 or older, with NSTEMI were enrolled and divided into two groups: young-old and old-old. MACE occurred in 11.8 % of the patients; LCI showed a borderline significance, but only in univariate analysis. Analysis in groups revealed ambiguous results. None of the examined indices was a predictor of MACE in the young-old group whereas all three of them were significant, but negative predictors in the old-old group. Finally, all-cause mortality at follow-up was 14.9 %. AC predicted 1-year mortality in the whole study population (OR = 1.1 (95% CI: 1-1.2; p = 0.02), but was insignificant in the multivariable model. Additionally, it was an independent predictor in the old-old group, but with borderline significance (OR = 1.14 (95% CI: 1-1.3, p = 0.036). AIP, AC and LCI should not be used as predictors of MACE and 1-year mortality among elderly patients with NSTEMI (Tab. 5, Ref. 23).


Congenital cysts of the infant larynx.
Congenital laryngeal cysts are a rare cause of neonatal airway obstruction. Two varieties can be distinguished, ductal cysts and saccular cysts. Treatment remains controversial, particularly with regard to saccular cysts, with some believing that endoscopic procedures leave cysts more prone to recurrence. We reviewed our management of congenital laryngeal cysts to determine the most effective intervention. A review of all children treated by our unit for congenital laryngeal cysts between 2001 and 2011. Demographic data, age at and mode of presentation were noted. Operation notes were reviewed to determine the nature of each laryngeal cyst and treatment methodology. Ten children were identified, six with a ductal cyst of the vallecula and four with a saccular cyst, giving an overall incidence of 3.49 cases per 100,000 live births. Children of Pakistani ancestry were disproportionately represented, accounting for 40% of cases. Saccular cysts presented earlier with symptoms of more severe airway compromise, whilst vallecular cysts tended to present later with feeding difficulties and failure to thrive. Two-thirds of children with vallecular cysts had co-existing laryngomalacia. Treatment by single-stage endoscopic marsupialisation was effective in all cases at a mean follow-up of thirteen months. Congenital laryngeal cysts are rare, although they appear to be more common in the British-Pakistani population. Presentation depends on cyst size and proximity to the glottis and can be associated with laryngomalacia. Endoscopic marsupialisation is an effective means of treatment for ductal cysts and saccular cysts confined to the larynx.


Receptors for glucocorticoids in the lens epithelium of the calf.
The calf lens epithelium contains a specific cytoplasmic receptor for glucocorticoids. This binding protein has a high affinity for dexamethasone (average dissociation constant, 8 x 10(-9) mole per liter), a low capacity (average, 550 femtomoles per milligram of protein), extreme heat sensitivity, and exhibits a pattern of competition similar to that of glucocorticoid receptors in other tissues. This provides direct biochemical evidence that these tissues may function as a target organ for glucocorticoids.