Subcutaneous Implantable Cardioverter-Defibrillators in Patients With Congenital Heart Disease.
Very few data have been published on the use of subcutaneous implantable cardioverter-defibrillators (S-ICDs) in patients with congenital heart disease (CHD). The aim of this study was to analyze outcomes associated with S-ICDs in patients with CHD. This nationwide French cohort including all patients with an S-ICD was initiated in 2020 by the French Institute of Health and Medical Research. Characteristics at implantation and outcomes were analyzed in patients with CHD. From October 12, 2012, to December 31, 2019, among 4,924 patients receiving an S-ICD implant in 150 centers, 101 (2.1%) had CHD. Tetralogy of Fallot, univentricular heart, and dextro-transposition of the great arteries represented almost one-half of the population. Patients with CHD were significantly younger (age 37.1 ± 15.4 years vs 50.1 ± 14.9 years; P < 0.001), more frequently female (37.6% vs 23.0%; P < 0.001), more likely to receive an S-ICD for secondary prevention (72.3% vs 35.9%; P < 0.001), and less likely to have severe systolic dysfunction of the systemic ventricle (28.1% vs 53.1%; P < 0.001). Over a mean follow-up period of 1.9 years, 16 (15.8%) patients with CHD received at least 1 appropriate shock, with all shocks successfully terminating the ventricular arrhythmia. The crude risk of appropriate S-ICD shock was twice as high in patients with CHD compared with non-CHD patients (annual incidences of 9.0% vs 4.4%; HR: 2.1; 95% CI: 1.3-3.4); however, this association was no longer significant after propensity matching (especially considering S-ICD indication, P = 0.12). The burden of all complications (HR: 1.2; 95% CI: 0.7-2.1; P = 0.4) and inappropriate shocks (HR: 0.9; 95% CI: 0.4-2.0; P = 0.9) was comparable in both groups. In this nationwide study, patients with CHD represented 2% of all S-ICD implantations. Our findings emphasize the effectiveness and safety of S-ICD in this particularly high-risk population. (S-ICD French Cohort Study [HONEST]; NCT05302115).


A novel nomogram for predicting extraurothelial recurrence in patients with upper urinary tract urothelial carcinoma after radical nephroureterectomy.
We aimed to establish and validate a nomogram for extraurothelial recurrence (EUR) after radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). The data of 521 patients with UTUC after RNU from 2 medical centers were retrospectively studied and were used as training cohort (n = 301) and external validation cohort (n = 220). We used the least absolute shrinkage and selection operator (LASSO) to select variables for multivariable Cox regression, and included independent risk factors into nomogram models predicting EUR-free survival (EURFS). Multiple parameters were used to validate the nomogram, including the concordance index (C-index), the calibration plots, the time-dependent receiver-operator characteristics curve (ROC), and the decision curve analysis (DCA). Patients were stratified into three risk groups according to total points calculated by nomograms. The differences of EURFS in each group were analyzed by the Kaplan-Meier analysis. Four variables were screened through LASSO regression. Bladder cancer history, Ki-67, lymphovascular invasion (LVI), and pathological T stage were shown to be independent predictive factors for EUR. The C-indexes of the model were 0.793 and 0.793 in training and validation cohorts, respectively. In comparison with prediction based on categorized pathological T stage, the DCA curves for 5-year EUR exhibited better performance. The 5-year EURFS rates were 92.2%, 63.8%, and 36.2% in patients stratified to the low-, medium-, and high-risk group. Our study provided a new nomogram to predict the probability of EUR in UTUC patients underwent RNU, with perfect performance in discrimination ability and clinical net benefit. The application of the model may help urologists to choose proper treatment and monitoring.


Impact of Cold-Water Immersion Compared with Passive Recovery Following a Single Bout of Strenuous Exercise on Athletic Performance in Physically Active Participants: A Systematic Review with Meta-analysis and Meta-regression.
Studies investigating the effects of cold-water immersion (CWI) on the recovery of athletic performance, perceptual measures and creatine kinase (CK) have reported mixed results in physically active populations. The purpose of this systematic review was to investigate the effects of CWI on recovery of athletic performance, perceptual measures and CK following an acute bout of exercise in physically active populations. Systematic review with meta-analysis and meta-regression. A systematic search was conducted in September 2021 using Medline, SPORTDiscus, Scopus, Web of Science, Cochrane Library, EmCare and Embase databases. Studies were included if they were peer reviewed and published in English, included participants who were involved in sport or deemed physically active, compared CWI with passive recovery methods following an acute bout of strenuous exercise and included athletic performance, athlete perception and CK outcome measures. Studies were divided into two strenuous exercise subgroups: eccentric exercise and high-intensity exercise. Random effects meta-analyses were used to determine standardised mean differences (SMD) with 95% confidence intervals. Meta-regression analyses were completed with water temperature and exposure durations as continuous moderator variables. Fifty-two studies were included in the meta-analyses. CWI improved the recovery of muscular power 24 h after eccentric exercise (SMD 0.34 [95% CI 0.06-0.62]) and after high-intensity exercise (SMD 0.22 [95% CI 0.004-0.43]), and reduced serum CK (SMD - 0.85 [95% CI - 1.61 to - 0.08]) 24 h after high-intensity exercise. CWI also improved muscle soreness (SMD - 0.89 [95% CI - 1.48 to - 0.29]) and perceived feelings of recovery (SMD 0.66 [95% CI 0.29-1.03]) 24 h after high-intensity exercise. There was no significant influence on the recovery of strength performance following either eccentric or high-intensity exercise. Meta-regression indicated that shorter time and lower temperatures were related to the largest beneficial effects on serum CK (duration and temperature dose effects) and endurance performance (duration dose effects only) after high-intensity exercise. CWI was an effective recovery tool after high-intensity exercise, with positive outcomes occurring for muscular power, muscle soreness, CK, and perceived recovery 24 h after exercise. However, after eccentric exercise, CWI was only effective for positively influencing muscular power 24 h after exercise. Dose-response relationships emerged for positively influencing endurance performance and reducing serum CK, indicating that shorter durations and lower temperatures may improve the efficacy of CWI if used after high-intensity exercise. Emma Moore is supported by a Research Training Program (Domestic) Scholarship from the Australian Commonwealth Department of Education and Training. Open Science Framework: 10.17605/OSF.IO/SRB9D.


Two new species of the genus Xizicus (Orthoptera: Tettigoniidae: Meconematinae) in China.
Two new species of the genus Xizicus are described, namely Xizicus (Eoxizicus) uncicercus Mao & Shi sp. nov. and Xizicus (Eoxizicus) dischidus Di, Han & Shi sp. nov. from China, in addition, photographs of morphological structure of the species are provided. All type specimens are deposited in the Museum of Hebei University, Baoding, P. R. China.


Relationship Between Patient Position and Pain Severity During Shock Wave Lithotripsy for Renal Stones With the MODULITH SLX-F2 Lithotripter: A Matched Case-Control Study.
We evaluated the association between shock wave lithotripsy (SWL)-related pain and patient positioning during SWL. We retrospectively reviewed the medical records of 162 patients who underwent their first SWL session for single renal stones from May 2010 to August 2011. One hundred thirteen patients underwent SWL in the supine position and 49 did so in the lateral position. To evaluate an unbiased estimation of the positional effect on pain severity during SWL, both groups (supine vs. lateral) were matched according to sex, age, body mass index, stone location, and stone size. Thirty-four patients from each group were selected for analysis. Pain was evaluated with an average visual analogue scale (VAS-avg) and maximum visual analogue scale (VAS-max). Analgesic usage was also compared between the groups. All patients (n=34) in the supine group had radio-opaque stones compared with only 47.1% of the patients in the lateral group (n=16). The VAS-avg and VAS-max of the lateral group were significantly lower than those of the supine group (1.2±1.0 and 3.1±1.7 for VAS-avg and 2.5±1.8 and 4.7±1.9 for VAS-max, respectively, p<0.05). However, analgesic usage between groups did not differ significantly (17.6% in the supine group vs. 5.9% in the lateral group, p=0.259). In a subgroup analysis confined to patients with radio-opaque stones, the supine group still suffered more pain. Patients with renal stones suffered more SWL-related pain in the supine position than in the lateral position. During SWL, positioning of patients should be considered a predictive factor for SWL-related pain.


At least three different RNA polymerase holoenzymes direct transcription of the agarase gene (dagA) of Streptomyces coelicolor A3(2).
Using a combination of gel filtration and anion exchange FPLC, three different RNA polymerase holoenzymes from Streptomyces coelicolor A3(2) have been separated. Each holoenzyme transcribes from only one of the four promoters of the S. coelicolor A3(2) dagA gene. Holoenzyme reconstitution experiments identified the sigma factors responsible for recognition of two of the promoters. The previously identified E sigma 49 transcribes from the dagA p3 promoter, whereas a novel species, E sigma 28, recognizes the dagA p2 promoter. Circumstantial evidence suggests that the third holoenzyme, which transcribes from the dagA p4 promoter, is the previously identified E sigma 35. This level of transcriptional complexity supports the idea that RNA polymerase heterogeneity may play a central role in the regulation and coordination of gene expression in this biochemically and morphologically complex bacterium.


Association of Diabetes Mellitus and Cholangiocarcinoma: Update of Evidence and the Effects of Antidiabetic Medication.
Diabetes mellitus (DM) is a risk factor for cancer in many organs and associated with an increased risk of cholangiocarcinoma (CCA). The molecular linkage between these diseases has been demonstrated in preclinical studies, which have highlighted the role of hyperinsulinemia and hyperglycemia in the carcinogenesis and progression of CCA. Recent studies on the emerging role of antidiabetic medication in the development and progression of CCA showed a subclass of antidiabetic drug with a therapeutic effect on CCA. Although associations between CCA, insulin analogues and sulfonylureas are unclear, incretin-based therapy is likely associated with an increased risk for CCA, and may lead to CCA progression, as demonstrated by in vitro and in vivo experiments. In contrast, biguanides, especially metformin, exert an opposite effect, associated with a reduced risk of CCA and inhibited in vitro and in vivo CCA progression. The association between incretin-based therapy and the risk of CCA needs further clarification, as metformin is being studied in an ongoing clinical trial. Understanding the association between DM and CCA is critical for preventing the development of CCA in patients with DM, and for establishing the appropriateness of antidiabetic medication to treat CCA. Determining how metformin affects CCA can lead to repurposing this safe and well-known drug for improving CCA treatment, regardless of the diabetes status of patients.


Cotreatment with human growth hormone and gonadotropins for induction of ovulation: a controlled clinical trial.
A randomized, double-blind, placebo-controlled trial of cotreatment with biosynthetic, human sequence, growth hormone (GH), and human menopausal gonadotropins (hMG) for induction of ovulation was performed in 16 women with amenorrhea and anovulatory infertility. Patients were randomly allocated to treatment with hMG + GH (24 IU on alternate days, total dose 144 IU) or hMG + placebo. Those who received placebo were given GH in a subsequent course of treatment. On cotreatment with GH compared with placebo, there was a significant reduction in the required dose of hMG, duration of treatment, and the daily effective dose of gonadotropins. Serum insulin-like growth factor-I (IGF-I) rose during treatment with GH but not with placebo. We conclude that growth hormone augments the response of the human ovary to stimulation by gonadotropins. These results suggest a role for the use of GH in induction of ovulation.


Leishmania infantum expresses a mitochondrial nuclease homologous to EndoG that migrates to the nucleus in response to an apoptotic stimulus.
It is increasingly accepted that single-celled organisms, such as Leishmania parasites, are able to undergo a cell death process that resembles apoptosis in metazoans and is induced by a variety of stimuli. However, the molecular mechanisms that participate and regulate this death process are still very poorly described, and very few of the participating molecules have been identified. Because DNA degradation is probably the most frequently characterized event during programmed cell death in Leishmania parasites, we have focused on identifying a candidate nuclease responsible for this effect during the cell death process. The results presented herein demonstrate that Leishmania infantum promastigotes express a nuclease similar to the endonuclease G of higher eukaryotes which, according to its predicted structure, belongs to the beta beta alpha metal superfamily of nucleases. Its cation dependence resembles that of the EndoGs present in other organisms and, similarly to them, it is inhibited by moderate concentrations of K+ or Na+. L. infantum EndoG contains a signal peptide that causes its translocation to the mitochondrion where it is maintained under normal growth conditions. However, under the pressure of a death stimulus such as edelfosine treatment, L. infantum EndoG is released from the single mitochondrion and translocates to the nucleus, where it is thought to participate in the process of DNA degradation that is associated with programmed cell death. Our results also demonstrate that overexpression of the nuclease in edelfosine-treated promastigotes causes a significant increase in the percentage of TUNEL-positive parasites.


Molecular targeted therapy and immunotherapy in advanced hepatocellular carcinoma: a systematic review and Bayesian network meta-analysis based on randomized controlled trials.
The aim of this study was to compare and rank different targeted therapies or immunotherapies for advanced hepatocellular carcinoma based on efficacy. A systematic search of the PubMed, EMBASE, and Cochrane Library databases was conducted. All systematic treatment regimens that reported comparisons with sorafenib were included in this analysis. The primary outcome measures were overall survival (OS) and progression-free survival (PFS), and other outcome measures included the objective response rate (ORR) and safety analysis according to reported treatment-related adverse events. A total of 29 RCTs involving 13376 patients were included in the analysis, including 10 single-agent therapies and 17 combination therapies. Compared with sorafenib, sintilimab plus IBI305 (HR: 0.57, 95% CI: 0.43-0.75), camrelizumab plus rivoceranib (HR: 0.62, 95% CI: 0.49-0.78), and atezolizumab plus bevacizumab (HR: 0.66, 95% CI: 0.52-0.83) ranked in the top three in terms of OS. PD-1/PD-L1 inhibitors combined with anti-vascular endothelial growth factor (anti-VEGF)-targeting drugs have shown better therapeutic effects in the systematic treatment of patients with advanced hepatocellular carcinoma, and the combination of targeted and immune therapy modes should be further developed.


Comparison of the transmission potential of two genetically distinct Sindbis viruses after oral infection of Aedes aegypti (Diptera: Culicidae).
Within mosquitoes, arboviruses encounter barriers to infection and dissemination that are critical determinants of vector competence. The molecular mechanisms responsible for these barriers have yet to be elucidated. The prototype Sindbis (SIN) strain, AR339, and viruses derived from this strain, such as TR339 virus, have limited infection and transmission potential in the medically important arthropod vector, Aedes aegypti (L.). However, the Malaysian SIN virus strain, MRE16, disseminates in nearly 100% of Ae. aegypti 14 d after oral infection. Here, we compare the spatial and temporal infection patterns of MRE16 and TR339 viruses in Ae. aegypti. The results indicate that a midgut escape barrier is primarily responsible for the significantly lower dissemination and transmission potentials observed after oral infection with TR339 virus. MRE16 and TR339 viruses now represent a well-characterized model system for the further study of virus determinants of vector infection, particularly determinants affecting the midgut escape barrier in Ae. aegypti.


Evaluation of three neutral capillary coatings for the determination of analyte-cyclodextrin binding constants by affinity capillary electrophoresis. Application to N,N'-disubstituted piperazine derivatives.
The performances of three neutral static coatings (hydroxypropyl cellulose, polyethylene oxide and poly(N,N-dimethylacrylamide) have been evaluated in order to determine the binding constants of the complexes formed between four polycationic compounds (piperazine derivatives) and four cyclodextrins of pharmaceutical interest (β-CD, HP-β-CD, Me-β-CD and sulfobutyl ether-β-CD) by affinity capillary electrophoresis. The physically-adsorbed poly(N,N-dimethylacrylamide) coating proves to be the more efficient to mask the silanol groups of the capillary wall since the lowest electroosmotic flow was measured for this coating. Moreover, it drastically reduces the adsorption of the compounds since it allows a correct repeatability of their migration time, higher efficiencies of the peaks and no baseline shift. Then, it was verified for four complexes that this coating allows a correct determination of the binding constants avoiding the CD adsorption which is responsible of an undervaluation of binding constants. The highest binding constants are obtained using the anionic sulfobutyl ether-β-CD (SBE-β-CD). The structure of the complex formed between the tacrine derivative and the SBE-β-CD was further investigated through 2D ROESY NMR experiments and structure-binding constant relationships. Results suggest that the inclusion in the SBE-β-CD cavity occurs through the aliphatic ring portion of the tacrine moiety.


Assessing the Extended In-Use Stability of the Infliximab Biosimilar PF-06438179/GP1111 Following Preparation for Intravenous Infusion.
PF-06438179/GP1111 (PF-SZ-IFX) is an infliximab biosimilar. We evaluated the extended in-use physicochemical and biological stability of PF-SZ-IFX upon preparation for intravenous infusion. Two batches of PF-SZ-IFX were reconstituted to a concentration of 10 mg/mL and subsequently diluted to 0.4 and 4.0 mg/mL, representing the clinically relevant range for intravenous infusion. Dilution was performed in polyethylene saline infusion bags, which are commonly used in clinical practice. To simulate product handling under worst-case conditions, reconstituted solutions were stored for up to 30 days at 5 ± 3 °C and up to 14 days at 25 ± 2 °C (60 ± 5% relative humidity); diluted solutions were stored for up to 30 days under the same sets of conditions. Physicochemical and biological stability were evaluated according to pH, osmolality, appearance, particulate content, protein concentration, proportions of molecular weight variants and charge variants and potency. Standard and state-of-the-art analytical techniques were employed, including imaged isoelectric focusing, size exclusion chromatography, reducing sodium dodecyl sulphate capillary electrophoresis and functional cell-based bioassay. Across batches and concentrations of PF-SZ-IFX, all parameters resided within the predefined acceptance criteria, including pH, osmolality, particulate content, clarity, protein concentration, molecular weight variants, charge variants and potency, for up to 30 days under both storage conditions tested (up to 14 days for reconstituted samples stored at 25 ± 2 °C). Physicochemical and biological analyses demonstrated that the infliximab biosimilar PF-SZ-IFX was not affected by extended storage of the diluted preparations used for intravenous infusion.


Prognostic value of respiratory parameters for COVID-19 patients in the emergency department: results from the EC-COVID study.
While several studies have evaluated the prognostic weight of respiratory parameters in patients with COVID-19, few have focused on patients' clinical conditions at the first emergency department (ED) assessment. We analyzed a large cohort of ED patients recruited within the EC-COVID study over the year 2020, and assessed the association between key bedside respiratory parameters measured in room air (pO2, pCO2, pH, and respiratory rate [RR]) and hospital mortality, after adjusting for key confounding factors. Analyses were based on a multivariable logistic Generalized Additive Model (GAM). After excluding patients who did not perform a blood gas analysis (BGA) test in room air or with incomplete BGA results, a total of 2458 patients were considered in the analyses. Most patients were hospitalized on ED discharge (72.0%); hospital mortality was 14.3%. Strong, negative associations with hospital mortality emerged for pO2, pCO2 and pH (p-values: < 0.001, < 0.001 and 0.014), while a significant, positive association was observed for RR (p-value < 0.001). Associations were quantified with nonlinear functions, learned from the data. No cross-parameter interaction was significant (all p-values were larger than 0.10), suggesting a progressive, independent effect on the outcome as the value of each parameter departed from normality. Our results collide with the hypothesized existence of patterns of breathing parameters with specific prognostic weight in the early stages of the disease.


MR imaging in clinically suspected acute cholecystitis. A comparison with ultrasonography.
The diagnostic value of fast pulse sequences in MR imaging was compared with US in patients with clinically suspected acute cholecystitis. In a prospective study of 94 patients, 35 were examined with both MR and US within 24 h. MR diagnoses were acute cholecystitis in 23, gallbladder and common bile duct stones in 3, other pathologic conditions of the abdomen in 7 and normal in 2 patients. US diagnoses were acute cholecystitis in 17, gallbladder stones in 8, other pathologic conditions of the abdomen in 2, normal in 5 and non-conclusive in 3 patients. MR has a higher sensitivity than US for diagnosing acute cholecystitis and, with increased accessibility, may be the first imaging method.


The Role of NG2 Proteoglycan in Glioma.
Neuron glia antigen-2 ((NG2), also known as chondroitin sulphate proteoglycan 4, or melanoma-associated chondroitin sulfate proteoglycan) is a type-1 membrane protein expressed by many central nervous system (CNS) cells during development and differentiation and plays a critical role in proliferation and angiogenesis. 'NG2' often references either the protein itself or the highly proliferative and undifferentiated glial cells expressing high levels of NG2 protein. NG2 glia represent the fourth major type of neuroglia in the mammalian nervous system and are classified as oligodendrocyte progenitor cells by virtue of their committed oligodendrocyte generation in developing and adult brain. Here, we discuss NG2 glial cells as well as NG2 protein and its expression and role with regards to CNS neoplasms as well as its potential as a therapeutic target for treating childhood CNS cancers.


Safety of Withholding Perioperative Hydrocortisone for Patients With Pituitary Adenomas With an Intact Hypothalamus-Pituitary-Adrenal Axis: A Randomized Clinical Trial.
Pituitary adenoma is the second most common primary brain tumor. Perioperative hydrocortisone has been used for decades to avoid postoperative adrenal insufficiency. Recent studies suggest that withholding perioperative hydrocortisone may be safe for patients with an intact hypothalamus-pituitary-adrenal (HPA) axis. To assess the safety of withholding hydrocortisone during the perioperative period of pituitary adenoma surgery for patients with an intact HPA axis. A parallel-group, triple-masked, noninferiority randomized clinical trial was conducted at Peking Union Medical College Hospital from November 1, 2020, to January 31, 2022, among 436 patients aged 18 to 70 years with an intact HPA axis undergoing surgery for pituitary adenomas. Hydrocortisone supplementation protocol (intravenous and subsequent oral hydrocortisone, using a taper program) or no-hydrocortisone protocol. The primary outcome was the incidence of new-onset adrenal insufficiency (morning cortisol level, <5 μg/dL with adrenal insufficiency-related symptoms) during the perioperative period (on the day of operation and the following 2 days). The secondary outcome was the incidence of adrenal insufficiency in postoperative month 3. Analysis was on an intention-to-treat basis. Of the 436 eligible patients, 218 were randomly assigned to the hydrocortisone group (136 women [62.4%]; mean [SD] age, 45.4 [13.0] years) and 218 to the no-hydrocortisone group (128 women [58.7%]; mean [SD] age, 44.5 [13.8] years). All patients completed 3-month postoperative follow-up. The incidence of new-onset adrenal insufficiency during the perioperative period was 11.0% (24 of 218; 95% CI, 6.9%-15.2%) in the no-hydrocortisone group and 6.4% (14 of 218; 95% CI, 3.2%-9.7%) in the hydrocortisone group, with a difference of 4.6% (95% CI, -0.7% to 9.9%), meeting the prespecified noninferiority margin of 10 percentage points. The incidence of adrenal insufficiency at the 3-month follow-up was 3.7% (8 of 218) in the no-hydrocortisone group and 3.2% (7 of 218) in the hydrocortisone group (difference, 0.5%; 95% CI, -3.0% to 3.9%). Incidences of new-onset diabetes mellitus (1 of 218 [0.5%] vs 9 of 218 [4.1%]), hypernatremia (9 of 218 [4.1%] vs 21 of 218 [9.6%]), hypokalemia (23 of 218 [10.6%] vs 34 of 218 [15.6%]), and hypocalcemia (6 of 218 [2.8%] vs 19 of 218 [8.7%]) were lower in the no-hydrocortisone group than in the hydrocortisone group. Lower preoperative morning cortisol levels were associated with higher risks of the primary event (<9.3 µg/dL; odds ratio, 3.0; 95% CI, 1.5-5.9) and the secondary event (<8.8 µg/dL; odds ratio, 7.8; 95% CI, 2.6-23.4) events. This study found that withholding hydrocortisone was safe and demonstrated noninferiority to the conventional hydrocortisone supplementation regimen regarding the incidence of new-onset adrenal insufficiency among patients with an intact HPA axis undergoing pituitary adenomectomy. ClinicalTrials.gov Identifier: NCT04621565.


Diametral measurements of the upper spinal cord for stereotactic pain procedures: experimental and clinical study.
Stereotactic percutaneous pain procedures, percutaneous cordotomy, trigeminal tractotomy, and extralemniscal myelotomy are routinely performed with computed tomography (CT) guidance. This new imaging technique enables one to measure the spinal cord diameters for each patient uniquely. Significant differences have been recognized between the measurements obtained with CT and the reference values given for such procedures. To confirm the reliability of CT measurements, two experimental models were used. In the first stage, an artificial neck and spinal cord model was set up and diameters of the spinal cord were remeasured with CT. In the second stage, spinal cord diameters of the upper cervical region on 10 mongrel dogs were initially taken with CT, then standard laminectomy was performed and diameters of the same region were measured under the operating microscope. The experimental studies confirmed that CT measurements of the upper cervical cord are reliable. In clinical application, diametral measurements of the spinal cord at occiput C-1 level were carried out in 30 patients who underwent percutaneous trigeminal tractotomy and extralemniscal myelotomy. The anteroposterior diameter at this level was measured at 7.0-12.8 mm and the transverse diameter ranges between 9.3-14 mm. At the level of C-1-C-2, these measurements were performed over 63 patients who experienced percutaneous cordotomy. In this group the anteroposterior (A-P) diameter was measured as 7.0-11.4 mm, and the transverse diameter as 9.0-14.0 mm. Our clinical experiences and the results of the experimental measurements demonstrate that CT imaging gives accurate diametral values that would favorably influence the surgical procedures, and thus, with CT imaging it is possible to perform main stereotactic destructive pain procedures safely, effectively and selectively.


Species-related differences in the capsaicin-sensitive innervation of the rat and guinea-pig ureter.
1. Comparison of the tissue content of calcitonin gene-related peptide (CGRP)-immunoreactivity (IR) and tachykinin (TK)-IR in the rat and guinea-pig ureter showed that in the rat tissue levels of CGRP-IR were 33-fold higher than those of TK-IR. In the guinea-pig ureter, both peptides were present in nearly the same concentration. 2. The in-vitro release of neuropeptides from guinea-pig and rat ureters was investigated using capsaicin as a stimulus for afferent neurons. Capsaicin induced the simultaneous release of CGRP-IR and TK-IR from the guinea-pig ureter while in the rat only the release of CGRP-IR was detectable. 3. It is known that TK potently stimulate and CGRP inhibits ureteric smooth muscle contractions. When the effect of capsaicin on ureteric motility was investigated in guinea-pig and rat, only in the guinea-pig ureter a stimulatory action ascribable to capsaicin-induced TK release was observed thus supplementing the results obtained by radioimmunoassay. 4. The results show that considerable species differences exist concerning the ratio of CGRP and TK which is stored and released from ureteric afferent nerve terminals. As a consequence, different functional responses are obtained in both species upon stimulation of these neurons by capsaicin. In the rat ureter, the capsaicin-sensitive innervation seems to be only inhibitory while in the guinea-pig stimulatory and inhibitory transmitters are released. The physiological significance of the simultaneous release of transmitters with opposing effects needs further investigation.


mTOR signaling: RAG GTPases transmit the amino acid signal.
mTOR (mammalian target of rapamycin) is a highly conserved nutrient-responsive regulator of cell growth that is found in all eukaryotes. The mechanism by which amino acids signal to mTOR has remained one of the largest outstanding questions in the field. Two recent complimentary studies provide compelling evidence that the Rag family of small GTPases is both necessary and sufficient to transmit a positive signal from amino acids to mTOR.


A comparative study of deep learning-based knowledge-based planning methods for 3D dose distribution prediction of head and neck.
In this paper, we compare four novel knowledge-based planning (KBP) algorithms using deep learning to predict three-dimensional (3D) dose distributions of head and neck plans using the same patients' dataset and quantitative assessment metrics. A dataset of 340 oropharyngeal cancer patients treated with intensity-modulated radiation therapy was used in this study, which represents the AAPM OpenKBP - 2020 Grand Challenge dataset. Four 3D convolutional neural network architectures were built. The models were trained on 64% of the data set and validated on 16% for voxel-wise dose predictions: U-Net, attention U-Net, residual U-Net (Res U-Net), and attention Res U-Net. The trained models were then evaluated for their performance on a test data set (20% of the data) by comparing the predicted dose distributions against the ground-truth using dose statistics and dose-volume indices. The four KBP dose prediction models exhibited promising performance with an averaged mean absolute dose error within the body contour <3 Gy on 68 plans in the test set. The average difference in predicting the D99 index for all targets was 0.92 Gy (p = 0.51) for attention Res U-Net, 0.94 Gy (p = 0.40) for Res U-Net, 2.94 Gy (p = 0.09) for attention U-Net, and 3.51 Gy (p = 0.08) for U-Net. For the OARs, the values for the D m a x ${D_{max}}$ and D m e a n ${D_{mean}}$ indices were 2.72 Gy (p < 0.01) for attention Res U-Net, 2.94 Gy (p < 0.01) for Res U-Net, 1.10 Gy (p < 0.01) for attention U-Net, 0.84 Gy (p < 0.29) for U-Net. All models demonstrated almost comparable performance for voxel-wise dose prediction. KBP models that employ 3D U-Net architecture as a base could be deployed for clinical use to improve cancer patient treatment by creating plans with consistent quality and making the radiotherapy workflow more efficient.


Cardiovascular assessment of fetal mice by in utero echocardiography.
To establish a developmental profile of fetal mouse cardiovascular parameters, we analyzed a large body of ultrasound measurements obtained by in utero echocardiography of C57BL/6J fetal mice from embryonic day 12.5 to 19.5 (term). Measurements were obtained using two-dimensional (2D), spectral Doppler and M-mode imaging with standard clinical cardiac ultrasound imaging planes. As these studies were conducted as part of a large scale mouse mutagenesis screen, stringent filtering criteria were used to eliminate potentially abnormal fetuses. Our analysis showed heart rate increased from 190 to 245 beats per minute as the mouse fetus grew from 8 mm at embryonic day 12.5 to 18.7 mm at term. This was accompanied by increases in peak outflow velocity, E-wave, E/A ratio and ventricular dimensions. In contrast, the A-wave, myocardial performance index and isovolemic contraction time decreased gradually. Systolic function remained remarkably stable at 80% ejection fraction. Analysis of intra- and interobserver variabilities showed these parameters were reproducible, with most comparing favorably to clinical ultrasound measurements in human fetuses. A comprehensive database was generated comprising 23 echocardiographic parameters delineating fetal mouse cardiovascular function from embryonic day 12.5 to term. This database can serve as a standard for evaluating cardiovascular pathophysiology in genetically altered and mutant mouse models.


A homozygous NOTCH3 mutation p.R544C and a heterozygous TREX1 variant p.C99MfsX3 in a family with hereditary small vessel disease of the brain.
Mutations in the TREX1 and NOTCH3 genes cause retinal vasculopathy with cerebral leukodystrophy (RVCL) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), respectively. Both are hereditary small vessel diseases of the brain (HSVDB). We performed mutational analyses of TREX1 in genomic DNA from 39 unrelated patients who were NOTCH3-negative in genetic testing, selected out of 72 unrelated consecutive patients with HSVDB. Only one patient had a TREX1 sequence variation, a heterozygous TREX1 c.294dupA, putatively resulting in a truncated protein, p.C99MfsX3. The medical history of the patient's family was scrutinized, which revealed that heterozygous TREX1 p.C99MfsX3 was not segregating with the HSVDB. Re-examination of the NOTCH3 sequence data of the proband led to the identification of a homozygous NOTCH3 c.1630C>T (p.R544C) mutation, which segregated with the HSVDB in the family. The proband had a slightly more severe phenotype in comparison with her heterozygous p.R544C sister. TREX1 mutation is not a common cause of HSVDB. TREX1 p.C99MfsX3 is not a dominant mutation. Homozygosity of the NOTCH3 p.R544C has a modestly deleterious effect on the CADASIL phenotype. The NOTCH3 mutation may cause CADASIL through a gain-of-toxic function effect, which can be modified by other genetic or environmental factors and results in the phenotypic variation of CADASIL.


Organization of membrane-associated proteins in lipid bilayers.
Lateral organization of proteins in biomembranes is vitally important to membrane functions such as signal transduction, endocytosis, and membrane trafficking. One of the major goals in current biomembrane science is to reveal the microscopic mechanism of membrane-associated protein organization in biomembranes. Here, we investigate the structural organization of membrane-associated proteins in lipid bilayers by combining self-consistent field theory with density functional theory. The present study can simultaneously take into account the entropy effect of lipids, depletion effect of membrane-associated proteins due to the presence of lipid headgroups as well as the effect of interfacial interaction. By varying the volume fraction of lipids, we examine various effects on protein organization, and reveal that a close-packed crystal structure appears at low lipid volume fractions due to interfacial energy and weak depletion effect, whereas a chain structure with branches occurs at high lipid volume fractions mainly due to strong depletion. The present results may provide some theoretical insight into further experiments on organization of membrane proteins.


Nurses' knowledge on assessment and management of cancer therapy-associated oral mucositis.
This study aimed to explore baseline nursing knowledge on assessment and management of patients at risk for developing cancer therapy-associated oral mucositis (OM) at a tertiary hospital in Ghana. A descriptive generic qualitative study design was conducted. The study population were nurses who cared for patients diagnosed with cancer. Participants were recruited using a purposive non-probability sampling technique. Data were obtained through face-to-face interviews using semi-structured interview guide. Data collection and analysis were done concurrently. The study found that nurses had knowledge on the pre-treatment assessment of clients undergoing cancer treatment; however, they had insufficient knowledge on the standardized tool for the assessment of OM. They also lack a definitive approach to prevent and treat OM. Nurses provided general education on cancer treatment but paid little attention to the education on the possible side effect that includes OM. Additionally, insufficient knowledge level of nurses on cancer treatment-associated mucositis and lack of structured protocol for OM coupled with unavailable tools for assessing the oral mucosa were also identified as militating against the management of OM. Findings from this study will guide policy that will improve the care that clients who are at risk of oral mucositis receive.


Lower levels sex hormone-binding globulin independently associated with metabolic syndrome in pre-elderly and elderly men in China.
To examine the relationship between sex hormone-binding globulin (SHBG) and the metabolic syndrome (MetS) in pre-elderly and elderly men in China. A cross-sectional study was done among 437 men, aged 45 to 94 years old. Early morning fasting sera were assayed for total testosterone (TT), SHBG and other biochemical markers. Free testosterone (FT) was calculated. The SHBG level of the MetS group was significantly lower than those without MetS 35.70 (25.18, 47.10) nmol/L vs. 41.90 (31.80, 55.20) nmol/L; P < 0.001). As the number of MetS components increases, SHBG and TT levels became lower. SHBG correlated with age, as did TT and most of metabolic components. Body mass index (BMI), high density lipoprotein-cholesterol (HDL-C), triglyceride (TG), and TT remained independently associated with SHBG by multivariate regression analysis. In a logistic regression taking MetS as the dependent variable, SHBG (95% confidence interval (95% CI): 0.975-0.994, P = 0.018) and homeostasis model assessment for insulin resistance (HOMA-IR) (95%CI: 1.535-2.647, P < 0.001) were included in the final model. Lower SHBG is independently associated with MetS among pre-elderly and elderly men. SHBG may be an independent predictor of MetS, but the mechanism of how SHBG is involved in MetS requires further studied.


Task-based and Resting State Functional MRI in Children.
Functional MR imaging (MRI) is a valuable tool for presurgical planning and is well established in adult patients. The use of task-based fMRI is increasing in pediatric populations because it provides similar benefits for pre-surgical planning in children. This article reviews special adaptations that are required for successful applications of task-based fMRI in children, especially in the motor and language systems. The more recently introduced method of resting state fMRI is reviewed and its relative advantages and disadvantages discussed. Common pitfalls and other systems and networks that may be of interest in special circumstances also are reviewed.


The actin cytoskeleton: an essential component for enhanced TNFalpha production by adherent monocytes.
Monocyte adherence induces the formation of focal adhesions, the interaction sites of intracellular signaling molecules and cytoskeletal proteins such as actin. We previously demonstrated that adherence potentiates human monocyte LPS-induced TNFalpha production. Hence, we hypothesized that the actin cytoskeleton is integral to adherence-induced priming for enhanced LPS-induced TNFalpha production. In contrast to nonadherent cells, LPS induced significant transcription of TNFalpha mRNA and production of TNFalpha in adherent monocytes. Disrupting the actin cytoskeleton with cytochalasin D (CD) in adherent monocytes inhibited LPS-induced TNFalpha production by 55%, thereby abrogating adherence-induced priming. Moreover, CD pretreatment abrogated adherence-induced activation of Pyk2, a major focal adhesion kinase, and ERK 1/2, a component of the mitogen-activated protein kinase (MAPK) signaling pathway, and it completely inhibited LPS-induced ERK 1/2 activation. However, CD treatment of nonadherent monocytes failed to inhibit cytokine production. In conclusion, the actin cytoskeleton is integral in the reprogramming of the monocyte for enhanced cytokine production and in maintaining this "primed" state.


Comparative study of ureteral stents following endoureterotomy in the porcine model: 3 vs 6 weeks and 7F vs 14F.
The aim of the study was to determine the optimal stent size and stenting duration following retrograde endoureterotomy of experimental ureteral strictures. Twenty healthy Large White female pigs were randomly divided into four groups, depending on stent size (7F vs 14F) and stenting duration (3 weeks vs 6 weeks). Three additional pigs were used as the control group. The internal ureteral diameter was measured 2 cm below the lower pole of the right kidney. Histopathological changes of the urinary tract, ultrasonographic and fluoroscopic studies, urine culture, and serum urea and creatine levels were analyzed during the different phases of the study. The study was divided into three phases. Phase I included premodel documentation of the normal urinary tract and laparoscopic ureteral stricture creation. During the second phase 1 month later, the diagnosis and endourologic treatment of strictures were performed. Phase III began 4 weeks after stent removal; follow-up imaging studies and postmortem evaluation of all animals were performed. Ureteral strictures developed in all animals 4 weeks after model creation. Results from ureteral diameter measurements and pathological studies revealed no statistically significant intergroup differences. However, prevalence of urinary infection proved to be directly related to stent size (14F) and permanence (6 weeks). The chi square results suggest a statistically significant relationship between the urinary tract infection and recurrent strictures (alpha = 0.046). We recommend the use of 7F stents for a period of 3 weeks or less, as these are more easily positioned and result in the reduction of secondary side effects (lower infection rate, less intramural ureteral lesions). A significant relationship between urinary tract infection and stricture recurrence was found in this experimental study.


Compartmental biodistribution of a monoclonal antibody against human lung adenocarcinoma grown in athymic mice.
The biodistribution of the radioiodinated monoclonal antibody KS1/4 and of its F(ab) and F(ab')2 fragments were studied in tumor-bearing nude mice. Intravenous administration of the intact antibody resulted in the highest tumor retention and tumor/blood ratios. No metabolites or antigen-antibody conjugates were detectable, in serum, by HPLC analyses. Reasonable correlations were obtained between the estimated time-course of KS1/4 and experimental biodistribution data using an eight-compartment linear radiopharmacokinetic model, suggesting that such models may be useful in predicting the biodistribution and effective targeting of this monoclonal antibody.


Effects of electroacupuncture on the neuronal activity of the arcuate nucleus of the rat hypothalamus.
Electroacupuncture (EA) effects on the spontaneous unit activities of 143 neurons in the hypothalamic arcuate nucleus (ARH) which were electrophysiologically identified to project to the median eminence were investigated using anesthetized rats weighing about 300 g. Stimuli were delivered unilaterally to a meridian point of Ho-Ku in the forepaw as rectangular pulses of 5 ms duration, intensity 300 to 500 microA, for 15 min at 3 and 45 Hz. Unit activities of ARH cells were extracellularly recorded and the mean firing rates were compared before and after EA stimulation. Stimulation at 3 or 45 Hz induced a long-lasting and naloxone-reversible suppression of the magnitude of the digastric electromyogram (dEMG) in the jaw opening reflex to 48 to 56% of the control value. Based upon the EA effects on the spontaneous firing rate, the ARH cells were classified into three types: the rate either increased (type I), decreased (type II), or did not change (type III). Type I, II, and III neurons composed 56, 40, and 4% of the recorded neurons (N = 45) when EA stimulation was applied at 3 Hz, and 27, 70, and 3% (N = 37) at 45 Hz, respectively. The distribution of the three types of ARH neurons after EA stimulation at 3 Hz was significantly different (P less than 0.05, chi-square test) from that at 45 Hz.


Mayo Adhesive Probability (MAP) score of non-donated kidney aids in predicting post-operative renal function following donor nephrectomy.
To examine the association of preoperative Mayo Adhesive Probability (MAP) scores in the donor (MAPd) and non-donor kidneys (MAPnd) with post-donation renal function. Three hundred thirty-one patients undergoing hand assisted laparoscopic donor nephrectomy (HALDN) were reviewed. MAPd and MAPnd were obtained. Estimated glomerular filtration rate (eGFR) was recorded preoperatively and at 1 day, 1 month, and 6 months postoperatively. Two hundred females and 131 males were evaluated with median BMI 26.4 kg/m2 (range 17.1-39.6) and median age 45 years (range 19-78). MAPd score was 0 for 231 patients (69.8%) and > 0 for 100 patients (30.2%). MAPnd score was 0 for 234 patients (70.7%) and > 0 for 97 patients (29.3%). The median preoperative eGFR was 86.6 ml/min/1.73m2 (range 48.8-138.4). After adjusting for preoperative eGFR, BMI, ASA score, and kidney sidedness, postoperative eGFR was associated with MAP score in the non-donated kidney (p = 0.014) but not in the donated kidney (p = 0.24). Compared to donors with MAPnd = 0, donors with a MAPnd > 0, mean eGFR was - 2.33 ml/min/1.73m2 lower at postoperative day 1 (95% CI - 4.24 to - 0.41, p = 0.018), - 3.02 ml/min/1.73m2 lower at 1 month (95% CI - 5.11 to - 0.93, p = 0.005), and - 2.63 ml/min/1.73m2 lower at 6 months postoperatively (95% CI - 5.01 to - 0.26, p = 0.030). MAP score > 0 in the non-donated kidney is associated with worse renal function in the 6 months following HALDN.


Interferon-gamma potentiates antibody affinity in mice with a genetically controlled defect in affinity maturation.
Interferon-gamma (IFN-gamma), the tetrapeptide tuftsin and the synthetic nonapeptide from interleukin-1 beta (IL-1 beta) (amino acids 163-171) have previously been shown to act on macrophages and/or T cells and to enhance antibody titres to T cell-dependent antigens. The ability of these immunomodulatory agents to potentiate antibody affinity in addition to antibody titre has been studied in a line of mice that fail to demonstrate normal maturation of antibody affinity (low N/M mice). The results presented here confirm that each of the agents potentiate antibody levels following simultaneous injection with a T cell-dependent antigen but demonstrate that only IFN-gamma is able to enhance antibody affinity in these mice. The observation that IFN-gamma can enhance both antibody affinity and antibody levels suggests that it could be an important adjuvant for vaccine use.


Generalized dermatitis due to codeine. Cross-sensitization among opium alkaloids.
Opium alkaloids can cause immunological reactions. Cross-sensitization among them must be considered in these situations.


Early outcomes of spinal growth tethering for idiopathic scoliosis with a novel device: a prospective study with 2 years of follow-up.
Adolescent idiopathic scoliosis is a 3D spine deformity that worsens during the whole growth. New methods for spinal growth modulation with flexible spinal implants have been described to avoid progression of the deformity during growth spurt. The main limitations are that no specific ancillaries and devices are available, which makes the surgery technically demanding. We have developed a new method of spinal growth tethering using minimal invasive videothoracoscopic approach. Fixation is performed with staples and synthetic ligament on the lateral aspect of vertebral bodies on main curvature convexity. Patients with progressive thoracic idiopathic scoliosis despite the brace treatment were included. The clinical and radiological examinations were compared before and 2 years after surgery. Six patients with flexible thoracic curves with a mean age 11.2 ± 1.2 years and a mean Cobb angle 45° ± 10° (35-60) were operated. All were skeletally immature. At last follow-up, the Cobb angle was stable. None of the patient underwent fusion. The procedure allowed a stabilization of the deformity during growth spurt. Validated devices and further studies with longer term follow-up are needed to confirm the efficiency of this technique. This small cohort of patients is a source of reflection for further medical devices developments. Level 4 case series comparing to not randomized studies.


Molecular determinants of CaV2.1 channel regulation by calcium-binding protein-1.
Presynaptic Ca(V)2.1 channels, which conduct P/Q-type Ca(2+) currents, initiate synaptic transmission at most synapses in the central nervous system. Regulation of Ca(V)2.1 channels by CaM contributes significantly to short term facilitation and rapid depression of synaptic transmission. Short term synaptic plasticity is diverse in form and function at different synapses, yet CaM is ubiquitously expressed. Differential regulation of Ca(V)2.1 channels by CaM-like Ca(2+) sensor (CaS) proteins differentially affects short term synaptic facilitation and rapid synaptic depression in transfected sympathetic neuron synapses. Here, we define the molecular determinants for differential regulation of Ca(V)2.1 channels by the CaS protein calcium-binding protein-1 (CaBP1) by analysis of chimeras in which the unique structural domains of CaBP1 are inserted into CaM. Our results show that the N-terminal domain, including its myristoylation site, and the second EF-hand, which is inactive in Ca(2+) binding, are the key molecular determinants of differential regulation of Ca(V)2.1 channels by CaBP1. These findings give insight into the molecular code by which CaS proteins differentially regulate Ca(V)2.1 channel function and provide diversity of form and function of short term synaptic plasticity.


Insight From Molecular Dynamics Simulations on the Crystallization Tendency of Indomethacin Polymorphs in the Undercooled Liquid State.
The crystallization tendency of 2 crystalline polymorphs of indomethacin (Iα, Iγ) in the undercooled melt has been investigated using molecular dynamics simulations. The main thermodynamical and dynamical physical parameters involved in the nucleation and growth processes have been determined. A careful attention has been given to the crystal-liquid interfacial free energy which remains really challenging to determine from experiments. The present work particularly sheds the light on the importance of the interplay between the solid-liquid interfacial free energy and the driving force for crystallization. The nucleation and the growth rates have been also estimated in the framework of the classical nucleation theory and some growth modes (normal mode, two-dimensional nucleation, and screw dislocation).


E1A expression dysregulates IL-8 production and suppresses IL-6 production by lung epithelial cells.
The adenoviral protein E1A has been proposed to play a role in the pathophysiology of COPD, in particular by increasing IL-8 gene transcription of lung epithelial cells in response to cigarette smoke-constituents such as LPS. As IL-8 production is also under tight post-transcriptional control, we planned to study whether E1A affected IL-8 production post-transcriptionally. The production of IL-6 by E1A-positive cells had not been addressed and was studied in parallel. Based on our previous work into the regulation of IL-8 and IL-6 production in airway epithelial cells, we used the lung epithelial-like cell line NCI-H292 to generate stable transfectants expressing either E1A and/or E1B, which is known to frequently co-integrate with E1A. We analyzed IL-8 and IL-6 production and the underlying regulatory processes in response to LPS and TNF-alpha. Stable transfectants were generated and characterized with immunohistochemistry, western blot and flow cytometry. IL-8 and IL-6 protein production was measured by ELISA. Levels of IL-8 and IL-6 mRNA were measured using specific radiolabeled probes. EMSA was used to assess transcriptional activation of relevant transcription factors. Post-transcriptional regulation of mRNA half-life was measured by Actinomycin D chase experiments. Most of the sixteen E1A-expressing transfectants showed suppression of IL-6 production, indicative of biologically active E1A. Significant but no uniform effects on IL-8 production, nor on transcriptional and post-transcriptional regulation of IL-8 production, were observed in the panel of E1A-expressing transfectants. E1B expression exerted similar effects as E1A on IL-8 production. Our results indicate that integration of adenoviral DNA and expression of E1A and E1B can either increase or decrease IL-8 production. Furthermore, we conclude that expression of E1A suppresses IL-6 production. These findings question the unique role of E1A protein in the pathophysiology of COPD, but do not exclude a role for adenoviral E1A/E1B DNA in modulating inflammatory responses nor in the pathogenesis of COPD.


Monoclonal antibody ONS-M21 recognizes integrin alpha3 in gliomas and medulloblastomas.
The monoclonal antibody ONS-M21 recognizes an antigen found on the surface of glioma and medulloblastoma cells but does not react with the antigens of normal brain tissue. We purified and identified the 140-kDa protein by means of an antibody-binding affinity column. This 140-kDa antigen has sequences homologous to the amino-terminal region and five parts of the internal domain of integrin alpha3. When the integrin alpha3-related sequences was amplified and used to analyse the mRNA of glioma and medulloblastoma surgical specimens, the transcription level of integrin alpha3 mRNA appeared to be quantitatively correlated with the grade of malignancy. These findings suggest that the ONS-M21 antibody, which reacts with integrin alpha3, might be useful in the diagnosis of gliomas and medulloblastomas.


Local excitation and interference of surface phonon polaritons studied by near-field infrared microscopy.
We demonstrate that mid-infrared surface phonon polariton excitation, propagation and interference can be studied by scattering-type near-field optical microscopy (s-SNOM). In our experiments we image surface phonon polaritons (SPPs) propagating on flat SiC crystals. They are excited by weakly focused illumination of single or closely spaced metal disks we fabricated on the SiC surface by conventional photolithography. SPP imaging is performed by pseudo-heterodyne interferometric detection of infrared light scattered by the metal tip of our s-SNOM. The pseudo-heterodyne technique simultaneously yields optical amplitude and phase images which allows us to measure the SPP wave vector--including its sign--and the propagation length and further to study SPP interference. High resolution imaging of SPPs could be applied to investigate for example SPP focusing or heat transfer by SPPs in low dimensional nanostructures.


Risk of hypoglycemia in Japanese people with type 2 diabetes mellitus who initiated or switched to insulin glargine 300 U/mL: A subgroup analysis of 12-month post-marketing surveillance study (X-STAR study).
This study investigated the hypoglycemia risk in people with type 2 diabetes (T2D) who initiated or switched to insulin glargine 300 U/mL (Gla-300) by stratifying them by age and renal function. We examined data from 4621 people with T2D (1227 insulin-naïve and 3394 insulin-experienced) of the X-STAR study, a prospective, observational, 12-month study conducted from December 2015 to August 2018 in Japan. Participants were stratified by age (<65, 65 to <75, and ≥75 years) and estimated glomerular filtration rate (eGFR) (≥90, 60 to <90, 30 to <60, and <30 mL/min/1.73 m2). Hypoglycemia was defined according to the Ministry of Health, Labour and Welfare manual of Japan. No apparent increase in the proportion of people who experienced hypoglycemia was found in all subgroups. The proportions were 2.9-3.5% and 2.7-5.2% of insulin-naïve and insulin-experienced people, respectively, for age subgroups, and 2.4-4.7% and 4.6-4.8%, respectively, for eGFR subgroups. The result was similar for HbA1c levels below and at or above 7.0% in all age subgroups. Our study found no apparent increase in the hypoglycemia risk in people with older age and renal impairment who were administered Gla-300. These results would provide reassuring information on Gla-300 use.


Proto-oncogene erbA expression and increased abundance of progesterone receptors in the mouse uterus after passive immunisation against progesterone before implantation.
Passive immunisation with a monoclonal anti-progesterone antibody (DB3) prevents pregnancy in the mouse, and antibody is localised in the endometrium before the onset of implantation. BALB/c female mice were injected intraperitoneally with 9 nmol of DB3 (a dose known to cause 100% infertility) 32 h post coitum, and the uterus was removed at various times after injection. Using a monoclonal anti-progesterone receptor antibody (PR6), expression of progesterone receptors was found to be abundant in uterine tissue of DB3-treated mice; this was associated with substantial progesterone receptor mRNA levels and with maximum localisation of DB3 antibody as detected by anti-idiotype antibody. Control animals treated with an equal amount of the mouse myeloma protein P3 showed very low levels of progesterone receptor in the uterus. DB3 treatment also affected uterine expression of the proto-oncogene erbA product (which shows primary sequence homology with the progesterone receptor) as revealed by specific antiserum to the ERBA protein and by in situ hybridisation with a cDNA probe to v-erbA. Time-course studies indicated that the erbA gene was expressed at a high level before progesterone receptor expression increased, that its expression was dependent on the presence of the embryo and that erbA expression persisted longer in DB3-treated females. The observations suggest that anti-progesterone immunisation has a direct effect within the uterus, involving persistence of proto-oncogene erbA expression (which itself may represent an early maternal response to pregnancy) and increased progesterone receptor levels resulting from an unopposed oestrogen effect derived from local ligand withdrawal.


Factors associated with thrombocytopenia in patients with dengue fever: a retrospective cohort study.
Some patients with dengue fever tend to develop thrombocytopenia during the course of infection and are thus vulnerable to haemorrhagic manifestations and other complications. However, the factors associated with the development of thrombocytopenia are unknown. We aimed to identify factors associated with an increased risk of thrombocytopenia and haematological changes in patients with confirmed dengue fever. Retrospective cohort study. Brazilian multicentre primary care databases. 387 patients had positive laboratory serological confirmation of dengue infection during 2014. The data were identified from two databases: Notification of Injury Information System (SINAN) and Municipal Laboratory. The presence of thrombocytopenia (platelet count <1 50×109/L). The associations of factors that predisposed patients to thrombocytopenia and haematological changes were analysed using logistic regression. ORs and 95% CIs were calculated. Among 387 patients, 156 had both dengue and thrombocytopenia. The risk factors associated with thrombocytopenia included male sex (OR: 1.77, 95% CI: 1.16 to 2.71, p=0.007), age of 46-64 years (OR: 2.20, 95% CI: 1.15 to 4.21, p=0.009) or ≥65 years (OR: 3.02, 95% CI: 1.40 to 6.50, p=0.002), presence of leucopenia (OR: 6.85, 95% CI: 4.27 to 10.99, p<0.001) and high mean corpuscular haemoglobin (MCH) levels (OR: 2.00, 95% CI: 1.29 to 3.12, p=0.005). Older age, male sex, presence of leucopenia and high MCH levels were identified as risk factors associated with the development of thrombocytopenia in this population.


Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases.
TREX1 is an exonuclease that digests DNA in the cytoplasm. Loss-of-function mutations of TREX1 are linked to Aicardi-Goutieres Syndrome (AGS) and systemic lupus erythematosus (SLE) in humans. Trex1(-/-) mice exhibit autoimmune and inflammatory phenotypes that are associated with elevated expression of interferon (IFN)-induced genes (ISGs). Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates the IFN pathway. Upon binding to DNA, cGAS is activated to catalyze the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce IFNs and other cytokines. Here we show that genetic ablation of cGas in Trex1(-/-) mice eliminated all detectable pathological and molecular phenotypes, including ISG induction, autoantibody production, aberrant T-cell activation, and lethality. Even deletion of just one allele of cGas largely rescued the phenotypes of Trex1(-/-) mice. Similarly, deletion of cGas in mice lacking DNaseII, a lysosomal enzyme that digests DNA, rescued the lethal autoimmune phenotypes of the DNaseII(-/-) mice. Through quantitative mass spectrometry, we found that cGAMP accumulated in mouse tissues deficient in Trex1 or DNaseII and that this accumulation was dependent on cGAS. These results demonstrate that cGAS activation causes the autoimmune diseases in Trex1(-/-) and DNaseII(-/-) mice and suggest that inhibition of cGAS may lead to prevention and treatment of some human autoimmune diseases caused by self-DNA.


Unprecedented energy storage in metal-organic complexes via constitutional isomerism.
The essence of any electrochemical system is engraved in its electrical double layer (EDL), and we report its unprecedented reorganization by the structural isomerism of molecules, with a direct consequence on their energy storage capability. Electrochemical and spectroscopic analyses in combination with computational and modelling studies demonstrate that an attractive field-effect due to the molecule's structural-isomerism, in contrast to a repulsive field-effect, spatially screens the ion-ion coulombic repulsions in the EDL and reconfigures the local density of anions. In a laboratory-level prototype supercapacitor, those with β-structural isomerism exhibit nearly 6-times elevated energy storage compared to the state-of-the-art electrodes, by delivering ∼535 F g-1 at 1 A g-1 while maintaining high performance metrics even at a rate as high as 50 A g-1. The elucidation of the decisive role of structural isomerism in reconfiguring the electrified interface represents a major step forward in understanding the electrodics of molecular platforms.


The adverse effects of synthetic acaricide tau-fluvalinate (tech.) on winter adult honey bees.
Currently several pyrethroids (e.g., flumethrin and tau-fluvalinate) are used in apiculture worldwide as acaricides/miticides. The long half-lives of pyrethroids in synthetic acaricides applied to hive matrices, may adversely affect the health of bee colony. The potentially adverse effects of synthetic acaricide/miticide tau-fluvalinate (tech.) on winter honeybees were assessed in this study (OECD 245 2017). No dose-dependent mortality in in vitro reared winter honeybees was observed after chronic oral 10-day exposure to syrup (50% w/v) spiked with a maximum concentration of 750 μg a.i./kg diet and its 1/10 concentration. The No Observed Effect Concentration is ≥ 750 μg a.i./kg diet. Tau-fluvalinate testing for the sublethal effects on bee immune system showed up-regulated gene expression encoding abaecin, lysozyme, and defensin in both tested groups, however the expression of hymenoptaecin gene was reduced. Moreover, tau-fluvalinate significantly induced levels of DNA damage in exposed bees, which can result in adverse genotoxic effect.


Lack of platelet-activating factor release on acute myocardial ischemia in the isolated interventricular septum of rabbit heart.
The effects of platelet-activating factor (PAF) on myocardial injury after 1 h global ischemia-30 min reperfusion were investigated in isolated arterially perfused interventricular septum of rabbit heart. PAF did not significantly affect developed tension, +/- dT/dtmax, resting tension and the times of active state in non-ischemic septa. The recovery of developed tension was significantly reduced by PAF (100 nM), after an ischemia-reperfusion challenge, from the control value of 20.9 +/- 3.5% to 10.5 +/- 1.8%, without a change in the resting tension (15.7 +/- 2.8 vs. 15.6 +/- 1.3 g). BN 52021 (20 microM), alone did not modify either parameter of ischemic damage, but antagonized the aggravating effect of PAF. Evidence of PAF activity was not found in any of the samples of the effluent perfusate obtained from ischemic control experiments. On the basis of the present results, we suggest a direct role for PAF in aggravating the myocardial damage induced by ischemia, and discard heart cells as the source of PAF in this state.


Expression of the lac operon in RNA polymerase mutants of Escherichia coli K12.
Three temperature-sensitive mutant strains for RNA polymerase beta or beta' subunits (carrying mutations tsx, A2R7 and R120) were used in order to investigate the dependence of the induced lac expression on stimulation by cyclic AMP after the shift to non-permissive temperature. High temperature lowered the rate of beta-galactosidase synthesis. However, the low rate of synthesis could be strongly increased by cyclic AMP (30, 2.4 and 5.7-fold increases for tsX, A2R7 and R120 mutants, respectively). At the permissive temperature stimulation by cyclic AMP was less than 1.4-fold (minimal medium supplemented with glycerol). The results suggest that the maximal expression of the lac operon is saturated, that is, a hypothetical increase in RNA polymerase or cAMP-CRP concentration in the cell with not enhance the expression. The concept of saturation explains why it was possible to increase the beta-galactosidase synthesis in conditions of limited promoter binding activity of RNA polymerase through increase in concentration of cyclic AMP-CRP complex in the cell (addition of cyclic AMP) to the values higher than that observed on glycerol.


ParA ATPases can move and position DNA and subcellular structures.
Prokaryotic chromosomes and plasmids can be actively segregated by partitioning (par) loci. The common ParA-encoding par loci segregate plasmids by arranging them in regular arrays over the nucleoid by an unknown mechanism. Recent observations indicate that ParA moves plasmids and chromosomes by a pulling mechanism. Even though ParAs form filaments in vitro it is not known whether similar structures are present in vivo. ParA of P1 forms filaments in vitro at very high concentrations only and filament-like structures have not been observed in vivo. Consequently, a 'diffusion-ratchet' mechanism was suggested to explain plasmid movement by ParA of P1. We compare this mechanism with our previously proposed filament model for plasmid movement by ParA. Remarkably, ParA homologues have been discovered to arrange subcellular structures such as carboxysomes and chemotaxis sensory receptors in a regular manner very similar to those of the plasmid arrays.


Effects of sodium intake during two parities on Na status in blackface sheep.
A low-sodium diet was given to Blackface ewes over two reproductive seasons. This diet provided a total of 3-7 mmol/d except during lactation when the intake was about 11 mmol/d. Control ewes were given the same diet supplemented with sodium chloride to provide recommended levels which were about tenfold that of the experimental diet. The output of Na in urine and faeces from ewes given the low-Na diet was very low, about 3 mmol/d, from early in the experiment and continued at about this level throughout. Lambs born to low-Na ewes and given a low-Na diet similar to that of their dams during lactation, grew, after weaning, more slowly than corresponding lambs from control ewes, but at 6 months of age when six from each group were killed, tissue Na contents were only slightly lower in experimental than control lambs. Fluids and tissues obtained at the end of the second lactation from four ewes of each group that had suckled twin lambs, were analysed for Na and potassium. The Na concentration in saliva and rumen fluid of low-Na ewes was about half that of control ewes and there were corresponding increases in K: the differences were significant. Although Na concentrations for experimental ewes were generally lower than those for control ewes in the tissues analysed (liver, kidney, heart, brain and bone), the difference was significant only for the heart (P less than 0.05). Haemoglobin and packed cell volume were significantly elevated in low-Na ewes (P less than 0.01), indicating decreased body fluid volume.(ABSTRACT TRUNCATED AT 250 WORDS)


An anatomical study of the recurrent laryngeal nerve: its branching patterns and relationship to the inferior thyroid artery.
The aim of this study was to provide information about the morphology and topography of the recurrent laryngeal nerve (RLN), its external features and branches, as well as its relationship to the inferior thyroid artery, the inferior horn of the thyroid cartilage and the thyroid gland. The RLNs in 50 adult cadavers (100 sides) were dissected and analyzed. A communicating loop connecting one branch of the RLN to another or a twig originating from the cervical sympathetic trunk was present in 13 of 100 sides. A double left RLN appeared in 2 sides; a right non-recurrent inferior laryngeal nerve appeared in one side. All of the RLNs, including looped ones, bifurcated into laryngeal branches and extralaryngeal branches, with most of the former further dividing into the anterior and posterior branches entering the larynx. The relations of the RLN to the inferior thyroid artery, the inferior horn of the thyroid cartilage and the thyroid gland were inconstant. The information gained from this study will be of value in thyroid surgery.


Comparison of Vectra three-dimensional stereophotogrammetry measurement and tape measurement in the evaluation of perioperative volume change of the lower abdomen in association with lymphatic microsurgery.
Although microsurgical treatment for lower extremity lymphedema (LEL) can improve lower abdominal morphology, methods to evaluate the volume change of the lower abdomen have yet to be established. This study aimed to determine the accuracy and reproducibility of three-dimensional stereophotogrammetry (3DSM) in measuring the volume change in the lower abdomen. The perioperative volume changes in the lower abdomen were estimated using tape measurement (TM) and 3DSM in 26 patients with LEL. Thirteen patients with suprapubic lymphedema underwent abdominoplasty simultaneously. Each of them underwent multiple lymphaticovenular anastomoses (LVAs), and five of them underwent vascularized lymph node transfer, simultaneously. Thirteen patients with pelvic lymphatic fluid underwent multiple LVAs. Two patients underwent this surgery twice. When assessed on the Internal Society of Lymphology scale, eight patients were Stage I, 10 patients were Stage II, four patients were late Stage II, and four patients were Stage III. The difference between the two measurement methods and reproducibility of each method were analyzed. During a mean follow-up period of 6 months, all patients had no postoperative complications and their chief complaint improved. The calculated reduction volume between TM and 3DSM showed a high correlation (p < .0001, r = .84). The reduction volume based on TM was significantly larger than 3DSM (991.1 ± 460.3 ml vs. 862.3 ± 333.5 ml, p = .02). The interrater ICC was 0.94 and 0.98 based on TM and 3DSM, respectively. 3DSM may be a useful method for assessment of the lower abdominal morphology due to its high accuracy and reproducibility.


[Natural history of dilated cardiomyopathy].
Seventy-seven patients with dilated cardiomyopathy (50 M and 27 F, aged 38 +/- 16 yrs) were followed up until Dec 31, 1985. Haemodynamic investigation was performed in all cases, and all pressure and left ventricular quantitative angiography parameters were collected. In no case did the coronary angiogram show significant lesions. Mean values of haemodynamic parameters for surviving and deceased patients were compared. Forty-six patients survived and 28 died during the follow-up period. Although all patients had an enlarged left ventricle and depressed contractility, survivors had either greater pressure/end systolic volume ratio or a greater stress/end systolic volume ratio. Survival curves confirm a particularly severe prognosis for patients with Suga index less than 1 or stress to end systolic volume ratio less than 2.5. Mass to volume ratio seems to affect two-year but not late survival. NYHA class does not indicate early survival. In conclusion, left ventricular function is obviously related to prognosis in these patients, but it seems still difficult to assess life expectancy from these parameters alone.


A functional-based approach to the retention in thin layer chromatographic screening systems.
A QSRR approach, based on functional group counts, useful for prediction of the retention of any small organic solute with small molecule in seven TLC screening systems is presented. The equations are based on 154 possible substituents as the only molecular descriptors involved. The model optimization was performed by uninformative variable elimination-partial least squares (UVE-PLS), reducing the variables involved. The final equations, with 7-32 variables, explain 32-60% of overall explained variance and their predictive ability (Q(2)) includes in range 25-54% (LOO crossvalidation) and 12-43% (external validation). Their simplicity allows to computation without any complicated software.


Association between parental occupations, educational levels, and household income and children's psychological adjustment in Japan.
Most research on the association between parental or family socio-economic status and psychological adjustment in children has been performed mainly in Western countries, while there is limited evidence of such research in Asian countries. We examined the association of parental occupation and educational levels and household income with children's psychological adjustment in Japan. This was a cross-sectional study. Study subjects were 6329 children aged 3 years. Children's psychological adjustment was assessed using the Strengths and Difficulties Questionnaire. Compared with having an unemployed father, having a father who worked in an administrative and managerial or clerical job was associated with a lower prevalence of peer problems. Compared with having an unemployed mother, having a mother who worked in the professional and engineering, sales, service, or manufacturing process area was associated with a lower prevalence of low prosocial behaviors, whereas having a mother who worked in the clerical, service, or manufacturing process area was associated with an increased prevalence of emotional problems. Having a mother who worked in a clerical area was associated with a higher prevalence of conduct problems. Higher paternal and maternal educational levels were inversely associated with the prevalence of conduct problems and hyperactivity but were positively associated with low prosocial behaviors. A higher household income was inversely associated with the prevalence of emotional problems, conduct problems, and hyperactivity. Parental occupation, educational levels, and household income may affect children's psychological adjustment in Japan.


Enriching the biological space of natural products and charting drug metabolites, through real time biotransformation monitoring: The NMR tube bioreactor.
Natural products offer a wide range of biological activities, but they are not easily integrated in the drug discovery pipeline, because of their inherent scaffold intricacy and the associated complexity in their synthetic chemistry. Enzymes may be used to perform regioselective and stereoselective incorporation of functional groups in the natural product core, avoiding harsh reaction conditions, several protection/deprotection and purification steps. Herein, we developed a three step protocol carried out inside an NMR-tube. 1st-step: STD-NMR was used to predict the: i) capacity of natural products as enzyme substrates and ii) possible regioselectivity of the biotransformations. 2nd-step: The real-time formation of multiple-biotransformation products in the NMR-tube bioreactor was monitored in-situ. 3rd-step: STD-NMR was applied in the mixture of the biotransformed products to screen ligands for protein targets. Herein, we developed a simple and time-effective process, the "NMR-tube bioreactor", that is able to: (i) predict which component of a mixture of natural products can be enzymatically transformed, (ii) monitor in situ the transformation efficacy and regioselectivity in crude extracts and multiple substrate biotransformations without fractionation and (iii) simultaneously screen for interactions of the biotransformation products with pharmaceutical protein targets. We have developed a green, time-, and cost-effective process that provide a simple route from natural products to lead compounds for drug discovery. This process can speed up the most crucial steps in the early drug discovery process, and reduce the chemical manipulations usually involved in the pipeline, improving the environmental compatibility.


Improving the effectiveness of multidisciplinary team meetings on skin cancer: Analysis of the National Cancer Research UK survey responses.
Skin cancer is the most common form of cancer in the UK, comprising at least 25% of all new cancer diagnoses. Many patients require referral to the local or specialist skin cancer multidisciplinary team (MDT) for ongoing management. However, national data have shown that Specialist Skin Cancer MDTs are costly and do not currently meet NICE standards for composition and quoracy. Innovative solutions to these problems are therefore warranted. We performed a secondary comparative analysis of 3563 quantitative responses to two Cancer Research UK commissioned surveys along with subanalysis of 282 skin cancer MDT respondents. Good uniformity was observed amongst skin respondents in the belief that risk stratification and prioritization of complex cases were the most important factors compared to other cancer MDT members. The most important priorities for areas requiring change to MDT working deemed by the skin MDT were 1) imaging and pathology results ready for the meeting, 2) time to discuss patients in detail, 3) clear meeting owner in charge, and 4) clear agenda, in advance of the meeting. There was agreement (median Likert score 4) amongst skin MDT respondents that patients should be placed on protocolized treatment pathways. The responses of skin MDT respondents analyzed in the current study support changes to meeting attendance, preparation, and protocolized streaming. In line with other studies, we support tumor-specific guidance for streamlining MDT discussions. We also encourage stakeholders to adopt an evidence-based approach to test, develop, and reassess changes in this herculean task.


Patient Decisions Regarding Fetal Monitoring in the Periviable Period and Perinatal and Maternal Outcomes.
Management of delivery at periviable gestation requires complex counseling and decision making, including difficult choices about monitoring and potential cesarean delivery (CD) for fetal benefit. Our objective was to characterize decisions that patients make regarding fetal monitoring and potential CD for fetal benefit when delivering in the periviable period, and associations with perinatal and obstetric outcomes. We hypothesize that a significant number of patients forgo monitoring and potential CD for fetal benefit in the periviable period when offered the opportunity to do so. Retrospective cohort study of nonanomalous singleton pregnancies delivering between 230/7 and 256/7 weeks at a tertiary care center from 2015 to 2020 as based on our institutional clinical practice. Since 2015, these patients are offered the ability to accept or decline fetal monitoring, potential CD for fetal benefit, and active resuscitation of a liveborn neonate. The frequency of patients desiring potential CD for fetal benefit was identified, and associations with CD and intrapartum demise were analyzed. Fifty subjects were included. Seventy-eight percent (n = 39) desired monitoring and potential CD for fetal benefit, and 84% (n = 42) desired resuscitation if the neonate was born alive. This varied by gestational age: 55% (6/11) of patients delivering between 230/7 and 236/7 weeks desired fetal monitoring and potential CD for fetal benefit, while 90% (19/21) of patients delivering between 250/7 and 256/7 weeks desired fetal monitoring and potential CD for fetal benefit (p = 0.02). Sixty-nine percent of pregnancies in which potential CD for fetal benefit was desired resulted in CD (27/39), of which 85% were classical (23/27). Intrapartum fetal demise occurred in 45% (5/11) of pregnancies in which monitoring was not performed. While a majority of patients delivering between 230/7 and 256/7 weeks desired monitoring and potential CD for fetal benefit, this varied significantly by gestational age. The decision to perform monitoring and potential CD for fetal benefit was associated with a high frequency of CD, while the decision to forgo monitoring was associated with high frequency of intrapartum demise. · Patients desires vary in the setting of periviable delivery.. · Periviable monitoring is associated with cesarean delivery.. · Forgoing monitoring is associated with intrapartum demise..


[Efficacy and safety of patients immunization with chronic obstructive pulmonary disease with monoclonal antibodies].
Chronic obstructive pulmonary disease (COPD) is characterized by a high level of morbidity and mortality and is associated with significant social and economic damage to the health system and society. COPD and COVID-19 have many potentially negative relationships that can lead to worse outcomes of COVID-19, including impaired lung function, old age and the presence of concomitant diseases Aim. To assess efficacy and safety of the drug Tixagevimab + Cilgavimab for the pre-contact prevention of COVID-19 infection in patients with COPD. A total of 324 male patients were included in the study, who were treated or monitored at the Regional Clinic Hospital №3 and the Regional Pulmonological Center of Chelyabinsk in April-May 2022. The main endpoints of observation, for 3 and 6 months, to assess the effectiveness were the dynamics of shortness of breath according to The Modified Medical Research Council Dyspnea Scale - mMRC, the The forced expiratory volume in 1 second, the number of exacerbations, emergency calls, hospitalizations, polymerase chain reaction for SARS-CoV-2. Local and general reactions after immunization were evaluated. The drug Evusheld (150 mg Tixsagevimab +150 mg Cilgavimab, AstraZeneca) was used for immunization. The effectiveness of pre-contact prevention of COVID-19 was 88.8%. The administration of the drug does not provoke an exacerbation of the underlying disease. The main clinical and functional indicators have positive dynamics by the 6th month of follow-up. The drug is well tolerated and has no significant both early and late complications.


Community perspectives and conservation needs for Dugongs (Dugong dugon) along the Andaman coast of Thailand.
The dugong is classified as vulnerable to extinction by the World Conservation Union on the basis of declines in area or extent of occupancy, habitat quality, and actual or potential levels of exploitation. In Thailand, the largest groups of dugongs are found near islands off the Andaman coast. The authors conducted a 2-year project that included dugong population and habitat assessment as well as interviews with local fishers. The results indicate declining populations of dugongs. The largest threat to dugongs is incidental catch in fishing nets. The numbers of deaths reported place the dugong population along the Andaman Sea in danger of extirpation. Other threats include seagrass destruction both from fishing and coastal development and the use of dugong parts for medicinal purposes. Villagers still show strong ties with dugongs, and the majority favor establishing more large protected areas for the species. These should arise from an integrated national dugong and seagrass conservation strategy formulated by concerned stakeholders from government, non-governmental organizations, scientists, and local communities. The strategy needs to be both top down and bottom up in its formation to balance existing and potential uses as well as conflicts between artisanal and commercial fishers. The strategy should include the development of educational materials and enforceable regulations, as well as the designation of community-protected seagrass beds and a system of dugong sanctuaries along the Andaman coast. An integrated management plan is needed urgently, with the continued input of concerned scientists, to monitor and increase knowledge of dugong behavior and distribution.


A steady-state random-order mechanism for the oxidative deamination of norvaline by glutamate dehydrogenase.
The kinetic mechanism of glutamate dehydrogenase with the monocarboxylic substrate norvaline was examined by using initial-rate steady-state kinetics and inhibition kinetics. To a first approximation the reaction mechanism can be described as a rapid-equilibrium random-order one. Binding synergism between the monocarboxylic substrate and coenzyme is not observed. Dissociation constants for NAD+ and 2-oxoglutarate calculated from the kinetic data assuming a rapid-equilibrium random-order model are in good agreement with independently obtained estimates. Lineweaver-Burk plots with varied norvaline concentration are not strictly linear, and it is concluded that a steady-state random-order model more accurately reflects the observed kinetics with norvaline as substrate.


A familial syndrome of diaphyseal cortical thickening of the long bones, bowed legs, tendency to fracture and icthyosis.
The clinical and radiological features of a dominant bone disorder found in six members of the same family are described. The bone disorder was mainly characterized by endosteal cortical thickening of long tubular bones and bowing of the weight-bearing ones. The clinical symptoms were waddling gait, muscle weakness and leg pains, and there was a tendency to fractures. All affected individuals had icthyosis of slight or moderate degree.


[Effect of sulfonylurea preparations on the course of pregnancy and the state of the fetuses of female rats with alloxan prediabetes, latent diabetes and mild forms of manifest diabetes].
The influence of antidiabetic sulphanylamides, used before the occurrence of pregnancy, on the weight of fetuses and placentae was revealed in rats with alloxan "prediabetes", latent diabetes, and manifest diabetes. Diabetes compensation before the occurrence of pregnancy in rats with "prediabetes" and latent diabetes by means of chlorpropamide, and in rats with manifest diabetes with chlorpropamide together with biguanides led to a significant reduction of the weight of fetuses and prevented their death.


[Prevalence of cholelithiasis. Results of an epidemiologic study using sonography in East Germany].
In two middle-sized towns in the northern part of the German Democratic Republic, a random sample of the population and unselected subjects, respectively, were examined for gallbladder stones (GS) by ultrasound. The prevalence of cholelithiasis (sum of GS detected by ultrasound and history of cholecystectomy for GS) ist higher than in other European populations screened by similar methods. It is suggested that dietary habits are responsible for this finding. About one third of subjects with GS had complications of GS and about one third gave a history of cholecystectomy for GS. The frequency of nonspecific dyspeptic complaints was the same in persons with GS as in persons without GS.


Molecular pathology of pulmonary edema in forensic autopsy cases with special regard to fatal hyperthermia and hypothermia.
Fatalities due to an extreme ambient temperature might present with poor or nonspecific pathologies; thus, the diagnosis of the cause of death in such cases is one of the most difficult tasks in forensic pathology. The present study investigated the molecular pathology of alveolar damage involving pulmonary edema with special regard to hyperthermia (heatstroke) and hypothermia (cold exposure) in forensic autopsy cases (total, n=122; within 48 h postmortem). Intrapulmonary mRNA and immunohistochemical expressions of matrix metalloproteinases (MMPs), intercellular adhesion molecule-1 (ICAM-1), claudin-5 (CLDN-5) and aquaporins (AQPs) were examined. Relative mRNA quantification using Taqman real-time PCR assay demonstrated higher expressions of all markers except for AQP-5 in fatal hyperthermia, and higher expression of MMP-9 in fatal hypothermia. Acute cardiac death, mechanical asphyxiation, fire fatality and intoxication did not present any characteristic findings. In immunostaining, only MMPs showed evident differences among the causes of death: MMP-9 was intensely positive in most cases of hyperthermia and hypothermia, but MMP-2 expression was evident only in hyperthermia. These findings suggest alveolar damage involving pulmonary edema, characteristic of fatal hyperthermia and hypothermia. Systematic analysis of gene expressions using real-time PCR might be a useful procedure in forensic death investigation.


Modified grade 4 osteotomy for the correction of post-traumatic thoracolumbar kyphosis: A retrospective study of 42 patients.
Many surgical procedures have been developed for the treatment of post-traumatic thoracolumbar kyphosis. But there is a significant controversy over the ideal management. The aim of this study was to illustrate the technique of modified grade 4 osteotomy for the treatment of post-traumatic thoracolumbar kyphosis and to evaluate clinical and radiographic results of patients treated with this technique.From May 2013 to May 2018, 42 consecutive patients experiencing post-traumatic thoracolumbar kyphosis underwent the technique of modified grade 4 osteotomy, and their medical records were retrospectively collected. Preoperative and postoperative sagittal Cobb angle, visual analog scale (VAS), Oswestry disability index (ODI), and American Spinal Injury Association (ASIA) were recorded. The average follow-up period was 29.7 ± 14.2 months.The operation time was 185.5 ± 26.8 minutes, the intraoperative blood loss was 545.2 ± 150.1 mL. The Cobb angles decreased from 38.5 ± 3.8 degree preoperatively to 4.2 ± 2.6 degree 2 weeks after surgery (P < .001). The VAS reduced from 6.5 ± 1.1 preoperatively to 1.5 ± 0.9 at final follow-up (P < .001), and the ODI reduced from 59.5 ± 15.7 preoperatively to 15.9 ± 5.8 at final follow-up (P < .001). Kyphotic deformity was successfully corrected and bony fusion was achieved in all patients. Neurologic function of 7 cases was improved to various degrees.Modified grade 4 osteotomy, upper disc, and upper one-third to half of pedicle are resected, is an effective treatment option for post-traumatic thoracolumbar kyphosis. However, the long-term clinical effect still needs further studies.


Risk factors for elbow pain in Little League baseball players: a cross-sectional study focusing on developmental factors.
The incidence of Little League elbow is increasing. However, the risk factors for Little League elbow, especially those related to development have not previously been investigated. The purpose of this study was to investigate the risk factors for elbow pain in Little League baseball players while focusing on the developmental factors. A total of 654 baseball players aged 6-12 years, all male, participated in this study. Participants completed an original questionnaire that included items assessing demographic data, developmental factors (increase in height and increase in weight over the preceding 12 months), and baseball-related factors. Multiple regression analysis was used to identify the risk factors for elbow pain during the 12 months prior to the study. The data collected for 392 players without omissions or blank answers were submitted to statistical analysis. We found that 19.1% of Little League baseball players had experienced elbow pain in the 12 months leading up to the study. The analysis revealed that height (Odds Ratio [OR], 1.10; 95% confidence interval [95%CI], 1.03-1.17) and increase in height (OR, 1.16; 95%CI, 1.00-1.34) were risk factors that increased the risk of elbow pain after adjustment for demographic data, developmental data, and baseball-related factors. Our results suggested that an increase over height in the last 12 months may predispose young baseball players to elbow pain.


The school Lifesavers study-A randomised controlled trial comparing the impact of Lifesaver only, face-to-face training only, and Lifesaver with face-to-face training on CPR knowledge, skills and attitudes in UK school children.
Lifesaver (www.life-saver.org.uk) is an immersive, interactive game that can be used for basic life support training. Users 'resuscitate' a victim of cardiac arrest in a filmed scenario and move their device up and down to simulate cardiac compressions. Randomised controlled trial of 3 UK schools (81 students) comparing Lifesaver, face-to-face (F2F) training, and a combination of both. Primary outcomes: mean chest compression rate and depth. flow fraction, CPR performance, and attitude survey. Outcomes measured immediately, 3 and 6 months. Primary outcomes: Mean chest compression depth was suboptimal in all groups due to body size. F2F performed better than Lifesaver initially (-11.676; 95% CI -18.34 to -5.01; p=0.0001) but no difference at 3 months (p=0.493) and 6 months (p=0.809). No difference in mean compression rates for Lifesaver vs F2F (-11.89; 95% CI -30.39 to -6.61; p=0.280) and combined vs Lifesaver (0.25; 95% CI -17.4 to -17.9; p=0.999). all groups had flow fraction >60% after training. Combined group performed better for skills assessment than Lifesaver (4.02; 95% CI 2.81-5.22; p=0.001) and F2F (1.76; 95 CI 0.51-3; p=0.003); and the same at 6 months (1.92; 95% CI 0.19-3.64; p=0.026 and 1.96; 95% CI 0.17-3.75; p=0.029). Use of Lifesaver by school children, compared to F2F training alone, can lead to comparable learning outcomes for several key elements of successful CPR. Its use can be considered where resources or time do not permit formal F2F training sessions. The true benefits of Lifesaver can be realised if paired with F2F training.


A density functional theory study of phenyl formation initiated by ethynyl radical (C2H*) and ethyne (C2H2).
An ab initio computational density functional theory (DFT) was used to study the formation of the first cyclic molecule (phenyl) initiated by the ethynyl radical (C(2)H*). The study covers a competition reaction between the addition reactions of C(2)H* with ethyne (C(2)H(2)) and some molecular re-arrangement schemes. The minimum energy paths of the preferred cyclic formation route were characterized. A thorough thermochemical analysis was performed by evaluating the differences in the energy of activation (DeltaE), enthalpy (DeltaH), and Gibb's free energy (DeltaG) of the optimized stable and transition state (TS) molecules. The reaction temperatures were set to normal (T = 298 K) and combustion (T = 1,200 K) conditions.