Human Th17 cells.
The discovery in mice of a new lineage of CD4+ effector T helper (Th) cells that selectively produce IL-17 has provided exciting new insights into immune regulation, host defence, and the pathogenesis of autoimmune and other chronic inflammatory disorders. This population of CD4+ Th cells, which has been termed 'Th17', indeed plays an apparently critical role in the pathogenesis of some murine models of autoimmunity. Interestingly, murine Th17 cells share a common origin with Foxp3+ T regulatory cells, because both populations are produced in response to transforming growth factor-beta, but they develop into Th17 cells only when IL-6 is simultaneously produced. Initial studies in humans have confirmed the existence of Th17 cells, but they have shown that the origin of these cells in humans differs from that in mice, with IL-1beta and IL-23 being the major cytokines responsible for their development. Moreover, the presence in the circulation and in various tissues of Th cells that can produce both IL-17 and interferon-gamma, as well as the flexibility of human Th17 clones to produce interferon-gamma in addition to IL-17 in response to IL-12, suggests that there may be a developmental relationship between Th17 and Th1 cells, at least in humans. Resolving this issue has great implications in tems of establishing the respective pathogenic roles of Th1 and Th17 cells in autoimmune disorders. In contrast, it is unlikely that Th17 cells contribute to the pathogenesis of human allergic IgE-mediated disorders, because IL-4 and IL-25 (a powerful inducer of IL-4) are both potent inhibitors of Th17 cell development.


The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis.
BACKGROUND; Combined oral contraceptives (COCs) reduce levels of androgen, especially testosterone (T), by inhibiting ovarian and adrenal androgen synthesis and by increasing levels of sex hormone-binding globulin (SHBG). Although this suppressive effect has been investigated by numerous studies over many years, to our knowledge no systematic review concerning this issue had been performed. This systematic review and meta-analysis was performed to evaluate the effect of COCs on concentrations of total T, free T and SHBG in healthy women and to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T and free T. A review of the literature was performed using database searches (MEDLINE, EMBASE and the Cochrane Central Register of Clinical Trials) and all publications (from inception date until July 2012) investigating the effect of COCs on androgen levels in healthy women were considered eligible for selection. Three reviewers were involved in study selection, data extraction and critical appraisal. For the meta-analysis, data on total T, free T and SHBG were extracted and combined using random effects analysis. Additional subgroup analyses were performed to evaluate differences between the various types of COCs (e.g. estrogen dose, type of progestin) and the assays used to assess total T or free T. A total of 151 records were identified by systematic review and 42 studies with a total of 1495 healthy young women (age range: 18-40 years) were included in the meta-analysis. All included studies were experimental studies and 21 were non-comparative. Pooling of the results derived from all the included papers showed that total T levels significantly decreased during COC use [mean difference (MD) (95% confidence interval, CI) -0.49 nmol/l (-0.55, -0.42); P < 0.001]. Significantly lower levels of free T were also found [relative change (95% CI) 0.39 (0.35, 0.43); P < 0.001], with a mean decrease of 61%. On the contrary, SHBG concentrations significantly increased during all types of COC use [MD (95% CI) 99.08 nmol/l (86.43, 111.73); P < 0.001]. Subgroup analyses revealed that COCs containing 20-25 µg EE had similar effects on total and free T compared with COCs with 30-35 µg EE. In addition, suppressive effects on T levels were not different when comparing different types of progestins. However, subgroup analyses for the estrogen dose and the progestin type in relation to changes in SHBG levels did show significant differences: COCs containing second generation progestins and/or the lower estrogen doses (20-25 µg EE) were found to have less impact on SHBG concentrations. The current literature review and meta-analysis demonstrates that COCs decrease circulating levels of total T and free T and increase SBHG concentrations. Due to the SHBG increase, free T levels decrease twice as much as total T. The estrogen dose and progestin type of the COC do not influence the decline of total and free T, but both affect SHBG. The clinical implications of suppressed androgen levels during COC use remain to be elucidated.


Energy system digitization in the era of AI: A three-layered approach toward carbon neutrality.
The transition toward carbon-neutral electricity is one of the biggest game changers in addressing climate change since it addresses the dual challenges of removing carbon emissions from the two largest sectors of emitters: electricity and transportation. The transition to a carbon-neutral electric grid poses significant challenges to conventional paradigms of modern grid planning and operation. Much of the challenge arises from the scale of the decision-making and the uncertainty associated with the energy supply and demand. Artificial intelligence (AI) could potentially have a transformative impact on accelerating the speed and scale of carbon-neutral transition, as many decision-making processes in the power grid can be cast as classic, though challenging, machine-learning tasks. We point out that to amplify AI's impact on carbon-neutral transition of the electric energy systems, the AI algorithms originally developed for other applications should be tailored in three layers of technology, markets, and policy.


Repeated pancreatectomy for metachronous duodenal and pancreatic metastases of renal cell carcinoma.
A 50-year-old woman had undergone left nephrectomy for renal cell carcinoma 13 years previously. Ten years later, a solitary metastatic tumor had been detected in the pancreatic tail and she had undergone subsequent resection of the pancreatic tail and spleen. Three years after surgery, she was admitted to our hospital for severe anemia resulting from gastrointestinal tract bleeding. Esophagogastroduodenoscopy revealed a 3-cm solid tumor at the oral side of the papilla of Vater. Histology of the bioptic duodenal tissue revealed inflammatory granulation without malignancy. Computed tomography showed a well-contrasted hypervascular tumor in the descending portion of the duodenum. We diagnosed the patient with metachronous duodenal metastasis of renal cell carcinoma and performed a pancreaticoduodenectomy. An ulcerated polypoid mass was detected at the oral side of the papilla of Vater. Histology revealed clear cell carcinoma coated by granulation tissue across the surface of the tumor. Immunohistology demonstrated that the cells were positive for vimentin, CD10 and epithelial membrane antigen and negative for CK7. After a repeated pancreatectomy, the patient had no symptoms of gastrointestinal bleeding and maintained good glucose tolerance without insulin therapy because the remnant pancreas functioned well. In conclusion, for the diagnosis of patients who have previously undergone nephrectomy and present with gastrointestinal bleeding, the possibility of metastasis to the gastrointestinal tract, including the duodenum, should be considered. With respect to surgical treatment, the pancreas should be minimally resected to maintain a free surgical margin during the first surgery taking into account further metachronous metastasis to the duodenum and pancreas.


Usefulness of the CHA2DS2-VASc and HAS-BLED Scores in Predicting the Risk of Stroke Versus Intracranial Bleeding in Patients With Atrial Fibrillation (from the FibStroke Study).
CHA2DS2-VASc and HAS-BLED scores stratify the risk of thromboembolic and bleeding events respectively in patients with atrial fibrillation. There is only little information on how they differentiate which of the 2 clinically most important complications (ischemic stroke [IS] or an intracranial bleeding [IB]) the patient is more prone to suffer. We evaluated both scores in patients with either of these major complications. The FibStroke Study collected data on all patients with atrial fibrillation with either an IS or an IB event between 2003 and 2012 in 4 Finnish hospital districts. Individual electronic patient records were manually reviewed to collect the study data. To assess the relative risk of IS and IB, an IS/IB-ratio was calculated by dividing the absolute number of ISs with the absolute number of IBs within each score category. A total of 3,816 (82.7%) ISs and 798 (17.3%) IBs were detected in 3,909 patients. In general, ISs occurred more often than IBs in patients on oral anticoagulation in each score category (ratio 1.6 to 5.1). The ratio decreased below 1, however, only with very high HAS-BLED scores (>4). Moreover, 221 ISs and 53 IBs occurred in patients with HAS-BLED > CHA2DS2-VASc, of whom only 19.7% were on anticoagulation. In conclusion, IS was the predominant intracranial event irrespective of CHA2DS2-VASc score, HAS-BLED score ≤4, or use of oral anticoagulation, also in patients with low estimated thromboembolic risk (CHA2DS2-VASc 0 to 1). Furthermore, the HAS-BLED score predicted the excess of IBs over ISs only at very high-risk levels.


Lower limb power rehabilitation (LLPR) using interactive video game for improvement of balance function in older people.
Declined balance functions have adverse effects on elderly population. Lower limbs muscle power training is currently an emerging concept in rehabilitation on individuals with decreased balance and mobility. In this prospective, controlled study, we used a human-computer interactive video-game-based rehabilitation device (LLPR) for training of lower limb muscle power in the elderly. Forty (aged >65 years) individuals were recruited from the community. Twenty participants in the exercise group received 30-min training, twice a week, using the LLPR system. The LLPR system allows participants to perform fast speed sit-to-stand (STS) movements. Twenty age-matched participants in the control group performed slow speed STS movements, as well as strengthening and balance exercises, with the same frequency and duration. The results were compared after 12 sessions (6 weeks) of training. The mechanical and time parameters during STS movement were measured using the LLPR system. Modified falls efficacy scale (MFES), Tinetti Performance-Oriented Mobility Assessment (POMA), function reach test, five times sit to stand (FTSS) and Timed Up and Go (TUG) were administered to participants as clinical assessments. Results showed that in the exercise group, all the mechanical and time parameters showed significant improvement. In control group, only the maximal vertical ground reaction force (MVGRF) improved significantly. For clinical assessments (balance, mobility, and self-confidence), exercise group showed significantly better scores. The STS movements in video-game-based training mimic real life situations which may help to transfer the training effects into daily activities. The effectiveness of lower limb muscle training is worthy of further investigation.


Increased circulating myeloid-derived suppressor cells correlate with clinical cancer stage, metastatic tumor burden, and doxorubicin-cyclophosphamide chemotherapy.
Abnormal accumulation of myeloid-derived suppressor cells (MDSC) is an important mechanism of tumor immune evasion. Cyclophosphamide (CTX) has also been shown in non-tumor bearing animals to cause transient surges in MDSC. Knowledge of MDSC is primarily based on preclinical work, and to date only few published studies have involved cancer patients. The goal of this study was to test the hypothesis that circulating MDSC levels correlate with clinical cancer stage, CTX-based chemotherapy, and metastatic tumor burden. Whole blood was collected from 106 newly diagnosed solid tumor patients (stages I-IV). Percentages of circulating MDSC (Lin(-/Lo), HLA DR-, CD33(+)CD11b(+)) were determined prior to initiation of systemic therapy. In 17 early stage breast cancer patients receiving doxorubicin-cyclophosphamide chemotherapy every 14 days (ddAC) blood was collected on day 1 of each cycle. Circulating MDSC were significantly increased in cancer patients of all stages relative to healthy volunteers. A significant correlation between circulating MDSC and clinical cancer stage was also observed. Moreover, among stage IV patients, those with extensive metastatic tumor burden had the highest percent and absolute number of MDSC. Significant increases in circulating MDSC were observed with ddAC when compared with pretreatment levels. Circulating MDSC levels correlate with clinical cancer stage, ddAC, and metastatic tumor burden. This information must be incorporated into the design of future trials exploring immune-based therapeutic strategies. Pharmacologic modulation of MDSC should also be tested in future clinical trials.


Podocyte-Specific Deletion of Murine CXADR Does Not Impair Podocyte Development, Function or Stress Response.
The coxsackie- and adenovirus receptor (CXADR) is a member of the immunoglobulin protein superfamily, present in various epithelial cells including glomerular epithelial cells. Beside its known function as a virus receptor, it also constitutes an integral part of cell-junctions. Previous studies in the zebrafish pronephros postulated a potential role of CXADR for the terminal differentiation of glomerular podocytes and correct patterning of the elaborated foot process architecture. However, due to early embryonic lethality of constitutive Cxadr knockout mice, mammalian data on kidney epithelial cells have been lacking. Interestingly, Cxadr is robustly expressed during podocyte development and in adulthood in response to glomerular injury. We therefore used a conditional transgenic approach to elucidate the function of Cxadr for podocyte development and stress response. Surprisingly, we could not discern a developmental phenotype in podocyte specific Cxadr knock-out mice. In addition, despite a significant up regulation of CXADR during toxic, genetic and immunologic podocyte injury, we could not detect any impact of Cxadr on these injury models. Thus these data indicate that in contrast to lower vertebrate models, mammalian podocytes have acquired molecular programs to compensate for the loss of Cxadr.


Modern atrial and ventricular leads for permanent cardiac pacing.
Three hundred and fifteen transvenous pacing leads of various modern designs have been assessed over a period of three years. Of these, 103 were implanted in the atrium and 212 in the ventricle. Screw-in leads in the right atrial appendage and short tined leads in the ventricle have resulted in the virtual elimination of lead displacement, and a very low incidence of other lead related problems. In two lead systems it has been found advantageous to have both leads constructed of urethane.


Prospective evaluation of the relationship of patient age and paclitaxel clinical pharmacology: Cancer and Leukemia Group B (CALGB 9762).
To prospectively evaluate the pharmacokinetics and toxicity profile of paclitaxel in relation to patient age in adults > or = 55 years old. Paclitaxel was administered at 175 mg/m2 for 3 hours to 153 patients, 46 of whom were > or = 75 years of age. Pharmacokinetic and toxicity assessments were performed. Data were analyzed by cohort (cohort 1, age 55 to 64 years; cohort 2, age 65 to 74 years; cohort 3, age > or = 75 years). Paclitaxel concentration versus time (AUC) and total-body clearance (CL(tb)) data were available for 122 patients (cohort 1, 46 patients; cohort 2, 44 patients; cohort 3, 32 patients). Mean paclitaxel AUC increased across cohorts (P = .01). Mean (SE) AUCs were 22.4 (2.5) micromol/L x hour, 26.2 (2.8) micromol/L x hour, and 31.7 (5.6) micromol/L x hour for cohorts 1, 2, and 3, respectively. There was a corresponding significant (P = .007) age-related decrease in mean (SE) paclitaxel CL(tb) (cohort 1, 11.0 [0.7] L/h/m2; cohort 2, 9.3 [0.6] L/h/m2; cohort 3, 8.2 [0.6] L/h/m2). Patients in cohort 3 experienced significantly lower absolute neutrophil count nadirs than did younger groups (P = .02). There was also a significant increase in percentage of patients with > or = grade 3 neutropenia across age cohorts (cohort 1, 22%; cohort 2, 35%; cohort 3, 49%; P = .006). However, the increased exposure of patients to paclitaxel and increased neutropenia were not reflected in adverse clinical sequelae such as hospitalization for toxicity (P = .82), receiving intravenous antibiotics (P = .21), or experiencing a temperature more than 38 degrees C (P = .45). Although paclitaxel CL(tb) decreases with increasing patient age, there is great interpatient variability. Cooperative group studies to evaluate the effect of aging on pharmacokinetics are feasible.


Variation in newborn size according to pregnancy weight change by trimester.
The timing of maternal weight change in pregnancy may be an important determinant of the newborn's size. The purpose was to identify effects of maternal weight change by trimester on newborn size, under the hypothesis that low weight gain early in pregnancy predicts proportionately smaller newborns. Women planning to become pregnant were followed by clinic visits and questionnaires through delivery. This study includes 389 women and their singleton infants born at a gestational age of > or = 241 d. In multiple regression analyses including a variety of potential confounders, maternal weight gain in the first and second trimesters predicted newborn weight (1-kg weight gain in the first trimester predicted a 31-g increase in newborn weight, P < 0.0007, and 1-kg weight gain in the second trimester predicted a 26-g increase in newborn weight, P < 0.007), but weight gain in the third trimester did not. Newborn ponderal index (in kg/m(3)) was predicted by weight gain in the first (1-kg weight gain predicted an added 0.21 units, P < 0.0003) and third (1-kg weight gain predicted an added 0.12 units, P < 0.03) trimesters but not in the second trimester. Newborn weight was 211 g lower (P < 0.006) and ponderal index 1.2 units lower (P < 0.02) in infants born to women who lost weight in the first trimester. The use of measured prepregnancy weight in tests of the effect on newborn size of weight gain by time in pregnancy produces different results than does the use of recalled prepregnancy weight. Maternal weight change in the first trimester of pregnancy more strongly influences newborn size than does weight change in the second or third trimester.


A study of the responsibilities of chief residents in anesthesiology with a suggested job description.
We requested information concerning the job description for the chief resident in anesthesiology from 50 different programs. Thirty-two responses were returned, with 9 responses that no such job description existed at their institutions. Eighteen of the remaining 23 respondents had a written job description for the position. Considerable variation existed in the various aspects of the position among institutions. Differences were found in the selection process, administrative duties, number of committee memberships, and educational responsibilities. We present a suggested description of the responsibilities for a chief resident in anesthesiology.


Primary Succession on a Hawaiian Dryland Chronosequence.
We used measurements from airborne imaging spectroscopy and LiDAR to quantify the biophysical structure and composition of vegetation on a dryland substrate age gradient in Hawaii. Both vertical stature and species composition changed during primary succession, and reveal a progressive increase in vertical stature on younger substrates followed by a collapse on Pleistocene-aged flows. Tall-stature Metrosideros polymorpha woodlands dominated on the youngest substrates (hundreds of years), and were replaced by the tall-stature endemic tree species Myoporum sandwicense and Sophora chrysophylla on intermediate-aged flows (thousands of years). The oldest substrates (tens of thousands of years) were dominated by the short-stature native shrub Dodonaea viscosa and endemic grass Eragrostis atropioides. We excavated 18 macroscopic charcoal fragments from Pleistocene-aged substrates. Mean radiocarbon age was 2,002 years and ranged from < 200 to 7,730. Genus identities from four fragments indicate that Osteomeles spp. or M. polymorpha once occupied the Pleistocene-aged substrates, but neither of these species is found there today. These findings indicate the existence of fires before humans are known to have occupied the Hawaiian archipelago, and demonstrate that a collapse in vertical stature is prevalent on the oldest substrates. This work contributes to our understanding of prehistoric fires in shaping the trajectory of primary succession in Hawaiian drylands.


The twin arginine transport system appears to be essential for viability in Sinorhizobium meliloti.
The twin arginine transport (Tat) system is responsible for transporting prefolded proteins to the periplasmic space. The Tat pathway has been implicated in many bacterial cellular functions, including motility, biofilm formation, and pathogenesis and symbiosis. Since the annotation of Sinorhizobium meliloti Rm1021 genome suggests that there may be up to 94 putative Tat substrates, we hypothesized that characterizing the twin arginine transport system in this organism might yield unique data that could help in the understanding of twin arginine transport. To initiate this work we attempted a targeted mutagenesis of the tat locus. Despite repeated attempts using a number of different types of media, the attempts at mutation construction were unsuccessful unless the experiment was carried out in a strain that was merodiploid for tatABC. In addition, it was shown that a plasmid carrying tatABC was stable in the absence of antibiotic selection in a tat deletion background. Finally, fluorescence microscopy and live/dead assays of these cultures show a high proportion of dead and irregularly shaped cells, suggesting that the loss of tatABC is inversely correlated with viability. Taken together, the results of this work provide evidence that the twin arginine transport system of S. meliloti appears to be essential for viability under all the conditions that we had tested.


Prediction of bacteremia using TREAT, a computerized decision-support system.
Prediction of bloodstream infection at the time of sepsis onset allows one to make appropriate and economical management decisions. The TREAT computerized decision-support system uses a causal probabilistic network, which is locally calibrated, to predict cases of bacteremia. We assessed the system's performance in 2 independent cohorts that included patients with suspected sepsis. Both studies were conducted in Israel, Italy, and Germany. Data were collected prospectively and were entered into the TREAT system at the time that blood samples were obtained for culture. Discriminative power was assessed using a receiver-operating characteristics curve. In the first cohort, 790 patients were included. The area under the receiver-operating characteristics curve for prediction of bacteremia using the TREAT system was 0.68 (95% confidence interval [CI], 0.63-0.73). We used TREAT's prediction values to draw thresholds defining a low-, intermediate-, and high-risk groups for bacteremia, in which 3 (2.4%) of 123, 62 (12.8%) of 483, and 55 (29.9%) of 184 patients were bacteremic, respectively. In the second cohort, 1724 patients were included. The area under the receiver-operating characteristics curve was 0.70 (95% CI, 0.67-0.73). The prevalence of bacteremia observed in the low-, intermediate-, and high-risk groups defined by the first cohort were 1.3% (4 of 300 patients), 13.2% (150 of 1139 patients), and 28.1% (80 of 285 patients), respectively. The low-risk groups in the 2 cohorts comprised 15%-17% of all patients. Performance was stable in the 3 sites. Using variables available at the time that blood cultures were performed, the TREAT system successfully stratified patients on the basis of the risk for bacteremia. The system's predictions were stable in 3 locations. The TREAT system can define a low-risk group of inpatients with suspected sepsis for whom blood cultures may not be needed.


Moment in History. In the beginning.
The purpose of this editorial is to give the reader a picture of the earliest days in the delivery of chronic dialysis. It is viewed by a psychiatrist who was asked to help evaluate patients in one of the first hemodialysis centers, not only in the United States, but in the world.


Prospective Evaluation of Structural Allograft Transplantation for Osteochondral Lesions of the Talar Shoulder.
Structural or bulk osteochondral allograft transplantation for shoulder talar osteochondral lesions as a salvage procedure has demonstrated efficacy in several retrospective reviews. The purpose of this study was to evaluate prospectively patients who received fresh structural allograft transplantation to the talus. Prospective evaluation of a consecutive series of patients who underwent fresh structural allograft transplantation for an osteochondral lesion of the talus (OLT) was performed. Preoperative magnetic resonance imaging (MRI) and/or computed tomography (CT) and plain radiographs were obtained on all patients. The following patient-reported outcomes questionnaires were administered preoperatively and yearly after surgery: 100-mm visual analog scale (VAS) pain scale, American Orthopaedic Foot & Ankle Society (AOFAS) Ankle-Hindfoot Scale, Short Form 36 (SF-36), and the Short Musculoskeletal Functional Assessment (SMFA). Preoperative and postoperative radiographs were assessed for allograft incorporation and subsequent arthritis. Fourteen patients with an average age of 40 years (range, 18-69) and a mean follow-up of 55 months (range, 24-97) underwent structural fresh osteochondral allograft transplantation to the talar shoulder. The average size of the OLT was 2269 mm3 (range, 813-8366) based on CT imaging and 5797 mm3 (range, 1136-12 489) based on MRI imaging. There was significant ( P < .05) improvement in the VAS pain, AOFAS scale, SF-36, and SMFA scores. Five (36%) of the patients required additional surgery for pain and stiffness. Two patients had cartilage delamination and were considered treatment failures. Therefore, the success rate was 86% (12/14). Significant improvement in pain and function was achieved with structural allograft transplantation for large OLTs at midterm follow-up. This was a safe and effective treatment option in this small series for large OLTs. Level IV, prospective case series.


[Ultrasonically guided antegrade pyelography in kidney transplantations].
The indications for, and technique of ultrasound-guided antegrade pyelography of renal transplants are illustrated by eight patients. Because of the detailed anatomical information which the antegrade method provides, it is superior to other diagnostic methods for the investigation of ureteric obstruction or fistulae. The severity of renal pelvis dilatation as shown by sonography must not be taken as a criterian for the grade of obstruction, since transplants may show dilated collecting systems, even in the absence of obstruction. In our view, real time sonography with a suitable probe provides the best means of achieving successful puncture of the renal pelvis. The combination of ultrasound-guided puncture and radiological contrast examination of the ureter is the best diagnostic method available and lead, in all eight cases, to immediate and definitive treatment.


Hormones modulate adipocyte membrane potential ATP and lipolysis via free fatty acids.
The hypothesis that lipolytic hormones reduce the mitochondrial electrical potential in rat white adipocytes via free fatty acids (FFA) was examined. Hormonal effects on plasma and mitochondrial membrane potentials were evaluated with [3H]triphenylmethylphosphonium (TPMP+) and 86Rb+. FFA generation was controlled by varying medium albumin concentrations. In 4.0% albumin buffer, adrenocorticotropin or l-epinephrine increased intracellular FFAs, produced cellular TPMP+ efflux, ATP depletion, release of FFAs and glycerol, and no change in 86Rb+ distribution. In 0.5% albumin buffer, greater intracellular FFA accumulation accompanied greater TPMP+ and ATP depletion, significant loss of cell-associated 86Rb+, and a concomitant inhibition of FFA and glycerol release. Exogenous addition of FFAs mimicked the effect of hormones on adipocyte TPMP+ distribution. TPMP+ and 86Rb+ uptake into adipocyte "ghosts" were unaffected by hormones. We suggest that mitochondrial membrane depolarization is a metabolic response to hormones via FFA accumulation by white adipocytes. The additional hormonal effects that were observed in 0.5% albumin buffer may be related to inhibition of lipolysis secondary to intracellular ATP depletion.


Early initiation of cinacalcet for the treatment of secondary hyperparathyroidism in hemodialysis patients: a three-year clinical experience.
Despite the availability of standard therapy (vitamin D sterols and phosphate binders) for the treatment of secondary hyperparathyroidism (SHPT) in hemodialyzed (HD) patients, a significant percentage of patients still fail to achieve targets recommended by the Kidney Disease Outcomes Quality Initiative (K/DOQI) of the National Kidney Foundation for parathyroid hormone (PTH), calcium, and phosphorus. The calcimimetic cinacalcet (CN) has been shown to be an effective treatment for SHPT, significantly reducing serum PTH while simultaneously lowering calcium, phosphorus, and calcium-phosphorus product levels, thus increasing the proportion of patients achieving the K/DOQI targets for bone mineral parameters. The aim of this study was to evaluate if early treatment with CN had beneficial effects in HD patients with mild-to-moderate SHPT in whom conventional treatments had failed to achieve NKF-K/DOQI targets for PTH, serum-corrected calcium, and phosphorus while minimizing the risk of paradoxical hypercalcemia and/or hyperphosphatemia. Clinical practice data were collected monthly, starting from 6 months prior to, and up to 36 months after, the start of CN therapy. CN was started at a dose of 30 mg daily or every other day, and titrated thereafter to achieve intact PTH (iPTH) <300 pg/mL. The dose of concomitant vitamin D and phosphate binders were also adjusted in order to achieve K/DOQI targets. Data from 32 patients were collected, 28 of whom had been treated with CN for at least 36 months at the time of data analysis. At baseline, patients had serum iPTH >300 pg/mL (570 ± 295 pg/mL) and/or serum-corrected calcium >9.5 mg/dL. CN induced significant decreases in iPTH, calcium, and calcium-phosphorus product with respect to baseline levels. The percentage of patients within K/DOQI target levels at baseline, 12, 24, and 36 months was 0, 81.2, 83.3, and 86.2% for iPTH; 34.4, 65.6, 86.6, and 89.6% for serum-corrected calcium; 40.6, 56.2, 69.6, and 72.4% for phosphorus; and 37.5, 62.5, 80, and 82.7% for calcium-phosphorus product. The mean dose of CN at the end of the observation period was 38 mg/day. The mean dose of concomitant medication (calcitriol, Al-containing phosphate binders, and sevelamer) decreased from baseline to 36 months. Early treatment with CN in HD patients with SHPT increases the proportion of patients achieving and maintaining K/DOQI targets with a low dose of CN (38 mg/day). These results suggest that the metabolic control obtained with low-dose CN administered early in the course of SHPT can be maintained or increased over time.


Further evaluation of colostomy in penetrating colon injury.
Our objective was to compare, in a randomized prospective format, complication rates associated with primary repair versus fecal diversion in penetrating colon injury. During a 72-month period, 181 patients with penetrating colon injuries were entered in a randomized prospective study at an urban Level I trauma center. After intraoperative identification of colon injuries, patients were randomized to a primary repair or a diversion group. Randomization was independent of previously identified risk factors, including severity of colon injury, presence of hypotension, blood loss, extent of fecal contamination, and time from injury to operation. Five patients initially entered in the study protocol were removed because they died in the immediate postoperative period (< 24 hours). One hundred seventy-six patients were studied, of which 89 were randomized to primary repair and 87 to diversion. The average age in the diversion group was 26.4 years and it was 28.0 years in the primary repair group (P > 0.05). The average Penetrating Abdominal Trauma Index for the diversion group was 22.3, and it was 23.7 for the primary repair group (P > 0.05). There were 18 (21%) septic related complications in the diversion group and 16 (18%) in the primary repair group (P > .05). With respect to risk factors, complication rates were not higher in one study group versus the other. We conclude that, in the civilian population, all penetrating colon injuries should be managed with primary repair.


Health-Related Quality of Life for Parents of Infants with Bronchopulmonary Dysplasia.
To determine how bronchopulmonary dysplasia (BPD) affects health-related quality of life (HRQL) among infants from NICU hospitalization through 1-year postdischarge. This was a prospective cohort study of infants with BPD and their parents. Parent HRQL was measured with the PedsQL Family Impact Module before NICU discharge and 3- and 12-months post-discharge. At 12 months, parent-reported child health outcomes included questions from the Test of Respiratory and Asthma Control in Kids, Warner Initial Developmental Evaluation of Adaptive and Functional Skills, and National Survey of Children with Special Health Care Needs. HRQL change over time was assessed by multivariable linear regression. Of 145 dyads, 129 (89%) completed 3-month follow-up, and 113 (78%) completed 12-month follow-up. In the NICU, lower HRQL was associated with earlier gestational age, postnatal corticosteroids, outborn status, and gastrostomy tubes. At 3 months, lower HRQL was associated with readmissions and home oxygen use. At 12 months, lower HRQL was associated with parent-reported difficulty breathing, lower developmental scores, and not playing with other children. At 3 and 12 months, 81% of parents reported similar or improved HRQL compared with the NICU period. Parents reporting infant respiratory symptoms experienced less improvement. BPD affects parent HRQL over the first year. Most parents report similar or better HRQL after discharge compared with the NICU stay. Less improvement is reported by parents of infants experiencing respiratory symptoms at 12 months. Efforts to improve parent HRQL should target respiratory symptoms and social isolation.


Isolation from the rumen of a new acetogenic bacterium phylogenetically closely related to Clostridium difficile.
Five strains of filamentous acetogenic bacterium were isolated from high dilutions of ruminal content of newborn lambs. These Gram-positive spore-forming bacteria grew either chemolithotrophically with H2+ CO2 or chemo-organotrophically with glucose, cellobiose, fructose, maltose, mannose and syringic acid. The DNA base composition of the five strains were between 29.1 and 31.3 mol% G + C. Their temperature and pH optimum for growth were 35-40 degrees C and 6.5-7.0, respectively. The full 16S rRNA gene sequence analysis of the reference strain indicated that it was most closely related to Clostridium difficile. The sequence similarity value between the 16S rRNA gene of the reference strain and this pathogenic strain was 99.7%.


Secretome analysis: Reading cellular sign language to understand intercellular communication.
A significant portion of mammalian proteomes is secreted to the extracellular space to fulfill crucial roles in cell-to-cell communication. To best recapitulate the intricate and multi-faceted crosstalk between cells in a live organism, there is an ever-increasing need for methods to study protein secretion in model systems that include multiple cell types. In addition, post-translational modifications further expand the complexity and versatility of cellular communication. This review aims to summarise recent strategies and model systems that employ cellular co-culture, chemical biology tools, protein enrichment and proteomic methods to characterize the composition and function of cellular secretomes. This is all geared towards gaining better understanding of organismal biology in vivo mediated by secretory signaling.


Ensemble Neural Networks (ENN): A gradient-free stochastic method.
In this study, an efficient stochastic gradient-free method, the ensemble neural networks (ENN), is developed. In the ENN, the optimization process relies on covariance matrices rather than derivatives. The covariance matrices are calculated by the ensemble randomized maximum likelihood algorithm (EnRML), which is an inverse modeling method. The ENN is able to simultaneously provide estimations and perform uncertainty quantification since it is built under the Bayesian framework. The ENN is also robust to small training data size because the ensemble of stochastic realizations essentially enlarges the training dataset. This constitutes a desirable characteristic, especially for real-world engineering applications. In addition, the ENN does not require the calculation of gradients, which enables the use of complicated neuron models and loss functions in neural networks. We experimentally demonstrate benefits of the proposed model, in particular showing that the ENN performs much better than the traditional Bayesian neural networks (BNN). The EnRML in ENN is a substitution of gradient-based optimization algorithms, which means that it can be directly combined with the feed-forward process in other existing (deep) neural networks, such as convolutional neural networks (CNN) and recurrent neural networks (RNN), broadening future applications of the ENN.


The prognostic value of initial serum lactate for survival in postcardiac arrest patients undergoing cardiac catheterization.
We sought to investigate the prognostic value of serum lactate on survival in patients postcardiac arrest. Patients who experience cardiac arrest, in- or out-of-hospital, may have a poor outcome. Initial electrocardiograms may suggest ischemia as an underlying cause and urgent referral for catheterization occurs. It remains unclear which of these patients may suffer a poor outcome. We retrospectively reviewed all patients at our institution taken for urgent catheterization after cardiac arrest between January 2014 and September 2018. Three hundred and eighty four patients were referred urgently to the cath lab during this period, 50 with prior arrest. Sixty six percent underwent coronary intervention. The mean age of the entire cohort was 57 years. Thirty four percent were female, 40% had a history of coronary artery disease, and 94% were intubated at the time of cardiac catheterization. Overall survival to discharge was 40%. Survival in patients who underwent coronary intervention compared with those who did not was similar (45.5 vs. 29.4%, p = .27). Mean lactate level in survivors versus nonsurvivors was 4.7 ± 3.8 and 9.8 ± 4.7 mmol/L, respectively (p < .05). When divided into tertiles by serum lactate (< 4.5, 4.5-9, 9 mmol/L), survival to discharge was 75, 29.4, and 17.6%, respectively (p < .05). Initial serum lactate and age were independent predictors of in-hospital mortality. In patients undergoing cardiac catheterization following cardiac arrest, routine measurement of serum lactate is a useful and available laboratory test that may help identify patients at risk for a poor outcome.


Association Between Alkaline Phosphatase and Clinical Outcomes in Patients With Spontaneous Intracerebral Hemorrhage.
Background: Spontaneous intracerebral hemorrhage (ICH) is associated with high rates of mortality and morbidity. Alkaline phosphatase (ALP) is related to increased risk of cardiovascular events and is also closely associated with adverse outcomes after ischemic or hemorrhagic stroke. However, there are limited data about the effect of ALP on clinical outcomes after ICH. Therefore, we aimed to investigate the relationship between serum ALP level and prognosis in ICH patients. Methods: From January 2014 to September 2016, 939 patients with spontaneous ICH were enrolled in our study from 13 hospitals in Beijing. Patients were categorized into four groups based on the ALP quartiles (Q1, Q2, Q3, Q4). The main outcomes were 30-day, 90-day, and 1-year poor functional outcomes (modified Rankin Scale score of 3-6). Multivariable logistic regression and interaction analyses were performed to evaluate the relationships between ALP and clinical outcomes after ICH. Results: In the logistic regression analysis, compared with the third quartile of ALP, the adjusted odds ratios of the Q1, Q2, and Q4 for 30-day poor functional outcome were 1.31 (0.80-2.15), 1.16 (0.71-1.89), and 2.16 (1.32-3.55). In terms of 90-day and 1-year poor functional outcomes, the risks were significantly higher in the highest quartile of ALP compared with the third quartile after adjusting the confounding factors [90-day: highest quartile OR = 1.86 (1.12-3.10); 1-year: highest quartile OR = 2.26 (1.34-3.80)]. Moreover, there was no significant interaction between ALP and variables like age or sex. Conclusions: High ALP level (>94.8 U/L) was independently associated with 30-day, 90-day, and 1-year poor functional outcomes in ICH patients. Serum ALP might serve as a predictor for poor functional outcomes after ICH onset.


[Skin involvement in Hodgkin's disease].
We report a case of a previously diagnosed patient of Hodgkin's disease, nodular sclerosis type and IVLDB stage. This patient subsequently presented a dermatologic nodule. A specimen cutaneous biopsy was performed and the histopathologic study demonstrated a dermal infiltrate with many classic Reed-Sternberg giant cells. These findings were consistent with the skin involvement in Hodgkin's disease. Specific cutaneous lesions are rare in this lymphoma and therefore it may be argued that our patient had a lymphomatoid papulosis. However, the protracted clinical course would not support this concept, because the dermatologic lesion responded to chemotherapy and it is well-known that the clinical course of the lymphomatoid papulosis is unaffected by these treatments. We concluded that our patient is a case of specific skin involvement in Hodgkin's disease.


The making and breaking of paternity secrets in donor insemination.
This paper analyses the complex issues faced by regulators of the infertility treatment industry in response to the social and technological changes that heralded a new openness in knowledge about genetics, paternity and the concomitant need for donor offspring to know their genetic origins. The imperative for full information about their donor and biological father, who contributed to their creation and half of their genome, was an outcome unanticipated by the architects of the donor insemination programme. Genetic paternity testing realised the possibility of fixed and certain knowledge about paternity. This paper outlines medicine's role in the formation of normative families through the use of donor insemination. Extending information from an Australian study on the use of DNA paternity testing, it analyses what the social and scientific changes that have emerged and gained currency in the last several decades mean for the new 'openness' and the role of paternity testing in this context. It concludes with recommendations about how to deal with the verification of paternity in linking donor conceived adult children to their donor.


New insights into diabetes mellitus and its complications: a narrative review.
Diabetes is a metabolic disorder accompanied by complications of multiple organs and systems. Diabetic nephropathy (DN) is one of the most prevalent lethal complications of diabetes. Although numerous biomarkers have be clarified for early diagnosis of DN, renal biopsy is still the gold standard. As a noninvasive imaging diagnostic method, blood oxygen level-dependent (BOLD) MRI can help understand the kidney oxygenation status and fibrosis process and monitor the efficacy of new drugs for DN via monitoring renal blood oxygen levels. Recent studies have shown that noncoding RNAs including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) were all involved in the development of DN, which could be exploited as therapeutic strategy to control DN. Dyslipidemia is also a common complication of diabetes. Apolipoprotein M (apoM), as a novel apolipoprotein, may be related to the development and progression of diabetes, which need to further investigation. Obstructive sleep apnea (OSA) is another common complication of diabetes and is an independent risk factor for cardiovascular disease (CVD). At present, there is no simple, effective and rapid diagnostic method to early identification of OSA in patients with diabetes. A nomogram consisted of waist-to-hip ratio, smoking status, body mass index, serum uric acid, HOMA-IR and history of fatty liver might be an alternative method to early assess the risk of OSA.


Electrophysiological studies of chilean squid axons under internal perfusion with sodium-rich media.
Electrophysiological properties of giant axons of Chilean squid were examined by intracellular perfusion combined with various recording techniques. The amplitude of the action potential of the axons perfused with equal sodium concentrations (0.35M) on both sides of the membrane was approximately 75 millivolts (glutamate salts being used internally); the resting potential recorded with a calomel electrode was roughly 45 mv. These observations confirm and extend previous data, obtained from Chilean squid axons, which show that the amplitude of the action-potential overshoot does not agree with the Nernst equation applied to sodium ion. The discrepancy between these results and those obtained by others is attributed to differences in the procedures used to determine the resting potential.


miR-34a induces the downregulation of both E2F1 and B-Myb oncogenes in leukemic cells.
To elucidate new molecular mechanisms able to downregulate the mRNA levels of key oncogenes, such as B-Myb and E2F1, in a therapeutic perspective. B-Myb and E2F1 mRNA levels were evaluated in primary B chronic lymphocytic leukemia (B-CLL, n = 10) and acute myeloid leukemia (AML, n = 5) patient cells, in a variety of p53(wild-type) and p53(mutated/deleted) leukemic cell lines, as well as in primary endothelial cells and fibroblasts. Knockdown experiments with siRNA for p53 and E2F1 and overexpression experiments with miR34a were conducted to elucidate the role of these pathways in promoting B-Myb downregulation. In vitro exposure to Nutlin-3, a nongenotoxic activator of p53, variably downregulated the expression of B-Myb in primary leukemic cells and in p53(wild-type) myeloid (OCI, MOLM) and lymphoblastoid (SKW6.4, EHEB) but not in p53(mutated) (NB4, BJAB, MAVER) or p53(deleted) (HL-60) leukemic cell lines. The transcriptional repression of B-Myb was also observed in primary normal endothelial cells and fibroblasts. B-Myb downregulation played a critical role in the cell-cycle block in G(1) phase induced by Nutlin-3, as shown by transfection experiments with specific siRNA. Moreover, we have provided experimental evidence suggesting that miR-34a is a central mediator in the repression of B-Myb both directly and through E2F1. Owing to the role of B-Myb and E2F1 transcription factors in controlling cell-cycle progression of leukemic cells, the downregulation of these oncogenes by miR-34a suggests the usefulness of therapeutic approaches aimed to modulate the levels of miR-34a.


Hepatic and muscle clearance of physostigmine in the rat.
Physostigmine (Phy) was rapidly metabolized by rat liver after iv (100 micrograms/kg) or im (650 micrograms/kg) administration. The half-life of Phy in liver after iv and im administration was found to be 24 and 26 min, respectively, indicating that Phy does not show dose-dependent kinetics. The half-life of Phy in muscle after iv administration was 20 min. The extraction ratio and the clearance from the liver and muscle were calculated. Hepatic clearance ws found to be 23.08 ml/min/kg (34.90% of systemic clearance) and the intrinsic clearance from the liver was 83.73 ml/min/kg. The percentage dose was found to be maximal in the muscle and the clearance was about 5.2 ml/min/kg. It appears that 30-40% of radioactivity was bound to the liver precipitate and could not be washed off by 10% trichloroacetic acid or organic solvents. Phy and the metabolites, eseroline (Es), M1, M2, and M3 were separated by HPLC, collecting the radioactive fractions. The time course of radioactivity per gram of liver after iv dosing (100 micrograms/kg), showed the major metabolite to be M1, followed by M2 and Es, whereas after im dosing (650 micrograms/kg), Es was present in larger amounts than were other metabolites. Phy appeared to be slowly metabolized in the muscle after iv administration. Liver played a major role in the metabolism of Phy.


Associations Between Childhood Abuse and COVID-19 Hyperarousal in Adulthood: The Role of Social Environment.
Childhood abuse increases risk for high levels of distress in response to future stressors. Interpersonal social support is protective for health, particularly during stress, and may be particularly beneficial for individuals who experienced childhood abuse. Investigate whether childhood abuse predicts levels of posttraumatic stress disorder (PTSD) symptoms related to the COVID-19 pandemic, and test whether the perceived availability of social companionship preceding the pandemic moderates this relationship. During Phase 1, adults (N = 120; Age M[SD] = 19.4 [0.94]) completed a retrospective measure of childhood adversity along with a measure of perceived availability of opportunities for social engagement immediately preceding the pandemic. Two weeks after the COVID-19 pandemic declaration, participants completed the Impact of Event Scale-Revised (IES-R) with respect to the pandemic. Hierarchical linear regression analyses examined the interaction between childhood abuse and the perceived availability of social companionship preceding the pandemic as a predictor of PTSD symptoms. Adjusting for covariates, the interaction between childhood abuse and perceived availability of others to engage with before the onset of the pandemic was a significant predictor of IES-hyperarousal (β = -0.19, t = -2.06, p = 0.04, ΔR 2 = 0.032, CI: [-0.31 to -0.01]). Levels of perceived opportunities for social companionship before the pandemic associates with levels of hyperarousal related to the pandemic, particularly for individuals who experienced high levels of childhood abuse. More research is needed to understand how to mitigate the higher levels of distress related to the pandemic for these individuals in order to reduce risk for future psychiatric disorders.


A widespread viral entry mechanism: The C-end Rule motif-neuropilin receptor interaction.
Many phylogenetically distant animal viruses, including the new coronavirus severe acute respiratory syndrome coronavirus 2, have surface proteins with polybasic sites that are cleaved by host furin and furin-like proteases. Other than priming certain viral surface proteins for fusion, cleavage generates a carboxy-terminal RXXR sequence. This C-end Rule (CendR) motif is known to bind to neuropilin (NRP) receptors on the cell surface. NRPs are ubiquitously expressed, pleiotropic cell surface receptors with important roles in growth factor signaling, vascular biology, and neurobiology, as well as immune homeostasis and activation. The CendR-NRP receptor interaction promotes endocytic internalization and tissue spreading of different cargo, including viral particles. We propose that the interaction between viral surface proteins and NRPs plays an underappreciated and prevalent role in the transmission and pathogenesis of diverse viruses and represents a promising broad-spectrum antiviral target.


Adherence to Depression Treatment in Primary Care: A Randomized Clinical Trial.
Nonadherence to antidepressant medication is common and leads to poor outcomes. Early nonadherence is especially problematic. To test the effectiveness of a psychosocial intervention to improve early adherence among older patients whose primary care physician newly initiated an antidepressant for depression. The Treatment Initiation and Participation Program (TIP) was offered in a 2-site randomized clinical effectiveness study between January 2011 and December 2014 at primary care practices in New York, New York, and Ann Arbor, Michigan. Analyses began in February 2016. All participants were middle-aged and older adults (aged ≥55 years) who received newly initiated depression treatment by their primary care physician and recruited within 10 days of their prescription. Analyses were intention-to-treat. Participants were randomly assigned to the intervention (TIP) or treatment as usual. Participants in the TIP group identified and addressed barriers to adherence, including stigma, misconceptions, and fears about treatment, before developing a personalized adherence strategy. The Treatment Initiation and Participation Program was delivered in three 30-minute contacts scheduled during a 6-week period just after the antidepressant was prescribed. The primary outcome was self-reported adherence on the Brief Medication Questionnaire, with adequate early adherence defined as taking 80% or more of the prescribed doses at 6 and 12 weeks. The secondary outcome was depression severity. In total, 231 middle-aged and older adults (167 women [72.3%] and 64 men [27.7%]) without significant cognitive impairment were randomly assigned to the TIP intervention (n = 115) or treatment as usual (n = 116). Participants had a mean (SD) age of 67.3 (8.4) years. Participants in the TIP group were 5 times more likely to be adherent at 6 weeks (odds ratio, 5.54; 95% CI, 2.57 to 11.96; χ21 = 19.05; P < .001) and 3 times more likely to be adherent at both 6 and 12 weeks (odds ratio, 3.27; 95% CI, 1.73 to 6.17; χ21 = 13.34; P < .001). Participants in the TIP group showed a significant earlier reduction (24.9%) in depressive symptoms (95% CI, 13.9 to 35.9; t337 = 4.46; adjusted P < .001). In both groups, participants who were 80% adherent at weeks 6 and 12 had a 15% greater improvement in depressive symptoms from baseline over the course of treatment (95% CI, -0.2 to -30; t369 = 1.93; P = .051). The Treatment Initiation and Participation Program is an effective intervention to improve early adherence to pharmacotherapy. Improved adherence can promote improvement in depression. clinicaltrials.gov Identifier: NCT01301859.


NK cell terminal differentiation: correlated stepwise decrease of NKG2A and acquisition of KIRs.
Terminal differentiation of NK cells is crucial in maintaining broad responsiveness to pathogens and discriminating normal cells from cells in distress. Although it is well established that KIRs, in conjunction with NKG2A, play a major role in the NK cell education that determines whether cells will end up competent or hyporesponsive, the events underlying the differentiation are still debated. A combination of complementary approaches to assess the kinetics of the appearance of each subset during development allowed us to obtain new insights into these terminal stages of differentiation, characterising their gene expression profiles at a pan-genomic level, their distinct surface receptor patterns and their prototypic effector functions. The present study supports the hypothesis that CD56dim cells derive from the CD56bright subset and suggests that NK cell responsiveness is determined by persistent inhibitory signals received during their education. We report here the inverse correlation of NKG2A expression with KIR expression and explore whether this correlation bestows functional competence on NK cells. We show that CD56dimNKG2A-KIR+ cells display the most differentiated phenotype associated to their unique ability to respond against HLA-E+ target cells. Importantly, after IL-12+IL-18 stimulation, reacquisition of NKG2A strongly correlates with IFN-gamma production in CD56dimNKG2A- NK cells. Together, these findings call for the reclassification of mature human NK cells into distinct subsets and support a new model, in which the NK cell differentiation and functional fate are based on a stepwise decrease of NKG2A and acquisition of KIRs.


Enhancing clinical concept extraction with distributional semantics.
Extracting concepts (such as drugs, symptoms, and diagnoses) from clinical narratives constitutes a basic enabling technology to unlock the knowledge within and support more advanced reasoning applications such as diagnosis explanation, disease progression modeling, and intelligent analysis of the effectiveness of treatment. The recent release of annotated training sets of de-identified clinical narratives has contributed to the development and refinement of concept extraction methods. However, as the annotation process is labor-intensive, training data are necessarily limited in the concepts and concept patterns covered, which impacts the performance of supervised machine learning applications trained with these data. This paper proposes an approach to minimize this limitation by combining supervised machine learning with empirical learning of semantic relatedness from the distribution of the relevant words in additional unannotated text. The approach uses a sequential discriminative classifier (Conditional Random Fields) to extract the mentions of medical problems, treatments and tests from clinical narratives. It takes advantage of all Medline abstracts indexed as being of the publication type "clinical trials" to estimate the relatedness between words in the i2b2/VA training and testing corpora. In addition to the traditional features such as dictionary matching, pattern matching and part-of-speech tags, we also used as a feature words that appear in similar contexts to the word in question (that is, words that have a similar vector representation measured with the commonly used cosine metric, where vector representations are derived using methods of distributional semantics). To the best of our knowledge, this is the first effort exploring the use of distributional semantics, the semantics derived empirically from unannotated text often using vector space models, for a sequence classification task such as concept extraction. Therefore, we first experimented with different sliding window models and found the model with parameters that led to best performance in a preliminary sequence labeling task. The evaluation of this approach, performed against the i2b2/VA concept extraction corpus, showed that incorporating features based on the distribution of words across a large unannotated corpus significantly aids concept extraction. Compared to a supervised-only approach as a baseline, the micro-averaged F-score for exact match increased from 80.3% to 82.3% and the micro-averaged F-score based on inexact match increased from 89.7% to 91.3%. These improvements are highly significant according to the bootstrap resampling method and also considering the performance of other systems. Thus, distributional semantic features significantly improve the performance of concept extraction from clinical narratives by taking advantage of word distribution information obtained from unannotated data.


CT features of acquired cystic kidney disease-associated renal cell carcinoma.
Acquired cystic kidney disease-associated renal cell carcinoma (ACKD-RCC) is a relatively recently described entity with scarce literature describing its imaging appearance (1, 2). The purpose of this study was to determine typical and potentially unique features of ACKD-RCC on CT scan that could aid lesion identification. A retrospective review of the CT scans of 24 patients with 29 histologically proven ACKD-RCC lesions was performed. Imaging features were recorded based on consensus readings of two radiologists. Tumors ranged in size from 1.2 to 5 cm. Nineteen lesions were right-sided and 10 left-sided. Nineteen lesions were exophytic. One patient had bilateral lesions and three patients had multiple lesions in the same kidney. All lesions had well-defined margins with 21 round, 7 lobulated and 1 crescentic in shape. On non-enhanced exam 4 lesions were hypodense, 16 iso-dense and 9 hyperdense; 5 had gross calcifications. Twenty two patients had contrast-enhanced CT exams, with 13 lesions demonstrating homogeneous enhancement (solid pattern) and 14 having inhomogeneous enhancement (cystic or mixed solid and cystic pattern). Only 1 patient had metastatic disease. Eight patients had a history of renal transplants. ACKD-RCCs are well-defined lesions of variable size that are almost always rounded and most often exophytic. They occasionally have calcifications and are not uncommonly hyperdense on non-enhanced exam. They are most often iso-dense on non-enhanced exam and can be solid, cystic or mixed in attenuation on enhanced exam.


The Human Coparental Bond Implicates Distinct Corticostriatal Pathways: Longitudinal Impact on Family Formation and Child Well-Being.
Alloparental care, the cooperative care of offspring by group members other than the biological mother, has been widely practiced since early hominin evolution to increase infant survival and thriving. The coparental bond-a relationship of solidarity and commitment between two adults who join their effort to care for children-is a central contributor to children's well-being and sociality; yet, the neural basis of coparenting has not been studied in humans. Here, we followed 84 first-time co-parents (42 couples) across the first 6 years of family formation, including opposite-sex and same-sex couples, measured brain response to coparental stimuli, observed collaborative and undermining coparental behaviors in infancy and preschool, assayed oxytocin (OT) and vasopressin (AVP), and measured coparenting and child behavior problems at 6 years. Across family types, coparental stimuli activated the striatum, specifically the ventral striatum and caudate, striatal nodes implicated in motivational goal-directed social behavior. Psychophysiological interaction analysis indicated that both nodes were functionally coupled with the vmPFC in support of the human coparental bond and this connectivity was stronger as collaborative coparental behavior increased. Furthermore, caudate functional connectivity patterns differentiated distinct corticostriatal pathways associated with two stable coparental behavioral styles; stronger caudate-vmPFC connectivity was associated with more collaborative coparenting and was linked to OT, whereas a stronger caudate-dACC connectivity was associated with increase in undermining coparenting and was related to AVP. Finally, dyadic path-analysis model indicated that the parental caudate-vmPFC connectivity in infancy predicted lower child externalizing symptoms at 6 years as mediated by collaborative coparenting in preschool. Findings indicate that the coparental bond is underpinned by striatal activations and corticostriatal connectivity similar to other human affiliative bonds; highlight specific corticostriatal pathways as defining distinct coparental orientations that underpin family life; chart brain-hormone-behavior constellations for the mature, child-orientated coparental bond; and demonstrate the flexibility of this bond across family constellations and its unique contribution to child well-being.


Adherence to Pro-Vegetarian Food Patterns and Risk of Oesophagus, Stomach, and Pancreas Cancers: A Multi Case-Control Study (The PANESOES Study).
We aimed to evaluate the association between three previously defined pro-vegetarian (PVG) food patterns and the cancers of the oesophagus, stomach, and pancreas in a multi case-control study. We analyzed data from a multi-case hospital-based study carried out in two Mediterranean provinces in Spain. A total of 1233 participants were included in the analyses: 778 incident cancer cases, histologically confirmed (199 oesophagus, 414 stomach, and 165 pancreas) and 455 controls. A dietary assessment was performed using a validated food frequency questionnaire (FFQ). Three PVG food patterns (general, healthful, and unhealthful) were estimated using 12 food groups for the general PVG (gPVG), scoring positive plant-based foods and negative animal-based foods, and 18 food groups, for the healthful (hPVG) and unhealthful (uPVG) food patterns. Multinomial logistic regression was used to estimate relative risk ratios (RRR) and confidence intervals (95% CI) for quintiles of adherence to PVG patterns and as a continuous variable. The RRR (95% CI) for the highest vs. the lowest quintile of gPVG were, RRR = 0.37 (0.32, 0.42) for the oesophagus, RRR = 0.34 (0.27, 0.43) for the stomach, and RRR = 0.43 (0.35, 0.52) for pancreas cancer. For the hPVG, the RRR were RRR = 0.72 (0.58, 0.90) for the oesophagus, RRR = 0.42 (0.34, 0.52) for the stomach, and RRR = 0.74 (0.59, 0.92) for pancreas cancer. The uPVG was associated with a higher risk of stomach cancer RRR = 1.76 (1.42, 2.18). Higher adherence to gPVG and hPVG food patterns is associated with a lower risk of oesophageal, stomach, and pancreas cancers, while a higher adherence to a uPVG food pattern is associated with a higher risk of stomach cancer.


Intraoperative pathologic evaluation of central compartment lymph nodes in patients undergoing lobectomy for unilateral papillary thyroid carcinoma.
Although papillary thyroid carcinoma (PTC) has an excellent prognosis, it can cause central lymph node metastasis (CLNM) which can increase local recurrence. Intraoperative pathologic evaluation (IOPE) can provide evidence regarding CLNM and help surgeons determine the appropriate surgical approach. The aim of this study was to evaluate the efficacy of IOPE and to determine risk factors associated with CLNM in unilateral PTC without preoperative clinical evidence of CLNM. Medical charts of 227 patients who had unilateral PTC without clinical lymph node metastasis preoperatively were reviewed retrospectively. They were scheduled for thyroid lobectomy and prophylactic central lymphadenectomy (CND) from January 1, 2017 to December 31, 2017. Total follow-up period was 47.6 ± 10.6 months. CLNM was identified in 57 (25.1%) patients during IOPE and in 72 (31.7%) patients during final pathological analysis. The sensitivity and specificity of IOPE were 76.4% and 98.7%, respectively. IOPE through central lymph node dissection was safely performed with low complications (vocal cord palsy, 5.7%; hypoparathyroidism, 22.8%). Age < 55 years, echogenic foci on preoperative ultrasonography, and extrathyroidal extension at final pathological report were significantly associated with an increased risk of CLNM (p = 0.006, p < 0.001, and p < 0.001, respectively). In terms of oncological outcomes, there was no significant difference between the true negative and false negative results in IOPE. IOPE can safely provide accurate information for determining disease status and surgical extent. Further long-term studies are needed to evaluate clinical benefits of IOPE.


Alterations in glycosaminoglycan metabolism in beta-aminopropionitrile-treated chick embryos.
1. Na(2) (35)SO(4), [1-(14)C]glucosamine and [1-(14)C]acetate were used as precursors of the sulphated glycosaminoglycans to study the biochemical effect of beta-aminopropionitrile in chick embryos. The incorporation of all three precursors was decreased in the treated embryos between days 7 and 10 of embryonic development. No inhibition of incorporation of these precursors occurred between days 16 and 20 of embryonic development at the dosages of beta-aminopropionitrile used. 2. beta-Aminopropionitrile treatment also decreased the amount of N-acetylhexosamines in the chick embryo and decreased the percentage of the hexosamine esterified by nucleotides. Respiration was decreased by homogenates prepared from treated embryos. Likewise, UDP-xylosyl- and UDP-galactosyl-transferase activities were decreased in treated embryos and cartilage from embryos and growing chicks. 3. The data suggest that beta-aminopropionitrile, in addition to the known lathyrogenic activity, either is or gives rise to a potent metabolic poison that interferes with basic cellular metabolism. The results are consistent with a decreased rate of ATP generation as an explanation for the decrease in glycosaminoglycan synthesis.


The "Phase-of-the-Moon" paradox in uncertainty estimation.
In chemical measurement, many extraneous influences affect the magnitude of an analytical signal and thereby contribute to the uncertainty of the result. Some of these influences are predictable: others can be quite unexpected, the weather for example. Atomic spectrometry can be affected by gusts of wind that cause pressure changes in the fume extraction system. That makes the flame or plasma move relative to the instrument optics. There are tales of a spectrography laboratory where precision was degraded on the mornings when cleaners had applied a wax polish to the floor. The solvent of the polish contained enough UV-absorbing compounds to attenuate the light transmission in air-path spectrometers. But the phase of the Moon is predictable and any conceivable effect it could have on measurement uncertainty can be derived from physics.


Nutrients in urine: energetic aspects of removal and recovery.
The analysis of different removal and recovery techniques for nutrients in urine shows that in many cases recovery is energetically more efficient than removal and new-production from natural resources. Considering only the running electricity and fossil energy requirements for the traditional way of wastewater treatment and fertiliser production, the following specific energy requirements can be calculated: 45 MJ kg(-1)N for denitrification in a WWTP, 49 MJ kg(-1)p for P-precipitation in a WWTP, 45 MJ kg(-1)N for N-fertiliser and 29 MJ kg(-1)p for P-fertiliser production. These numbers are higher than the values derived for thermal volume reduction of urine (35 MJ kg(-1)N for eliminating 90% water) or production of struvite (102 MJ kg(-1)N, including 2.2 kg P). Considering only the electricity and fossil energy for the traditional way of wastewater treatment and fertiliser production, the energy value of 1 PE urine is 0.87 MJ PE(-1) d(-1) (fertiliser value: 0.44, wastewater treatment: 0.43 MJ PE(-1) d(-1)). A more detailed life cycle assessment (LCA) of the entire urine collection system, including the required materials and the environmental burden, support the energy analysis. The LCA compares conventional denitrification in a wastewater treatment plant with collecting urine in households, reducing the volume by evaporation and using it as a multi-nutrient fertiliser. The primary energy consumption for recovery and reuse of urine, including the nutrients N, P and K, is calculated with 65 MJ kg(-1)N, compared with 153 MJ kg(-1)N derived for the conventional 'recycling over the atmosphere'.


Crystal structure of type-III geranylgeranyl pyrophosphate synthase from Saccharomyces cerevisiae and the mechanism of product chain length determination.
Geranylgeranyl pyrophosphate synthase (GGPPs) catalyzes a condensation reaction of farnesyl pyrophosphate with isopentenyl pyrophosphate to generate C(20) geranylgeranyl pyrophosphate, which is a precursor for carotenoids, chlorophylls, geranylgeranylated proteins, and archaeal ether-linked lipid. For short-chain trans-prenyltransferases that synthesize C(10)-C(25) products, bulky amino acid residues generally occupy the fourth or fifth position upstream from the first DDXXD motif to block further elongation of the final products. However, the short-chain type-III GGPPs in eukaryotes lack any large amino acid at these positions. In this study, the first structure of type-III GGPPs from Saccharomyces cerevisiae has been determined to 1.98 A resolution. The structure is composed entirely of 15 alpha-helices joined by connecting loops and is arranged with alpha-helices around a large central cavity. Distinct from other known structures of trans-prenyltransferases, the N-terminal 17 amino acids (9-amino acid helix A and the following loop) of this GGPPs protrude from the helix core into the other subunit and contribute to the tight dimer formation. Deletion of the first 9 or 17 amino acids caused the dissociation of dimer into monomer, and the Delta(1-17) mutant showed abolished enzyme activity. In each subunit, an elongated hydrophobic crevice surrounded by D, F, G, H, and I alpha-helices contains two DDXXD motifs at the top for substrate binding with one Mg(2+) coordinated by Asp(75), Asp(79), and four water molecules. It is sealed at the bottom with three large residues of Tyr(107), Phe(108), and His(139). Compared with the major product C(30) synthesized by mutant H139A, the products generated by mutant Y107A and F108A are predominantly C(40) and C(30), respectively, suggesting the most important role of Tyr(107) in determining the product chain length.


Anticipatory synergy adjustments: preparing a quick action in an unknown direction.
We studied a mechanism of feed-forward control of a multi-finger action, namely anticipatory synergy adjustments (ASAs), prior to a quick force correction in response to a change in the gain of the visual feedback. Synergies were defined as co-varied across trials adjustments of commands to fingers that stabilized (decreased variance of) the total force. We hypothesized that ASAs would be highly sensitive to prior information about the timing of the action but not to information on its direction, i.e., on whether the gain would go up or down. The subjects produced accurate constant total force by pressing with four fingers on individual force sensors. The feedback signal could change from veridical (the sum of finger forces) to modified, with the middle finger force multiplied by 0.2 or by 1.8. The timing of the gain change and its direction could be known or unknown to the subject in advance. When the timing of the gain change was known, ASA was seen as a drop in the synergy index starting about 250-300 ms prior to the first visible correction of the total force. When the gain change timing was unknown, ASAs started much later, less than 100 ms prior to the total force correction. The magnitude of synergy index changes was significantly larger under the "time known" conditions. Information on the direction of the visual gain change had no effect on the ASA timing, while the ASA magnitude was somewhat larger when this information was not available to the subject. After the total force correction, the synergy index was significantly larger for the force signal computed using the modified gain values as compared to the synergy index value for the actual total force. We conclude that ASAs represent an important feed-forward motor control mechanism that allows preparing for a quick action even when the direction of the action is not known in advance. The results emphasize the subtle control of multi-finger synergies that are specific to the exact contributions of individual fingers to performance variables. The data fit well the central back-coupling hypothesis of synergies and the idea of control with referent body configurations.


Effects of cationic head group structure on cytotoxicity and mitochondrial actions of amphiphilic ionic liquids.
Ionic liquids (ILs) are a class of low melting point salts with physicochemical properties that make them suitable for a range of industrial applications. Accumulating evidence suggests that certain ILs are cytotoxic and potential environmental pollutants, thus understanding the structural features that promote IL cytotoxicity is important. Amphiphilic ionic liquids (AmILs), a class of ILs with lipophilic N-alkyl chains, containing aromatic head groups are generally more cytotoxic than their aliphatic counterparts, however the impact of other head group properties are less clear. This study therefore sought to provide new structure activity relationship (SAR) insights regarding the role of the cationic head group on AmIL cytotoxicity. A series of AmILs bearing a range of structurally diverse aromatic cations varying in size, charge, and lipophilicity was synthesised and screened against human MDA-MB-231 breast cancer cells. It was found that larger and more lipophilic head groups increased cytotoxicity, although the magnitude of the changes were modest. The mitochondrial effects of representative ILs were assessed. The AmILs induced mitochondrial dysfunction in MDA-MB-231 cells at cytotoxic concentrations, suggesting that they target mitochondria. The new SAR information from this study may assist in the design of AmILs with controlled cytotoxicity.


Deficit irrigation strategies combined with controlled atmosphere preserve quality in early peaches.
Due to the water scarcity in the Mediterranean countries, irrigation must be optimized while keeping fruit quality. The effect of deficit irrigation strategies on changes in quality parameters of the early "Flordastar" peaches was studied. The deficit irrigation was programmed according to signal intensity of the maximum daily trunk shrinkage; deficit irrigation plants were irrigated to maintain maximum daily trunk shrinkage signal intensity values close to 1.4 or 1.3 in the case of DI1 or DI2 plants, respectively. Results were compared to a control watered at 150% crop evapotranspiration. Fruits were stored up to 14 days at 0 ℃ and 95% Relative Humidity (RH) in air or in controlled atmosphere (controlled atmosphere; 3-4 kPa O2 and 12-14 kPa CO2), followed by a retail sale period of 4 days at 15 ℃ and 90-95% Relative Humidity in air. Weight losses were lower in controlled atmosphere stored peaches from deficit irrigation. Air-stored fruits developed a more intense red color due to a faster ripening, which was not affected by the type of watering. At harvest, deficit irrigation peaches showed higher soluble solids content, which provided a better sensory evaluation. The soluble phenolic content was initially higher (55.26 ± 0.18 mg gallic acid equivalents/100 g fresh weight) and more stable throughout postharvest life in DI1 fruits than in those from the other irrigation treatments. Concerning vitamin C, control fruits at harvest showed higher ascorbic acid than dehydroascorbic acid content (5.43 versus 2.43 mg/100 g fresh weight, respectively), while water stressed peaches showed the opposite results. The combination of DI2 and controlled atmosphere storage allowed saving a significant amount of water and provided peaches with good overall quality, maintaining the bioactive compounds analyzed.


Handgrip Strength Asymmetry and Weakness Are Associated With Future Morbidity Accumulation in Americans.
Klawitter, L, Vincent, BM, Choi, BJ, Smith, J, Hammer, KD, Jurivich, DA, Dahl, LJ, and McGrath, R. Handgrip strength asymmetry and weakness are associated with future morbidity accumulation in americans. J Strength Cond Res 36(1): 106-112, 2022-Identifying strength asymmetries in physically deconditioned populations may help in screening and treating persons at risk for morbidities linked to muscle dysfunction. Our investigation sought to examine the associations between handgrip strength (HGS) asymmetry and weakness on accumulating morbidities in aging Americans. The analytic sample included 18,506 Americans aged ≥50 years from the 2006-2016 Health and Retirement Study. Handgrip strength was measured on each hand with a handgrip dynamometer, and persons with an imbalance in strength >10% between hands had HGS asymmetry. Men with HGS <26 kg and women with HGS <16 kg were considered as weak. Subjects reported the presence of healthcare provider-diagnosed morbidities: hypertension, diabetes, cancer, chronic lung disease, cardiovascular disease, stroke, arthritis, and psychiatric problems. Covariate-adjusted ordinal generalized estimating equations analyzed the associations for each HGS asymmetry and weakness group on future accumulating morbidities. Of those included in our study, subjects at baseline were aged 65.0 ± 10.2 years, 9,570 (51.7%) had asymmetric HGS, and 996 (5.4%) were weak. Asymmetry alone and weakness alone were associated with 1.09 (95% confidence interval [CI]: 1.04-1.14) and 1.27 (CI: 1.11-1.45) greater odds for future accumulating morbidities, respectively. Having both HGS asymmetry and weakness was associated with 1.46 (CI: 1.29-1.65) greater odds for future accumulating morbidities. Handgrip-strength asymmetry, as another potential indicator of impaired muscle function, is associated with future morbidity status during aging. Exercise professionals and related practitioners should consider examining asymmetry and weakness with handgrip dynamometers as a simple and noninvasive screening method for helping to determine muscle dysfunction and future chronic disease risk.


Successful acquisition of an olfactory discrimination paradigm by South African fur seals, Arctocephalus pusillus.
The present study demonstrates that South African fur seals, Arctocephalus pusillus, can successfully be trained to discriminate between objects on the basis of odor cues. Using a task based on a food-rewarded two-choice discrimination of simultaneously presented odor stimuli the animals acquired the basic operant conditioning paradigm within 480 to 880 stimulus contacts. Moreover, the fur seals could readily transfer to new S+ and S- stimuli, were capable of distinguishing between fish- and non-fish odors as well as between two fish odors, and were able to remember the reward value of previously learned odor stimuli even after 2- and 15-week breaks. The precision and consistency of the fur seals' performance in tests of discrimination ability and memory demonstrate the suitability of this paradigm for assessing olfactory function in this pinniped. An across-species comparison of several measures of olfactory learning capabilities such as speed of initial task acquisition and ability to master transfer tasks shows that A. pusillus is similar in performance to non-human primates, but inferior to rodents such as mice and rats. The results support the assumption that fur seals may use olfactory cues for social communication and food selection and that the sense of smell may play an hitherto underestimated role in the control of their behavior.


Quantum Monte Carlo for noncovalent interactions: an efficient protocol attaining benchmark accuracy.
Reliable theoretical prediction of noncovalent interaction energies, which are important e.g. in drug-design and hydrogen-storage applications, is one of the longstanding challenges of contemporary quantum chemistry. In this respect, the fixed-node diffusion Monte Carlo (FN-DMC) method is a promising alternative to the commonly used "gold standard" coupled-cluster CCSD(T)/CBS method due to its benchmark accuracy and favourable scaling, in contrast to other correlated wave function approaches. This work is focused on the analysis of protocols and possible trade-offs for FN-DMC estimations of noncovalent interaction energies, and proposes an efficient yet accurate computational protocol using simplified explicit correlation terms with a favorable O(N(3)) scaling. It achieves results in excellent agreement (mean unsigned error ∼0.2 kcal mol(-1)) with respect to the CCSD(T)/CBS data on a number of complexes, including benzene/hydrogen, the T-shape benzene dimer, stacked adenine-thymine complex and a set of small noncovalent complexes (A24). The high accuracy and reduced computational costs predestinate the reported protocol for practical interaction energy calculations of large noncovalent complexes, where the CCSD(T)/CBS is prohibitively expensive.


[Biofeedback therapy for constipation and fecal incontinence].
Constipation and fecal incontinence are problems that are frequently encountered in daily practice. Over the last decade biofeedback therapy has emerged as a useful adjunct for the treatment of these problems. Biofeedback therapy is a learning process that is based on "operant conditioning" techniques. Biofeedback training aims to restore a degree of continence that enables patients to resume their activities to a satisfactory level with good success rates and prolonged benefits. The technique requires height levels of motivation not only in the patients but also in the instructor who is providing verbal feedback about the adequacy of a patients performance.


Piloting a digital campaign to promote awareness of the Louisiana TelePrEP program among sexual and gender minority young adults.
Despite the proven efficacy of pre-exposure prophylaxis (PrEP) in preventing HIV acquisition, PrEP is underutilized by sexual and gender minority young adults in the 13 states in the United States "South." In this paper, we describe the process we used to develop a digital campaign to promote awareness and engagement of sexual and gender minority young adults in the Louisiana Department of Health's TelePrEP Program and provide campaign performance metrics. In Phase 1, we conducted formative research that informed campaign development and strategy. In total, 109 sexual and gender minority young adults completed a survey of PrEP constructs (e.g., facilitators, barriers). We also conducted three, sequential focus groups to iteratively generate, revise and refine the digital material. In collaboration with our strategic marketing partner (SMP), we developed 3 different ads and 1 video ad to promote on web and mobile-in app display, as well as Facebook, Instagram, and YouTube. Phase 2 focused on campaign implementation and evaluation (e.g., number of impressions, user activities on LA TelePrEP landing page). In the first few weeks of the campaign, data from tracking pixels indicated minimal activities on the landing page. We paused to revamp the campaign. Our SMP determined that a more young adult-focused landing page could bolster engagement. We created a new landing page and reran the campaign for 33 days. We saw substantially more user activities on the new landing page (n = 382) compared to the LA TelePrEP landing page (n = 185). Overall, we had 730,665 impressions and 475 link clicks. By collaborating with our SMP, we effectively and efficiently translated our community-engaged formative research into relevant and engaging digital content. This pilot study is one of the first to demonstrate the importance of using tracking pixels to monitor real-time user data to optimize performance of a digital PrEP campaign.


[Comparative research on synaptic transmission in the sympathetic ganglia of rabbits and frogs during acetylcholinesterase inhibition].
Organophosphorus inhibitor of acetylcholinesterase (AChE) armin (1 x 10(-6) M) induced a variety of pre- and postsynaptic effects resulting from the AChE inhibition and subsequent accumulation of acetylcholine (ACh) in the synaptic cleft. The intensity of postsynaptic effects (level of neuron depolarization, degree of action potential depression) was shown to be different in the ganglia of frog and rabbit. This could be explained by differences in the total amount of ACh released in response to nerve stimulation as well as at rest. Both muscarinic and nicotinic cholinoreceptors were involved in the process of sustained depolarization of the neurons in the rabbit superior cervical ganglion after AChE inhibition. In frog ganglion neurons the nicotinic receptors did not participate in depolarization evidently due to their fast desensitization. The activation of presynaptic muscarinic receptors resulted in decrease of ACh released by nerve stimulation seems to weaken depolarization and blockade of synaptic transmission in sympathetic ganglia treated by AChE inhibitors.


Can the use of growth hormone reduce the postoperative fatigue syndrome?
Convalescence after surgery is characterized by a period of fatigue (POF). If we assume that the POF syndrome has a multifactorial etiology, it is clear that the aim of therapeutic measures should be to reduce the response to surgical stress. The purpose of the present study was to determine if administering exogenous human growth hormone (hGH) can prevent the development or reduce the duration of the POF. We carried out a placebo-controlled randomized double-blind trial with 48 patients after elective cholecystectomy (placebo, or control group, n = 26; hGH-treated group, n = 22). Eligibility criteria were strict so as to introduce as few variables as possible. The results obtained in the study show that for moderate surgical injury (cholecystectomy in metabolically healthy subjects) the administering of low doses of hGH (8 IU/day) minimized the POF syndrome (Christensen score). Furthermore, a positive nitrogen balance was achieved in the hGH-treated group during the postoperative period from the first 24 hours onward. This finding correlates with the significant increase in serum levels of hGH (p < 0.05) and insulin-like growth factor 1 (IGF-1) (p < 0.001). On the other hand, anthropometric measurements in the hGH-treated group revealed a slight but continuous decrease in body weight and thickness of the triceps skinfold; however, arm muscle circumference did not significantly change during the postoperative period. These findings are related to the effects of the application of exogenous growth hormone, which preserves or increases lean body mass and reduces adipose tissue mass. The serum transferrin level proved to be a reliable biochemical indicator of POF.


Temperate-Water Immersion as a Treatment for Hyperthermic Humans Wearing American Football Uniforms.
Cold-water immersion (CWI; 10°C) can effectively reduce body core temperature even if a hyperthermic human is wearing a full American football uniform (PADS) during treatment. Temperate-water immersion (TWI; 21°C) may be an effective alternative to CWI if resources for the latter (eg, ice) are unavailable. To measure rectal temperature (Trec) cooling rates, thermal sensation, and Environmental Symptoms Questionnaire (ESQ) scores of participants wearing PADS or shorts, undergarments, and socks (NOpads) before, during, and after TWI. Crossover study. Laboratory. Thirteen physically active, unacclimatized men (age = 22 ± 2 years, height = 182.3 ± 5.2 cm, mass = 82.5 ± 13.4 kg, body fat = 10% ± 4%, body surface area = 2.04 ± 0.16 m2). Participants exercised in the heat (40°C, 50% relative humidity) on 2 days while wearing PADS until Trec reached 39.5°C. Participants then underwent TWI while wearing either NOpads or PADS until Trec reached 38°C. Thermal sensation and ESQ responses were collected at various times before and after exercise. Temperate-water immersion duration (minutes), Trec cooling rates (°C/min), thermal sensation, and ESQ scores. Participants had similar exercise times (NOpads = 38.1 ± 8.1 minutes, PADS = 38.1 ± 8.5 minutes), hypohydration levels (NOpads = 1.1% ± 0.2%, PADS = 1.2% ± 0.2%), and thermal sensation ratings (NOpads = 7.1 ± 0.4, PADS = 7.3 ± 0.4) before TWI. Rectal temperature cooling rates were similar between conditions (NOpads = 0.12°C/min ± 0.05°C/min, PADS = 0.13°C/min ± 0.05°C/min; t12 = 0.82, P = .79). Thermal sensation and ESQ scores were unremarkable between conditions over time. Temperate-water immersion produced acceptable (ie, >0.08°C/min), though not ideal, cooling rates regardless of whether PADS or NOpads were worn. If a football uniform is difficult to remove or the patient is noncompliant, clinicians should begin water-immersion treatment with the athlete fully equipped. Clinicians should strive to use CWI to treat severe hyperthermia, but when CWI is not feasible, TWI should be the next treatment option because its cooling rate was higher than the rates of other common modalities (eg, ice packs, fanning).


The use of molecular typing to evaluate the dissemination of antimicrobial resistance among Gram-negative rods in Brazilian hospitals.
Antimicrobial resistance has increased rapidly in Brazil and worldwide during the past few years, giving rise to a growing necessity for antimicrobial resistance surveillance programs. These programs have been instituted in order to monitor bacterial resistance in various regions, and to guide empirical antimicrobial therapy. We evaluated the use of molecular typing in multicenter surveillance programs. We also studied the dissemination modes of selected resistance profiles. Antimicrobial susceptibility to various antimicrobial agents was evaluated by the reference broth microdilution method. Bacterial isolates with selected susceptibility patterns were characterized by pulsed field-gel electrophoresis (PFGE). A total of 119 Gram-negative bacteria were molecularly typed, including 22 imipenem-resistant Pseudomonas aeruginosa, 26 ESBL-producing Escherichia coli, 27 cefoxitin-resistant-ESBL-producing Klebsiella pneumoniae, 33 Enterobacter spp., 8 Citrobacter spp., and 3 S. marcescens isolates resistant to ceftazidime. The isolates were from clinically apparent bacteremia of patients hospitalized in medical centers located in 13 cities of 11 Brazilian states. Our molecular typing results revealed a great genetic diversity among isolates of the same species. However, some major PFGE patterns were found in more than one isolate. All repeated PFGE patterns were detected in only 2 isolates, which were isolated within the same institutions or in different medical centers. We conclude that the ability to characterize organisms phenotypically and genotypically is a powerful epidemiologic tool and it provides unique information that is very important for multicenter surveillance programs.


Neuronal histamine inhibits methamphetamine-induced locomotor hyperactivity in mice.
Whether central histaminergic (HAergic) neurons mediate the regulation of methamphetamine (MAMP)-induced hyperactivity was clarified. L-histidine (HIS; 500 and 1000 mg/kg i.p.) reduced the locomotor hyperactivity induced by MAMP (1 mg/kg i.p.) in mice, and the effect was significant only at 1000 mg/kg. HIS significantly elevated brain histamine (HA) levels, in both doses, whereas telemethylhistamine (t-MH) levels were elevated only at 1000 mg/kg. Pretreatment with alpha-fluoromethylhistidine, a histidine decarboxylase inhibitor, suppressed both behavioral and biochemical effects of HIS. Metoprine, a HA-N-methyltransferase inhibitor, increased brain HA levels, decreased t-MH levels and suppressed the MAMP-induced locomotor hyperactivity. It is concluded that central HAergic systems may play an inhibitory role on the MAMP-induced locomotor hyperactivity.


Assessment: symptomatic treatment for muscle cramps (an evidence-based review): report of the therapeutics and technology assessment subcommittee of the American academy of neurology.
A Food and Drug Administration advisory in 2006 warned against the off-label use of quinine sulfate and its derivatives in the treatment of muscle cramps. Physicians are faced with a difficult scenario in choosing a treatment regimen for patients with muscle cramps. This American Academy of Neurology assessment systematically reviews the available evidence on the symptomatic treatment of muscle cramps. A total of 563 potential articles were reviewed, of which 24 met the inclusion criteria of prospective trials evaluating the efficacy of a particular treatment on muscle cramps as a primary or secondary outcome. There are Class I studies showing the efficacy of quinine derivatives for treatment of muscle cramps. However, the benefit is modest and there are adverse effects from published prospective trials as well as case reports. There is one Class II study each to support the use of Naftidrofuryl, vitamin B complex, lidocaine, and diltiazem in the treatment of muscle cramps. Although likely effective (Level A), quinine derivatives should be avoided for routine use in the management of muscle cramps because of the potential of toxicity, but in select patients they can be considered for an individual therapeutic trial once potential side effects are taken into account. Vitamin B complex, Naftidrofuryl, and calcium channel blockers such as diltiazem are possibly effective and may be considered in the management of muscle cramps (Level C). Further studies are needed to identify agents that are effective and safe for the treatment of muscle cramps.


Sugar and Spice Make Bacteria Not Nice: Protein Glycosylation and Its Influence in Pathogenesis.
Protein glycosylation is a post-translational modification that occurs across the whole tree of life. In the recent years, multiple N- and O-glycosylation mechanisms have been identified and characterized in diverse bacterial species, including human pathogens. This review focuses on bacterial protein glycosylation and its impact in pathogenesis. Bacteria carry N- and O-glycosylation systems that are mediated by an oligosaccharyltransferase (OTase). In OTase-dependent glycosylation mechanisms, an oligosaccharide is synthesized on a lipid carrier and subsequently transferred to proteins en bloc by an OTase. Multiple proteins are glycosylated using this mechanism. OTase-independent glycosylation refers to the pathway in which Protein N- and O-glycosyltransferases (PGTases) sequentially add monosaccharides onto the target proteins. This pathway is employed for glycosylation of flagella and autotransporters. By exploiting glycosylation machineries, it is now possible to generate tailor-made glycoconjugates by attaching polysaccharides derived from lipopolysaccharide or capsule biosynthesis onto a protein of choice. These glycoproteins can be used in developing vaccines and diagnostics of bacterial infections. Furthermore, both N- and O-glycosylation systems are promising targets for antibiotic development. Recently, the discovery of GTase toxins produced by bacterial pathogens and secreted into the host cells has greatly expanded. These proteins are a key factor in host-pathogen interactions and are required by certain pathogenic bacteria to establish a successful infection. The exact functions of bacterial glycoproteins in pathogenesis are just starting to emerge. Understanding these roles is key for new opportunities in the prevention of bacterial infections, which is crucial in times when antibiotic resistance continues to increase.