Early Electroencephalographic Features Predicting Cerebral Physiology and Functional Outcomes After Pediatric Traumatic Brain Injury.
We investigated whether early electroencephalographic features predicted intracranial pressure (ICP), cerebrovascular pressure reactivity, brain tissue oxygenation, and functional outcomes in patients with pediatric traumatic brain injury (TBI). This was a retrospective analysis of a prospective data set of 63 patients with pediatric TBI. Electroencephalographic features were collected in the first 24 h of recording to predict values of ICP, pressure reactivity index (PRx), and brain tissue oxygenation (PbtO2) through the initial 7 days of critical care monitoring, in addition to Glasgow Outcome Scale Extended-Pediatric Revision (GOSE-Peds) scores at 12 months. Electroencephalographic features were averaged over all surface electrodes and included seizures, interictal epileptiform discharges, suppression percentage, complexity, the alpha/delta power ratio, and both absolute asymmetry indices and power in beta (13-20 Hz), alpha (8-13 Hz), theta (4-7 Hz) and delta (0-4 Hz) bands. Demographic data and injury severity scores, such as the Glasgow Coma Scale (GCS) and Pediatric Risk of Mortality III (PRISM III) scores, at presentation were also assessed. Univariate and multiple linear regression with guided stepwise variable selection was used to find combinations of risk factors that best explain variability in ICP, PRx, PbtO2, and GOSE-Peds values, and best fit models were applied to pediatric age strata. We hypothesized that suppression percentage and the alpha/delta power ratio in the first 24 h of recording predict ICP, PRx, PbtO2, and GOSE-Peds values. Best subset model selection identified that increased suppression percentage and PRISM III scores predicted increased ICP (R2 = 79%, Akaike information criterion [AIC] = 332.30, root mean square error [RMSE] = 6.62), with suppression percentages < 5% (slope = - 5687.0, p = 0.0001) and ≥ 45% (slope = 9825.9, p = 0.0000) being predictive of dose of intracranial hypertension. When accounting for age and GCS score, increased suppression percentage predicted increased PRx values, suggestive of inefficient cerebrovascular pressure reactivity (R2 = 53%, AIC = 3.93, RMSE = 0.23), with suppression percentages ≥ 5% (p = 0.0033) and ≥ 45% (p = 0.0027) being predictive of median PRx values ≥ 0.3. Lower GCS scores, the presence of seizures, and increased suppression percentages each were independently associated with higher GOSE-Peds scores (R2 = 52%, AIC = 194.04, RMSE = 1.58), suggestive of unfavorable outcomes, with suppression percentages ≥ 5% (p = 0.0005) and ≥ 45% (p = 0.0000) being predictive of GOSE-Peds scores ≥ 5. At the univariate level, no electroencephalographic or clinical feature was associated with differences in PbtO2 values. Increased electroencephalographic suppression percentage on the initial day of monitoring may identify patients with pediatric TBI at risk of increased ICP, inefficient cerebrovascular pressure reactivity, and unfavorable outcomes.


Studies of oligoadenylate formation on a poly (U) template.
We have studied a variety of condensation reactions involving poly (U) as template and isomeric adenosine dinucleotides as substrates. We find that [3'-5']-linked dinucleotides such as A3pA and pA3pA are better acceptors than the corresponding [2'-5']-linked compounds, while ImpA2pA is a better donor than ImpA3pA. The reaction between A2pA and ImpA3pA, for example, yields only 4% of product while the reaction of A3pA with ImpA2pA yields 86% of product. The more efficient condensation reactions of dimers are about as efficient as the self-condensation of ImpA. They yield a few percent of material in which five or more substrate molecules are linked together. The percentage of the natural [3'-5']-linkage in the product varies greatly, from as little as 1% to as much as 45%.


Prevalence of Comorbid Factors in Patients With Recurrent Clostridioides difficile Infection in ECOSPOR III, a Randomized Trial of an Oral Microbiota-Based Therapeutic.
Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter "VOS," formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI. Adults with rCDI were randomized to receive VOS or placebo (4 capsules daily for 3 days) following standard-of-care antibiotics. In this post hoc analysis, the rate of rCDI through week 8 was assessed in VOS-treated participants compared with placebo for subgroups including (i) Charlson comorbidity index (CCI) score category (0, 1-2, 3-4, ≥5); (ii) baseline creatinine clearance (<30, 30-50, >50 to 80, or >80 mL/minute); (iii) number of CDI episodes, inclusive of the qualifying episode (3 and ≥4); (iv) exposure to non-CDI-targeted antibiotics after dosing; and (v) acid-suppressing medication use at baseline. Of 281 participants screened, 182 were randomized (59.9% female; mean age, 65.5 years). Comorbidities were common with a mean overall baseline age-adjusted CCI score of 4.1 (4.1 in the VOS arm and 4.2 in the placebo arm). Across all subgroups analyzed, VOS-treated participants had a lower relative risk of recurrence compared with placebo. In this post hoc analysis, VOS reduced the risk of rCDI compared with placebo, regardless of baseline characteristics, concomitant medications, or comorbidities.


Intraoperative Neurophysiological Monitoring in Syringomyelia Surgery: A Multimodal Approach.
Syringomyelia can be associated with multiple etiologies. The treatment of the underlying causes is first-line therapy; however, a direct approach to the syrinx is accepted as rescue treatment. Any direct intervention on the syrinx requires a myelotomy, posing a significant risk of iatrogenic spinal cord (SC) injury. Intraoperative neurophysiological monitoring (IONM) is crucial to detect and prevent surgically induced damage in neural SC pathways. We retrospectively reviewed the perioperative and intraoperative neurophysiological data and perioperative neurological examinations in ten cases of syringomyelia surgery. All the monitored modalities remained stable throughout the surgery in six cases, correlating with no new postoperative neurological deficits. In two patients, significant transitory attenuation, or loss of motor evoked potentials (MEPs), were observed and recovered after a corrective surgical maneuver, with no new postoperative deficits. In two cases, a significant MEP decrement was noted, which lasted until the end of the surgery and was associated with postoperative weakness. A transitory train of neurotonic electromyography (EMG) discharges was reported in one case. The surgical plan was adjusted, and the patient showed no postoperative deficits. The dorsal nerve roots were stimulated and identified in the seven cases where the myelotomy was performed via the dorsal root entry zone. Dorsal column mapping guided the myelotomy entry zone in four of the cases. In conclusion, multimodal IONM is feasible and reliable and may help prevent iatrogenic SC injury during syringomyelia surgery.


Tiger frog virus ORF080L protein interacts with LITAF and impairs EGF-induced EGFR degradation.
Tiger frog virus (TFV) belongs to the genus Ranavirus, family Iridoviridae, and causes severe mortality in commercial cultures in China. TFV ORF080L is a gene homolog of lipopolysaccharide-induced TNF-α factor (LITAF), which is a regulator in endosome-to-lysosome trafficking through its function in the endosomal sorting complex required for transport machinery. The characteristics and biological roles of TFV ORF080L were identified. TFV ORF080L was predicted to encode an 84-amino acid peptide (VP080L). It had high-sequence identity with mammalian LITAF, but lacked the N-terminus of LITAF, which contains two PPXY motifs. Transcription and protein level analyses showed that TFV ORF080L was a late viral gene. Localization in the virons also showed that TFV VP080L was a viral structural protein. Immunofluorescence staining showed that TFV ORF080L was predominantly colocalized with plasma membrane and partly distributed with the late endosome in infected HepG2 cells. SiRNA-mediated TFV ORF080L silencing decreased viral reproduction. Moreover, TFV ORF080L interacted with human/zebrafish LITAF and impaired EGF-induced EGFR degradation, thereby indicating that TFV ORF080L played a role in endosome-to-lysosome trafficking. These findings suggested that TFV ORF080L might negate the function of cellular LITAF to impair endosomal sorting and trafficking. Results provide a clue to the link between the dysregulated endosomal trafficking and iridovirus pathogenesis.


The BARD1 Cys557Ser polymorphism and breast cancer risk: an Australian case-control and family analysis.
BARD1 was first identified as a BRCA1-interacting protein with tumour-suppressor functions. Some association studies suggested that the BARD1 Cys557Ser variant might be associated with increased risk of breast cancer, but the evidence remains uncertain. We found that the BARD1 Cys557Ser variant was carried by 50 of 1,136 cases (4.4%) and 30 of 623 controls (5.0%) from the population-based Australian Breast Cancer Family Study, 14 of 324 (4.3%) cases from the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), and 30 of 760 controls (4.0%) from the Australian Ovarian Cancer Study. Case-control comparisons showed no evidence that the variant frequency differed by case-control status (P >or= 0.3). Segregation analysis of 14 kConFab variant-carrying families containing 157 genotyped individuals provided no evidence of segregation with disease. We conclude that the BARD1 Cys557Ser variant is not associated with breast cancer risk.


Evidence-based medicine in treatment and rehabilitation of spinal cord injured.
The interest for evidence-based medicine (EBM) has grown, due to the enormous and exponentially increasing amount of medical literature published. EBM is 'the integration of best research evidence with clinical expertise and patient values'. The steps in the EBM process are (1) convert the need for information into a question; (2) find the best evidence; (3) critically evaluate the evidence; (4) integrate the critical appraisal with clinical expertise and the patient's unique biology, values, and circumstances; (5) evaluate the process and seek ways to improve effectiveness and efficiency. Both limitations related to the accumulation of evidence and the use and possible misuse of EBM in the health care are important to be aware of in the daily clinical environment. For use of EMB in treatment and rehabilitation of spinal cord injury MEDLINE is the most sensitive source for evidence due to its comprehensiveness and up to date maintenance, and the best pre-appraised evidence source is the Cochrane Library and Best Evidence. Clinical Practice Guidelines may provide a good summary of the actual evidence. In spite of limitations and dangers related to EMB, health care professionals generally agree that they should strive to incorporate evidence-based interventions into the multifaceted clinical decision-making process, including the individual patient values and circumstances.


Multiplexed Protein Biomarker Detection with Microfluidic Electrochemical Immunoarrays.
Electrochemistry is a multidisciplinary field encompassing the study of analytes in solution for detection and quantification. For the medical field, this brings opportunities to the clinical practice of disease detection through measurements of disease biomarkers. Specifically, panels of biomarkers offer an important future option that can enable physicians' access to blood, saliva, or urine bioassays for screening diseases, as well as monitoring the progression and response to therapy. Here, we describe the simultaneous detection of eight protein cancer biomarkers in a 30-min assay by a microfluidic electrochemical immunoarray.


Developing a sense of scents: plasticity in olfactory placode formation.
The sense organs of the vertebrate head arise predominantly from sensory placodes. The sensory placodes have traditionally been grouped as structures that share common developmental and evolutionary characteristics. In attempts to build a coherent model for development of all placodes, the fascinating differences that make placodes unique are often overlooked. Here I review olfactory placode development with special attention to the origin and cell movements that generate the olfactory placode, the derivatives of this sensory placode, and the degree to which it shows plasticity during development. Next, through comparison with adenohypophyseal, and lens placodes I suggest we revise our thinking and terminology for these anterior placodes, specifically by: (1) referring to the peripheral olfactory sensory system as neural ectoderm because it expresses the same series of genes involved in neural differentiation and differentiates in tandem with the olfactory bulb, and (2) grouping the anterior placodes with their corresponding central nervous system structures and emphasizing patterning mechanisms shared between placodes and these targets. Sensory systems did not arise independent of the central nervous system; they are part of a functional unit composed of peripheral sensory structures and their targets. By expanding our analyses of sensory system development to also include cell movements, gene expression and morphological changes observed in this functional unit, we will better understand the evolution of sensory structures.


Successful repair of an aortoesophageal fistula with aneurysm from esophageal diverticulum.
Aortoesophageal fistula is a rare, frequently fatal, cause of upper gastrointestinal bleeding, and there are few reported survivors of it. We report a successful surgical case of aortoesophageal fistula associated with an infective thoracic aortic aneurysm. The patient had been diagnosed as having an esophageal diverticulum 8 months before admission. The aortoesophageal fistula was completely resected, followed by esophagojejunum anastomosis and patch closure for the entry of the aneurysm and omental coverage to the wall of the descending aorta in one stage. In this case, esophageal diverticulum was diagnosed before the development of an aortoesophageal fistula associated with an aneurysm.


Semisupervised Deep Learning for the Detection of Foreign Materials on Poultry Meat with Near-Infrared Hyperspectral Imaging.
A novel semisupervised hyperspectral imaging technique was developed to detect foreign materials (FMs) on raw poultry meat. Combining hyperspectral imaging and deep learning has shown promise in identifying food safety and quality attributes. However, the challenge lies in acquiring a large amount of accurately annotated/labeled data for model training. This paper proposes a novel semisupervised hyperspectral deep learning model based on a generative adversarial network, utilizing an improved 1D U-Net as its discriminator, to detect FMs on raw chicken breast fillets. The model was trained by using approximately 879,000 spectral responses from hyperspectral images of clean chicken breast fillets in the near-infrared wavelength range of 1000-1700 nm. Testing involved 30 different types of FMs commonly found in processing plants, prepared in two nominal sizes: 2 × 2 mm2 and 5 × 5 mm2. The FM-detection technique achieved impressive results at both the spectral pixel level and the foreign material object level. At the spectral pixel level, the model achieved a precision of 100%, a recall of over 93%, an F1 score of 96.8%, and a balanced accuracy of 96.9%. When combining the rich 1D spectral data with 2D spatial information, the FM-detection accuracy at the object level reached 96.5%. In summary, the impressive results obtained through this study demonstrate its effectiveness at accurately identifying and localizing FMs. Furthermore, the technique's potential for generalization and application to other agriculture and food-related domains highlights its broader significance.


Observation of intermediate states of the human prion protein by high pressure NMR spectroscopy.
Prions as causative agents of transmissible spongiform encephalopathies (TSEs) in humans and animals are composed of the infectious isomer, PrPSc, of the cellular prion protein, PrPC. The conversion and thus the propensity of PrPC to adopt alternative folds leads to the species-specific propagation of the disease. High pressure is a powerful tool to study the physico-chemical properties of proteins as well as the dynamics and structure of folding intermediates. Conformational intermediates of the human prion protein huPrPC were characterized by a combination of hydrostatic pressure (up to 200 MPa) with two-dimensional NMR spectroscopy. All pressure effects showed to be reversible and there is virtually no difference in the overall pressure response between the folded core of the N-terminal truncated huPrPC(121-230) and the full-length huPrPC(23-230). The only significant differences in the pressure response of full-length and truncated PrP suggest that E168, H187, T192, E207, E211 and Y226 are involved in a transient interaction with the unfolded N-terminus. High-pressure NMR spectroscopy indicates that the folded core of the human prion protein occurs in two structural states N1 and N2 in solution associated with rather small differences in free enthalpies (3.0 kJ/mol). At atmospheric pressure approximately 29% of the protein are already in the pressure favored conformation N2. There is a second process representing two possible folding intermediates I1 and I2 with corresponding average free enthalpies of 10.8 and 18.6 kJ/mol. They could represent preaggregation states of the protein that coexist at ambient pressure with a very small population of approximately 1.2% and less than 0.1%. Further the pressure response of the N-terminus indicates that four different regions are in a fast equilibrium with non-random structural states whose populations are shifted by pressure. We identified pressure stabilized folding intermediates of the human prion protein. The regions reflecting most strongly the transition to the intermediate states are the beta1/alpha1-loop and the solvent exposed side of alpha3. The most pressure-sensitive region (representing mainly intermediate I1) is the loop between beta-strand 1 and alpha-helix 1 (residue 139-141), indicating that this region might be the first entry point for the infectious conformer to convert the cellular protein.


Association between neck circumference and diabetes mellitus: a systematic review and meta-analysis.
Despite that several original researchers have investigated the association between neck circumference (NC) and the risk of diabetes mellitus (DM), their results remain controversial. This review aimed to quantitatively determine the risk of DM in relation to the NC. We conducted a literature search of PubMed, Embase, and the Web of Science from these databases' inception through September 2022 to identify observational studies that examined the association between NC and the risk of DM. A meta-analysis of the random-effects model was applied to combine the results of the enrolled studies. Sixteen observational studies involving 4,764 patients with DM and 26,159 participants were assessed. The pooled results revealed that NC was significantly associated with the risk of type 2 DM (T2DM) (OR = 2.17; 95% CI: 1.30-3.62) and gestational DM (GDM) (OR = 1.31; 95% CI: 1.17-1.48). Subgroup analysis revealed that after controlling for BMI, the relationship between the NC and T2DM remained statistically significant (OR = 1.94; 95% CI: 1.35-2.79). Moreover, the pooled OR of T2DM was found to be 1.16 (95% CI: 1.07-1.27) for an increment per each centimeter in the NC. Integrated epidemiological evidence supports the hypothesis that a greater NC is associated with an increased risk of T2DM and GDM.


Elaboration of tetravalent antibody responses against dengue viruses using a subunit vaccine comprised of a single consensus dengue envelope sequence.
Dengue viruses (DENVs) are re-emerging pathogens transmitted by mosquitoes mainly in tropical and subtropical regions. Each year, they are estimated to infect 390 million people globally. The major challenge confronting dengue vaccine development is the need to induce balanced, long lasting tetravalent immune responses against four co-circulating virus serotypes (DENV-I, -II, -III, -IV), because primary infection by any one of which may predispose infected individuals to more severe diseases during a heterotypic secondary infection. Another difficulty is to select representative strains in vaccine design to provide cross-protection against most circulating virus strains. In this study, aimed at developing a tetravalent subunit vaccine with a representative single protein, we designed two vaccines (named cE80(D4) and cE80(max)) based on the consensus sequences of the ectodomain of envelope protein of 3127 DENV strains, and then expressed them in the baculovirus expression system. Both vaccines were capable of eliciting specific antibodies against all four DENV serotypes, and the predominant IgG subtype elicited by the two vaccines was IgG1. Moreover, these vaccines activated both type I and type II antigen-specific helper T cells that secreted IFN-γ and IL-4, respectively. This proof-of-concept study has set foundation for further optimization of a single protein-based tetravalent DENV vaccine.


CYP2C subfamily, primarily CYP2C9, catalyses the enantioselective demethylation of the endocrine disruptor pesticide methoxychlor in human liver microsomes: use of inhibitory monoclonal antibodies in P450 identification.
1. The endocrine disruptor pesticide methoxychlor undergoes O-demethylation by mammalian liver microsomes forming chiral mono-phenolic (1,1,1-trichloro-2-(4-hydroxyphenyl)-2-(4-methoxyphenyl)ethane, i.e. mono-OH-M) and achiral bis-phenolic oestrogenic metabolites. Human liver microsomes (HLM) generated primarily the S-mono-OH-M. 2. Inhibitory monoclonal antibodies (MAb) identified those P450s catalysing the enantioselective O-demethylation of methoxychlor. In HLM, O-demethylation was inhibited by MAb anti-2C9 (30-40%), diminishing the per cent of S-mono-OH-M from about 80 to 55-60%. MAb anti-CYP1A2, 2A6, 2B6, 2C8, 2C19, 2D6 and 3A4 did not affect the demethylation rate in HLM. Nevertheless, MAb anti-CYP1A2 decreased the formation of R-mono-OH-M from 21-23 to 10-17%, indicating that CYP1A2 exhibits a role in generating the R-enantiomer. 3. Among cDNA-expressed human P450s (supersomes), CYP2C19 was the most active in demethylation, but in HLM, CYP2C19 appeared inactive (no inhibition by MAb anti-CYP2C19). There was a substantial difference in the per cent inhibition of demethylation by MAb anti-CYP2C9 and anti-rat CYP2C (MAb inhibiting all human CYP2C forms) and in altering the enantioselectivity, suggesting that demethylation by combined CYP2C8, 2C18 and 2C19 was significant (20-30%). 4. Polymorphism of methoxychlor demethylation was examined with supersomes and HLM-expressing CYP2C9 allelic variants. CYP2C9*1 and 2C9*2 were highly active; however, CYP2C9*3 appeared inactive.


Crossing our quality chasm: heeding the case for graduate preparation of nurse managers and leaders.
As outlined by the Institute of Medicine's Future of Nursing, it is expected that nurses in direct care will be baccalaureate prepared. What then should be the expectation for educating nurse managers? This article compares the Baccalaureate Essentials with the American Nurses Credentialing Center and American Organization of Nurse Executives certification examination content for nurse managers to evaluate if baccalaureate education prepares these leaders for management roles in order to provide additional support for graduate education of nurse managers.


Next generation sequencing in the clinical domain: clinical advantages, practical, and ethical challenges.
There has been an academic "gold rush" with researchers mining the deep seams of whole-exome and whole-genome sequencing since 2008. Although undoubtedly a major advance initially for identifying new disease-associated genes for rare monogenetic disorders--more recently, common and complex conditions have been successfully studied using these techniques. With great power comes great responsibility, however, and we must not forget that next generation sequencing produces unique ethical conundrums and validation challenges. We review the progression of published papers using whole-exome sequencing from a clinical and technical viewpoint before then reflecting on the key arguments that need to be fully understood before these tools can become a routine part of clinical practice and we ask what may be the role for the biomedical scientists?


Fluvoxamine may prevent onset of psychosis: a case report of a patient at ultra-high risk of psychotic disorder.
There is emerging evidence that antidepressants may be effective in preventing patients with non-specific and psychotic-like prodromal symptoms, defined as patients at ultra-high risk (UHR) of psychotic disorder, from transitioning to psychosis. However, the mechanism of such an effect is still unknown. We report the case of a 19-year-old Japanese man determined to be at UHR of psychotic disorder in whom fluvoxamine (one of the antidepressants with sigma-1 receptor agonism) showed preventive effects on psychotic-like prodromal symptoms. Our patient's depressive symptoms were reduced and maintained below remission as a result of treatment with 100 mg/day of fluvoxamine. In addition, it is likely that an additional dose of fluvoxamine (50 mg/day) improved his psychotic-like prodromal symptoms directly, independent of its antidepressive effects. Fluvoxamine, a sigma-1 receptor agonist, may be effective in preventing patients at UHR of psychotic disorder from onset of psychosis via its neuroprotective/neurotropic actions, independent of its antidepressive effects.


Mammary gland development in prolactin receptor knockout mice.
A germ line null mutation of the prolactin receptor gene has been produced by replacing exon 5 with the Tk-NEO cassette. Heterozygous females showed almost complete failure of lactation following their first pregnancy when mated at 6-8 weeks of age. The severity of this phenotype was reduced when heterozygotes were mated at 20 weeks and was absent following a second pregnancy when assessed by pup survival, although a longer lag time prior to weight increase at normal rates was seen in these litters. Histological and whole mount analysis of virgin mammary glands showed that heterozygous glands were smaller in size due to a less developed ductal structure with fewer branch points. Virgin knockout glands were small, composed of sparse, large, poorly branched ducts. This work provides an ideal model to further study the role of the prolactin receptor and its ligands in mammary development and physiology.


Effects of gonadotropin inducible ovarian transcription factor 1 in the paraventricular nucleus on fluid intake after dehydration of ovariectomized female rats.
What is the central question of this study? Giot1, the gene for gonadotropin inducible ovarian transcription factor 1 (GIOT1), is upregulated in osmotically challenged rats: does Giot1 gene expression in the paraventricular nucleus have a role in controlling fluid intake following dehydration and what is the role of ovarian hormones in the modulation of GIOT1 actions? What is the main finding and its importance? GIOT1 acts to regulate water and salt intake as well as hormone secretion after dehydration. The identification of genes that participate in the hormone and behavioural responses involved with hydromineral homeostasis is essential for future exploration of novel drug targets for the treatment of metabolic disease. In order to maintain body fluid balance after dehydration, hypothalamic neurons of the paraventricular nucleus (PVN) are activated to promote secretion of vasopressin (AVP) and oxytocin (OXT) from the neurohypophysis, and to modulate the behavioural allostatic responses of thirst and salt appetite. Gonadotropin inducible transcription factor (GIOT1) is a Krüppel-type zinc finger protein induced by gonadotropins and oestradiol (E2). This transcription factor is expressed in the hypothalamus, specifically in the PVN where expression of Giot1 mRNA increases following hydromineral challenges such as water deprivation or salt loading, although its physiological role is not clear. We hypothesize that GIOT1 has a central role in the integrated homeostatic and allostatic responses to disturbances in hydromineral balance, especially in the presence of female gonadal hormones. Female rats with intact ovaries or ovariectomized rats were subjected to specific microinjection of a lentiviral vector mediating Giot1 knockdown in the PVN. Three weeks after injection, rats were subjected to 48 h water deprivation, and thereafter water and salt intake were evaluated. Giot1 knockdown in PVN reduced water and saline intake as well as AVP and OXT secretion. Furthermore, Giot1 knockdown had profound effects on gene expression in the PVN, reducing the abundance of transcripts encoded by the Avp, Oxt, Nr4a1 and Crh genes. In conclusion, the present study shows for the first time that GIOT1 in the PVN regulates both transcription and fluid intake, although any connection to ovarian hormones remains to be established.


A pathologist's view of terrorist violence.
The experience of the Northern Ireland State Pathology Service is drawn on to illustrate the forensic aspects of death by shooting and bombing caused by terrorists. The investigations into these deaths have to contend with rumours and allegations which can inflame feelings in the community or mislead the investigators and this aspect is dealt with. The conclusion is reached that when terrorist violence erupts there must be a forensic service able to cope and maintain the usual high standards of scientific investigation.


Changes in the chemical characteristics of water-extracted organic matter from vermicomposting of sewage sludge and cow dung.
The chemical changes of water-extractable organic matter (WEOM) from five different substrates of sewage sludge enriched with different proportions of cow dung after vermicomposting with Eisenia fetida were investigated using various analytical approaches. Results showed that dissolved organic carbon, chemical oxygen demand, and C/N ratio of the substrates decreased significantly after vermicomposting process. The aromaticity of WEOM from the substrates enhanced considerably, and the amount of volatile fatty acids declined markedly, especially for the cow dung substrate. Gel filtration chromatography analysis showed that the molecular weight fraction between 10(3) and 10(6) Da became the main part of WEOM in the final product. 1H nuclear magnetic resonance spectra revealed that the proportion of H moieties in the area of 0.00-3.00 ppm decreased, while increasing at 3.00-4.25 ppm after vermicomposting. Fluorescence spectra indicated that vermicomposting caused the degradation of protein-like groups, and the formation of fulvic and humic acid-like compounds in the WEOM of the substrates. Overall results indicate clearly that vermicomposting promoted the degradation and transformation of liable WEOM into biological stable substances in sewage sludge and cow dung alone, as well as in mixtures of both materials, and testing the WEOM might be an effective way to evaluate the biological maturity and chemical stability of vermicompost.


Teenage dating abuse, rape, and violence: The dermatologist's role.
Teenage dating abuse, rape, and violence are considered major public health problems that affect the lives of millions of teenagers in the United States. Dermatologists have traditionally become involved in these cases when confronted with patients who have unexplained bruising or other skin injuries and/or sexually transmitted diseases that raise the possibility that they could be victims of sexual abuse and violence. This contribution explores the role of the dermatologist in the diagnosis and management of teen dating abuse. We suggest some screening questions that might help to broach these serious issues with teen patients when the suspicion of dating abuse arises. We also provide a list of resources and hotlines that offer advice on how best to handle teen dating abuse. Some legal issues concerning the physician's role in managing teen dating abuse, rape, and violence are also discussed.


Hydrolyzed Collagen Powder Dressing Improves Wound Inflammation, Perfusion, and Breaking Strength of Repaired Tissue.
Objective: Hydrolyzed collagen-based matrices are widely used as wound care dressings. Information on the mechanism of action of such dressings is scanty. The objective of this study was to test the effect of a specific hydrolyzed collagen powder (HCP), which is extensively used for wound care management in the United States. Approach: The effects of HCP on resolution of wound inflammation, perfusion, closure, and breaking strength of the repaired skin were studied in an experimental murine model. Results: In early (day 7) inflammatory phase of wound macrophages, HCP treatment boosted phagocytosis and efferocytosis of wound-site macrophages. In these cells, inducible reactive oxygen species were also higher on day (d) 7. HCP treatment potentiated the expression of anti-inflammatory interleukin (IL)-10 cytokine and proangiogenic vascular endothelial growth factor (VEGF) production. Excisional wounds dressed with HCP showed complete closure on day 21, while the control wounds remained open. HCP treatment also demonstrated improved quality of wound healing as marked by the improved breaking strength of the closed wound tissue/repaired skin. Innovation: These data represent first evidence on the mechanism of action of clinically used HCP. Conclusion: HCP dressing favorably influenced both wound inflammation and vascularization. Improved breaking strength of HCP-treated repaired skin lays the rationale for future studies testing the hypothesis that HCP-treated closed wounds would show fewer recurrences.


Recovery of renal function after 72 days of anuria caused by ureteral obstruction.
We report a case of restored renal function following 72 days of ureteral obstruction causing anuria, while the patient was maintained with regular hemodialysis. Easy accessibility to hemodialysis might jeopardize the kidney, which could have maintained its function if treated otherwise.


Botulism.
Botulism is a rare disease with 4 naturally occurring syndromes: foodborne botulism is caused by ingestion of foods contaminated with botulinum toxin, wound botulism is caused by Clostridium botulinum colonization of a wound and in situ toxin production, infant botulism is caused by intestinal colonization and toxin production, and adult intestinal toxemia botulism is an even rarer form of intestinal colonization and toxin production in adults. Inhalational botulism could result from aerosolization of botulinum toxin, and iatrogenic botulism can result from injection of toxin. All forms of botulism produce the same distinct clinical syndrome of symmetrical cranial nerve palsies followed by descending, symmetric flaccid paralysis of voluntary muscles, which may progress to respiratory compromise and death. The mainstays of therapy are meticulous intensive care (including mechanical ventilation, when necessary) and timely treatment with antitoxin.


Use of pulse oximetry as a noninvasive indicator of intravascular volume status.
The use of pulse oximetry as a noninvasive method to assess intravascular volume status is described. Pulse oximeters providing a continuous display of the pulse waveform offer a new method of estimating relative volume status during positive-pressure ventilation. Like intraarterial pressure tracings, the peaks of the pulse waveform demonstrate increased variation in response to positive-pressure ventilation when a patient becomes hypovolemic. Pulse oximeter waveform tracings were compared with central venous pressure and intraarterial pressure tracings in 12 patients undergoing major operative procedures. A significant correlation (r = 0.61) was seen between pulse waveform variation and systolic pressure variation, which has previously been shown to be a sensitive indicator of hypovolemia. When data from individual patients were analyzed separately, the correlation between pulse waveform variation and systolic pressure variation was as high as 0.88.


A cross-sectional study to compare levels of psychiatric morbidity between young people and adults exposed to violence in a large urban center.
Teenagers and young adults are more exposed to violence and traumatic events than adults, and these factors can be associated with mental disorders. This paper aims at investigating whether young people are more exposed to violence and traumatic events and to compare pattern of mental disorders with adults. Cross-sectional study using the Composite International Diagnostic Interview, conducted between 2007 and 2008 with a randomly selected sample of 15 to 75 year-old residents of São Paulo, Brazil. Two thousand five hundred thirty-six participants were divided into two groups: 1096 (43.2 %) young people (15 to 24 years), and 1440 (56.8 %) adults (25 to 75 years). 12-month exposure to traumatic events was higher among young people (32.1 % vs. 20.6 %; p < 0.001). Assaultive violence was reported by 13.4 % of young people and 8.6 % of adults (p = 0.012); 20.1 % of young people and 13 % of adults reported suffering other injury or shocking events (p < 0.001); sudden death/life threatening illness of a close person was declared by 6.1 % of young people and 3.2 % of adults (p = 0.017). Prevalence of alcohol related disorders was higher among young people (5.4 % vs. 2.5 %; P = 0.032); depressive disorders were more prevalent among adults (9.0 % vs. 4.7 %; P = 0.004). Alcohol related disorders were associated to assaultive violence among young people (OR = 3.4; 95 % CI = 1.36 to 8.52; p = 0.004) and adults (OR = 2.38; 95 % CI = 1.23 to 4.61; p = 0.002). Phobic/anxiety disorders were associated to other injury or shocking events among young people (OR = 1.28; 95 % CI = 0.67 to 2.44; p = 0.025). Major depressive disorder was associated to assaultive violence among young people (OR = 2.27; 95 % CI = 1.09 to 4.74; p = 0.004) and adults (OR = 1.28; 95 % CI = 0.85 to 1.93; p = 0.009). Exposure to violence and traumatic events was higher among young people. Alcohol related disorders, depression and phobic/anxiety disorders were significantly higher among young people exposed to traumatic events. Despite the study design, high exposure to violence and traumatic events in this age group can be considered important factors in triggering mental disorders in this vulnerable age period.


Text Parsing-Based Identification of Patients with Poor Glaucoma Medication Adherence in the Electronic Health Record.
To assess the feasibility of automated text parsing screening of physician notes in the electronic health record (EHR) to identify glaucoma patients with poor medication compliance. Cross-sectional study. An automated EHR extraction identified a cohort of patients at the University of Michigan with a diagnosis of glaucoma, ≥40 years old, taking ≥1 glaucoma medication, and having no cognitive impairment. Self-reported medication adherence was assessed with 2 validated instruments: the Chang scale and the Morisky medication adherence scale. In tandem, a text parsing tool that abstracted data from the EHR was used to search for combinations of the following words in patient visit notes: "not," "non," "n't," "no," or "poor" accompanied by "adherence," "adherent, "adhering," "compliance," "compliant," or "complying." The proportion of patients with self-reported poor adherence was compared between the EHR extraction and text parsing identification using a Fisher exact test. Among 736 participants, 20.0% (n = 147) self-reported poor adherence and 6.1% (n = 45) had EHR documentation of poor adherence (P < .0001). Using text parsing as a pre-screening tool, 22 of the 45 patients (48.9%) with non-adherence identified by text parsing also self-reported poor medication adherence compared to the 20.0% by self-report overall (P < .0001). Text parsing physician notes to identify patients' noncompliance to their medications identified a larger proportion of patients who then self-reported poor medication adherence than an automated EHR pull alone but was limited by the small number of patients identified. Optimizing the documentation of medication adherence would maximize the utility of this automated approach to identify medication noncompliance.


A reappraisal of Simpson's introduction of chloroform.
To examine the introduction of the use of chloroform in childbirth, assessing the role of Sir James Young Simpson, the various motives for the innovation, and the health and sociological consequences for those involved in childbirth. A review of the attitudes of mothers, midwives, obstetricians and family practitioners, based on contemporary publications and subsequent historical analyses. The context in which chloroform was introduced was fundamentally important to its widespread acceptance in the UK. The use of this drug carried serious implications for the childbearing woman, as well as the practice and status of those who provided her care. The implications of the introduction of chloroform in childbirth were short, medium and long term. The changes associated with the acceptance of this drug may bear comparison with those relating to certain, current, pain-control methods.


Protection of ischemic myocardium by exogenous phosphocreatine. I. Morphologic and phosphorus 31-nuclear magnetic resonance studies.
A phosphorus 31-nuclear magnetic resonance method was used to study the effect of exogenous phosphocreatine on the isolated perfused rat heart. The hearts were chemically arrested by St. Thomas' Hospital solution and made totally ischemic for 35 minutes at 37 degrees C. In the presence of phosphocreatine, 10 mmol/L, during ischemia, almost complete recovery of heart function and phosphocreatine content and 61% recovery of adenosine triphosphate content were observed after 30 minutes of postischemic reperfusion; in the control experiments without phosphocreatine, contractile function, intracellular phosphocreatine, and adenosine triphosphate contents were restored to 33%, 43%, and 26% of their normal values, respectively. Ultrastructural studies with a lanthanum tracer method showed remarkable protection of sarcolemma against ischemic injury by exogenous phosphocreatine at the level of the glycocalyx.


Increased hepatic efficacy of urea synthesis from alanine in insulin-dependent diabetes mellitus.
The relation of urea synthesis rate to blood alanine concentration was assessed in seven healthy controls and in 18 patients with insulin-dependent diabetes mellitus (HbAlc = 8.4 +/- 1.0% (mean +/- SD)). Following an overnight fast alanine was infused at 2 mmol h-1 kg-1 body weight. The hourly rate of urea synthesis was determined as the urinary excretion of urea corrected for accumulation of urea in total body water and intestinal hydrolysis. The functional hepatic nitrogen clearance, i.e. the relation of urea synthesis rate to blood alanine concentration, was calculated as the slope of linear regression of urea synthesis rates on blood alanine concentrations. Fasting glucagon concentrations were 85 +/- 26 ng l-1 in controls and 161 +/- 35 ng l-1 (P less than 0.01) in patients. The functional hepatic nitrogen clearances were 21.8 +/- 4.4 l h-1 in controls and 44.7 +/- 12.4 l h-1 (P less than 0.001) in patients. By multiple step-wise linear regression analysis the functional hepatic nitrogen clearance was found to correlate independently to fasting glucagon concentration, duration of diabetes, change in blood glucose and insulin following alanine infusion (r2 = 0.74). In a simple linear regression analysis the functional hepatic nitrogen clearance correlated strongly to fasting glucagon concentration (r2 = 0.54). In conclusion the kinetics of urea synthesis in insulin-dependent diabetes is changed in favour of increased conversion of alanine-N to urea-N at any blood amino acid concentration. The increased FHNC correlates strongly with hyperglucagonaemia.


[Increase of depressive symptoms among adolescents during the first COVID-19 lockdown in Germany : Results from the German family panel pairfam].
The COVID-19 pandemic has fundamentally changed social life within a very short time. Lockdown policies often consider the tradeoff between containing the spread of the pandemic and negative consequences for the economy. Policymakers should pay more attention to the psychological and social impacts of the lockdown. How did the mental health of adolescents in Germany change during the first wave of the COVID-19 pandemic and the lockdown? Analyses are based on longitudinal data from nationwide randomly selected anchors of the German family panel pairfam. The age group considered here, born between 2001 and 2003, was surveyed for the first time in 2018/2019 in the course of a refreshment sample, and 854 of these adolescents and young adults aged 16-19 also participated in the COVID-19 supplementary survey from May to July 2020 (first lockdown). Depressiveness is assessed with the State-Trait Depression Scale. During the first lockdown, adolescents show a significant increase in depressive symptoms. Prior to the lockdown, 10.4% had clinically relevant depressive symptoms [95% CI: 8.4; 12.5]. In spring 2020, the prevalence increased to 25.3% [95% CI: 22.4; 28.2]. Young women have a significantly higher risk of developing depressive symptoms than men of the same age. Immigrant background is an equally strong risk factor. The prevalence of depressive symptoms among adolescents with an immigrant background increased from 11% to 33%. To address this increased mental health risk and the inequalities, policymakers and society should ensure access and availability of target-group-specific and low-threshold prevention and counselling.


The Emergency Surgery Frailty Index (EmSFI): development and internal validation of a novel simple bedside risk score for elderly patients undergoing emergency surgery.
Frailty assessment has acquired an increasing importance in recent years and it has been demonstrated that this vulnerable profile predisposes elderly patients to a worse outcome after surgery. Therefore, it becomes paramount to perform an accurate stratification of surgical risk in elderly undergoing emergency surgery. 1024 patients older than 65 years who required urgent surgical procedures were prospectively recruited from 38 Italian centers participating to the multicentric FRAILESEL (Frailty and Emergency Surgery in the Elderly) study, between December 2016 and May 2017. A univariate analysis was carried out, with the purpose of developing a frailty index in emergency surgery called "EmSFI". Receiver operating characteristic curve analysis was then performed to test the accuracy of our predictive score. 784 elderly patients were consecutively enrolled, constituting the development set and results were validated considering further 240 consecutive patients undergoing colorectal surgical procedures. A logistic regression analysis was performed identifying different EmSFI risk classes. The model exhibited good accuracy as regard to mortality for both the development set (AUC = 0.731 [95% CI 0.654-0.772]; HL test χ2 = 6.780; p = 0.238) and the validation set (AUC = 0.762 [95% CI 0.682-0.842]; HL test χ2 = 7.238; p = 0.299). As concern morbidity, our model showed a moderate accuracy in the development group, whereas a poor discrimination ability was observed in the validation cohort. The validated EmSFI represents a reliable and time-sparing tool, despite its discriminative value decreased regarding complications. Thus, further studies are needed to investigate specifically surgical settings, validating the EmSFI prognostic role in assessing the procedure-related morbidity risk.


Simple Tips for Ear Lobule Reconstruction-"Lobuloplasty Revisited".
Lobuloplasty is one of the most common procedures done in outpatient basis. It is performed by a wide spectrum of surgeons ranging from general surgeon to plastic surgeon. Inspite of the innumerous techniques used, the ultimate aim of the surgery is to obtain a soft supple lobule with a well-hidden cosmetic scar without the complication of recurrence. Single site local anaesthesia, scoring and undermining of the lobule flaps and the introduction of a small cartilage piece in recurrent cases can change the outcome of the patients result. This article explains how subtle changes are still possible in common procedures like lobuloplasty to change the outcome of the results.


The mediation of mutagenicity and clastogenicity of heavy metals by physicochemical factors.
Heavy metals are an important class of environmental hazards, and as the use of heavy metals metals in industry continues to increase, larger segments of the biota, including human beings, will be exposed to increasing levels of these toxicants. As many heavy metals are mutagenic and clastogenic, they cause teratogenic and/or carcinogenic effects. Studies with microbes and representatives of the aquatic biota have shown that the toxicity of heavy metals is mediated by the physicochemical characteristics of natural environments. A few studies have also indicated that such abiotic factors (e.g. pH, chelating agents, inorganic anionic and cationic composition) mediate the mutagenicity and clastogenicity of heavy metals. These studies indicate that the physicochemical characteristics of natural environments may also potentiate or attenuate the mutagenicity and clastogenicity of heavy metals to the indigenous biota. Furthermore, studies with laboratory animals have shown that the acute and chronic toxicity, including the teratogenicity and carcinogenicity, of heavy metals is mediated by physicochemical factors. A similar dependence of the mutagenicity and clastogenicity of heavy metals by the physicochemical characteristics unique to specific body fluids and tissues may explain the association of specific heavy metal-induced tumors with specific tissues. There is an apparent need to develop genotoxicity tests that incorporate into their procedures the mediating influence of physicochemical factors (pH, for example), as the use of only standardized procedures may hinder the detection of heavy metal, as well as of organic, genotoxins whose mutagenicity or clastogenicity is altered by conditions other than those used in the standardized assay, thereby producing false negative results.


Athletic performance and serial weight changes during 12- and 24-hour ultra-marathons.
The principal objective of this study was to evaluate serial weight changes in athletes during 12- and 24-hour ultra-marathons and to correlate these changes with athletic performance, namely the distance covered. This was a prospective study. The 2003 Soochow University international ultra-marathon. Fifty-two race participants. 12- or 24-hour ultra-marathon. Body weight changes were measured before, at 4-hour intervals during, and immediately after the 12- and 24-hour races. Significant overall decreases in body weight were apparent at the conclusion of both races. The mean relative body weight change after the 12-hour race was -2.89 +/- 1.56%, ranging from 0 to 6.5%. The mean relative body weight change after the 24-hour race was -5.05 +/- 2.28%, ranging from -0.77% to -11.40%. Of runners in the 24-hour race, 26% lost greater than 7% of baseline body weight during the race. During both the 12- and 24-hour races, the greatest weight change (decrease) occurred during the first 4 hours. Weight remained relatively stable after 8 hours, although a further decrease was apparent between 16 and 20 hours in the 24-hour participants. Weight change had no bearing on performance in the 12-hour race, whereas weight loss was positively associated with performance in the 24-hour race. Our findings demonstrate that the majority of weight decrease/dehydration in both the 12- and 24-hour races occurred during the first 8 hours. Hence, to maintain body weight, fluid intake should be optimized in the first 8 hours for both 12- and 24-hour runners and in 16 to 20 hours for 24-hour marathon runners.


The haplotype-resolved genome assembly of autotetraploid rhubarb Rheum officinale provides insights into its genome evolution and massive accumulation of anthraquinones.
Rheum officinale, a member of the Polygonaceae family, is an important medicinal plant that is widely used in traditional Chinese medicine. Here, we report a 7.68-Gb chromosome-scale assembly of R. officinale with a contig N50 of 3.47 Mb, which was clustered into 44 chromosomes across four homologous groups. Comparative genomics analysis revealed that transposable elements have made a significant contribution to its genome evolution, gene copy number variation, and gene regulation and expression, particularly of genes involved in metabolite biosynthesis, stress resistance, and root development. We placed the recent autotetraploidization of R. officinale at ∼0.58 mya and analyzed the genomic features of its homologous chromosomes. Although no dominant monoploid genomes were observed at the overall expression level, numerous allele-differentially-expressed genes were identified, mainly with different transposable element insertions in their regulatory regions, suggesting that they functionally diverged after polyploidization. Combining genomics, transcriptomics, and metabolomics, we explored the contributions of gene family amplification and tetraploidization to the abundant anthraquinone production of R. officinale, as well as gene expression patterns and differences in anthraquinone content among tissues. Our report offers unprecedented genomic resources for fundamental research on the autopolyploid herb R. officinale and guidance for polyploid breeding of herbs.


Shrimp thioredoxin is a potent antioxidant protein.
Thioredoxin (TRX) is a main component of the redox homeostasis machinery in the cell and it is required for ribonucleotide reductase function among others. In invertebrates, the redox balance is compromised during disease and changes in the physiological state and it is one of the components of the innate immune response. In this work, the shrimp (Litopenaeus vannamei) LvTRX cDNA was sequenced, cloned and over-expressed in bacteria to further characterize the function of the recombinant protein. LvTRX was able to reduce insulin disulfides and it was a better antioxidant compared to reduced glutathione and ascorbic acid, by means of the Trolox Equivalent Antioxidant Capacity (TEAC) assay. Interestingly, LvTRX contains aside of the canonical active site CXXC disulfide motif, one Cys (C73) residue in the interface of a putative dimer previously reported for human TRX. Using qRT-PCR, we found that shrimp LvTRX is mainly expressed in gills and pleopods; the variation of LvTRX mRNA upon hypoxia and re-oxygenation is not statistically significant. LvTRX stands as an important antioxidant that must be considered in future physiological and immune challenges studies.


Immunocytochemical demonstration of 5-hydroxytryptamine (serotonin) and vertebrate neuropeptides in the nervous system of excysted cysticercoid larvae of the rat tapeworm, Hymenolepis diminuta (Cestoda, Cyclophyllidea).
The localisation and distribution of 5-hydroxytryptamine (5-HT, or serotonin) and a number of vertebrate neuropeptides in the nervous system of excysted (0-24 h) cysticercoid larvae of Hymenolepis diminuta were determined by an indirect immunofluorescence technique in whole-mount preparations. In the central nervous system, cell bodies and nerve fibres immunoreactive to 5-HT are present in the main commissure, lateral and rostellar ganglia, and the longitudinal nerve cords and their connectives. In the peripheral nervous system, immunoreactive nerve fibres occur in a poorly developed nerve plexus within each sucker. Among the vertebrate peptides tested, antisera to pancreatic polypeptide (PP), polypeptide YY (PYY), peptide histidine isoleucine (PHI) and gastrin-releasing peptide (GRP) gave positive results. Immunoreactivity to PP and PYY paralleled that of 5-HT, with greater numbers of cell bodies present in the different locations within the scolex nervous system, and the sucker plexus being more prominent. The number of PP-reactive cells in the lateral ganglia and main lateral, longitudinal nerve cords increased over the 24-h period in culture. Results with antisera of different specificities to PP and PYY suggest that the immunoreactivity may be due to a peptide with closer structural affinity to PYY than to PP. Immunoreactivity to PHI is restricted to the main lateral nerve cords in the body of 0-h worms, extending into the median nerve cords by 12 h and 24 h. Immunoreactivity to GRP became evident after 12 h in culture and was confined to the longitudinal nerve cords, in particular the median nerve cords. The results are discussed in relation to the proposed transmitter and regulatory roles of 5-hydroxytryptamine and the neuropeptides.


Multiple proinsulin-secreting tumors of the pancreas treated by laparoscopic distal pancreatectomy and splenectomy.
Patients with pancreatic tumors that induce hypoglycemia present with a myriad of symptoms. Laboratory testing can frequently result in data challenging to the clinician to confirm the biochemical diagnosis. Proinsulin, in addition to insulin levels, may be essential in evaluating and diagnosing an insulinoma. The objective of this case report is to demonstrate the potential importance of proinsulin levels in the evaluation of tumor-induced hypoglycemia. We report a 49-year-old woman with an unusual clinical presentation. Unlike many patients with tumor-induced hypoglycemia, her fasting glucose levels were fairly unimpressive, her insulin levels were undetectable during a prolonged fast, and she had elevated proinsulin levels. The inpatient fast was remarkable for levels of serum glucose 53 mg/dl or higher, a serum insulin <2 uIU/ml, C-peptide 0.7-1.1 (nl 0.8-3.1 ng/ml), and proinsulin 29.2-36.8 pmol/l (nl < or = 18.8 pmol/l). CT scanning of the abdomen revealed multiple pancreatic lesions. A laparoscopic distal pancreatectomy led to the removal of multiple neuroendocrine tumors, which stained only for proinsulin and not for other pancreatic tumor markers. Postoperatively, she normalized her biochemical serum studies and has remained symptom-free 2 years later. The measurement of proinsulin plays an important part in the diagnostic workup of neuroendocrine tumors causing hypoglycemia. These potentially malignant tumors can be treated adequately with minimally invasive surgery.


Interobserver variability of an open-source software for tear meniscus height measurement.
Different values of the lower tear meniscus height (TMH) can be obtained depending on the method and technique of measurement employed. The aim of this study was to analyse the interobserver variability of a method for measuring TMH by using an open source software. On a group of 176 subjects, two videos of the central lower tear meniscus, first under slit-lamp illumination and ten minutes later under Tearscope illumination, were generated by a digital camera attached to a slit-lamp. Images were extracted from each video by a masked observer. Two further observers measured in a masked and randomized order the TMH in each illumination method by using an open source software based on Java (NIH ImageJ). TMH was measured from the lower lid to the upper limit of the tear meniscus for both slit-lamp (TMH-SL) and Tearscope (TMH-Tc) illumination methods. Subsequently, in different order, observers assigned a four-grading and a healthy/abnormal subjective classification to each central meniscus. No significant differences were found between the TMH measurements obtained by both investigators in slit-lamp or Tearscope image datasets (t-test; both p≥0.136). When comparing TMH measurements stratified by grade, only interobserver significant differences were observed for grades 3 and 4 with silt-lamp (t-test; both p≤0.009). Significant differences on TMH results between subjective subgroups were observed for both illumination techniques (ANOVA, all p≤0.045). This study showed a useful tool to objectively measure TMH by photography.


Can the simplified magnetic resonance index of activity be used to evaluate the degree of activity in Crohn's disease?
A simplified magnetic resonance index of activity (MaRIAs) was recently proposed. Our aim was to verify whether MaRIAs can accurately assess the activity degree of CD. We retrospectively analyzed the MRI, ileocolonoscopy, fecal calprotectin (FC), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) data of 93 CD patients. With the SES-CD as the gold standard, MaRIAs' accuracy, the correlation of MaRIAs and SES-CD, FC, ESR, CRP, and interevaluator reliability were assessed. MaRIAs ≥ 1 detected segments with active CD with 90.80% specificity and 81.37% sensitivity (area under the curve was 0.91, 95% confidence interval 0.87-0.94). MaRIAs score of 2 or more detected severe lesions with 88.89% specificity and 95.12% sensitivity (AUC was 0.96, 95% confidence interval was 0.94-0.98). The MaRIAs score showed a high correlation with the SES-CD in the terminal ileum, transverse colon, right colon, and left colon (r = 0.85, 0.91, 0.88, 0.86, P < 0.001) and a moderate correlation with the SES-CD in the rectum (r = 0.74, P < 0.001). The global MaRIAs score was highly correlated with the global SES-CD (r = 0.90, P < 0.001). The global MaRIAs score was positively correlated with the fecal calprotectin (FC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) (r = 0.77, r = 0.64, and r = 0.68). The intragroup correlation coefficient (ICC) of the two physicians was nice in the terminal ileum, the right colon, the transverse colon, the left colon and was moderately good in the rectum. MaRIAs can accurately evaluate the disease activity level of CD and are highly correlated with SES-CD and biomarkers. The interrater reliability of the two physicians was moderately good to nice.


Are antibiotics indicated as an initial treatment for patients with acute upper respiratory tract infections? A review.
To determine the effect of antibiotic treatment versus placebo in patients with acute upper respiratory tract infections. A systematic review and meta-analysis examined the effect of antibiotics versus placebo in randomised controlled trials to initially treat acute upper respiratory tract infections. Eight studies of children from age 6 months and adults up to the age of 49 years were found. The main outcome measures were general improvement and adverse effects. No benefit was demonstrated in terms of overall improvement from the use of antibiotics compared to placebo for patients with acute upper respiratory tract infections RR=0.89 (95%CI 0.77-1.04). There was also a significant increase in adverse effects (mainly gastrointestinal) using a random effects model with a relative risk RR=2.71 (95%CI 1.08-6.83). Initial use of antibiotics do not benefit patients with acute upper respiratory tract infections and are associated with an increase in adverse effects.


Phospholipid and fatty acid compositions of Rhizobium leguminosarum biovar trifolii ANU843 in relation to flavone-activated pSym nod gene expression.
The phospholipid and associated fatty acid compositions of the bacterial symbiont of clover, Rhizobium leguminosarum biovar trifolii wild-type ANU843, was analyzed by two-dimensional silica thin-layer chromatography, fast atom bombardment-mass spectrometry, flame-ionization detection gas-liquid chromatography and combined gas-liquid chromatography/mass spectrometry. The phospholipid composition included phosphatidylethanolamine (15%), N-methylphosphatidylethanolamine (47%), N,N-dimethylphosphatidylethanolamine (9%), phosphatidylglycerol (19%), cardiolipin (5%) and phosphatidylcholine (2%). Fatty acid composition included predominantly cis-11-octadecenoic acid, lower levels of cis-9-hexadecenoic acid, hexadecanoic acid, 11-methyl-11-octadecenoic acid, octadecanoic acid, 11,12-methyleneoctadecanoic acid, eicosanoic acid and traces of branched, and di- and triunsaturated fatty acids. The influence of expression of the "nodulation" genes encoding symbiotic functions on the composition of these membrane lipids was examined in wild-type cells grown with or without the flavone inducer, 4',7-dihydroxyflavone and in mutated cells lacking the entire symbiotic plasmid where these genes reside, or containing single transposon insertions in selected nodulation genes. No significant changes in phospholipid or associated fatty acid compositions were detected by the above methods of analysis.


Use of computerized interview scheduling program for pediatric surgery match applicants.
Pediatric surgery fellowship applicants and programs coordinate over 20 interviews per cycle. We hypothesized that replacing e-mail and phone communication with a computerized-scheduling program (CSP) could benefit both parties. We used a CSP to schedule 2016 interviews. Time to schedule and e-mail communication per applicant was compared to 2015, when traditional scheduling was used. Additionally, 2016 interviewees were surveyed about their experience with the CSP vs. traditional means. Analysis was performed using descriptive statistics and a Student's T-test. We found a significant decrease in mean scheduling time from 14.4 to 1.7h (p<0.001) and in e-mails exchanged from 3.4 to 1.0 (p<0.0001). Survey respondents reported 92% satisfaction with the CSP, and 87% found it easier to schedule interviews. Applicants also reported quicker finalization of interview dates (96%), improved access to interview slots (71%), and easier coordination of additional services and time off (63%). Notably, the mean longest time reported to schedule interviews using traditional methods was 7days (range 1-30). Overall, 84% supported widespread adoption of CSPs. Using CSPs improved the scheduling process for the significant majority of interviewees, and our program. If widely adopted, this could greatly improve the efficiency of pediatric surgery interview scheduling. N/A.


Apoptotic cell death following exposure to fluoride in rat alveolar macrophages.
Since inhaled fluoride is implicated in the acute respiratory failure, cytotoxic effects of fluoride on alveolar macrophages, primary target cells of inhaled toxicants, were investigated. The LC50 of sodium fluoride was estimated to be 0.41 mM, while 1 mM sodium chloride, bromide and iodide had virtually no effects on the viability of alveolar macrophages. Photomicroscopic observation revealed that nuclei of the fluoride-exposed alveolar macrophages were fragmented. The ladder formation was observed when DNA isolated from fluoride-exposed alveolar macrophages was electrophoresed in agarose gel. These results suggest that cytotoxicity of fluoride is associated with apoptosis in rat alveolar macrophages.


Synthetic genomics and the construction of a synthetic bacterial cell.
The first synthetic cellular organism was created in 2010 and based on a very small, very simple bacterium called Mycoplasma mycoides. The bacterium was called synthetic because its DNA genome was chemically synthesized rather than replicated from an existing template DNA, as occurs in all other known cellular life on Earth. The experiment was undertaken in order to develop a system that would allow creation of a minimal bacterial cell that could lead to a better understand of the first principles of cellular life. The effort resulted in new synthetic genomics techniques called genome assembly and genome transplantation. The ability of scientists to design and build bacteria opens new possibilities for creating microbes to solve human problems.


Median nerve entrapment. Pronator teres syndrome. Surgical anatomy and correlation with symptom patterns.
The surgical anatomy of interest in the pronator teres syndrome was studied to shed light on the ramifying pattern of the median nerve, the number of its muscular branches and their branching levels and to pinpoint the location of the fibrous bands which may cause median nerve entrapment. The fibrous arch of the pronator teres muscle (pronator arch) was found to lie 3 cm to 7.5 cm below Hueter's line, that of the flexor digitorum superficialis muscle (superficialis arch), which is distal to the pronator arch, was found to lie 6.5 cm below Hueter's line in its most proximal position. Symptom patterns in terms of muscle weakness caused by median nerve entrapment at different levels were also evaluated.


Rapidly sintering of interconnected porous Ti-HA biocomposite with high strength and enhanced bioactivity.
In this work, interconnected porous Ti-HA biocomposites with enhanced bioactivity, high porosity and compressive strength were prepared by spark plasma sintering (SPS) and space holder method. Pore characteristics, mechanical properties, corrosion behaviors and in vitro bioactivity of the porous Ti-HA were investigated. Results showed that porous Ti-HA with 5-30wt% HA contents possessed not only low elastic modulus of 8.2-15.8GPa (close to that of human bone) but also high compressive strength (86-388MPa). Although the HA partially decomposed and formed secondary phases, the sintered porous Ti-HA can still be good bioactivity. The homogeneity and the thickness of apatite layer increased significantly with the increase of HA. But with the thickness of apatite layer increased, micro-cracks appeared on the surface of porous Ti-30%HA. A model was built to discuss the current distribution and sintering mechanism of HA on Ti matrix during SPS process. It indicated that the excessive addition of HA would deteriorate the sintering quality, thus decreasing the mechanical properties and corrosion resistance. However, the combination of interconnected pore characteristics, low elastic modulus, high compressive strength and enhanced bioactivity might make porous Ti-HA biocomposites prepared by SPS a promising candidate for hard tissue implants.


High-fat diet in mice led to increased severity of spermatogenesis impairment by lead exposure: perspective from gut microbiota and the efficacy of probiotics.
The mechanism of multifactorial spermatogenesis impairment is unclear. This study aimed to investigate the reproductive toxicity of lead (Pb) in mice fed a high-fat diet (HFD) and to delineate the important role of gut microbiota. Results showed that, compared with mice fed a normal diet (ND), Pb exposure caused more severe spermatogenesis impairment in HFD-fed mice, including decreased sperm count and motility, seminiferous tubule injury, serum and intratesticular testosterone decline, and downregulated expression level of spermatogenesis-related genes. Besides, 16S sequencing indicated that HFD-fed mice had increased severity of gut microbiota dysbiosis by Pb exposure compared to ND-fed mice. With fecal microbiota transplantation, the same trend of spermatogenesis impairment occurred in recipient mice, which confirmed the important role of gut microbiota. Moreover, probiotics supplementation restored the gut microbial ecosystem, and thus improved spermatogenic function. Our work suggested that a population with HFD might face more reproductive health risks upon Pb exposure, and revealed an intimate linkage between microbiota dysbiosis and spermatogenesis impairment, accompanied by the potential usefulness of probiotics as prophylactic and therapeutic. © 2022 Society of Chemical Industry.


The role of childhood BMI in predicting early adulthood dysglycemia: Tehran lipid and glucose study.
Increased adiposity is associated with insulin resistance and glycemic disturbances. We aimed to determine whether childhood overweight or obesity are independent factors in predicting adulthood dysglycemia (prediabetes or type 2 diabetes). In this population-based cohort study, 1290 normoglycemic subjects aged 3-11 years were followed for incidence of dysglycemia. Cox-proportional hazard models were employed to evaluate the association of obesity and overweight with incidence of dysglycemia by adjustments for age, sex, parental risk factors and baseline individual risk factors. The participants, with a mean age of 7.7 ± 2.5 years, were followed for a median of 14.9 years. During follow up, 158 subjects developed dysglycemia (18 type 2 diabetes, 140 prediabetes), contributing to a total cumulative incidence of 24.7%. The unadjusted HR for developing adult dysglycemia were 1.6 (95% CI; 1.0-2.4) and 1.7 (95% CI; 1.0-3.0) in overweight and obese children, respectively. Further adjustments for age, sex, parental risk factors and baseline individual risk factors changed the results in both overweight and obese children. These findings show that overweight or obesity in childhood have no independent role for developing adulthood dysglycemia.


Malnutrition in Community-Dwelling Elderly in Turkey: A Multicenter, Cross-Sectional Study.
This study aimed to investigate the prevalence of malnutrition and explore the somatic, psychological, functional, and social or lifestyle characteristics linked to malnutrition in elderly people at a hospital in Turkey. This study included 1030 patients older than 65 years of age who were seen at the internal medicine and geriatrics outpatient clinics of the study centers in Istanbul, Ankara, Duzce, Corum, Mardin, Malatya, and Diyarbakir provinces between January and December 2014. All patients underwent Mini Nutritional Assessment (MNA) and Geriatric Depression Scale (GDS) tests via one-on-one interview method. The demographic properties of the patients were also recorded during this interview. Among 1030 patients included in this study, 196 (19%) had malnutrition and 300 (29.1%) had malnutrition risk. The malnutrition group and the other groups were significantly different with respect to mean GDS score, income status, educational status, the number of children, functional status (ADL, IADL), the number of patients with depression, and the number of comorbid disorders. According to the results of the logistic regression analysis, age (OR=95% CI: 1.007-1.056; p=0.012), BMI (OR=95% CI: 0.702-0.796; p<0.001), educational status (OR=95% CI: 0.359-0.897; p=0.015), comorbidity (OR=95% CI: 2.296-5.448; p<0.001), and depression score (OR=95% CI: 1.104-3.051; p=0.02) were independently associated with malnutrition. Our study demonstrates that age, depression, BMI, comorbidity, and the educational status were independently associated with malnutrition in an elderly population.


Decomposition of CO2 emission intensity in Chinese MIs through a development mode extended LMDI method combined with a production-theoretical approach.
An improved understanding of the influence of development mode on carbon intensity (CI) can aid China's manufacturing industries (MIs) to reduce CI without affecting the development of Chinese MIs. To demonstrate the relationship between the development mode and CI well, this work provides the following contributions: (a) The driving factors of Chinese MIs' CI are decomposed by a development mode extended Logarithmic Mean Divisia Index method (LMDI)); (b) The impact of the factors of industrial development mode is analyzed by comprehensively by the extended LMDI combined with production -theoretical decomposition analysis (PDA). (c) The disparities of the driving factors in different industrial classifications are evaluated by applying the development mode extended LMDI combined with PDA in Chinese MIs between 2000 and 2015. Results showed that, (1) at the entire MIs' level, the effects of ratio of energy consumption to R&D (RI) and potential carbon intensity (PCI) were the two leading contributors to the CI decline in Chinese MIs. (2) In terms of the cumulative effects at the subsectoral level, PCI had the largest curbing effect on the CI of all subsectors, and investment intensity (II) had the greatest stimulating effect on the CI of all subsectors. (3) Among the three industrial classifications, the middle-end MIs experienced the largest carbon intensity decline from the 10th Five-Year Plan (FYP) to the 12th FYP, followed by the low- and high-end MIs. RI and PCI decreased the CI of Chinese MIs in all industrial classifications and economic development stages. Potential energy efficiency and II were the two major contributors to CI improvement in all industrial classifications and economic development stages.


Four cases of desmosis coli: severe chronic constipation, massive dilatation of the colon, and hypoperistalsis due to of changes in the colonic connective-tissue net.
We present four patients 5, 10, 12, and 17 years of age, each with a long history of severe constipation and hypoperistalsis of the gut. Three had partial or total resection of the colon, all had enterostomies, and only one maintains normal bowel function after reanastomosis. We report the clinical courses, radiologic findings, and operative procedures for all four cases. Preoperative full-thickness biopsies and the resected colon specimens revealed a complete or incomplete lack of the mesh network of collagen. The connective-tissue layer between the circular and longitudinal muscles was missing. Contrary to expectations, the enteric nervous system (ENS) was normal or near-normal in the affected areas. Hypo- and dysganglionosis was found additionally in some proximal segments of colon and/or small bowel. This combination of clinical symptoms and pathological findings is called desmosis of the colon with reference to a working hypothesis in a preliminary report by Meier-Ruge in 1998. Aplastic or hypoplastic desmosis may be the reason for the disturbed gut motility. Histologic examination should thus not only exclude changes of the ENS.


Early-Life Effects of Vitamin D: A Focus on Pregnancy and Lactation.
Vitamin D is an endocrine regulator of calcium and bone metabolism. Yet, its effects include other systems, such as innate and adaptive immunity. Unique to pregnancy, circulating 1,25-dihydroxyvitamin D (1,25[OH]2D) increases early on to concentrations that are 2-3 times prepregnant values. At no other time during the lifecycle is the conversion of 25-hydroxyvitamin D (25[OH]D) to 1,25(OH)2D directly related and optimized at ≥100 nmol/L. Vitamin D deficiency appears to affect pregnancy outcomes, yet randomized controlled trials of vitamin D supplementation achieve mixed results depending on when supplementation is initiated during pregnancy, the dose and dosing interval, and the degree of deficiency at the onset of pregnancy. Analysis of trials on an intention-to-treat basis as opposed to the use of 25(OH)D as the intermediary biomarker of vitamin D metabolism yields differing results, with treatment effects often noted only in the most deficient women. Immediately after delivery, maternal circulating 1,25(OH)2D concentrations return to prepregnancy baseline, at a time when a breastfeeding woman has increased demands of calcium, beyond what was needed during the last trimester of pregnancy, making one question why 1,25(OH)2D increases so significantly during pregnancy. Is it to serve as an immune modulator? The vitamin D content of mother's milk is directly related to maternal vitamin D status, and if a woman was deficient during pregnancy, her milk will be deficient unless she is taking higher doses of vitamin D. Because of this relative "deficiency," there is a recommendation that all breastfed infants receive 400 IU vitamin D3/day starting a few days after birth. The alternative - maternal supplementation with 6,400 IU vitamin D3/day, effective in safely raising maternal circulating vitamin D, that of her breast milk, and effective in achieving sufficiency in her recipient breastfeeding infant - remains a viable option. Additional research is needed to understand vitamin D's influence on pregnancy health and the effect of maternal supplementation on breast milk's immune signaling.


Nine differentially expressed genes from a post mortem study and their association with suicidal status in a sample of suicide completers, attempters and controls.
Several lines of evidence indicate that suicidal behaviour is partly heritable, with multiple genes implicated in its aetiology. We focused on nine genes (S100A13, EFEMP1, PCDHB5, PDGFRB, CDCA7L, SCN2B, PTPRR, MLC1 and ZFP36) which we previously detected as differentially expressed in the cortex of suicide victims compared to controls. We investigated 84 variants within these genes in 495 suicidal subjects (299 completers and 196 attempters) and 1513 controls (109 post-mortem and 1404 healthy). We evaluated associations with: 1) suicidal phenotype; 2) possible endophenotypes for suicidal behaviour. Overall positive results did not survive the correction threshold. However, we found a nominally different distribution of EFEMP1 genotypes, alleles and haplotypes between suicidal subjects and controls, results that were partially replicated when we separately considered the subgroup of suicide completers and post-mortem controls. A weaker association emerged also for PTPRR. Both EFEMP1 and PTPRR genes were also related to possible endophenotypes for suicidal behaviour such as anger, depression-anxiety and fatigue. Because of the large number of analyses performed and the low significance values further replication are mandatory. Nevertheless, neurotrophic gene variants, in particular EFEMP1 and PTPRR, may have a role in the pathogenesis of suicidal behaviour.


The protein effect in the structure of two ferryl-oxo intermediates at the same oxidation level in the heme copper binuclear center of cytochrome c oxidase.
Identification of the intermediates and determination of their structures in the reduction of dioxygen to water by cytochrome c oxidase (CcO) are particularly important to understanding both O2 activation and proton pumping by the enzyme. In this work, we report the products of the rapid reaction of O2 with the mixed valence form (CuA(2+), heme a(3+), heme a3(2+)-CuB(1+)) of the enzyme. The resonance Raman results show the formation of two ferryl-oxo species with characteristic Fe(IV)=O stretching modes at 790 and 804 cm(-1) at the peroxy oxidation level (PM). Density functional theory calculations show that the protein environment of the proximal H-bonded His-411 determines the strength of the distal Fe(IV)=O bond. In contrast to previous proposals, the PM intermediate is also formed in the reaction of Y167F with O2. These results suggest that in the fully reduced enzyme, the proton pumping ν(Fe(IV)=O) = 804 cm(-1) to ν(Fe(IV)=O) = 790 cm(-1) transition (P→F, where P is peroxy and F is ferryl) is triggered not only by electron transfer from heme a to heme a3 but also by the formation of the H-bonded form of the His-411-Fe(IV)=O conformer in the proximal site of heme a3. The implications of these results with respect to the role of an O=Fe(IV)-His-411-H-bonded form to the ring A propionate of heme a3-Asp-399-H2O site and, thus, to the exit/output proton channel (H2O) pool during the proton pumping P→F transition are discussed. We propose that the environment proximal to the heme a3 controls the spectroscopic properties of the ferryl intermediates in cytochrome oxidases.


Sporadic rapid-onset dystonia-parkinsonism presenting as Parkinson's disease.
We report on a 38-year-old patient with rapid-onset dystonia-parkinsonism (RDP) with a missense mutation in the Na/K-ATPase alpha3 subunit (ATP1A3). Asymmetrical parkinsonian symptoms evolved over a year. After a stable episode of another 2.5 years, overnight he developed oromandibular dystonia and more severe parkinsonian symptoms. We conclude that RDP should be considered as a rare cause of levodopa-unresponsive parkinsonism even if there is no family history and the classic presentation is lacking.


Evaluating the appropriateness of care: a study of cesarean section rates.
The Maryland Hospital Associations Quality Indicator Project was initiated in 1987 to evaluate ten inpatient care outcome indicators. One of these indicators, cesarean sections, has been a primary focus of the project's efforts thus far. Data on 270 C-sections performed in six Maryland hospitals were gathered and analyzed by a committee that included expert clinicians and representatives from medical societies. A protocol for C-sections was then developed listing the elements that required documentation in the records of patients having C-sections. For monitoring purposes, the protocol was converted into a data collection and evaluation form that was subsequently tested for its validity and practical value. The pilot test showed that the form was a viable tool for collecting information and that the direction and magnitude of association between data elements was as expected.


Influence of cicloxilic acid on energy production by hepatocyte mitochondria during acute ethanol intoxication.
Liver mitochondria from acute ethanol intoxicated rats show a highly significant uncoupling of oxidative phosphorylation. cis-2-Hydroxy-2-phenyl-cyclohexanecarboxylic acid (cicloxilic acid) early normalizes the P/O ratio and, therefore, the mitochondrial energy producing mechanisms. The significance of these phenomena and the possible role of cicloxilic acid on mitochondrial energy-production are discussed.


Granulocytic sarcoma - a rare presentation of a breast lump.
This report describes a woman who presented with a breast lump, which was initially misdiagnosed as lymphoma, but later turned out to be granulocytic sarcoma of the breast.


Dupilumab Treatment of Atopic Dermatitis in Routine Clinical Care: Baseline Characteristics of Patients in the PROLEAD Prospective, Observational Study.
Dupilumab is the first biologic licensed to treat patients with moderate-to-severe atopic dermatitis (AD) who require systemic therapy. PROLEAD was designed to document the real-world effectiveness and safety of dupilumab in patients with moderate-to-severe AD. The present study aims to describe the baseline characteristics of patients treated with dupilumab in Germany. PROLEAD is a national, multicentre, prospective, non-interventional study, with a 2-year observation period. Adults with moderate-to-severe AD treated with dupilumab were included. Baseline characteristics, physician assessments, and patient-reported outcomes (PROs) were collected. The study involved 126 sites throughout Germany. Of 839 patients assessed for eligibility, 828 were included, with baseline data available for 817 patients. Mean (standard deviation, SD) age of patients was 43.4 (15.8) years, with 396 (48.5%) patients being female. Overall, 66.6% of patients received their first diagnosis of AD during childhood. In total, 423 (51.8%) patients had co-existing atopic and type 2 inflammatory diseases, including allergic conjunctivitis (36.8%) and bronchial asthma (22.5%). Overall, 61.4% of patients had received systemic therapy, most commonly oral corticosteroids (49.9%). Approximately half of patients (51.3%) had received UV/phototherapy prior to baseline. Treatment with moderate-potent (Class 2) or potent (Class 3) topical corticosteroids was the most common concomitant treatment at baseline. However, 50.4% of patients had not received concomitant AD treatment with dupilumab at baseline. The most reported reason for initiating dupilumab was "Topical therapy alone was not sufficient" (95.1%). Mean (SD) physician assessments: EASI: 22.9 (14.5); SCORAD: 63.3 (16.2); IGA: 3.3 (0.7). Mean (SD) PROs: DLQI: 13.9 (7.1); peak pruritus NRS: 7.4 (2.3). Patients with moderate-to-severe AD present a long medical history, impaired quality of life, and high prevalence of co-existing type 2 inflammatory diseases. Dupilumab was used as a first-line systemic treatment in 38.6% of patients.


Construction of a 3D model of oligopeptidase B, a potential processing enzyme in prokaryotes.
A three dimensional structural model of oligopeptidase B (OpB) was constructed by homology modeling. High resolution X-ray structure of prolyl oligopeptidase (PEP), the only protein with sequential and functional homology was used as a template. Initial models of OpB were built by the MODELLER and were analysed by the PROCHECK programs. The best quality model was chosen for further refinement by two different techniques--either constrained molecular dynamics simulations or simulated annealing calculations starting from 500 K. The overall quality of each of the refined models was evaluated and the simulated annealing procedure found to be more effective. The refined model was analysed by different protein analysis programs including PROCHECK for the evaluation of the Ramachandran plot quality, PROSA for testing interaction energies and WHATIF for the calculation of packing quality. This structure was found to be satisfactory and also stable at room temperature as demonstrated by a 300 ps long unconstrained molecular dynamics simulation. Calculation of molecular electrostatic potentials revealed that the binding site of OpB is more negative than that of PEP, in accordance with the experimentally observed selectivity of OpB towards proteolysis at dibasic sites. A recently developed Monte Carlo docking method was used provide a structural rationale for the affinity differences measured between Z-Arg and Z-Arg-Arg substrates.


The effect of 5-fluorouracil and adriamycin on heterotransplantation of Noble rat prostatic tumors in congenitally athymic (nude) mice.
The Nb rat prostatic adenocarcinoma is a well-characterized, hormonally induced family of tumors that are all readily transplantable into congenitally athymic (nude) mice. Because of this versatile heterotransplantation model, multiple replicate copies of individual tumors can be studied "in rodent." We have extended this by studying the chemotherapeutic response of such tumors and believe that this provides a useful avenue for evaluation of cytotoxic agents. Indeed, this combination of both animal model systems may provide a useful experimental tool to evaluate tumor growth, histopathologic changes and responsiveness to appropriate therapy. We report herein that two Nb rat prostatic carcinomas (2 Pr-129-D-11A and Pr-90) and thie responsiveness to Adriamycin and 5-fluorouracil are objective by studying both growth rates and tumor histology.


Adhesion molecules and matrix metalloproteinases in Multiple Sclerosis: effects induced by Interferon-beta.
In Multiple Sclerosis (MS) pathology, early inflammation involves leukocyte migration across the blood-brain barrier (BBB) within the central nervous system. In this process, adhesion molecules (AMs), both membrane-bound and soluble-circulating forms, and matrix metalloproteinases (MMPs) certainly play a regulatory role. In MS, recombinant Interferon-beta (rIFNbeta) is effective in reducing gadolinium contrast-enhancing lesions on magnetic resonance imaging and this suggests that it may reduce BBB damage or even restore its integrity by different mechanisms that include interference with both AM and MMP pathways. This review will highlight the effects induced by rIFNbeta, both in vitro and in vivo, on cell-bound and soluble forms of AMs and on MMPs.


Ghrelin accelerates the healing of cysteamine-induced duodenal ulcers in rats.
Previous studies have shown that administration of ghrelin exhibits protective and therapeutic effects in the gut. The aim of the present investigation was to examine the influence of ghrelin administration on the course of cysteamine-induced duodenal ulcers, as well as effects on mucosal production of oxygen free radicals and duodenal antioxidant defense. Duodenal ulcers were induced in male Wistar rats by cysteamine administered intragastrically at the dose of 200 mg/kg in 1 ml of saline, 3 times at 4-h intervals. Starting 24 h after the first dose of cysteamine, rats were treated intraperitoneally twice a day with saline or ghrelin given at the dose of 4, 8 or 16 nmol/kg/dose. Seven days after administration of the first dose of cysteamine, the study was terminated. Induction of ulcers by cysteamine was accompanied by a reduction in duodenal blood flow, mucosal DNA synthesis and mucosal activity of superoxide dismutase (SOD); whereas mucosal concentration of interleukin-1β and malonyldialdehyde (MDA - an index of lipid peroxidation) were increased. Treatment with ghrelin increased healing rate of duodenal ulcers and enhanced duodenal blood flow, mucosal DNA synthesis and mucosal activity of SOD, and reduced mucosal concentration of interleukin-1β and MDA. Treatment with ghrelin increases the healing rate of duodenal ulcers and this effect is related, at least in part, to improvement of duodenal mucosal blood flow, mucosal cell proliferation and antioxidant defense, as well as being related to reduction in mucosal oxidative stress and inflammatory response.


Effect of ethanol on serum electrolytes and osmolality.
Rats and rabbits were injected ethanol 2 g/kg intraperitoneally. One hour after injection blood was analyzed for serum electrolytes and osmolality. Administration of ethanol caused decrease in serum sodium (p less than 0.0005), potassium (p less than 0.0005), calcium (p less than 0.0005), chloride (p less than 0.005), magnesium (p less than 0.0005) in rabbits. Further studies of intraperitoneal administration of ethanol in rats showed decrease in concentration of sodium (p less than 0.025), potassium (p less than 0.025), calcium (p less than 0.01) chloride (p less than 0.005) magnesium (p less than 0.005), phosphorus (p less than 0.025) and glucose (p less than 0.005). Administration of ethanol caused an increase in serum osmolality in both rabbits and rats (p less than 0.005, p less than 0.05). It is concluded that ethanol ingestion is probably the commonest cause of the hyperosmolar state. Although the osmotic and sedative effects of ethanol are pharmacologically unrelated, the presence of ethanol should be considered in comatose patients in whom the measured plasma osmolality appreciably exceeds that predicted on the basis of plasma glucose, urea and electrolytes concentration.


A double-blind study of two dosage regimens of lomefloxacin in bacteriologically proven exacerbations of chronic bronchitis of gram-negative etiology.
Lomefloxacin has been shown to produce high and sustained concentrations in serum and bronchial mucosa after once-daily administration. This study was designed to assess whether a dose response exists for 400 mg lomefloxacin given once daily or twice daily for 10 days in the treatment of acute bacterial exacerbations of chronic bronchitis of gram-negative etiology. A total of 100 adult patients with acute exacerbations of chronic bronchitis were enrolled at 10 study sites in Germany. Patients with confirmed bacterial pathogens in the baseline sputum culture (once-daily group n = 49, twice-daily group n = 47) were eligible for analysis of bacteriologic and clinical efficacy. The eradication rates for the most frequently isolated baseline pathogens, Haemophilus influenzae, Pseudomonas aeruginosa, and Klebsiella pneumoniae, were at least 75% for both treatment regimens. Overall, once-daily treatment eradicated baseline pathogens in 42 of 49 (85.7%) patients, while twice-daily treatment eradicated pathogens in 43 of 47 (91.5%). This difference was not statistically significant (p = 0.226). Clinically, 47 of 49 (95.9%) patients in the once-daily group and 46 of 47 (97.9%) in the twice-daily group were cured or improved (p = 0.307). Both regimens were well tolerated; there were no differences in the incidence (six patients in each group), types, or severity of adverse events, nor was there clinical evidence of theophylline interaction. The results of this study demonstrate that once-daily treatment with 400 mg lomefloxacin is as effective as twice-daily dosing with 400 mg in patients with acute bacterial exacerbations of chronic bronchitis.


Prognostic role of long non-coding RNA HNF1A-AS1 in Chinese cancer patients: a meta-analysis.
Long non-coding RNAs (LncRNAs) play important roles in tumorigenesis and progression. Recent studies have demonstrated that LncRNA HNF1A antisense RNA 1 (HNF1A-AS1) is aberrantly expressed in several types of cancers and is associated with poor outcomes. This meta-analysis was conducted to investigate the relationship between HNF1A-AS1 expression and clinical outcomes in cancer patients. We searched PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), and Wan Fang databases (updated until December 31, 2017) for literature. A total of eight studies with 789 cancer patients were finally included in the present meta-analysis. The results showed that high expression of HNF1A-AS1 significantly predicted poor overall survival (HR=3.10, 95% CI: 1.58-6.11, P=0.001), which was further validated using The Cancer Genome Atlas (TCGA) dataset. Moreover, high HNF1A-AS1 expression was also associated with advanced TNM stage (OR=3.32, 95% CI: 2.28-4.83, P<0.001), lymph node metastasis (OR=3.08, 95% CI: 1.95-4.85, P<0.001), and distant metastasis (OR=5.53, 95% CI: 1.94-15.77, P=0.001). Our results suggested that elevated HNF1A-AS1 was associated with poor clinical outcomes and might serve as a potential prognostic biomarker of cancer.


Enzymatic hydrolysis of green tea seed extract and its activity on 5alpha-reductase inhibition.
Two kaempferol glycosides were isolated from green tea seed extract (GTSE). After conducting a structure analysis, these two compounds were identified as kaempferol-3-O-[2-O-beta-D-galactopyranosyl-6-O-alpha-L-rhamnopyranosyl]-beta-D-glucopyranoside (compound 1) and kaempferol-3-O-[2-O-beta-D-xylopyranosyl-6-O-alpha-L-rhanmopyranosyl]-beta-D-glucopyranoside (compound 2). These two compounds were hydrolysed by o-glycolytic enzymes for the production of kaempferol. After performing several reactions, we found the optimum enzyme combination, a reaction with beta-galactosidase and hesperidinase. Finally, we produced kaempferol of above 95% purity. The 5alpha-reductase inhibition activities of GTSE hydrolysate (GTSE-H) containing kaempferol were evaluated by the contact cell-based metabolic method using a stable HEK 293 cell line. GTSE-H showed a good inhibition effect on HEK 293 cell lines both type 1 and type 2 on 5alpha-reductase. Especially, GTSE-H inhibited type 2 with kaempferol content dependency. The results indicate that the inhibition activity of hydrolysate on 5alpha-reductase type 2 increases in accordance with kaempferol content.