Can emergent treatments result in more severe errors?: An analysis of a large institutional near-miss incident reporting database.
Emergent radiation treatments may be subject to more errors because of the compressed time frame. Few data exist on the magnitude of this problem or how to guide safety improvement interventions. The purpose of this study is to examine patterns of near-miss events in emergent treatments using a large institutional incident reporting system. Events in the incident reporting database from February 2012 to October 2013 were reviewed prospectively by a multidisciplinary team to identify emergent treatments. Reports were scored for potential near-miss risk index (NMRI) on a 0 to 4 scale. Workflow steps of where events originated and were detected were analyzed. Events were categorized by use of the causal factor system from the Radiation Oncology Incident Learning System. Mann-Whitney U tests were used to compare mean NMRI score, and Fisher exact tests were performed to compare the proportion of high-risk events between emergent and nonemergent treatments and between emergent treatments on weekdays and weekends or holidays. Over the study period, approximately 1600 patients were treated, 190 of them emergently. Seventy-one incident reports were submitted for 55 unique patients. Fewer events were reported for emergent treatments than for nonemergent treatments (0.37 events per new treatment vs 0.86; P < .01). Mean risk index for emergent reports was 1.90 versus 1.48 for nonemergent reports (P < .01). Rate of NMRI 4 was 10% for emergent treatments versus 4% for nonemergent treatments (P < .01). Emergent treatments started on a weekend or holiday had a higher proportion of critical near-miss events than emergent treatments started during the week (37% vs 7.9%, P = .034). In this study, fewer near-miss incidents were reported per treatment course for emergent treatments. This may be attributable to reporting bias. More importantly, when emergent near misses occur, they are of greater severity.


Self-organized insulin-producing β-cells differentiated from human omentum-derived stem cells and their in vivo therapeutic potential.
Human omentum-derived mesenchymal stem cells (hO-MSCs) possess great potential to differentiate into multiple lineages and have self-renewal capacity, allowing them to be utilized as patient-specific cell-based therapeutics. Although the use of various stem cell-derived β-cells has been proposed as a novel approach for treating diabetes mellitus, developing an efficient method to establish highly functional β-cells remains challenging. We aimed to develop a novel cell culture platform that utilizes a fibroblast growth factor 2 (FGF2)-immobilized matrix to regulate the adhesion and differentiation of hO-MSCs into insulin-producing β-cells via cell-matrix/cell-cell interactions. In our study, we evaluated the in vitro differentiation potential of hO-MSCs cultured on an FGF2-immobilized matrix and a round-bottom plate (RBP). Further, the in vivo therapeutic efficacy of the β-cells transplanted into kidney capsules was evaluated using animal models with streptozotocin (STZ)-induced diabetes. Our findings demonstrated that cells cultured on an FGF2-immobilized matrix could self-organize into insulin-producing β-cell progenitors, as evident from the upregulation of pancreatic β-cell-specific markers (PDX-1, Insulin, and Glut-2). Moreover, we observed significant upregulation of heparan sulfate proteoglycan, gap junction proteins (Cx36 and Cx43), and cell adhesion molecules (E-cadherin and Ncam1) in cells cultured on the FGF2-immobilized matrix. In addition, in vivo transplantation of differentiated β-cells into animal models of STZ-induced diabetes revealed their survival and engraftment as well as glucose-sensitive production of insulin within the host microenvironment, at over 4 weeks after transplantation. Our findings suggest that the FGF2-immobilized matrix can support initial cell adhesion, maturation, and glucose-stimulated insulin secretion within the host microenvironment. Such a cell culture platform can offer novel strategies to obtain functional pancreatic β-cells from patient-specific cell sources, ultimately enabling better treatment for diabetes mellitus.


Evaluation of some immune and inflammatory responses in diabetes and HIV co-morbidity.
Co-existence of diabetes in the HIV infected reportedly further complicates the attendant impairment of immunity and increases susceptibility to opportunistic infections. This study aimed to evaluate some immune and inflammatory parameters in HIV and type 2 diabetes (T2D) co-morbidity: Immunoglobulin M and G (IgM and IgG), Interleukin-6, CD4+ T-cells and C-reactive protein. The study involved 200 subjects grouped according to their HIV and diabetes status: Group 1 'Diabetic HIV seropositive' (n=40), Group 2 'Non diabetic HIV seropositive'(n=60), Group 3 'Diabetic HIV seronegative'(n=50), and Group 4 'Control non diabetic HIV seronegative'(n=50). Blood samples were collected for testing. CRP levels were significantly elevated in diabetes and HIV co-morbidity compared to other groups. IL-6 levels were significantly higher in diabetics with or without HIV infection. In addition, IL-6 was significantly elevated in individuals with poor glycemic control (HbA1c > 9.0%) compared to those with good glycemic control. IgG and IgM levels in diabetic HIV seropositive subjects were highest compared with other groups. The increased IL-6, CRP, IgG, IgM and decreased CD4+ T cell counts observed in co-morbidity suggest that HIV and T2D co-morbidity exacerbate the immune and inflammatory impairment observed in either disease entity.


Resveratrol exhibits diverse anti-cancer activities through epigenetic regulation of E-cadherin and p21 in triple-negative breast cancer cells.
Triple-negative breast cancer (TNBC) has an aggressive phenotype and poor outcome, however no specific targeted therapy has been established for TNBC lacking germline BRCA1/2 pathogenic variants. To develop a novel therapeutic strategy, we explored the potential of resveratrol (RSV) for TNBC treatment. We investigated the effects of RSV on malignant phenotypes of TNBC cells as well as on apoptosis induced by ABT263, a specific inhibitor of BCL-2 and BCL-xL, using morphological observation, migration assay, β-galactosidase staining, and Hoechst staining. To elucidate the underlying mechanisms of RSV-mediated effects, expression levels and histone acetylation levels of cadherin 1 (CDH1, E-cadherin) and cyclin dependent kinase inhibitor 1A (CDKN1A, p21) were determined by RT-qPCR, western blotting, and chromatin immunoprecipitation. Furthermore, knockdown analysis was conducted to evaluate the involvement of E-cadherin and/or p21 in RSV potentiation on cytotoxic activity of ABT263. RSV treatment induced epithelial-like cellular morphology and suppressed the migration capacity in MDA-MB-231 and BT-549-Luc TNBC cells. β-galactosidase-positive cells were increased after RSV treatment, indicating the induction of cellular senescence, in MDA-MB-231 cells but not in BT-549-Luc cells. RSV increased the expression and histone acetylation of CDH1 and CDKN1A in both cells. Interestingly, pre-treatment with RSV enhanced the induction of apoptosis in the ABT263-treated MDA-MB-231 and BT-549-Luc cells, and knockdown of CDKN1A decreased ABT263-induced apoptosis in RSV-treated MDA-MB-231 cells. RSV represses the metastatic capacity and enhances the cytotoxic activity of ABT263 in TNBC cells. Our results suggested that RSV can potentially be used as a repressor of metastasis or a sensitizer to ABT263 for TNBC treatment via up-regulation of CDH1 and CDKN1A through epigenetic mechanisms.


Radiofrequency ablation associated to mucosal resection in the oesophagus: experience in a single centre.
Endoscopic resection (EMR) and radiofrequency ablation (RFA) form part of the treatment of Barrett's oesophagus (BO), dysplasia, superficial adenocarcinoma (OAC) associated with BO. Between June 2008 and April 2011, 34 patients underwent treatment with RFA (HALO system(®)), in a tertiary centre. For the study, patients were divided into two groups. Group 1 (16 patients of average 60 years old; 14 men, two women) received EMR and RFA. Group 2 (18 patients averaging 59 years age; 14 men, four women) received RFA without EMR in the year preceding the RFA. In group 1, high grade dysplasia (HGD) was eradicated in 12 cases (92%), low grade dysplasia (LGD) in three cases (100%). Complete response occurred in nine cases (56%), partial response in 100% of cases. Mean follow-up was 15 months. In group 2, HGD was eradicated in one patient (100%), LGD in three patients (64%). A complete response was achieved in eight patients, partial response in four cases (77%). Mean follow-up was 10 months. The complication rate for groups 1 and 2 was of 18% and 10% respectively. No complication prevented completion of treatment or continued monitoring. Recurrence was evaluated to 5% in both groups. RFA associated with EMR is feasible, offering probably better results and a very important advantage: a more complete histology before follow-up. Our results show effective treatment of BO and associated dysplasia with a low rate of complication. Nevertheless, when new techniques of BO ablation are used, the need to obtain histology before treatment should not be forgotten.


Activation of PPARγ reduces N-acetyl-cysteine -induced hypercorticoidism by down-regulating MC2R expression into adrenal glands.
We previously demonstrated that oral supplementation with antioxidants induced hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis, attested by hypercorticoidism, through an up-regulation of adrenocorticotrophic hormone (ACTH) receptors (MC2R) in adrenal. This study analyzed the role of peroxisome proliferator-activated receptor (PPAR)-γ on HPA axis hyperactivity induced by N-acetyl-cysteine (NAC). Male Swiss-Webster mice were orally treated with NAC for 1, 3, 5, 10, 15, or 18 consecutive days. The PPAR-γ agonist rosiglitazone and/or antagonist GW9662 were daily-injected i.p. for 5 consecutive days, starting concomitantly with NAC treatment. Rosiglitazone treatment inhibited NAC-induced adrenal hypertrophy and hypercorticoidism. Rosiglitazone also significantly reversed the NAC-induced increase in the MC2R expression in adrenal, but not steroidogenic acute regulatory protein (StAR). NAC treatment reduces the expression of PPARγ in the adrenals, but rosiglitazone did not restore the expression of this cytoprotective gene. In addition, GW9662 blocked the ability of rosiglitazone to decrease plasma corticosterone levels in NAC-treated mice. In conclusion, our findings showed that antioxidant supplementation induced a state of hypercorticoidism through down-regulation of PPARγ expression in the adrenals, in a mechanism probably related to a down-regulation of ACTH receptor expression.


Involvement of GABAergic transmission in the midbrain ventral tegmental area in the regulation of hippocampal theta rhythm.
Previously we indicated that the ventral tegmental area (VTA) may belong to the system regulating hippocampal theta rhythm. In the present study, we aimed at assessing the role of the GABAergic system of the VTA in regulation of hippocampal electric activity. Male Wistar rats received unilateral intra-VTA microinjection of either bicuculline (50ng/0.5μl, n=9), muscimol (100ng/0.5μl, n=10) or phaclofen (500ng/0.5μl, n=9). 1-min tail pinch stimulations were applied at 10-min intervals to evoke theta rhythm episodes in hippocampus. We analysed peak power (P(max)) and corresponding frequency (F(max)) of EEG signal at delta and theta bands. Bicuculline induced theta rhythm in both hippocampi with 0 latency, continuous for ca. 33min. Phaclofen also induced theta but in this group it appeared with latency (17.45±3.16min on average), lasted for ca. 33.6min and during this time was interrupted by periods of irregular activity of variable length. Tail pinch was not applied in these groups. Muscimol induced an opposite effect: depression of theta P(max) with simultaneous increase in delta P(max) and a decrease in F(max) delta during episodes of tail pinch-evoked theta. This effect had variable latency and no return to the control EEG could be observed. We propose that GABA activity in the VTA is of tonic character, so that abolition of this mechanism produces immediate effect, i.e. theta induction (strong by GABA(A) and weak by GABA(B) receptors blockade), whereas enhancing the already present GABAergic inhibition causes delayed, prolonged changes expressed as gradual loss of theta synchronisation.


Anomeric specificity of mannose phosphorylation by hexokinase.
In rat parotid or pancreatic islet homogenates incubated at 7 degrees C, hexokinase displayed a greater affinity for but a lower maximal velocity with the alpha-anomer, as distinct from beta-anomer, of D-mannose. The anomeric specificity of mammalian hexokinase was similar in the case of D-mannose and D-glucose, but represented a mirror image of that of yeast hexokinase.


Epidemiological investigations in regard to porcine reproductive and respiratory syndrome (PRRS) in Quebec, Canada. Part 1: biosecurity practices and their geographical distribution in two areas of different swine density.
Porcine reproductive and respiratory syndrome virus (PRRSV) is a considerable threat to the swine industry and implementing biosecurity measures is essential for the control of its transmission. The aims of this study were: (1) to describe biosecurity practices in production sites located in a moderate density (MD) and a high density (HD) pig area according to production type; (2) to group sites in different patterns according to their biosecurity practices; and (3) to determine the geographical distribution of sites according to biosecurity patterns. Biosecurity practices were selected based on PRRS epidemiology. A questionnaire was completed on 125 breeding sites (MD=54; HD=71) and 120 growing (HD) sites, between 2005 and 2008. Depending on area and production type, the frequency of biosecurity practices used ranged from 0 to 2% for barrier at site entrance, 0 to 19% for use of shower, 25 to 35% for washing truck between loads of pigs, 51 to 57% for absence of rendering or rendering without access to the site, and 26 to 51% for absence of gilt purchase or purchase with quarantine. Better practices pertaining to entrance protocol (i.e. "no-entry" sign, shower, ≥24 h downtime) were reported more frequently on breeding sites in the MD than the HD area (P<0.05). In the HD area, growing sites had in general a lower level of biosecurity than breeding sites. Using a two-step clustering procedure performed separately for breeding and growing sites, two different patterns were obtained for each production type, which corresponded to a high and low level of biosecurity. For breeding sites, a higher biosecurity level was observed at sites located away from other pig sites, set at more than 300 m from the public road, having higher sow inventory, or being part of an integrated production (P<0.05). Spatial clusters of sites for each biosecurity pattern were detected. This study identified some shortcomings regarding biosecurity that should be addressed before implementing any PRRSV regional control. Vicinity of sites with different biosecurity levels also suggests difficulties in planning priorities of intervention based on geographical distribution of sites.


Short- and long-term impact of sarcopenia on outcomes after emergency laparotomy: A systematic review and meta-analysis.
Sarcopenia refers to the progressive age and pathology-associated loss of skeletal muscle, which has been shown to independently predict mortality in patients undergoing major elective surgery. Emergency laparotomy is commonly performed for a range of procedures and is associated with high rates of mortality. However, the prognostic utility of sarcopenia after emergency laparotomy remains unknown. The aim of this study was to compare short and long-term survival between patients with and without sarcopenia undergoing emergency laparotomy. MEDLINE, EMBASE, and Scopus databases were systematically searched for articles comparing survival outcomes between adults with and without radiologically defined sarcopenia after emergency gastrointestinal surgery regardless of indication and approach (open/laparoscopic). The primary outcome was postoperative mortality. Sensitivity analysis of adjusted multivariate analyses was performed. Twenty articles comprising 6,737 patients were included. Sarcopenia was most commonly assessed using axial abdominal computerized tomography at L3, although cut-off thresholds were heterogeneous and rarely sex-specific. Postoperative mortality was higher among patients with sarcopenia than without in the in-hospital setting, and at 30- and 90-day follow-up on univariate but not on multivariate meta-analysis. However, mortality was significantly higher among sarcopenic cohorts in the 1-year (odds ratio 2.8, 95% confidence interval: 1.5-5.6; P = .002) follow-up period, despite adjusting for confounding preoperative and patient factors. The meta-analysis has shown sarcopenia to provide useful long-term prognostic information following emergency laparotomy. This may aid with preoperative risk assessment, patient counseling, and in perioperative decision-making for patients undergoing emergency laparotomy.


Clinical characteristics of 96 patients with drug-induced acute liver failure: a comparison between Traditional Chinese and Western Medicine.
To compare the causes, clinical symptoms, laboratory test results, and prognosis in patients with acute liver failure (ALF) induced by traditional Chinese medicines (TCM) and by Western Medicines (WM). The medical histories of patients who were diagnosed with drug-induced ALF (DALF) (n = 96) after hospitalization in the 302 Military Hospital between January 2010 and December 2015 were retrospectively examined. Fifty-eight of the 96 DALF patients (60.4%) had a hepatocellular pattern of DALF, 16 patients (16.7%) had a cholestatic pattern, and 22 patients (22.9%) had a mixed pattern. DALF resolved in 24 patients (25.0%). Twenty-five patients (26.0%) developed chronic liver injury, 43 patients (44.8%) died, and 4 patients (4.2%) underwent liver transplantation. There were 42 ALF patients (43.8%) who received WM, and 32 ALF patients (33.3%) who received TCM. TCM-induced ALF patients had a higher average age [42.4 ± 18.4) vs (33.5 ± 17.9) years, P = 0.04] and higher creatinine and urine nitrogen levels [(155.2 ± 108.8) vs (97.5 ± 130.4) mmol/L, P = 0.047; (9.1 ± 7.7) vs (4.3 ± 5.0) mmol/L, P = 0.002, respectively]. Patients with TCM-induced ALF exhibited an increased risk of renal injury [odds ratio (OR), 3.75; 95% confidence interval (CI), 1.330-10.577]. The 14 patients with TCM-induced ALF who died exhibited higher creatinine levels than the 18 patients with TCM-induced ALF patients who survived [(218.7 ± 111.6) vs (105.8 ± 78.4) mmol/L, P = 0.002]. They were also more likely to exhibit ascites (85.7% vs 44.4%, P = 0.017) and hepatorenal syndrome (78.6% vs 22.2%, P = 0.002). TCM-induced ALF was more likely to be accompanied by renal injury than was WM-induced ALF, especially in TCM-induced ALF patients who died.


Persistence of restrictions in quality of life from the first to the third year after diagnosis in women with breast cancer.
To assess whether detriments in quality of life (QOL) among women with breast cancer persist over years. QOL was assessed in a population-based cohort of 314 women with breast cancer from Saarland (Germany) 1 and 3 years after diagnosis and compared internally and with reference data from the general population. Three years after diagnosis, deficits in QOL were still apparent for role, emotional, cognitive, and social functioning and for the symptoms of insomnia, fatigue, dyspnea, and financial difficulties. Differences between breast cancer patients and women from the general population were predominantly found in younger ages. Compared with the QOL scores measured 1 year after diagnosis, only minor functional changes were observed, but recurrence of breast cancer during the follow-up interval had a deleterious effect on QOL. Deficits in role, emotional, cognitive, and social functioning persist over years in women with breast cancer and predominantly affect younger patients.


A novel method for encapsulation of macromolecules in liposomes.
Hemoglobin and alkaline phosphatase were each encapsulated in phosphatidylcholine liposomes using a dehydration-rehydration cycle for liposome formation. In this method, liposomes prepared by sonication are mixed in aqueous solution with the solute desired to be encapsulated and the mixture is dried under nitrogen in a rotating flask. As the sample is dehydrated, the liposomes fuse to form a multilamellar film that effectively sandwiches the solute molecules. Upon rehydration, large liposomes are produced which have encapsulated a significant fraction of the solute. The optimal mass ratio of lipid to solute is approx. 1:2 to 1:3. This method has potential application in large-scale liposome production, since it depends only on a controlled drying and rehydration process, and does not require extensive use of organic solvents, detergents, or dialysis systems.


Assessing Professional Fulfillment and Burnout Among CEOs and Other Healthcare Administrative Leaders in the United States.
The objective of this study was to evaluate the prevalence of burnout and professional fulfillment among healthcare administrative leaders and examine the association between burnout and professional fulfillment and personal and professional characteristics. Between June 7 and June 30, 2021, we performed a national survey of CEOs and other senior operational leaders to evaluate their personal work experience. Burnout and professional fulfillment-as well as a sleep-related impairment and self-valuation-were assessed using standardized instruments. Of the 5,994 members of the American College of Healthcare Executives who were sent an invitation to participate, 1,269 (21.2%), including 279 CEOs, submitted usable responses. The mean overall burnout score was 2.71 (range: 0-10), and 33% of participants had burnout scores that fell in the high range (unfavorable). Mean professional fulfillment score was 7.29 (range: 0-10), with 56.6% scoring in the high range (favorable). Burnout and professional fulfillment scores varied by role. On multivariable analysis, sleep-related impairment (OR for each 1-point increase = 1.29, 95% CI [1.19-1.41]; p < .001) and self-valuation (OR for each 1-point increase = 0.63, 95% CI [0.57-0.68]; p < .001) were independently associated with burnout after adjusting for all other variables. Results of this study suggest that healthcare leaders had lower burnout and professional fulfillment scores than clinicians. Nonetheless, one third of healthcare leaders had burnout scores that fell in the high range. At the individual level, improved sleep health and self-valuation appear to reduce risk of burnout and promote professional fulfillment.


Characterisation, whole-genome sequencing and phylogenetic analysis of three H3N2 avian influenza viruses isolated from domestic ducks at live poultry markets of Iran, 2017: First report.
Avian influenza type A viruses (AIV) can infect a broad range of hosts including human and birds, making them an important viral pathogen with zoonotic potential. Ducks are a known reservoir for many avian viruses including the AIV. To sequence the entire genome of duck-derived H3N2 and ran comprehensive phylogenetic analysis on them to study their origin. In this study, 962 cloacal swabs were collected from domestic ducks at several live poultry markets (LPMs) of Gilan, Mazandaran and Golestan provinces of Iran in the year 2017. Preliminary assays such as haemagglutination inhibition assay (HI), Neuraminidase Inhibition assay(NI) and RT-qPCR suggested that 0.5% of the birds were infected by H3 low pathogenic influenza viruses (LPAI). Three isolates were selected for whole genome sequencing. The cleavage site of the HA genes showed a PEKQTR/GLF motif, an indicator of LPAI. Furthermore, BLAST and phylogenetic analyses of the HA gene showed high homology to the Eurasian lineage of H3N8 AIV (95.5%-97.1% to several European and East Asian isolates). However, the NA genes showed high homology (at most 96.5-96.9%) to those belonging to AIV N2 subtype. Furthermore, internal genes showed high homology (96%-98%) to a variety of duck-origin subtypes and glycoprotein combinations, which were different for each segment. This showed a complex reassortment between different subtypes. This report is the first whole genome sequencing and complete characterisation of H3N2 AIV from Iran. Such surveillance should continue to study the evolution and possible emergence of viruses with pandemic potential.


[Substitution of thyroid hormones].
In patients with overt hypothyroidism the substitution with Levothyroxine is mandatory, whereas in patients with subclinical hypothyroidism it is dependent on further clinical signs and symptoms. The main parameter indicating sufficient substitution of Levothyroxine in patients with primary hypothyroidism is TSH, whereas in secondary hypothyroidism it is free T(4). At present Levothyroxine is the preparation of choice to restore euthyroidism in hypothyroid patients because it is assumed that the peripheral conversion from T(4) to T(3) provides the exact amount of T(3) needed by every organ. Intestinal absorption of Levothyroxin is around 80%, but only in acid environment and is significantly decreased by proton-pump inhibitors, antacids, atrophic gastritis and Helicobacter pylori infection. The usual required dosage of Levothyroxine is 1.5 microg/kg of body weight but is increased under these conditions as well as during early childhood and pregnancy, and is decreased in older people. The bioavailability of different Levothyroxin generics might change between 0.8 and 1.25. Therefore, the thyroid function of patients, receiving another brand of Levothyroxine has to be re-checked.


Stereotype threat affects financial decision making.
The research presented in this article provides the first evidence that one's decision making can be influenced by concerns about stereotypes and the devaluation of one's identity. Many studies document gender differences in decision making, and often attribute these differences to innate and stable factors, such as biological and hormonal differences. In three studies, we found that stereotype threat affected decision making and led to gender differences in loss-aversion and risk-aversion behaviors. In Study 1, women subjected to stereotype threat in academic and business settings were more loss averse than both men and women who were not facing the threat of being viewed in light of negative stereotypes. We found no gender differences in loss-aversion behavior in the absence of stereotype threat. In Studies 2a and 2b, we found the same pattern of effects for risk-aversion behavior that we had observed for loss-aversion behavior. In addition, in Study 2b, ego depletion mediated the effects of stereotype threat on women's decision making. These results suggest that individuals' decision making can be influenced by stereotype concerns.


Platelet-induced neutrophil activation: platelet-expressed fibrinogen induces the oxidative burst in neutrophils by an interaction with CD11C/CD18.
Mutual contacts and platelet-expressed fibrinogen seem to be required for the stimulation of neutrophils by activated platelets. The beta 2-integrins CD11b/CD18 and CD11c/CD18 are potential receptors for fibrinogen on neutrophils. In order to investigate whether binding of fibrinogen to these integrins is involved, monoclonal antibodies (MoAbs) and Gly-Pro-Arg-Pro (GPRP) peptide that inhibits fibrinogen binding to CD11c/CD18 were checked for their effects on the interaction of activated platelets and neutrophils. The luminol-amplified chemiluminescence (CL) as a measure for the oxidative burst of neutrophils was recorded simultaneously to the platelet aggregation in mixed cell suspensions. The adhesion of platelets and neutrophils was determined microscopically. The thromboxane A2 mimetic U46619 was used as a potent platelet agonist but that does not stimulate neutrophils. aggregation and a strong CL of neutrophils. The platelet-induced activation of neutrophils required added fibrinogen which fibronectin or thrombospondin could not substitute for. Cytochalasin D (Cyto D) that blocks actin polymerization totally abrogated the platelet-induced Cl of neutrophils. The MoAb OKM1 against CD11b, which blocks fibrinogen binding to CD11b/CD18 as well as the MoAbs IOT16 and IOT18 directed against CD11a and CD18, respectively, had no effect. In contrast, the MoAb LeuM5 which inhibits the binding of fibrinogen to CD11c/CD18 revealed a strong inhibition. Furthermore, GPRP peptide which CD11c/CD18 recognizes on the A alpha-chain of fibrinogen also strongly inhibited the platelet-induced CL of neutrophils, whereas control peptides such as Gly-His-Arg-Pro (GHRP) or Gly-Pro-Gly-Gly (GPGG) had no effect. In contrast to the platelet-induced CL of neutrophils, Cyto D, MoAb against CD11c and GPRP peptide did not inhibit the CL induced by FMLP and PAF in pure neutrophil suspensions. They also did not affect U46619-induced platelet aggregation. The adhesion of platelets and neutrophils was neither dependent on added fibrinogen nor inhibited by Cyto D, MoAb against CD11c and the GPRP-peptide. Therefore fibrinogen and actin polymerization seem not to be required for the adhesion of neutrophils to platelets. However, the activation of neutrophils depends on the interaction of CD11c/CD18 with the A alpha-chain of platelet-expressed fibrinogen and the contractile system of neutrophils.


Primary ciliary dyskinesia associated with multiple drug intolerance syndrome: a case report.
The term multiple drug intolerance syndrome is used for patients who express adverse drug reactions to three or more drugs without a known immunological mechanism. It is a distinct clinical entity, different from cross-reactivity. The symptoms can range from a benign rash to life threatening syndromes like drug reaction with eosinophilia and systemic symptoms. We report the case of an 8-year-old child with primary ciliary dyskinesia complicated by bronchiectasis who presented multiple drug intolerance syndrome.Through this observation; we discuss the diagnostic elements of this syndrome. In the absence of validated criteria for diagnosing multiple drug intolerance syndrome, a detailed history is essential, especially to identify the warning signs and the risk factors.


An 8-year-old-girl with juvenile dermatomyositis and autoimmune thyroiditis in Tanzania: a case report.
Juvenile dermatomyositis is an inflammatory disease of muscles, skin, and blood vessels of unknown cause affecting all age and ethnic groups, with a reported incidence of 1.9-4.1 per million. It manifests with weakness in axial and proximal muscles and typical skin lesions. Historically, the Bohan and Peter classification schema has been used to diagnose juvenile dermatomyositis. We report an 8-year-old African female child, who presented with features of juvenile dermatomyositis and a rare association with subclinical autoimmune thyroiditis. This case illustrates the typical presentation, diagnosis, and treatment outcomes of this highly misdiagnosed condition. Due to the limited resources and knowledge about this under-reported disease in resource-constrained settings, the characteristic manifestations of juvenile dermatomyositis can be easily missed and thus requires a high index of suspicion for earlier diagnosis and management.


Comparison between weight-adjusted, high-frequency, low-tidal-volume ventilation and atrial pacing with normal ventilation in high-power, short-duration atrial fibrillation ablation: Results of a pilot study.
Better contact force (CF) and catheter stability (CS) during atrial fibrillation (AF) ablation are associated with higher success rate. Changes in CF and CS are observed during respiratory movements and cardiac contraction. Previous studies have suggested that rapid atrial pacing (RAP) and high-frequency, low-tidal-volume ventilation (HFLTV) independently or in combination improve CS and CF and quality of lesions. Data from a body weight-adjusted HFLTV strategy associated with RAP in AF high-power, short-duration (HPSD) ablation are still lacking. This study aimed to compare the results of HPSD AF ablation using simultaneous weight-adjusted HFLTV and RAP and standard ventilation (SV) protocol. This was a prospective, nonrandomized study with 136 patients undergoing de novo ablation were divided into 2 groups: 70 in RAP (100 ppm) + HFLTV with 4 mL/kg of tidal volume and 25 breaths/min (group A) and 66 patients with SV in intrinsic sinus rhythm (group B). The ablation used 50 W, CF of 5 to 10 g and 10 to 20 g, and 40 mL/min flow rate on the posterior and anterior left atrial walls, respectively. There were no procedure-related complications. In group A, left atrial and total ablation times were 53.5 ± 8.3 minutes and 67.4 ± 10.1 minutes, respectively. Radiofrequency time was 19.7 ± 5.7 minutes, radioscopy time was 3.4 ± 1.8 minutes, 62 (88.6%) patients had first-pass isolation, 23 (33.3%) patients had elevation of luminal esophageal temperature, and 7 (10%) patients had recurrence. In group B, left atrial time was 56.7 ± 10.8 minutes, total ablation time was 72.4 ± 11.5 minutes, radiofrequency time was 22.4 ± 6.2 minutes, radioscopy time was 3.6 ± 3 minutes, 58 (87.9%) patients had first-pass isolation, and 20 (30.3%) patients had luminal esophageal temperature elevation. Weight-adjusted HFLTV with RAP in comparison with SV and intrinsic sinus rhythm in HPSD ablation is safe with no CO2 retention. The approach produced significantly reduced radiofrequency, left atrial, and total ablation times and better CF and local impedance drop indexes.


A statistically defined endpoint titer determination method for immunoassays.
Results of immunoassays for which no positive standards are available are often expressed as endpoint titers. The endpoint titer is defined as the reciprocal of the highest analyte dilution that gives a reading above the cutoff. Unfortunately, there is no generally accepted rule for the determination of these cutoff values. In enzyme-linked immunosorbent assays (ELISA) a value two or three times the mean background or negative control reading is sometimes used. Other investigators set the cutoff arbitrarily at a certain absorbance value. These procedures do not provide statistically meaningful information about the risk of overtitration or false low titers. We have solved this problem by devising a practical method for establishing a statistically valid cutoff. The procedure involves calculating the upper prediction limit using the Student t-distribution. The mathematical formula which defines the upper prediction limit is expressed as the standard deviation multiplied by a factor which is based on the number of negative controls and the confidence level (1 - alpha). Appropriate factors are provided for 2 to 30 negative controls and for confidence levels ranging from 95% to 99.9%. Our new method is more reliable than other nonstatistical procedures yet does not require sophisticated computation. It can be applied to a variety of immunoassays provided that negative controls are available.


Effect of milk feeding on intestinal bilirubin absorption in the rat.
The hypothesis that the etiologic mechanism of the late-onset, prolonged, unconjugated hyperbilirubinemia of the breast-fed infant, known as the breast milk jaundice syndrome, results from exaggeration of intestinal bilirubin absorption has been investigated in an adult rat model, which permits quantitative measurement of the enterohepatic circulation of bilirubin. After instillation of unconjugated bilirubin in buffer into the duodenum, 25% of the dose was absorbed and appeared in bile. Administration of bilirubin in human milk or cow milk formula resulted in a marked reduction in absorption to 2%. Administration of bilirubin in milk from mothers of infants with breast milk jaundice syndrome not only failed entirely to prevent the absorption of bilirubin, but enhanced late absorption, to produce a total absorption of 60% of the bilirubin dose. Thus, although normal milk significantly retarded intestinal bilirubin absorption and diminished the bilirubin load to the liver, milk from mothers of infants with breast milk jaundice syndrome appeared to enhance the enterohepatic circulation of bilirubin and to increase the total hepatic bilirubin load. This exaggeration of the enterohepatic circulation of bilirubin may be related to the increased concentrations in these milks of long-chain nonesterified fatty acids.


Quantifying Variability in Four U.S. Streams Using a Long-Term Dataset: Patterns in Biotic Endpoints.
Effective water resources assessment and management requires quantitative information on the variability of ambient and biological conditions in aquatic communities. Although it is understood that natural systems are variable, robust estimates of long-term variation in community-based structure and function metrics are rare in U.S. waters. We used a multi-year, seasonally sampled dataset from multiple sites (n = 5-6) in four streams (Codorus Creek, PA; Leaf River, MS; McKenzie and Willamette Rivers, OR) to examine spatial and temporal variation in periphyton chlorophyll a, and fish and macroinvertebrate metrics commonly used in bioassessment programs. Within-site variation of macroinvertebrate metrics and benthic chlorophyll a concentration showed coefficient of variation ranging from 16 to 136%. Scale-specific variability patterns (stream-wide, season, site, and site-season patterns) in standardized biotic endpoints showed that within-site variability patterns extended across sites with variability greatest in chlorophyll a and lowest in Hilsenhoff's Biotic Index. Across streams, variance components models showed that variance attributed to the interaction of space and time and sample variance accounted for the majority of variation in macroinvertebrate metrics and chlorophyll a, while most variation in fish metrics was attributed to sample variance. Clear temporal patterns in measured endpoints were rare and not specific to any one stream or assemblage, while apparent shifts in metric variability related to point source discharges were seen only in McKenzie River macroinvertebrate metrics in the fall. Results from this study demonstrate the need to consider and understand spatial, seasonal, and longer term variability in the development of bioassessment programs and subsequent decisions.


The Bone Microenvironment: a Fertile Soil for Tumor Growth.
Bone metastatic disease remains a significant and frequent problem for cancer patients that can lead to increased morbidity and mortality. Unfortunately, despite decades of research, bone metastases remain incurable. Current studies have demonstrated that many properties and cell types within the bone and bone marrow microenvironment contribute to tumor-induced bone disease. Furthermore, they have pointed to the importance of understanding how tumor cells interact with their microenvironment in order to help improve both the development of new therapeutics and the prediction of response to therapy.


The structural and molecular mechanisms of type II PETases: a mini review.
The advent of plastics has led to significant advances for humans, although the accompanying pollution has also been a source of concern for countries globally. Consequently, a biological method to effectively degrade polyethylene terephthalate (PET) has been an area of significant scientific interest. Following the report of the highly efficient PET hydrolase from the bacterium Ideonella sakaiensis strain 201-F6 (i.e., IsPETase) in 2016, its structure has been extensively studied, showing that it belongs to the type II PETase group. Unlike type I PETases that include most known cutinases, structural investigations of type II PETases have only been conducted since 2017. Type II PETases are further divided into type IIa and IIb enzymes. Moreover, even less research has been conducted on type IIa plastic-degrading enzymes. Here, we present a review of recent studies of the structure and mechanism of type II PETases, using the known structure of the type IIa PETase PE-H from the marine bacterium Pseudomonas aestusnigri in addition to the type IIb enzyme IsPETase as representatives. These studies have provided new insights into the structural features of type II PETases that exhibit PET catalytic activity. In addition, recent studies investigating the rational design of IsPETases are reviewed and summarized alongside a discussion of controversies surrounding PETase investigations.


The team checkup tool: evaluating QI team activities and giving feedback to senior leaders.
This tool can close the gap between hospital executives and frontline QI teams, improve knowledge of team activities, and help teams to identify and remedy barriers to progress.


Inotropic effect of triiodothyronine following myocardial ischemia and cardiopulmonary bypass: an experimental study in pigs.
A significant reduction (p less than 0.0001) in plasma-free triiodothyronine (T3), which is known to have an inotropic effect, has been documented in patients undergoing open-heart procedures. To investigate the effect of this observation, 22 pigs underwent 2 hours (Group 1, r = 10) or 3 hours (Group 2, r = 12) of myocardial ischemia during cardiopulmonary bypass (CPB) at 26 degrees C; the myocardium was protected by cardioplegic solution and cold saline solution at 30-minute intervals. After the pig was rewarmed to 37 degrees C, CPB was discontinued, and measurements of hemodynamic function were made 10 and 70 minutes later. Half of the pigs (Subgroup B) received 6 micrograms of T3 intravenously immediately after removal of the aortic cross-clamp; the remainder (Subgroup A) received no T3. After 2 hours of ischemia, untreated pigs showed significantly reduced myocardial function 10 minutes after discontinuation of CPB. By 70 minutes after the end of CPB, 2 of 5 untreated pigs (Subgroup A) had died of low cardiac output, but all 5 treated pigs (Subgroup B) survived. After 3 hours of ischemia, both groups showed some reduced function at 10 minutes, though the reduction was more marked in untreated animals. By 70 minutes, 4 of 6 untreated pigs had died of myocardial failure and all treated pigs remained alive (p less than 0.03). Surviving pigs in both groups still demonstrated some reduced function compared with values obtained before CPB. When all pigs are considered together, overall survival of those that did not receive T3 was significantly less than those that did (p less than 0.006).(ABSTRACT TRUNCATED AT 250 WORDS)


From bird's eye views to molecular communities: two-layered visualization of structure-activity relationships in large compound data sets.
The analysis of structure-activity relationships (SARs) becomes rather challenging when large and heterogeneous compound data sets are studied. In such cases, many different compounds and their activities need to be compared, which quickly goes beyond the capacity of subjective assessments. For a comprehensive large-scale exploration of SARs, computational analysis and visualization methods are required. Herein, we introduce a two-layered SAR visualization scheme specifically designed for increasingly large compound data sets. The approach combines a new compound pair-based variant of generative topographic mapping (GTM), a machine learning approach for nonlinear mapping, with chemical space networks (CSNs). The GTM component provides a global view of the activity landscapes of large compound data sets, in which informative local SAR environments are identified, augmented by a numerical SAR scoring scheme. Prioritized local SAR regions are then projected into CSNs that resolve these regions at the level of individual compounds and their relationships. Analysis of CSNs makes it possible to distinguish between regions having different SAR characteristics and select compound subsets that are rich in SAR information.


Maternal and child health and neighborhood context: the selection and construction of area-level variables.
Increasingly, maternal and child health researchers are employing the statistical approach of multilevel modeling analysis to simultaneously examine the relationship between contextual and individual determinants and maternal and child health outcomes. This review addresses the following questions: (1) What categories of neighborhood characteristics have been addressed? (2) How were those neighborhood characteristics operationalized? A literature review identified 31 relevant articles published between January 1999 and March 2004. The articles were read with special attention toward the measurement of neighborhood characteristics. Twelve categories of neighborhood characteristics represented in the articles include income/wealth, employment, family structure, population composition, housing, mobility, education, occupation, social resources, violence and crime, deviant behavior and physical conditions. A wide diversity of approaches was used to measure these characteristics. The most widely utilized source of data was that of administrative records from the census or local government authorities. Although most authors provided theoretical explanations of their choice to examine broad neighborhood constructs, few were explicit about why certain indicators were selected to measure these constructs. There are theoretical, methodological and practical barriers in the measurement of the neighborhood context which must be addressed for the field to move forward. These barriers are discussed and recommendations are made for addressing them in future research.


New Insight into the Mechanism and Function of Autophagy in Plant Cells.
Autophagy is a degradation pathway that is conserved throughout eukaryotic organisms and plays important roles in the tolerance of abiotic and biotic stresses. It functions as a housekeeping process to remove unwanted cell components under normal conditions, and is induced during stress and senescence to break down damaged cellular contents and to recycle materials. The target components are engulfed into specialized transport structures termed autophagosomes and are subsequently delivered to the vacuole for degradation. Here, we review milestones in the study of autophagy in plants, discuss recent advances in our understanding of the mechanism and physiological roles of plant autophagy, and highlight potential future directions of research.


Miniaturized soft centrifugal pumps with magnetic levitation for fluid handling.
Centrifugal pumps are essential mechanical components for liquid delivery in many biomedical systems whose miniaturization can promote innovative disease treatment approaches. However, centrifugal pumps are predominately constructed by rigid and bulky components. Here, we combine the soft materials and flexible electronics to achieve soft magnetic levitation micropumps (SMLMs) that are only 1.9 to 12.8 grams in weight. The SMLMs that rotate at a rotation speed of 1000 revolutions per min to pump liquids with various viscosities ranging from 1 to 6 centipoise can be used in assisting dialysis, blood circulation, and skin temperature control because of excellent biocompatibility with no organ damage. The development of SMLMs not only demonstrates the possibility to replace rigid rotating structures with soft materials for handling large volumes of fluids but also indicates the potential for fully flexible artificial organs that may revolutionize health care and improve the well-being of patients.


Consistency of sequence-based gene clusters.
In comparative genomics, differences or similarities of gene orders are determined to predict functional relations of genes or phylogenetic relations of genomes. For this purpose, various combinatorial models can be used to specify gene clusters--groups of genes that are co-located in a set of genomes. Several approaches have been proposed to reconstruct putative ancestral gene clusters based on the gene order of contemporary species. One prevalent and natural reconstruction criterion is consistency: For a set of reconstructed gene clusters, there should exist a gene order that comprises all given clusters. For permutation-based gene cluster models, efficient methods exist to verify this condition. In this article, we discuss the consistency problem for different gene cluster models on sequences with restricted gene multiplicities. Our results range from linear-time algorithms for the simple model of adjacencies to NP-completeness proofs for more complex models like common intervals.


The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance.
Perioperative opioids increase postoperative pain and morphine requirement, suggesting acute opioid tolerance. Furthermore, opioids elicit N-methyl-D-aspartate (NMDA)-dependent pain hypersensitivity. We investigated postfentanyl morphine analgesic effects and the consequences of NMDA-receptor antagonist (ketamine) pretreatment. The rat nociceptive threshold was measured by the paw-pressure vocalization test. Four fentanyl boluses (every 15 min) elicited a dose-dependent (a) increase followed by an immediate decrease of the nociceptive threshold and (b) reduction of the analgesic effect of a subsequent morphine administration (5 mg/kg): -15.8%, -46.6%, -85.1% (4 x 20, 4 x 60, 4 x 100 microg/kg of fentanyl, respectively). Ketamine pretreatment (10 mg/kg) increased the fentanyl analgesic effect (4 x 60 microg/kg), suppressed the immediate hyperalgesic phase, and restored the full effect of a subsequent morphine injection. Fentanyl also elicited a delayed dose-dependent long-lasting decrease of the nociceptive threshold (days) that was prevented by a single ketamine pretreatment before fentanyl. However, a morphine administration at the end of the fentanyl effects restored the long-lasting hyperalgesia. Repeated ketamine administrations were required to obtain a complete preventive effect. Although ketamine had no analgesic effect per se at the dose used herein, our results indicate that sustained NMDA-receptor blocking could be a fruitful therapy for improving postoperative morphine effectiveness. Fentanyl-induced analgesia is followed by early hyperalgesia (hours), acute tolerance to the analgesic effects of morphine, and long-lasting hyperalgesia (days). All these phenomena are totally prevented by repeated administrations of the NMDA-receptor antagonist, ketamine, simultaneously with fentanyl and morphine administration.


Excretion of N-mononitrosopiperazine in urine in workers manufacturing piperazine.
Piperazine has been shown to nitrosate in vivo to N-mononitrosopiperazine (MNPZ) by oral intake. Urine from workers exposed to piperazine in a chemical plant was analysed for nitrosamines by gas chromatography-thermal energy analysis. In five out of 11 exposed cases, MNPZ excretion in urine was 0.3 to 4.7 micrograms/24 h (during and after a work shift). In four cases, MNPZ was detected in some urine samples, and in two cases MNPZ was not detected (less than 0.1 ng/ml). The individual excretion was strongly dependent on piperazine exposure, which ranged from 0.06 to 1.7 mg/m3 (time-weighted average; Spearman's rank correlation 0.78, P = 0.01). The MNPZ excretion showed no significant correlation with nitrite or nitrate in saliva (both: r = 0.50, P = 0.10).


Nickel(II) removal by mixtures of Acorga M5640 and DP8R in pseudo-emulsion based hollow fiber with strip dispersion technology.
This work presents the investigation of Ni(II) extraction from aqueous solution through pseudo-emulsion based hollow fiber strip dispersion (PSEHFSD) containing the mixture 2-hydroxy-5-nonylbenzaldehyde oxime+di(2-ethylhexyl) phosphoric acid/Exxsol D100 as extractant in the form of a pseudo-emulsion with H₂SO₄. The organic and aqueous strip phases are separated when the stirring device is stopped. The permeation of Ni(II) is investigated as a function of various experimental variables: hydrodynamic conditions, feed pH, extractants mixture concentration in the pseudo-emulsion, initial Ni(II) concentration in feed phase, H₂SO₄ concentration in the pseudo-emulsion as strippant. In PEHFSD, pseudo-emulsion is an emulsion that is formed temporarily between organic and stripping solutions. In this investigation, feed was circulated through the lumen side in counter-current mode. The selectivity of 2-hydroxy-5-nonylbenzaldehyde oxime+di(2-ethylhexyl) phosphoric acid/Exxsol D100 based PEHFSD toward different metals was also examined.


Saturation mutagenesis of the Drosophila tRNA(Arg) gene B-Box intragenic promoter element: requirements for transcription activation and stable complex formation.
Transcription of eukaryotic tRNA genes is dependent on the A- and B-Box internal control regions (ICRs) and the upstream transcription modulatory region. The B-Box ICR spans nucleotides 52 to 62 and directs the primary binding of transcription factor C as the first step in the formation of a transcription complex. The conservation of the sequence of the B-Box in all tRNA species reflects its importance in both the expression of the gene and the processing, structure and function of the gene product. In order to identify the nucleotides essential to the promoter function of the B-Box ICR, site-directed mutagenesis was used to generate all the possible single point mutations at positions 52 to 58, 61 and 62 of a Drosophila melanogaster tRNA(Arg) gene. The effect of these mutations on gene transcription was evaluated using in vitro transcription and template exclusion competition assays. Optimal activity was displayed by the wild type tDNA(Arg) B-Box sequence but several other sequences supported in vitro transcription at wild type levels. The majority of mutants, however, showed lower efficiency in the in vitro transcription assay. Of the single point mutations, those at positions 53, 55, and 56 had a critical effect on gene function in Drosophila and HeLa transcription extracts and transcription factor interaction most likely requires base contacts at these positions. Since the effect of several of the point mutations cannot be explained in terms of possible major or minor groove contributions the possibility is raised that local DNA geometry also is an important determinant in specifying B-Box function.


An approach to evaluating the introduction of primary nursing in an acute medical unit for the elderly--II. Operationalizing the principles.
The first paper set out the 10 principles which formed the basis on which primary nursing has been introduced in an acute elderly care ward. This paper explores the problems of expressing these principles in terms which make it possible to demonstrate that changes in the way nurses approach their patients and their work have really taken place and suggest some of the research strategies which might be appropriate.


Prolyl-4-hydroxylase PHD2- and hypoxia-inducible factor 2-dependent regulation of amphiregulin contributes to breast tumorigenesis.
Hypoxia-elicited adaptations of tumor cells are essential for tumor growth and cancer progression. Although ample evidence exists for a positive correlation between hypoxia-inducible factors (HIFs) and tumor formation, metastasis and bad prognosis, the function of the HIF-α protein stability regulating prolyl-4-hydroxylase domain enzyme PHD2 in carcinogenesis is less well understood. In this study, we demonstrate that downregulation of PHD2 leads to increased tumor growth in a hormone-dependent mammary carcinoma mouse model. Tissue microarray analysis of PHD2 protein expression in 281 clinical samples of human breast cancer showed significantly shorter survival times of patients with low-level PHD2 tumors over a period of 10 years. An angiogenesis-related antibody array identified, amongst others, amphiregulin to be increased in the absence of PHD2 and normalized after PHD2 reconstitution. Cultivation of endothelial cells in conditioned media derived from PHD2-downregulated cells resulted in enhanced tube formation that was blocked by the addition of neutralizing anti-amphiregulin antibodies. Functionally, amphiregulin was regulated on the transcriptional level specifically by HIF-2 but not HIF-1. Our data suggest that PHD2/HIF-2/amphiregulin signaling has a critical role in the regulation of breast tumor progression and propose PHD2 as a potential tumor suppressor in breast cancer.


Staphylococcus aureus as a risk factor for bloodstream infection in children with postoperative mediastinitis.
Bloodstream infection (BSI) complicates postoperative mediastinitis in >50% of cases. In this retrospective cohort study from 1995-2003, postoperative mediastinitis caused by Staphylococcus aureus was an independent risk factor for the development of BSI (adjusted odds ratio, 6.4; 95% confidence interval, 1.4-29.3). Postoperative mediastinitis caused by S. aureus has a higher intrinsic risk of being complicated by BSI than mediastinitis caused by other pathogens.


The clinical and laboratory response to recombinant factor VIIA in trauma and surgical patients with acquired coagulopathy.
In bleeding patients who are coagulopathic, the clinical response to administration of recombinant factor VIIa (rFVIIa) relates to the changes in prothrombin time (PT). Retrospective review of all surgical and trauma patients who were coagulopathic and received factor VIIa at the authors' institution over the past 27 months. Academic tertiary referral facility and level I trauma center. Eighteen patients met inclusion criteria, 10 trauma and 8 surgical. Mean age 50 years (range, 17-84). Overall mortality was 39%. All but 1 patient (17/18) had resolution of coagulopathic bleeding with rFVIIa, and all clinical responders (n = 17) (defined as clinical cessation of bleeding within 24 hours determined by either attending surgeon or chief resident progress note) had a decrease in PT to normal range. In contrast, the single clinical nonresponder had an insignificant PT decrease (19 to 18 seconds). Prothrombin time decreased from 20 +/- 4 seconds to 12 +/- 2 seconds, p < 0.05 (n = 17). International Normalized Ratio (INR) decreased from 1.59 to 0.86, p < 0.05 (n = 17). Fibrinogen before administration was 299.73 (range, 105-564) (n = 15). pH before administration was 7.25 (+/-0.18) (n = 10). Patient temperature was 98.64 (+/-2.06). Effect in partial thromboplastin time (PTT) was inconsistent (50 +/- 49 seconds to 34 +/- 6 seconds, p > 0.05). Transfusion requirements for red blood cells (14 to 3 units) and plasma (12 to 3 units) were significantly reduced after rFVIIa. There were no significant differences in percentage PT decrease between dose > or =100 mcg/kg vs <100 mcg/kg, surgical vs trauma patients, survivors vs nonsurvivors, and those with pretreatment platelet count > or =100 K vs <100 K. The administration of rFVIIa caused a decrease in the PT in nearly all patients. There were an insufficient number of patients to support the use of PT as a clinical predictor of response; however, the data are suggestive of such utility. If the PT does not correct, then it is likely that there is a deficiency of other factors of the coagulation cascade.


Optimising the management of anaemia in patients with cancer with practice guidelines using erythropoiesis-stimulating proteins.
Anaemia, a common problem in patients with cancer, usually leads to severe fatigue, which can dramatically impair patients' quality of life (QOL). Nurses are in the ideal position to assess and monitor cancer patients at risk of anaemia and recommend appropriate supportive care measures to alleviate anaemia-related symptoms. Erythropoiesis-stimulating proteins (ESPs) can increase haemoglobin levels, reduce the need for red blood cell transfusions, and improve QOL in patients with cancer and anaemia. Evidence-based guidelines published by national and international organisations make specific recommendations for the appropriate use of ESPs. Nurses are key members of the multidisciplinary teams that develop practice-specific protocols, which are based on the national guidelines. The practice guidelines should describe protocols to identify patients at risk for anaemia and interventions to correct anaemia, with specific details on the choice of ESP and when such interventions should be initiated and halted. In addition, nurses should also recommend strategies to reduce patient burden, such as patient self-administration with prefilled pens or synchronisation of visits for ESPs with chemotherapy visits, which is made possible with the once-every-3-weeks extended dosing with darbepoetin alfa. The implementation of such practice guidelines should improve the quality of care provided to patients.


A safety assessment of coumarin taking into account species-specificity of toxicokinetics.
Coumarin (1,2-benzopyrone) is a naturally occurring fragrant compound found in a variety of plants and spices. Exposure to the general public is through the diet and from its use as a perfume raw material in personal care products. High doses of coumarin by the oral route are known to be associated with liver toxicity in rodents. Chronic oral bioassays conducted in the 1990s reported liver tumors in rats and mice and lung tumors in mice, raising concerns regarding the safety of coumarin. Since then, an extensive body of research has focused on understanding the etiology of these tumors. The data support a conclusion that coumarin is not DNA-reactive and that the induction of tumors at high doses in rodents is attributed to cytotoxicity and regenerative hyperplasia. The species-specific target organ toxicity is shown to be related to the pharmacokinetics of coumarin metabolism, with data showing rats to be particularly susceptible to liver effects and mice to be particularly susceptible to lung effects. A quantitative human health risk assessment that integrates both cancer and non-cancer effects is presented, confirming the safety of coumarin exposure from natural dietary sources as well as from its use as a perfume in personal care products.


Respiratory electron transfer activity in an asolectin-isooctane reverse micellar system.
Bovine heart submitochondrial particles (SMP) were solubilized in an asolectin isooctane reverse micellar system and the functionality of the respiratory chain was tested by spectroscopic and amperometric techniques. Electron transfer rate supported by NADH was very slow as evidenced by the low cytochrome reduction levels attained over long incubation periods. In the presence of KCN, NADH caused 34% and 12.5% reduction of the cytochromes aa3 and c, respectively, and negligible reduction of cytochrome b. Supplementation of the system with menadione rose the NADH-dependent reduction of all the cytochromes to levels that were close to the total content. However, no measurable O2 uptake activity took place in the presence of NADH plus menadione, or with ascorbate (or NADH) plus TMPD reducing systems. Therefore, it is suggested that in the organic medium, electron transfer from NADH to O2 is arrested at the terminal oxidase step. Cytochrome oxidase reduced by ascorbate (or NADH) plus TMPD seems to be trapped in its half reduced state (ie, a2+ a3(3+)). Although it is poorly reactive with O2, it can transfer electrons back to cytochrome c and TMPD. The electron transfer block to O2 was overcome when PMS was used instead of TMPD. This seems to be due to the recognized capacity of PMSH2 to carry out simultaneous reduction of both a CuA and a3 CuB redox centers of cytochrome oxidase. The cytochrome oxidase reaction in the organic solvent was highly sensitive to KCN (Ki 1.9 microM) and showed bell-shaped kinetics towards the PMS concentration and a sigmoidal response to water concentration, reaching its maximal turnover number (18 s-1) at 4 mM PMS and 1.1% (v/v) water.(ABSTRACT TRUNCATED AT 250 WORDS)


Single-molecule analysis of the microtubule cross-linking protein MAP65-1 reveals a molecular mechanism for contact-angle-dependent microtubule bundling.
Bundling of microtubules (MTs) is critical for the formation of complex MT arrays. In land plants, the interphase cortical MTs form bundles specifically following shallow-angle encounters between them. To investigate how cells select particular MT contact angles for bundling, we used an in vitro reconstitution approach consisting of dynamic MTs and the MT-cross-linking protein MAP65-1. We found that MAP65-1 binds to MTs as monomers and inherently targets antiparallel MTs for bundling. Dwell-time analysis showed that the affinity of MAP65-1 for antiparallel overlapping MTs is about three times higher than its affinity for single MTs and parallel overlapping MTs. We also found that purified MAP65-1 exclusively selects shallow-angle MT encounters for bundling, indicating that this activity is an intrinsic property of MAP65-1. Reconstitution experiments with mutant MAP65-1 proteins with different numbers of spectrin repeats within the N-terminal rod domain showed that the length of the rod domain is a major determinant of the range of MT bundling angles. The length of the rod domain also determined the distance between MTs within a bundle. Together, our data show that the rod domain of MAP65-1 acts both as a spacer and as a structural element that specifies the MT encounter angles that are conducive for bundling.


A novel GRK2 inhibitor alleviates experimental arthritis through restraining Th17 cell differentiation.
T helper type 17 (Th17) cell which is induced by interleukine-6 (IL-6)-signal transducers and activators of transcription 3 (STAT3) signaling is a central pro-inflammatory T cell subtype in rheumatoid arthritis (RA) and could be significantly reduced by paeoniflorin-6'-O-benzene sulfonate (CP-25) treatment with unclear mechanisms. This study was aimed to found out the mechanism of CP-25 in hampering Th17 cells differentiation in arthritic animals thus explore more therapeutic targets for RA. In mice with collagen-induced arthritis (CIA), both circulating and splenic Th17 subsets were expanded with increased STAT3 phosphorylation and decreased Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP1)-β-arrestin2 (arrb2)-STAT3 interaction in CD4+ helper T (Th) cells. Either CP-25 or paroxetine (PAR), an established G protein coupled receptor kinase 2 (GRK2) inhibitor treatment effectively relieved the joints inflammation of CIA mice with substantially reduced Th17 cell population through inhibiting STAT3 and restoring the SHP1-arrb2-STAT3 complex. Knockout of arrb2 exacerbated the clinical manifestations of collagen antibody-induced arthritis with upregulated Th17 cells. In vitro studies revealed that depletion of arrb2 or inhibition of SHP1 promoted Th17 cell differentiation. Moreover, stimulation of adenosine A3 receptor (A3AR) simultaneously promoted Th17 cell differentiation via accelerating abbr2-A3AR binding, which could be prevented through inhibiting GRK2 phosphorylation by CP-25 or PAR, or genetically reducing GRK2. This work has demonstrated that CP-25 or PAR treatment recovers the SHP1-arrb2-STAT3 complex which prevents STAT3 activation in Th cells through reducing arrb2 recruitment to A3AR by inhibiting GRK2 phosphorylation, leading to the reduction in Th17 cell differentiation and arthritis attenuation.


Gastrointestinal manifestations in PTEN hamartoma tumor syndrome.
The PTEN hamartoma tumor syndrome (PHTS) is a heterogeneous set of multisystem disorders caused by germline pathogenic variants in the PTEN tumor suppressor gene. Manifestations include developmental anomalies and proliferative lesions. Evidence of involvement of the GI tract has accrued over time, leading to the incorporation of GI manifestations (multiple hamartomas, glycogenic acanthosis and colorectal cancer) into the diagnostic criteria. Polyps of the upper and lower GI tract are found in most adult patients and in a significant fraction of children. Polyps tend to be of mixed histology, with a predominance of hamartomas and ganglioneuromas. PHTS patients are also at increased risk of colorectal cancer, and surveillance by colonoscopy is advised starting at the age of 35-40 years. A number of additional manifestations, including eosinophilic gastrointestinal disorders, have been observed in few or single cases, and their association with PHTS has yet to be determined.


Paralytic poliomyelitis in England and Wales, 1985-91.
To ascertain all cases of paralytic poliomyelitis in England and Wales during 1985-91 and to determine the source of infection in each case. Descriptive study of cases reported between 1985 and 1991. All health districts in England and Wales. Patients normally resident in England and Wales whose clinical features were consistent with paralytic poliomyelitis or with laboratory evidence of recent poliovirus infection and compatible symptoms. Clinical, epidemiological, and laboratory features in identified cases. Of 54 suspected cases of poliomyelitis, 33 were excluded, leaving 21 cases, of which 13 were vaccine associated (nine recipient and four contact) cases, five were imported cases, and three were cases whose source of infection was unknown. No cases due to indigenous wild polioviruses were identified; two were imported cases due to wild viruses. One patient died during the acute phase of the illness, and two children with previously unrecognised severe congenital immune deficiency died between one and two months after the onset of paralysis after the first or second dose of oral polio vaccine. The estimated risk of vaccine associated paralysis is 1.46 per million for the first dose, 0.49 for the second, zero for the third and fourth doses, and 0.33 for the fifth. Indigenous wild poliovirus seems to have been eradicated, although wild virus may be imported; improved surveillance of suspected cases including immediate notification and characterisation of the virus to ensure that eradication is maintained is essential.


Extraplexual neurotization of brachial plexus.
The authors reviewed 62 neurotizations of the brachial plexus in 71 patients performed between 1974 and 1989. The nerves used were the accessory, the motor or sensory branches of the cervical plexus, and the intercostals. Twenty-five suprascapular nerves, 19 musculocutaneous, 4 medial roots of the median nerve, and 12 lateral roots of the median nerve were neurotized. The authors concluded that useful results can be achieved using extraplexual neurotizations.


MLAGO: machine learning-aided global optimization for Michaelis constant estimation of kinetic modeling.
Kinetic modeling is a powerful tool for understanding the dynamic behavior of biochemical systems. For kinetic modeling, determination of a number of kinetic parameters, such as the Michaelis constant (Km), is necessary, and global optimization algorithms have long been used for parameter estimation. However, the conventional global optimization approach has three problems: (i) It is computationally demanding. (ii) It often yields unrealistic parameter values because it simply seeks a better model fitting to experimentally observed behaviors. (iii) It has difficulty in identifying a unique solution because multiple parameter sets can allow a kinetic model to fit experimental data equally well (the non-identifiability problem). To solve these problems, we propose the Machine Learning-Aided Global Optimization (MLAGO) method for Km estimation of kinetic modeling. First, we use a machine learning-based Km predictor based only on three factors: EC number, KEGG Compound ID, and Organism ID, then conduct a constrained global optimization-based parameter estimation by using the machine learning-predicted Km values as the reference values. The machine learning model achieved relatively good prediction scores: RMSE = 0.795 and R2 = 0.536, making the subsequent global optimization easy and practical. The MLAGO approach reduced the error between simulation and experimental data while keeping Km values close to the machine learning-predicted values. As a result, the MLAGO approach successfully estimated Km values with less computational cost than the conventional method. Moreover, the MLAGO approach uniquely estimated Km values, which were close to the measured values. MLAGO overcomes the major problems in parameter estimation, accelerates kinetic modeling, and thus ultimately leads to better understanding of complex cellular systems. The web application for our machine learning-based Km predictor is accessible at https://sites.google.com/view/kazuhiro-maeda/software-tools-web-apps , which helps modelers perform MLAGO on their own parameter estimation tasks.


The correction of post-traumatic pan facial residual deformity.
Disfiguring post-traumatic deformities of the midface sometimes persist even after the treatment. Such deformities, after healing, are among the most formidable challenges faced by the surgeons, apart from the psychological impact on the patients. Following the basic principles of craniofacial reconstruction and with newer techniques, better results can be achieved. Symmetry is key to proper reconstruction in general and face in particular. Proper facial projection and height must be re-established with harmonious occlusion. Our basic approach to the evaluation of deformities and particularly useful techniques for their correction are presented, with a representative case of malunited panfacial fracture that we treated with an iliac bone onlay grafting for zygoma along with correction of mandibular deformity by osteotomies.


Overview of the Commonly Used Methods for Food Allergens.
Food allergy has become a major public health problem worldwide. In the past two decades, development in molecular biology and immunology has led to many new techniques that had improved traditional methods in the food allergy field. These methods greatly facilitate identification, characterization, and quantification of food allergen and are certainly leading to better diagnostics and therapeutics for food allergic diseases. Here we review methods commonly used for food allergens.


Post-Mastectomy Patients in an Urban Safety-Net Hospital: How Do Safety-Net Hospital Breast Reconstruction Rates Compare to National Breast Reconstruction Rates?
Breast reconstruction (BR) has documented psychological benefits following mastectomy. Yet, racial/ethnic minority groups have lower reported rates of BR. We sought to evaluate the rate, type, and outcome of BR in a racially and ethnically diverse population within a safety-net hospital system. All patients who underwent mastectomy between October 2015 and July 2019 at Harbor-UCLA Medical Center were retrospectively examined. Rates and type of BR were analyzed according to patient characteristics (race/ethnicity, age, and body mass index), smoking status, cancer stage, and presence of diabetes mellitus. Breast reconstruction outcomes were also assessed. Of the 259 patients that underwent mastectomy, 87 (33.6%) received BR. Immediate BR was performed in 79 (30.5%) patients and delayed BR in 8 (3.1%). Of the 79 patients with immediate BR, 58 (73.4%) received implant-based BR and 21 (26.5%) autologous tissue. The BR failure rate was 10%, all implant-based. Increasing age and smoking negatively impacted BR rates. Black (P =.331) and Hispanic (P =.132) ethnicity were not independent predictors of decreased breast reconstruction. This study demonstrated that the rate, type, and quality of BR in this integrated safety-net hospital within a diverse population are comparable to national rates. When made available, historically underrepresented minority patients of Black and Hispanic ethnicity utilize BR.


Enhancing Mindfulness and Well-Being in Higher Education.
This article outlines the steps taken to establish the University of Wisconsin-Superior's Pruitt Center for Mindfulness and Well-Being. Major historical components include: gaining momentum; securing funding; developing mission and vision statements; launching the Pruitt Center; and recounting the services, programs, and impacts achieved to date. Through outlining experiences and lessons learned, others in higher education looking to enhance the well-being of their campus communities could benefit, regardless of whether creating a center is their goal. The process and rationale for creating and adopting the PERMANENT Model of Well-Being is also provided. Comparisons are made regarding the similarities and differences between the PERMANENT Model and two existing models: the PERMA Model and the Universidad Tecmilenio Well-being in Happiness Ecosystem. Also depicted is the intention concerning: 1) describing each domain of the PERMANENT Model of Well-Being, including Present Moment Awareness, the model's foundation; 2) the meaning behind the PERMANENT acronym, inspiring the notion of long-lasting well-being; 3) including the greater community; and 4) the model's process of learn, experience, reflect, and repeat, a reminder that all learning takes effort and practice. This process is supported by current mindfulness and well-being research, specifically as it relates to higher education.


Exceptional steric congestion in an in,in-bis(hydrosilane).
The synthesis and characterization of a macrobicyclic in,in-bis(hydrosilane) is described. A combination of crystallographic and computational data indicate that the central hydrogen-hydrogen nonbonded contact distance is the shortest for any crystallographically characterized compound.


Current concepts: I. The relationship between age-related changes in gene expression, protein turnover, and the responsiveness of an organism to stimuli.
A general decline in gene expression, translation and transcription, has been observed to occur with increasing age in a wide variety of organisms and tissues. Because the level of most enzymes and proteins remains relatively constant with increasing age, one would predict that the decline in gene expression would result in an age-related decline in protein turnover. Recent studies show that protein turnover in mouse liver and nematodes declines with increasing age. The decline in protein turnover could lead to an age-related decrease in the response of inducible enzymes to stimuli. This could explain the molecular basis for the decline in aging organisms to respond to a variety of environmental factors.


An assessment of risk understanding in Hispanic genetic counseling patients.
This study sought to identify if differences existed in risk comprehension and risk format understanding between genetic counseling patients of Hispanic and Caucasian ethnicity. A total of 107 questionnaires were collected, 56 from Hispanic patients, and 51 from Caucasian controls. Of the total population 41.1% (44/107) could not demonstrate sufficient risk understanding, which was 71.4% (40/56) of Hispanics and 7.8% (4/51) of Caucasians. Fractions were the best-understood format for all participants. However, both Hispanics and Caucasians had difficulties with the percentage risk format. Discrepancies were also noted in qualitative word format understanding. Awareness of differences in risk comprehension may affect the selection of counseling techniques and strategies utilized by genetic counselors when educating patients about risk related information.


Nursing work environment, value congruence and their relationships with nurses' work outcomes.
To explore the relationships between work environment, value congruence and nurses' work outcomes; as well as to test the moderating effects of value congruence. A poor nursing work environment in most of mainland China has negatively influenced nurses' job satisfaction, burnout and turnover intention. New insights such as improving nurses' value congruence should be proposed to better foster nurses. Cross-sectional data were selected from the Chinese Nurses' Environment of Work Status study. In total, 19149 valid samples were collected. Hierarchical regression analyses and simple slope analyses were performed. The correlation coefficients of the variables were all significant (p < .01) and in the expected direction. Value congruence moderated the relationship between nursing work environment and burnout (emotional exhaustion: β = 0.106, p < .01; depersonalization: β = 0.111, p < .01). Nursing work environment and value congruence were positively related to job satisfaction, and negatively related to burnout and turnover intention. The adverse impact of poor work environment on nurses' burnout can be buffered if nurses' value congruence is compatible with that of the organisation. Except for improving the organisational characteristics, value congruence is a useful concept that managers can leverage to improve positive outcomes for both the organisation and its nurses.


Draft genome sequence of Halomonas sp. strain KM-1, a moderately halophilic bacterium that produces the bioplastic poly(3-hydroxybutyrate).
We report the draft genome sequence of Halomonas sp. strain KM-1, which was isolated in Ikeda City, Osaka, Japan, and which produces the bioplastic poly(3-hydroxybutyrate). The total length of the assembled genome is 4,992,811 bp, and 4,220 coding sequences were predicted within the genome. Genes encoding proteins that are involved in the production and depolymerization of poly(3-hydroxybutyrate) were identified. The identification of these genes might be of use in the production of the bioplastic poly(3-hydroxybutyrate) and its monomer 3-hydroxybutyrate.


Structure and energetics of protein-protein interactions: the role of conformational heterogeneity in OMTKY3 binding to serine proteases.
Proteins with flexible binding surfaces can interact with numerous binding partners. However, this promiscuity is more difficult to understand in "rigid-body" proteins, whose binding results in little, or no, change in the position of backbone atoms. The binding of Kazal inhibitors to serine proteases is considered a classic case of rigid-body binding, although they bind to a wide range of proteases. We have studied the thermodynamics of binding of the Kazal serine protease inhibitor, turkey ovomucoid third domain (OMTKY3), to the serine protease subtilisin Carlsberg using isothermal titration calorimetry and have determined the crystal structure of the complex at very high resolution (1.1A). Comparison of the binding energetics and structure to other OMTKY3 interactions demonstrates that small changes in the position of side-chains can make significant contributions to the binding thermodynamics, including the enthalpy of binding. These effects emphasize that small, "rigid-body" proteins are still dynamic structures, and these dynamics make contributions to both the enthalpy and entropy of binding interactions.


Pre-S encoded surface proteins in relation to the major viral surface antigen in acute hepatitis B virus infection.
The role of pre-S encoded viral surface proteins in acute hepatitis B virus infection is still poorly understood. Binding sites for polymerized human serum albumin have been found to be encoded by the pre-s2 region of the hepatitis B virus genome. Recently, murine monoclonal antibodies against pre-s1 and pre-s2 encoded hepatitis B virus gene products were generated and used for their specific detection in serum. In sera from patients with acute hepatitis B, pre-s1 and pre-s2 antigen occurred in 16 of 20 and 15 of 20 patients, respectively. In the initial stage of the disease, pre-S gene products correlated with binding sites for polymerized human serum albumin, but not with hepatitis B surface antigen. Subsequently, pre-s1 and pre-s2 antigens were cleared from the serum of patients with acute hepatitis B before binding sites for polymerized human serum albumin and hepatitis B surface antigen. Possibly, the early clearance of pre-S markers can be of prognostic value in acute hepatitis B. The mechanisms of the early clearance of the pre-S antigens in acute hepatitis B remain to be elucidated. However, elimination by immunologic mechanisms appears likely.


Differential color tuning of the mesolimbic reward system.
Visual wavelengths are not only associated with the subjective experience of color but also have long been thought to regulate affect. Here we examined the attracting rewarding properties of opposite ends of the wavelength spectrum, as well as their individual variation. As reward is multifaceted, we sought convergent evidence from subjective and objective behavioral and attentional indices, as well as its neural reward system bases. On average, short (blue) relative to long (red) wavelengths were judged subjectively more pleasant and had objectively greater behavioral and attentional salience, regulating speed of simple color discriminations and perception of temporal order. Consistent with reward, these color effects were magnified following monetary reinforcement. Pronounced individual differences in color effects were related to reward but not punishment sensitivity, with blue relative to red preference associated with high relative to low reward sensitivity. An fMRI study revealed these individual differences were supported by color-dependent functional coupling between the visual cortices and mesolimbic reward circuitry. Our findings reveal the reward bases of color, demonstrating color is a potent regulator of perception, action, and neural dynamics.


Sex-associated differences in the immune response against fetal major histocompatibility antigens. II. Association of the female IgG1 with H-2K-encoded alloantigens.
Alloantibodies against the H-2b haplotype were produced in C3HeB female and male parental mice in response to transplantation of F1 fetal tissue (bones). In testing IgG1 and IgG2 antibodies by means of the FACS II we found striking sex-associated differences in the isotypes produced: female mice produced much more IgG1 than male mice, although they produced comparable amounts of IgG2. Using protein-A-sepharose-purified fractions of IgG1 and IgG2, raised in the parental females we found the specificity of this extra IgG1 to be directed against the H-2Kb private determinants, in contrast to the IgG2 which was found to be specific for H-2Kb, H-2Db and I-Ab subregion alloantigens. The relevance of the association between H-2K alloantigens and IgG1, in context of the fetal-maternal relationship is discussed.


Redox phospholipidomics analysis reveals specific oxidized phospholipids and regions in the diabetic mouse kidney.
While it is generally accepted that oxidative stress impacts the diabetic kidney and contributes to pathogenesis, there is a substantial lack of knowledge about the molecular entity and anatomic location of a variety of reactive species. Here we provide a novel "oxidative stress map" of the diabetic kidney - the first of its kind, and identify specific, oxidized and other reactive lipids and their location. We used the db/db mouse model and Desorption Electrospray Ionization (DESI) mass spectrometry combined with heatmap image analysis. We analyzed a comprehensive array of phospholipid peroxide species in normal (db/m) and diabetic (db/db) kidneys using DESI imaging. Oxilipidomics heatmaps of the kidneys were generated focusing on phospholipids and their potential peroxidized products. We identified those lipids that undergo peroxidation in diabetic nephropathy. Several phospholipid peroxides and their spatial distribution were identified that were specific to the diabetic kidney, with significant enrichment in oxygenated phosphatidylethanolamines (PE) and lysophosphatidylethanolamine. Beyond qualitative and semi-quantitative information about the targets, the approach also reveals the anatomic location and the extent of lipid peroxide signal propagation across the kidney. Our approach provides novel, in-depth information of the location and molecular entity of reactive lipids in an organ with a very heterogeneous landscape. Many of these reactive lipids have been previously linked to programmed cell death mechanisms. Thus, the findings may be relevant to understand what impact phospholipid peroxidation has on cell and mitochondria membrane integrity and redox lipid signaling in diabetic nephropathy.


Upcoming diagnostic biomarkers with promising prospects in neurological disorders.
An exponential increase in the prevalence of neurological disorders requires substantial steps to be taken for their prevention and treatment. Neurodiagnostic biomarkers are gaining momentum presently in order to enhance the diagnostic accuracy of neurodegenerative disorders, to precisely assess their advancement and to monitor the efficiency of therapeutic interventions. Therefore, the primary focus of the present review is the recent development in this field of neurodiagnostic biomarkers, and the current state of biomarker exploration in the context of various neurodegenerative diseases. This review encompasses an updated and detailed account of specific (β-Amyloid, Tau and Phospho-tau 181, Tar-DNA binding protein-43, Progranulin, a-synuclein, Clusterin, etc) and non-specific (genetic, synaptic, inflammatory and coagulation) neurodiagnostic biomarkers and the recent advances in this growing field. This comprehensive review also suggests the utilization of neurodiagnostic markers in network approaches and personalized medication that will eventually improvise the existing diagnostic and therapeutic complexities of neurodiagnostic biomarkers.


Bioinspired 3D structures with programmable morphologies and motions.
Living organisms use spatially controlled expansion and contraction of soft tissues to achieve complex three-dimensional (3D) morphologies and movements and thereby functions. However, replicating such features in man-made materials remains a challenge. Here we report an approach that encodes 2D hydrogels with spatially and temporally controlled growth (expansion and contraction) to create 3D structures with programmed morphologies and motions. This approach uses temperature-responsive hydrogels with locally programmable degrees and rates of swelling and shrinking. This method simultaneously prints multiple 3D structures with custom design from a single precursor in a one-step process within 60 s. We suggest simple yet versatile design rules for creating complex 3D structures and a theoretical model for predicting their motions. We reveal that the spatially nonuniform rates of swelling and shrinking of growth-induced 3D structures determine their dynamic shape changes. We demonstrate shape-morphing 3D structures with diverse morphologies, including bioinspired structures with programmed sequential motions.


Beneficial effects of γ-aminobutyric acid on right ventricular pressure and pulmonary vascular remodeling in experimental pulmonary hypertension.
It has been reported that activation of the sympathetic nervous system and increase in plasma norepinephrine (NE) levels are observed in patients with pulmonary hypertension (PH). γ-Aminobutyric acid (GABA) is one of the major inhibitory neurotransmitters in the central nervous system and suppresses peripheral sympathetic neurotransmission. This study investigated whether chronic treatment with GABA prevents the development of monocrotaline (MCT)-induced PH. To elucidate the relationship between the development of PH and sympathetic nerve activity, hemodynamic parameters, cardiac functions, and plasma NE concentrations as well as cardiac endothelin-1 (ET-1) contents of MCT-induced PH rats were evaluated with or without GABA treatment. Rats were injected with MCT (60 mg/kg) or saline subcutaneously and these rats were randomly divided into GABA (500 mg/kg/day for 4 weeks)- or vehicle-treated groups, respectively. MCT-treated rats had higher right ventricular systolic pressures, right ventricle-to-left ventricle plus septum weight ratios, pulmonary arterial medial thickening, and plasma NE levels than those of saline-injected rats. MCT-induced alternations were significantly attenuated by treatment with GABA. In MCT-induced PH rats with or without GABA treatment, plasma NE levels were positively correlated with right ventricular systolic pressure. Right ventricular endothelin-1 (ET-1) contents were increased by MCT injection, but these increments were not affected by treatment with GABA. These results suggest that plasma NE levels play an important role in the development of MCT-induced PH in rats and that GABA exerts a preventive effect against MCT-induced PH by suppressing the sympathetic nervous system but not the cardiac ET-1 system.


Partial rupture of the Achilles tendon during a simulated fire ground task: insights obtained from a case report for the prevention and reporting of musculoskeletal injury.
In this case report an incumbent firefighter partially ruptured his right Achilles tendon during a study of the physical demands of firefighting. Kinematics and kinetics of the lower limbs and trunk were collected while the firefighter performed two simulated fire ground tasks. From this unexpected event, two insights were obtained that should be considered in all future injury prevention and reporting efforts. (i) Consider the full anatomical linkage--the right ankle and knee kinematics leading up to the onset of injury trial were comparable to all preceding repetitions. However, there was a notable difference in the left knee starting position before the initiation of movement of the 37th hose-advance trial. (ii) Consider the cumulative load--the task in question comprised forward and backward phases. A marked difference was observed in the frontal-plane ankle moment during the return phase of the trial preceding the injury. Additionally, the magnitude of the left side vertical ground reaction force was comparable across all trials, suggesting that loads experienced by the right limb were also similar. This would indicate that the tolerance of the Achilles tendon and not the magnitude of the loading was altered. The unfortunate injury captured in this work provides insight into the complexity of characterizing the pathways of injury. It is recommended that future injury prevention and reporting efforts consider individuals' physical demands (at work and in life) and document the nature of loading (i.e., frequency, duration, magnitude, type) when considering the mechanism for injury.


Psychologic well-being of surgery residents after inception of the 80-hour workweek: a multi-institutional study.
The 80-hour workweek was adopted by US residency programs on July 1, 2003. Our published data from the preceding year indicated significant impairment in psychologic well-being among surgery residents. The purpose of this study was to determine whether psychologic well-being and academic performance of surgery residents improved after inception of the 80-hour workweek. A single-blinded survey of general surgery residents (n=130) across 4 US training programs was conducted after July 1, 2003, with the use of validated psychometric surveys (Symptom Checklist-90-R and Perceived Stress Scale) and the American Board of Surgery In-Training Examination; comparison was done with preceding year and societal data. Primary outcomes were "psychologic distress" and "perceived stress." Secondary outcomes were "somatization," "depression," "anxiety," "interpersonal sensitivity," "hostility," "obsessive-compulsive behavior," "phobic anxiety," "paranoid ideation," "psychoticism." and "academic performance." The impact of demographic variables was assessed. Mean psychologic distress improved from the preceding year (P < .01) but remained elevated, compared with societal norms (P < .001). The proportion of residents meeting the criteria for clinical psychologic distress (>or=90th percentile) decreased from 38% before, to 24% after, July 2003. Mean perceived stress remained elevated, compared with norms (P < .0001) without improvement from the preceding year. Overall academic performance was unchanged. Previously elevated secondary psychologic outcomes improved after July 2003 (P < .05), although obsessive-compulsive behavior, depression, interpersonal sensitivity, hostility, and anxiety failed to normalize. Male gender and single status were independent risk factors for psychologic distress. Inception of the 80-hour workweek is associated with reduced psychologic distress among surgery residents. The perception of stress and academic performance remains unchanged.


PRODH2-Mediated Proline Metabolism Boosts CAR T-cell Effector Function.
Overexpression of PRODH2 augments CAR T-cell proliferation, effector function, and memory phenotype.


Probing N⁶-methyladenosine (m⁶A) RNA Modification in Total RNA with SCARLET.
Posttranscriptional N (6)-methyladenosine (m(6)A) RNA modification is indispensable for cell development and viability; however, functional investigation of m(6)A biological function has been hindered by the lack of methods for its precise identification and quantitation. Here, we describe a method that accurately identifies m(6)A position and modification fraction in human messenger RNA (mRNA) and long noncoding RNA (lncRNA) at single-nucleotide resolution, termed as "site-specific cleavage and radioactive-labeling followed by ligation-assisted extraction and thin-layer chromatography (SCARLET)" (Fig. 1). This method combines two previously established techniques, site-specific cleavage and splint ligation, to probe the m(6)A RNA modification status at any mRNA/lncRNA site in the total RNA pool.