Assessment of Duration of Smoking Cessation Prior to Surgical Treatment of Non-small Cell Lung Cancer.
To define the relationship between the duration of smoking cessation and postoperative complications for patients with lung cancer undergoing surgical treatment. Smoking increases the risk of postoperative morbidity and mortality in patients with lung cancer undergoing surgical treatment. Although smoking cessation before surgery can mitigate these risks, the ideal duration of preoperative smoking cessation remains unclear. Using a uniquely compiled Veterans Health Administration dataset, we performed a retrospective cohort study of patients with clinical stage I non-small cell lung cancer undergoing surgical treatment between 2006 and 2016. We characterized the relationship between duration of preoperative smoking cessation and risk of postoperative complications or mortality within 30-days using multivariable restricted cubic spline functions. The study included a total of 9509 patients, of whom 6168 (64.9%) were smoking at the time of lung cancer diagnosis. Among them, only 662 (10.7%) patients stopped smoking prior to surgery. Longer duration between smoking cessation and surgery was associated with lower odds of major complication or mortality (adjusted odds ratio [aOR] for every additional week, 0.919; 95% confidence interval [CI], 0.850-0.993; P = 0.03). Compared to nonsmokers, patients who quit at least 3 weeks before surgery had similar odds of death or major complication (aOR, 1.005; 95% CI, 0.702-1.437; P = 0.98) whereas those who quit within 3 weeks of surgery had significantly higher odds of death or major complication (aOR, 1.698; 95% CI, 1.203-2.396; P = 0.003). Smoking cessation at least 3 weeks prior to the surgical treatment of lung cancer is associated with reduced morbidity and mortality. Providers should aggressively encourage smoking cessation in the preoperative period, since it can disproportionately impact outcomes in early-stage lung cancer.


Clear cell change in colonic tubular adenoma and corresponding colonic clear cell adenocarcinoma is associated with an altered mucin core protein profile.
Clear cell change is seen in <1% of colonic tubular adenomas (TAs) and remains incompletely characterized. Associated adenocarcinomas can also demonstrate a clear cell phenotype. Eleven TAs with at least focal clear cell change with or without associated invasive adenocarcinoma, from 10 patients were studied. The lesions were stained with periodic acid-Schiff (PAS)/PAS-diastase and immunolabeled with antibodies to MUC2, MUC5AC, MUC6, CK7, CK20, and CDX2. Eight of 11 (77%) TAs with clear cell change had focal to extensive high-grade dysplasia. Two were associated with invasive clear cell adenocarcinoma. The adenomas and adenocarcinomas ranged from 0.5 to 3.5 cm. PAS/PAS-diastase stains showed minimal PAS(+) material in the clear cells. On immunohistochemical studies, the clear cells had decreased MUC2 labeling compared with the surrounding conventional adenoma in 9 of 11 (88%) cases, including the 2 clear cell adenocarcinomas. In 3 of the 11 lesions, the background TA showed at least focal MUC5 immunoreactivity, their associated clear cell area had decreased MUC5 labeling in all 3 cases. No immunoreactivity to MUC6 was observed in the background TAs and clear cells in all cases. Compared with background TA, both increased and decreased expression of CK7, CK20 (in quantity), and CDX2 (in intensity) were observed in the clear cells of TAs and adenocarcinomas. One of the clear cell adenocarcinomas was CK20, CK7, CDX2 and the other was CK20, CK7, CDX2-focal positive. Thus, although the clear cells have different MUC protein profiles than the background adenomatous epithelium, invasive clear cell adenocarcinomas retained the typical CK20(+)/CK7(-) profile of conventional adenocarcinomas. Our results indicate that clear cell adenocarcinomas can be primary to the colorectum with identifiable precursors. Awareness of them and their immunoprofile allows distinction from clear cell lesions from other sites.


[A four-dimensional model of chronic schizophrenia based on the factorial structure of the Positive and Negative Syndrome Scale (PANSS). A study of a group of 153 chronic schizophrenic patients and comparison with the factorial structure of the BPRS].
The aim of the study is to explore the latent dimensions in chronic schizophrenia using factorial analysis methods. 153 subjects (89 males, 64 females) with a mean age of 38.83 years (sd = 10.15) meet the RDC criteria for chronic schizophrenia and were included in the study. They were 127 inpatients and 26 outpatients and the mean duration of the illness since the first psychotic episode was 14.69 years (sd = 9.64). The majority of the schizophrenics received antipsychotic treatment with a mean dose (in chlorpromazine-equivalent) of 401.86 mg (sd = 368.13). The schizophrenics were rated using the French versions of the Positive and Negative Syndrome Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS). Two successive principal components analyses (PCA) were carried out on the correlation matrix of the 30 PANSS and 18 BPRS items. The numbers of factors were limited using several guidelines : eigenvalues higher than 1, screen test and the parallel analysis of Horn. Then an orthogonal equamax rotation was made and the saturation value was chosen using and ad-hoc paradigm. The results have shown a four-factors solution for the PANSS with the following factors : negative, positive-hostility, disorganization-impulsivity, depressive-anxious. The composition of the four preceding factors was respectively : negative [N1, N2, N3, N4, N6, N7, G7, P4 (-)]; positive-hostility (P1, P2, P3, P5, P6, P7, G8, G9, G12, G15, G16); disorganization-impulsivity (G5, G10, G11, G13, G14, N5); depressive-anxious (G1, G2, G3, G4, G6). The ACP of the BPRS have shown a three factors solution (positive-disorganization, negative, depressive-anxious). The factorial structure of the PANSS was discussed with the different studies. Our results confirm the division of the productive symptomatology into two components, delusions-hallucinations and cognitive (disorganization). Moreover depressive and negative symptomatology constitute two separate dimensions. Contrary to the others studies we did not find an excited component, the corresponding items were found in the positive and disorganization factors. The inclusion of solely chronic schizophrenics could explain the lack of the excited component. Our data in chronic schizophrenia allow us to propose a four-dimensional model explaining the symptomatology of this disease.


Fetal alcohol syndrome (FAS) in C57BL/6 mice detected through proteomics screening of the amniotic fluid.
Fetal Alcohol Syndrome (FAS), a severe consequence of the Fetal Alcohol Spectrum Disorders, is associated with craniofacial defects, mental retardation, and stunted growth. Previous studies in C57BL/6J and C57BL/6N mice provide evidence that alcohol-induced pathogenesis follows early changes in gene expression within specific molecular pathways in the embryonic headfold. Whereas the former (B6J) pregnancies carry a high-risk for dysmorphogenesis following maternal exposure to 2.9 g/kg alcohol (two injections spaced 4.0 h apart on gestation day 8), the latter (B6N) pregnancies carry a low-risk for malformations. The present study used this murine model to screen amniotic fluid for biomarkers that could potentially discriminate between FAS-positive and FAS-negative pregnancies. B6J and B6N litters were treated with alcohol (exposed) or saline (control) on day 8 of gestation. Amniotic fluid aspirated on day 17 (n = 6 replicate litters per group) was subjected to trypsin digestion for analysis by matrix-assisted laser desorption-time of flight mass spectrometry with the aid of denoising algorithms, statistical testing, and classification methods. We identified several peaks in the proteomics screen that were reduced consistently and specifically in exposed B6J litters. Preliminary characterization by liquid chromatography tandem mass spectrometry and multidimensional protein identification mapped the reduced peaks to alpha fetoprotein (AFP). The predictive strength of AFP deficiency as a biomarker for FAS-positive litters was confirmed by area under the receiver operating characteristic curve. : These findings in genetically susceptible mice support clinical observations in maternal serum that implicate a decrease in AFP levels following prenatal alcohol damage.


Metformin ameliorates scleroderma via inhibiting Th17 cells and reducing mTOR-STAT3 signaling in skin fibroblasts.
Scleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β, IL-6, IL-17, and TNF-α play important roles in the pathogenesis of scleroderma. Because metformin, a medication used to treat diabetes, has effective immunoregulatory functions, we investigated its therapeutic function in scleroderma. Mice in a model of bleomycin-induced scleroderma were treated with metformin for 2 weeks. Histological assessment demonstrated protective effects of metformin against scleroderma. Metformin decreased the expression of pro-inflammatory factors in dermal tissue and lymphocytes. It also decreased mRNA expression of pro-inflammatory cytokines (IL-1β, IL-6, IL-17, and TNF-α) and fibrosis-inducing molecules both in vivo and in vitro. These results suggest that metformin treatment has anti-inflammatory effects on lymphocytes via the inhibition of IL-17 and cytokines related to Th17 differentiation, such as IL-1β, IL-6, and TNF-α. To investigate how metformin modulates the inflammatory process in skin fibroblasts, we measured mTOR-STAT3 signaling in skin fibroblasts and found that phosphorylated mTOR and phosphorylated STAT3 protein expression were decreased by metformin treatment. These results suggest that metformin has potential to treat scleroderma by inhibiting pro-inflammatory cytokines and anti-inflammatory activity mediated by mTOR-STAT3 signaling.


Isorhynchophylline Exerts Antinociceptive Effects on Behavioral Hyperalgesia and Allodynia in a Mouse Model of Neuropathic Pain: Evidence of a 5-HT1A Receptor-Mediated Mechanism.
Chronic neuropathic pain poses a significant health problem, for which effective therapy is lacking. The current work aimed to investigate the potential antinociceptive efficacy of isorhynchophylline, an oxindole alkaloid, against neuropathic pain and elucidate mechanisms. Male C57BL/6J mice were subjected to chronic constriction injury (CCI) by loose ligation of their sciatic nerves. Following CCI surgery, the neuropathic mice developed pain-like behaviors, as shown by thermal hyperalgesia in the Hargreaves test and tactile allodynia in the von Frey test. Repetitive treatment of CCI mice with isorhynchophylline (p.o., twice per day for two weeks) ameliorated behavioral hyperalgesia and allodynia in a dose-dependent fashion (5, 15, and 45 mg/kg). The isorhynchophylline-triggered antinociception seems serotonergically dependent, since its antinociceptive actions on neuropathic hyperalgesia and allodynia were totally abolished by chemical depletion of spinal serotonin by PCPA, whereas potentiated by 5-HTP (a precursor of 5-HT). Consistently, isorhynchophylline-treated neuropathic mice showed escalated levels of spinal monoamines especially 5-HT, with depressed monoamine oxidase activity. Moreover, the isorhynchophylline-evoked antinociception was preferentially counteracted by co-administration of 5-HT1A receptor antagonist WAY-100635. In vitro, isorhynchophylline (0.1-10 nM) increased the Emax (stimulation of [35S] GTPγS binding) of 8-OH-DPAT, a 5-HT1A agonist. Of notable benefit, isorhynchophylline was able to correct co-morbidly behavioral symptoms of depression and anxiety evoked by neuropathic pain. Collectively, these findings confirm, for the first time, the disease-modifying efficacy of isorhynchophylline on neuropathic hypersensitivity, and this effect is dependent on spinal serotonergic system and 5-HT1A receptors.


Reconstruction of nasal alar defects with freestyle facial artery perforator flaps.
In 2009, we have described the use of freestyle facial artery perforator flaps for one-stage nose reconstruction. Since then, several articles have reported the use of facial artery perforator flaps for nose reconstruction. The purpose of this article is to provide an update of the published technique after 10 years of experience. Since 2004, 21 patients have been treated with a freestyle facial artery perforator flap for one-stage reconstruction of the nasal ala. The flaps were 16 propellers, 4 V-Y, and 1 island transposition. A single venous congestion leading to a minor flap tip necrosis and a wound dehiscence was observed. All other flaps healed uneventfully. The V-Y design and multiple subunit reconstruction gave suboptimal results. It was concluded that indications for freestyle facial artery perforator flaps are total nasal alar subunit reconstruction or reconstruction of lateral alar defects when perforator anatomy allows. In these cases, freestyle facial artery perforator flaps are the first choice technique at our institution because they allow excellent results in one-stage operation. One-stage nasal ala reconstruction with freestyle facial artery perforator flaps.


Characterization and radiosensitivity of HPV-related oropharyngeal squamous cell carcinoma patient-derived xenografts.
Background: Oropharyngeal squamous cell carcinomas (OPSCC) are rising rapidly in incidence due to Human Papillomavirus (HPV) and/or tobacco smoking. Prognosis is better for patients with HPV-positive disease, but may also be influenced by tobacco smoking and other factors. There is a need to individualize treatment to minimize morbidity and improve prognosis. Patient-derived xenografts (PDX) is an emerging pre-clinical research model that may more accurately reflect the human disease, and is an attractive platform to study disease biology and develop treatments and biomarkers. In this study we describe the establishment of PDX models, compare PDX tumors to the human original, and assess the suitability of this model for radiotherapy research and biomarker development. Material and methods: Tumor biopsies from 34 patients with previously untreated OPSCC were implanted in immunodeficient mice, giving rise to 12 squamous cell carcinoma PDX models (7 HPV+, 5 HPV-). Primary and PDX tumors were characterized extensively, examining histology, immunohistochemistry, cancer gene sequencing and gene expression analysis. Radiosensitivity was assessed in vivo in a growth delay assay. Results: Established PDX models maintained histological and immunohistochemical characteristics as well as HPV-status of the primary tumor. Important cancer driver gene mutations, e.g., in TP53, PIK3CA and others, were preserved. Gene expression related to cancer stem cell markers and gene expression subtype were preserved, while gene expression related to hypoxia and immune response differed. Radiosensitivity studies showed high concordance with clinical observations. Conclusion: PDX from OPSCC preserves important molecular characteristics of the human primary tumor. Radiosensitivity were in accordance with clinically observed treatment response. The PDX model is a clinically relevant surrogate model of head and neck cancer. Perspectives include increased understanding of disease biology, which could lead to development of novel treatments and biomarkers.


A multicentre study to evaluate the impact of timing of caspofungin administration on outcomes of invasive candidiasis in non-immunocompromised adult patients.
Candida non-albicans species cause an increasing proportion of invasive candidiasis (IC). Prompt initiation of effective antifungal therapy has been shown to positively impact the outcomes of IC. Caspofungin is often reserved as a second-line agent after suboptimal response to initial therapy. We determined the impact of the timing of caspofungin administration on outcomes of IC. Medical records were reviewed on all hospitalized adults who received >or=72 h of caspofungin for IC (isolation of Candida species from blood, intra-abdominal or other sterile sites). Clinical data were extracted from medical charts and recorded. Patients were classified based on delayed initiation (DI; >3 days) versus early initiation (EI; <or=3 days) of caspofungin relative to the time the culture was obtained. A total of 169 patients received caspofungin for IC; Candida glabrata (n = 78, 46%) was the most common cause, followed by mixed species (n = 36, 21%), Candida albicans (n = 36, 21%), Candida parapsilosis (n = 9, 6%), Candida tropicalis (n = 6, 3%), Candida krusei and other species (n = 4, 2%). Infection sites were bloodstream related (n = 119, 71%), intra-abdominal (n = 44, 26%) and other sterile sites (n = 6, 3%). DI of caspofungin was associated with a lower response rate (35/62, 56% versus 82/107, 77%; P = 0.006), longer time to achieve clinical stability (10 versus 4 days; P = 0.002) and longer length of stay after isolation of the organism (28 versus 21 days; P = 0.007), compared with EI (n = 107). Non-albicans Candida species accounted for the majority of IC in caspofungin-treated patients. Improved outcomes were observed for patients initiated with caspofungin within 72 h of positive culture compared with those who received delayed therapy.


Turnover of mammalian phospholipids. Stable and unstable components in neoplastic mast cells.
1. Choline- and inositol-labelled phospholipids of exponentially growing or static neoplastic mast cells turn over by degradation and resynthesis of the entire molecule. Turnover follows a biphasic pattern, the unstable rapidly turning-over component accounting for 60-80% of labelled phospholipid. The residual stable component does not turn over any more than does protein or DNA. 2. Subcellular fractions and surface membranes of choline-labelled P815Y cells contain the same proportion of stable and unstable components as do whole cells. The unstable component is largely phosphatidylcholine; the stable component is relatively richer in sphingomyelin. 3. It is concluded that the phospholipids of neoplastic mast cells are of two classes, one of which is susceptible to continual enzymic degradation and resynthesis, and the other of which is metabolically stable.


Feasibility and safety of propofol sedation in flexible bronchoscopy.
Propofol is a sedative-hypnotic with a rapid onset of action. There are only limited data evaluating propofol for flexible bronchoscopy. We analysed the feasibility and safety of propofol for bronchoscopy in a high output tertiary care centre. Prospective data on patients undergoing flexible bronchoscopy at the University Hospital Basel, Switzerland, were analysed. Patient demographics, ASA class, Mallampati class, indication for bronchoscopy, bronchoscopic procedures, duration of examination, medication requirements, minor and major adverse events, haemodynamic parameters, as well as cough scores during the procedure were documented. Patients were followed up to discharge from the bronchoscopy suite. Data from 440 patients with a mean age 60 years (±15.5, 260 male) were analysed. The main indication for bronchoscopy was a suspicion of malignancy. The most common diagnostic procedures were bronchoalveolar lavage in 253 cases (31.5%) and bronchial washing in 174 cases (21.7%). The mean duration of the procedure was 19.6 min (±12.08). The mean propofol dose was 200 mg (±107.5) corresponding to 2.89 mg/kg (±1.70). Minor adverse events included oxygen desaturation in 72 (16.4%), hypotension in 68 (15.4%) and minor bleeding in 11 (2.5%) patients. No major adverse events were recorded. The median decline in systolic blood pressure after initiation of sedation was 14 mm Hg (3-28). A drop in systolic blood pressure greater than 20 mm Hg was observed in 166 of the 440 patients (37%). Propofol sedation for flexible bronchoscopy is feasible and safe.


Comparison of hydrochlorothiazide and hydrochlorothiazide plus bevantolol in hypertension.
The added hypotensive effect of bevantolol, a new cardioselective beta-blocker, was studied in 244 patients with mild to moderate essential hypertension following prior treatment with hydrochlorothiazide or placebo. After four weeks of monotherapy with 50 mg/day or 100 mg/day of hydrochlorothiazide or placebo, the mean diastolic blood pressure of the patients in these groups decreased from baseline by 8.6, 8.8, and 4.3 mmHg, respectively. During the subsequent four weeks of dual therapy with 400 mg/day of bevantolol added to the regimen, additional and uniform mean decreases of 7.5, 7.3, and 7.5 mmHg occurred, providing total mean diastolic pressure decreases from baseline of 16.1, 16.1, and 11.8 mmHg in the three groups, respectively. These diastolic pressures were significantly lower during dual therapy than during monotherapy and lower in both diuretic groups than in the placebo group during monotherapy and dual therapy (P less than 0.001). Fewer adverse reactions occurred during dual therapy than during monotherapy. The addition of bevantolol to a thiazide diuretic regimen provided safe and significantly better control of mild to moderate hypertension than did the diuretic alone.


Pefloxacin in lower respiratory tract infections.
To determine the efficacy and safety of pefloxacin in the treatment of lower respiratory tract infections, a multicentre trial involving four departments of respiratory diseases was performed. One hundred and eight patients were admitted to the study: most of them were affected with exacerbations of chronic bronchitis or with pneumonia complicating lung cancer. Isolation and identification of responsible microorganisms from bronchial secretions was possible in 78 patients. Seven patients were withdrawn, one for worsening of the underlying disease and six for early side-effects. Thus, of 108 patients recruited, 101 completed the course of therapy (pefloxacin 400 mg bd for 5-14 days) and could be submitted to final evaluation. Of these 43 (42.6%) were cured and 48 (47.5%) showed improvement. Eradication of responsible microorganisms was achieved in 70 (90.9%) of 77 patients microbiologically evaluated. Side-effects of moderate severity were observed in 12 patients (gastrointestinal disturbances in 11 and dyspnoea in one); these did not necessitate discontinuation of therapy.


Incisor root length in individuals with and without anterior open bite: a comparative CBCT study.
This study aimed to compare the root length of maxillary and mandibular incisors between individuals with open bite versus matched individuals with adequate overbite. This comparative, matched and retrospective study included 48 cone beam computed tomographies (CBCTs) obtained at a university radiological center. Scans belonged to 24 individuals with open bite (overbite ≤ 0 mm) and 24 individuals with adequate overbite (controls). Both groups were matched by age, sex, malocclusion classification and skeletal characteristics (ANB and FMA angles). Root length of each maxillary and mandibular incisor was measured in millimeters (mm) in a sagittal section from a perpendicular line to the enamel cement junction until the root apex (384 length measurements were made). The means of root length in both groups were compared using t-tests. In addition, correlations between variables were evaluated with the Pearson correlation coefficient (α = 0.05). In both groups, the root length of the upper central incisors was approximately 12 mm and the root length of the maxillary lateral incisors was approximately 13 mm (p˃ 0.05). Likewise, the root length of lower central incisors in both groups measured approximately 12 mm (p˃ 0.05). However, the mandibular lateral incisor roots of open bite patients were significantly longer than in the normal overbite patients (approximately 1 mm, p= 0.012 right side, p= 0.001 left side). Root length of maxillary incisors and central mandibular incisor is similar in individuals with or without open bite, but the mandibular lateral incisor roots in open bite patients were significantly longer than in the normal overbite patients.


Dietary patterns and risk of breast cancer.
Evidence is emerging that prudent/healthy dietary patterns might be associated with a reduced risk of breast cancer. Using data from the prospective Melbourne Collaborative Cohort Study, we applied principal factor analysis to 124 foods and beverages to identify dietary patterns and estimated their association with breast cancer risk overall and by tumour characteristics using Cox regression. During an average of 14.1 years of follow-up of 20 967 women participants, 815 invasive breast cancers were diagnosed. Among the four dietary factors that we identified, only that characterised by high consumption of fruit and salad was associated with a reduced risk, with stronger associations observed for tumours not expressing oestrogen (ER) and progesterone receptors (PR). Compared with women in the lowest quintile of the factor score, the hazard ratio for women in the highest quintile was 0.92 (95% confidence interval (CI)=0.70-1.21; test for trend, P=0.5) for ER-positive or PR-positive tumours and 0.48 (95% CI=0.26-0.86; test for trend, P=0.002) for ER-negative and PR-negative tumours (test for homogeneity, P=0.01). Our study provides additional support for the hypothesis that a dietary pattern rich in fruit and salad might protect against invasive breast cancer and that the effect might be stronger for ER- and PR-negative tumours.


Volume-of-interest (VOI) imaging in C-arm flat-detector CT for high image quality at reduced dose.
A novel method for flat-detector computed tomography was developed to enable volume-of-interest (VOI) imaging at high resolution, low noise, and reduced dose. For this, a full low-dose overview (OV) scan and a local high-dose scan of a VOI are combined. The first scan yields an overview of the whole object and enables the selection of an arbitrary VOI. The second scan of that VOI assures high image quality within the interesting volume. The combination of the two consecutive scans is based on a forward projection of the reconstructed OV volume that was registered to the VOI. The artificial projection data of the OV scan are combined with the measured VOI data in the raw data domain. Different projection values are matched by an appropriate transformation and weighting. The reconstruction is performed with a standard Feldkamp-type algorithm. In simulations, the combination of OV scan and VOI scan was investigated on a mathematically described phantom. In measurements, spatial resolution and noise were evaluated with image quality phantoms. Modulation transfer functions and noise values were calculated. Measurements of an anthropomorphic head phantom were used to validate the proposed method for realistic applications, e.g., imaging stents. In Monte Carlo simulations, 3D dose distributions were calculated and dose values were assessed quantitatively. By the proposed combination method, an image is generated which covers the whole object and provides the VOI at high image quality. In the OV image, a resolution of 0.7 lp/mm (line pairs per millimeter) and noise of 63.5 HU were determined. Inside the VOI, resolution was increased to 2.4 lp/mm and noise was decreased to 18.7 HU. For the performed measurements, the cumulative dose was significantly reduced in comparison to conventional scans by up to 93%. The dose of a high-quality scan, for example, was reduced from 97 to less than 7 mGy, while keeping image quality constant within the VOI. The proposed VOI application with two scans is an effective way to ensure high image quality within the VOI while simultaneously reducing the cumulative patient dose.


A Rare Case of Renal AA Amyloidosis Secondary to Sjogren's Syndrome.
AA amyloidosis is a rare complication of chronic inflammatory disorders and has been associated with rheumatoid arthritis and ankylosing spondylitis. We present a case of AA amyloidosis secondary to Sjogren's syndrome (SS). A 79-year-old woman presented with rapidly progressive renal failure and complaints of asthenia, anorexia and generalized oedema. She had severe renal failure (creatinine 6.0 mg/dl), with microscopic haematuria, nephrotic proteinuria and low serum albumin levels, and an increased erythrocyte sedimentation rate. Serum protein electrophoresis revealed a peak in the gamma globulin zone. The patient was started on haemodialysis and corticosteroids. Clinical results showed the patient met the diagnostic criteria for primary SS, and neoplastic haematological disease was excluded. Renal biopsy revealed a diagnosis of AA amyloidosis. Renal AA amyloidosis is a rare condition in patients with primary SS. However, in patients with proteinuria and/or renal failure, it should be included in the differential diagnosis and a renal biopsy should be performed. Sjogren's syndrome should be regarded as a predisposing condition for the development of renal AA amyloidosis.Sjogren's syndrome and renal AA amyloidosis have been diagnosed simultaneously in some patients.A renal biopsy should be performed in patients with Sjogren's syndrome and proteinuria and/or renal failure.


Assembly of 2.5 nm filaments from giardin, a protein associated with cytoskeletal microtubules in Giardia.
The giardins are a family of approximately 30000 Mr structural proteins found in microribbons attached to microtubules in the disc cytoskeleton of Giardia. After examining the solubility of giardins in various agents, a method has been developed to extract these polypeptides and subsequently precipitate them selectively. The giardin chains are soluble in 10 mM-HEPES/EDTA buffer at high pH and low ionic strength, but become insoluble in 10 mM-MES/EDTA buffer at pH 6.7 when the ionic strength is raised above 50 mM salt. By dialysing giardin extracts in turn against dissociating and reassembly buffers, the purification is obtained of a subset of giardin chains identified by sodium dodecyl sulphate/polyacrylamide gel electrophoresis as the cytoskeleton bands 14a, 14b and 15. The structures forming under assembly conditions are all composed of fine filaments, 2-3 nm in diameter. Filaments after the first cycle of assembly are found in bundles, narrow ribbons of two or three filaments, and large ordered tactoids. Assembly after a second cycle of solubilization yields a more uniform population of long ribbons. Both the tactoids and the second cycle ribbons are transversely banded at the 15 nm interval characteristic of microribbons in the cytoskeleton. Filaments in the tactoids are precisely placed at a centre-to-centre separation of 2.5 nm. Other structural features of the tactoids are discussed in relation to the association behaviour and possible dimensions of the giardin molecular subunit.


Evaluation of the Sepsis Flow Chip assay for the diagnosis of blood infections.
Blood infections are serious complex conditions that generally require rapid diagnosis and treatment. The big challenge is to reduce the time necessary to make a diagnosis with current clinical microbiological methods so as to improve the treatment given to patients. In this study, we assess for the first time the Sepsis Flow Chip assay, which is a novel diagnostic assay for simultaneous rapid-detection of the vast majority of bloodstream pathogens, including Gram-positive and Gram-negative bacteria and fungi, in the same assay, and for the detection of most common antibiotic resistance genes. The SFC assay is based on multiplex PCR and low density DNA arrays. Positive blood cultures from 202 consecutive bacteremia patients were analyzed by SFC assay and the results were compared with the results obtained by the gold standard methodology used in clinical microbiology diagnostic laboratories (EUCAST guidelines). SFC assay overall sensitivity and specificity for bacterial identification were 93.3% and 100% respectively and sensitivity and specificity for the identification of antibiotic genetic resistance determinants were 93.6% and 100% respectively. This is the first evaluation of SFC assay in clinical samples. This new method appears to be very promising by combining the high number of distinct pathogens and genetic resistance determinants identified in a single assay. Further investigations should be done to evaluate the usefulness of this assay in combination with clinical multidisciplinary groups (stewardship), in order for the results to be applied appropriately to the management of patients`infectious processes.


Sexual Initiation and Complex Recent Polydrug Use Patterns Among Male Sex Workers in Vietnam: A Preliminary Epidemiological Trajectory.
Little is known about the age of onset of sexual and drug risk and their association with complex patterns of recent drug use among male sex workers (MSW) in a developing country, such as Vietnam. The aim of this study was to determine whether latent class analysis (LCA) would aid in the detection of current individual and polydrug use combinations to predict how different trajectories of sexual and drug initiation contribute to different patterns of current illicit drug use. Data were collected from a cross-sectional survey administered to young MSWs between 2010 and 2011 in Vietnam (N = 710). LCA clustered participants into recent drug use groups, incorporating both the specific types and overall count of different drugs used. Men reported drug use within a 1 month period from an 11-item drug use list. LCA identified three distinct drug use classes: (1) alcohol use, (2) alcohol and tobacco use, and (3) high polydrug use. The current drug use classes are associated with sex worker status, housing stability, income level, educational attainment, marital status, sexual identity, and sexual preferences. High levels of drug use are strongly associated with being a recent sex worker, not having recent stable housing, higher than median income, more than a high school education, less likely to be currently in school and more likely to have non-homosexual preferences and heterosexual partners. An event history analysis approach (time-event displays) examined the timing of the age of onset of drug and sexual risks. Early ages of drug and sexual initiation are seen for all three classes. High current drug users show earlier onset of these risks, which are significantly delayed for moderate and low current drug users. LCA incorporating an overall count of different drugs detected three distinct current drug use classes. The data illustrates that the complexity of drug factors that must be accounted for, both in advancing our epidemiological understanding of the complexity of drug use and the use of drug and sexual risk initiation data to predict current drug use subtypes among high-risk populations.


Cardiac valve prostheses, anticoagulation, and pregnancy.
The course of 76 pregnancies is reported in 51 women who became pregnant after replacement of one or more heart valves. Age at conception ranged from 17 to 39 years (mean 25). There have been 71 deliveries and five women are still pregnant at the time of writing. In the 71 pregnancies, oral anticoagulants were given during 53, heparin during five, and no anticoagulants during 13. Fetal complications consisted of 12 spontaneous abortions (eight in pregnancies in which oral anticoagulants were given, three in which heparin was given, and one in which no anticoagulants were given), of 12 premature deliveries with seven stillbirths (three on oral anticoagulants and four without anticoagulants), and there were three neonatal deaths (in all all three instances oral anticoagulants had been given during pregnancy). The maternal complications were as follows. Two women with mitral valve prostheses on heparin had thromboembolic episodes. Four women on oral anticoagulants died and 11 developed haemorrhage or systemic embolism. Two of the deaths were caused by bacterial endocarditis, one was the result of obstruction of a mitral valve prosthesis, and one was due to haemorrhage. One patient developed pulmonary oedema during delivery which rapidly resolved. Seven patients had uterine bleeding after delivery (three of them were on heparin and one was on an antiplatelet agent).


Tinea genitalis: a new entity of sexually transmitted infection? Case series and review of the literature.
Investigation on recent cases of tinea genitalis after travelling to South East Asia. Patients with tinea in the genital region, which emerged after sex in South East Asia, underwent further assessment including microscopy, cultures and DNA analyses. The case series includes seven patients. In six patients, Trichophyton interdigitale (former Trichophyton mentagrophytes) was detected. Three patients suffered from a severe inflammatory reaction of the soft tissue and two of them needed hospitalisation due to severe pain. In four patients, cicatrising healing was noticed. Five patients were declared incapacitated for work. Sexual activity should be considered as a potentially important and previously underappreciated means of transmission of T. interdigitale. To avoid irreversible scarring alopecia, prompt initiation of antifungal treatment is essential and adequate isolation and identification of the pathogen is mandatory.


Tobacco and youth in the South East Asian region.
Tobacco use among youth in South-East asian countries was reviewed using available literature. Youth who are out-out-of school, earning, less educated and live in rural areas are more likely to use tobacco and start during the Preteen years. Better educated youth may know the health effects of smoking but the dangers of passive smoking are generally unknown. Youth are fairly unconcerned about the present or future effect of tobacco use on health but do favour tobacco control measures. Children and youth are more responsive than adults to tobacco education. In India, a manufactured smokeless tobacco product, gutkha, has been targeted toward youth and has become extremely popular. An evolving epidemic of oral submucous fibrosis attributed to to gutkha use has been documented among youth, with a resultant increase in oral cancer in lower age groups. Children in India are often illegally employed in bidi manufacturing. This review points out the need for specific actions.


"And Does That Necessarily Mean Absolutely Alzheimer's?" An Analysis of Questions Raised Following Amyloid PET Results Disclosure.
Amyloid PET scans provide individuals with mild cognitive impairment (MCI) information about their risk of progressing to Alzheimer's dementia (AD). Given the wide-ranging implications of this information, best practice guidelines are needed to support researchers and clinicians disclosing these high-stakes test results. To inform the development of such guidelines, this analysis aims to describe questions and concerns raised during the disclosure of amyloid PET results in the context of MCI. Qualitative description was performed to analyze (n = 34) transcripts of audio-recorded amyloid PET results disclosure sessions involving MCI care dyads. The analysis focused on characterizing the frequency and nature of questions raised during an open question-and-answer (Q&A) period following the return of scan results using a standardized protocol. Nearly all (n = 32/34) dyads posed questions during Q&A. Questions fell within six main categories with the most common being requests for clarification regarding AD/MCI, and next steps given the result. Questions were interspersed with comments reflecting the need for emotional support. Independently administered assessments of comprehension of results showed that, following the disclosure and Q&A, 31/32 participants with MCI and 31/31 care partners scored ≥4 on a 5-point scale. The number of questions asked by care partners during Q&A positively correlated with their level of comprehension (n = 31, Spearman's r = 0.370, p = 0.040). This analysis highlights the value of providing opportunities for patients and their family members to ask questions upon learning patients' brain amyloid status. Disclosing clinicians should be prepared to provide clarification, resources, and support to patients and families during the return of amyloid PET results.


The additive and interactive effects of parenting and temperament in predicting adjustment problems of children of divorce.
Investigated the interaction between parenting and temperament in predicting adjustment problems in children of divorce. The study utilized a sample of 231 mothers and children, 9 to 12 years old, who had experienced divorce within the previous 2 years. Both mothers' and children's reports on parenting, temperament, and adjustment variables were obtained and combined to create cross-reporter measures of the variables. Parenting and temperament were directly and independently related to outcomes consistent with an additive model of their effects. Significant interactions indicated that parental rejection was more strongly related to adjustment problems for children low in positive emotionality, and inconsistent discipline was more strongly related to adjustment problems for children high in impulsivity. These findings suggest that children who are high in impulsivity may be at greater risk for developing problems, whereas positive emotionality may operate as a protective factor, decreasing the risk of adjustment problems in response to negative parenting.


Biological and behavioural studies of rodents as a basis for control.
Domestic rodents, particularly those living in urban populations, represent a serious public health problem, and effective control measures are required to deal with this threat to human health. Because of the characteristic interactions between individual animals, certain behaviour patterns occur in rodent populations that are of particular concern to control biologists. The genus Rattus is an extremely diverse group whose ecological requirements are variable and flexible, while the genus Mus, on account of its small size, limited range, and modest requirements in terms of food and water, is also very difficult to control. For any control operation a knowledge of the growth dynamics of domestic rodent populations is needed; after a period of logarithmic growth, population increases cease when the habitat is fully exploited. Consequently, control operations that merely remove some animals lead only to renewed population growth. Trapping, poisoning, and predation are traditional control measures of this kind. Environmental modification is a more certain, but more difficult, approach. The use of chemosterilants offers some hope of radical control in the future, but at present, although some field trials have been made, these substances are not available for general use, one reason being their lack of specificity. Another problem connected with the use of chemosterilants is that, on account of the sexual behaviour and physiology of domestic rodents, it would be necessary to reach nearly 100% of the population to obtain effective control.


Antihyperglycemic effect of fraxetin on hepatic key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats.
Epidemiological studies have demonstrated that the diabetes mellitus is a serious health burden for both governments and healthcare providers. The present study was hypothesized to evaluate the antihyperglycemic potential of fraxetin by determining the activities of key enzymes of carbohydrate metabolism in streptozotocin (STZ) - induced diabetic rats. Diabetes was induced in male albino Wistar rats by intraperitoneal administration of STZ (40 mg/kg b.w). Fraxetin was administered to diabetic rats intra gastrically at 20, 40, 80 mg/kg b.w for 30 days. The dose 80 mg/kg b.w, significantly reduced the levels of blood glucose and glycosylated hemoglobin (HbA1c) and increased plasma insulin level. The altered activities of the key enzymes of carbohydrate metabolism such as glucokinase, glucose-6-phosphate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase and hepatic enzymes (aspartate transaminase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP)) in the liver tissues of diabetic rats were significantly reverted to near normal levels by the administration of fraxetin. Further, fraxetin administration to diabetic rats improved body weight and hepatic glycogen content demonstrated its antihyperglycemic potential. The present findings suggest that fraxetin may be useful in the treatment of diabetes even though clinical studies to evaluate this possibility may be warranted.


[Antibody-coated bacteria and localization of urinary tract infection].
The distinction between upper and lower urinary tract infection (UTI) is of great help in the management and treatment of these conditions. The antibody-coating technique was used to investigate urine of patients with nephrostomies, chronic and acute pyelonephritis, chronic and acute cystitis, of male patients with dysuria and significant bacteriuria and of female patients with indwelling catheters. Furthermore this indirect method was compared with FAIRLEY'S direct method for localization of UTI in female patients with indwelling catheters. All tests were positive in patients with nephrostomies and acute pyelonephritis. Out of 19 tests in patients with chronic pyelonephritis, 18 were positive and one negative. Antibody-coated bacteria were present in 4 out of 8 patients with chronic cystitis and in 2 out of 9 patients with acute cystitis. Out of 5 male patients with dysuria and significant bacteriuria, 3 had a positive test. Out of 25 women with indwelling catheters 20 exhibited antibody-coated bacteria in urine and 5 did not. In 9 female patients with indwelling catheters the UTI was localized in the upper tract 5 times by the Fairley technique but 7 times by determination of antibody-coated bacteria. The demonstration of antibody-coated bacteria in the urine is a simple and reliable method of localizing the site of a UTI. False positive results may be observed in patients with indwelling catheters and prostatitis; in both instances there is probably local antibody production and coating of the bacteria. As the test is relatively expensive and time-consuming, it is indicated only in special situations and is not considered a routine screening procedure.


Comparative Treatment Persistence and Adherence to Endothelin Receptor Antagonists Among Patients with Pulmonary Arterial Hypertension in Japan: A Real-World Administrative Claims Database Study.
Real-world data on the comparative effectiveness of endothelin receptor antagonists (ERAs; macitentan, bosentan, ambrisentan) for pulmonary arterial hypertension (PAH), particularly in Asian countries, are scarce. We evaluated the persistence of these ERAs before and after macitentan approval in Japan (2015). We used real-world data from the Japanese Medical Data Vision administrative claims database between April 2008 and November 2020. Patients with PAH were identified from the dataset. Persistence to ERA treatment before and after approval of macitentan in Japan was defined as the time between start of the index ERA and treatment discontinuation or death. Propensity score adjustment was applied to minimize confounding effects among treatment groups. In the pre-macitentan approval cohort, 153 and 51 patients received bosentan and ambrisentan, respectively. In the post-macitentan approval cohort, 331, 284, and 91 patients received macitentan, bosentan, and ambrisentan, respectively. Unadjusted median persistence for ambrisentan- and bosentan-treated patients was 19 and 10 months, respectively (adjusted HR 0.87 [95% CI 0.61-1.24]; P = 0.434 [bosentan as reference]). In the post-macitentan approval cohort, unadjusted median persistence was 18 months for macitentan-treated patients versus 6 and 8 months for ambrisentan- and bosentan-treated patients, respectively. Adjusted HRs for ambrisentan and bosentan were 1.48 (95% CI 1.12-1.95; P = 0.006) and 1.63 (95% CI 1.30-2.04; P < 0.001 [macitentan as reference]), respectively. Real-world data for Japanese patients with PAH showed that persistence was significantly higher for macitentan, versus ambrisentan and bosentan, since its approval.


Actin binding proteins: regulation of cytoskeletal microfilaments.
The actin cytoskeleton is a complex structure that performs a wide range of cellular functions. In 2001, significant advances were made to our understanding of the structure and function of actin monomers. Many of these are likely to help us understand and distinguish between the structural models of actin microfilaments. In particular, 1) the structure of actin was resolved from crystals in the absence of cocrystallized actin binding proteins (ABPs), 2) the prokaryotic ancestral gene of actin was crystallized and its function as a bacterial cytoskeleton was revealed, and 3) the structure of the Arp2/3 complex was described for the first time. In this review we selected several ABPs (ADF/cofilin, profilin, gelsolin, thymosin beta4, DNase I, CapZ, tropomodulin, and Arp2/3) that regulate actin-driven assembly, i.e., movement that is independent of motor proteins. They were chosen because 1) they represent a family of related proteins, 2) they are widely distributed in nature, 3) an atomic structure (or at least a plausible model) is available for each of them, and 4) each is expressed in significant quantities in cells. These ABPs perform the following cellular functions: 1) they maintain the population of unassembled but assembly-ready actin monomers (profilin), 2) they regulate the state of polymerization of filaments (ADF/cofilin, profilin), 3) they bind to and block the growing ends of actin filaments (gelsolin), 4) they nucleate actin assembly (gelsolin, Arp2/3, cofilin), 5) they sever actin filaments (gelsolin, ADF/cofilin), 6) they bind to the sides of actin filaments (gelsolin, Arp2/3), and 7) they cross-link actin filaments (Arp2/3). Some of these ABPs are essential, whereas others may form regulatory ternary complexes. Some play crucial roles in human disorders, and for all of them, there are good reasons why investigations into their structures and functions should continue.


Nurses' attitudes toward death and caring for dying patients.
To examine possible relationships among the demographic variables of nurses and their attitudes toward death and caring for dying patients. Descriptive. A private hospital and Visiting Nurses Association office in an ethnically diverse metropolitan area in the Midwest. 403 nurses, predominantly female (90%) and Caucasian (70%), with a mean age of 41.8 years. Participants completed the Frommelt Attitude Toward Care of the Dying Scale, the Death Attitude Profile-Revised (DAP-R), and a demographic questionnaire. Attitudes toward death and caring for dying people. DAP-R scores were related to sex, religious affiliation, and current contact with terminally ill patients. Frommelt scale scores (e.g., showing acceptance of death) were positively related to current contact with dying patients, negatively correlated with two DAP-R subscales (Fear of Death and Death Avoidance), and positively correlated with two other DAP-R subscales (Approach Acceptance and Neutral Acceptance). Nurses' attitudes toward death and their current contact with terminally ill patients were predictive of their attitudes toward caring for terminally ill patients. Professionals who are responsible for designing educational programs focused on nurses' attitudes toward caring for terminally ill patients may want to include an assessment of death attitudes and interventions aimed at decreasing negative attitudes and increasing positive attitudes toward death in such programs.


Simulation-Based Designing of Suitable Stimulation Factors for Presenting Two Phosphenes Simultaneously to Lower Side of Field of View.
Using a phosphene has been discussed as a means of informing the visually impaired of the position of an obstacle. Obstacles underfoot have a risk, so it is necessary to inform the visually impaired. A previous study clarified a method of presenting phosphene in three directions in the lower vision; however, the simultaneous presentation of these phosphenes has not been discussed. Another study discussing the effect of electrical interference when stimulating the eyeball with multiple electrodes indicated that it is important to select appropriate stimulation factors to avoid this effect. However, when the stimulation electrodes are arranged remarkably close, there is a high possibility that the stimulus factor presented in the previous study will not apply. In this study, a method for simultaneously presenting phosphenes in the lower vision is presented. The electrode arrangements reported in the previous study to present phosphene in the lower field of vision are used, and the difficulty in the simultaneous presentation of multiple phosphenes in the lower vision is the focus. In this paper, the method of designing the stimulation factors is discussed numerically when the electrodes are arranged remarkably close. As a result, it is shown that stimulation factors different from the previous research were appropriate depending on the distance between the electrodes.


The traT protein is able to normalize the phenotype of a plasmid-carried permeability mutation of Salmonella typhimurium.
The isolation of different classes of antibiotic-supersensitive outer membrane permeability mutants of Salmonella typhimurium has been described previously (Sukupolvi et al., 1984, Journal of Bacteriology 159, 704-712). One of these, the SS-A mutation, sensitizes the bacteria to gentian violet and to hydrophobic antibiotics. The phenotype of the SS-A mutant was restored to normal when a cloned fragment of the F plasmid, or the R plasmid R6-5, carrying the genes traS, T and D was introduced on a multicopy plasmid. The introduction of a plasmid carrying only the traT gene showed that this gene was sufficient to restore the phenotype. Only clones with functioning traT (irrespective of copy number) restored the normal antibiotic-resistant phenotype in the SS-A mutant. An incompatibility test using a donor strain which carried transposon Tn10 in the 60 MDa plasmid of S. typhimurium and a recipient in which Tn5 was placed close to the SS-A mutation indicated that the SS-A mutation was located in the 60 MDa virulence plasmid (previously called the cryptic plasmid) of S. typhimurium. The introduction of the large virulence plasmid carrying the SS-A mutant allele into wild-type S. typhimurium or Escherichia coli resulted in strains with a phenotype identical to that of the original SS-A mutant.


Supplementing metabolizable protein to ewes during late gestation: I. Effects on ewe performance and offspring performance from birth to weaning.
We hypothesized that a maternal diet greater in MP during the last third of gestation would yield improved offspring growth due to enhanced placental or mammary gland function. Our objective was to determine how MP intake during late gestation affected ewe and offspring performance from birth to weaning in ewes fed diets similar in total energy. In yr 1, maternal dietary treatments were applied at d 100 of gestation, were similar in total energy, and contained 60% of MP requirements (60MP1), 80% of MP requirements (80MP1), and 100% of the MP requirements (100MP1) on a DM basis during late gestation. In yr 2, maternal dietary treatments were similar in total energy and contained 60% of MP requirements (60MP2), 100% of the MP requirements (100MP2), and 140% of MP requirements (140MP2) on a DM basis during late gestation. In yr 1, there was no effect (P ≥ 0.30) of maternal MP restriction on gestation length, lamb birth weight, or milk production of the dam. At lambing, ewe BW (P = 0.02) and BCS (P = 0.01) increased linearly as MP in the diet increased. While there were no differences in lamb BW at birth, lamb weaning BW (P = 0.08) and ADG from birth to weaning (P = 0.10) tended to increase linearly as maternal MP intake increased. In yr 2, maternal BW increased with increased dietary MP. However, there were no significant effects (P ≥ 0.45) of maternal dietary treatment on maternal BCS or lamb birth weight. Moreover, lamb weaning weight and ADG were not influenced by maternal MP levels. These results suggest that ewes maintain and gain BW and BCS when consuming diets similar in total energy with increased MP during late gestation, but the increased MP had minimal effects on lamb performance through weaning.


Activation of toll-like receptor 4/nuclear factor-kappa B signaling by triggering a receptor expressed on myeloid cells 1 promotes alveolar macrophage M1 polarization and exacerbates septic acute lung injury.
Septic acute lung injury (ALI) is a life-threatening condition commonly occurring in the intensive care unit. Inflammation is considered as the basic pathological response of septic ALI. Triggering receptor expressed on myeloid cells 1 (TREM1) is a member of the immunoglobulin superfamily receptors that regulates the inflammatory response. However, the role of TREM1 in septic ALI has not yet been reported. Cell viability was tested using the MTT assay. TdT-mediated dUTP nick end labeling assay and flow cytometry were used for apoptosis. The level of protein was detected using western blot analysis. The levels of tumor necrosis factor-α and interleukin-1β were assessed using enzyme-linked immunosorbent assay. The lactate dehydrogenase content was assessed using the assay kit. Myeloperoxidase activity was determined using an assay. Histology of lung tissue was further analyzed through hematoxylin-eosin staining. We found that TREM1 knockdown by transfection with si-TREM1 inhibited lipopolysaccharide (LPS)-induced cell apoptosis of alveolar macrophage cell line MH-S. The LPS stimulation caused M1 polarization of MH-S cells, which could be reversed by TREM1 knockdown. In vivo assays proved that si-TREM1 injection improved lung injury and inflammation of cecal ligation and puncture-induced ALI in mice. In addition, TREM1 knockdown suppressed the activation of toll-like receptor 4/nuclear factor-kappa B signaling, implying the involvement of TLR4 in the effects of TREM1 in response to LPS stimulation. This study examined the proinflammatory role of TREM1 in septic ALI and its regulatory effect on alveolar macrophage polarization. These results suggest that TREM1 could potentially serve as a therapeutic target in the prevention and treatment of ALI.


Low central venous oxygen saturation in haemodynamically stabilized trauma patients is associated with poor outcome.
Central venous oxygen saturation (ScvO(2)) is suggested to reflect the adequacy of oxygen delivery, and the main objective of the present study was to determine whether ScvO(2) is associated with outcome in haemodynamically stabilized trauma patients. Haemodynamically unstable trauma patients receiving a central venous line within 1 h of admission were eligible for inclusion in this prospective observational study. The mean arterial pressure (MAP), lactate and ScvO(2) were recorded at inclusion and every 6 h for 36 h or until lactate was <2.0 mmol/l and ScvO(2) was >75% in two consecutive measurements. Patients with a MAP of ≥70 mmHg were considered to be haemodynamically stabilized. The outcome measure was complications defined as infections, delta sequential organ failure assessment score of >0, and mortality. Fifty patients with a median new injury severity score of 27 (17-34) were analysed. Complications occurred in 33 patients. An association between ScvO(2) following resuscitation to MAP ≥70 mmHg and complications was detected with an odds ratio of 0.94 (95% confidence interval; 0.89-0.99). This association was also significant when adjusted for injury severity. The result implies that a low ScvO(2) value is associated with more complications. The optimal cut-off for ScvO(2) to discriminate between patients who did or did not develop complications was found to be 66.5% (56-86%). These data suggest that low ScvO(2) in haemodynamically stabilized patients is associated with a poor outcome and that ScvO(2) represents a potential endpoint of resuscitation in trauma patients.


Sucrose-assisted loading of LiFePO4 nanoparticles on graphene for high-performance lithium-ion battery cathodes.
A simple approach for loading LiFePO4 (LFP) nanoparticles on graphene (G) that could assemble amorphous LiFePO4 nanoparticles into a stable, crystalline, graphene-modified layered materials (G-S-LFP, S=sucrose) by using graphene as building block and sucrose as a linker has yet to be developed. On the basis of differential scanning calorimetric and transmission electron microscopy analysis of the samples from controlled experiment, a possible mechanism was proposed to explain the "linker" process of LFP and graphene with sucrose as the linker. The electrochemical properties of the samples as cathode material for lithium-ion batteries were studied by cyclic voltammogrametry and galvanostatic methods. Results showed that G-S-LFP displayed superior lithium-storage capability with current density changes randomly form 0.5 to 10 C. The significant improvement for rate and cycle performance could be attributed to the high conductivity of the graphene host, the high crystallinity, and the layered structure.


An Astyanax mexicanus mao knockout line uncovers the developmental roles of monoamine homeostasis in fish brain.
Monoaminergic systems are conserved in vertebrates, yet they present variations in neuroanatomy, genetic components and functions across species. MonoAmine Oxidase, or MAO, is the enzyme responsible for monoamine degradation. While mammals possess two genes, MAO-A and MAO-B, fish possess one single mao gene. To study the function of MAO and monoamine homeostasis on fish brain development and physiology, here we have generated a mao knockout line in Astyanax mexicanus (surface fish), by CRISPR/Cas9 technology. Homozygote mao knockout larvae died at 13 days post-fertilization. Through a time-course analysis, we report that hypothalamic serotonergic neurons undergo fine and dynamic regulation of serotonin level upon loss of mao function, in contrast to those in the raphe, which showed continuously increased serotonin levels - as expected. Dopaminergic neurons were not affected by mao loss-of-function. At behavioral level, knockout fry showed a transient decrease in locomotion that followed the variations in the hypothalamus serotonin neuronal levels. Finally, we discovered a drastic effect of mao knockout on brain progenitors proliferation in the telencephalon and hypothalamus, including a reduction in the number of proliferative cells and an increase of the cell cycle length. Altogether, our results show that MAO has multiple and varied effects on Astyanax mexicanus brain development. Mostly, they bring novel support to the idea that serotonergic neurons in the hypothalamus and raphe of the fish brain are different in nature and identity, and they unravel a link between monoaminergic homeostasis and brain growth.


Cutaneous stimulation of the digits and lips evokes responses with different adaptation patterns in primary somatosensory cortex.
Neuromagnetic evoked fields were recorded to compare the adaptation of the primary somatosensory cortex (SI) response to tactile stimuli delivered to the glabrous skin at the fingertips of the first three digits (condition 1) and between midline upper and lower lips (condition 2). The stimulation paradigm allowed to characterize the response adaptation in the presence of functional integration of tactile stimuli from adjacent skin areas in each condition. At each stimulation site, cutaneous stimuli (50 ms duration) were delivered in three runs, using trains of 6 pulses with regular stimulus onset asynchrony (SOA). The pulses were separated by SOAs of 500 ms, 250 ms or 125 ms in each run, respectively, while the inter-train interval was fixed (5s) across runs. The evoked activity in SI (contralateral to the stimulated hand, and bilaterally for lips stimulation) was characterized from the best-fit dipoles of the response component peaking around 70 ms for the hand stimulation, and 8 ms earlier (on average) for the lips stimulation. The SOA-dependent long-term adaptation effects were assessed from the change in the amplitude of the responses to the first stimulus in each train. The short-term adaptation was characterized by the lifetime of an exponentially saturating model function fitted to the set of suppression ratios of the second relative to the first SI response in each train. Our results indicate: 1) the presence of a rate-dependent long-term adaptation effect induced only by the tactile stimulation of the digits; and 2) shorter recovery lifetimes for the digits compared with the lips stimulation.


Computers and the orthopaedic office.
The advance of today's medicine could be linked very closely to the history of computers through the last twenty years. In the beginning the first attempt to build a computer was trying to help us with mathematical calculations. This has changed recently and computers are now linked to x-ray machines, CT scanners, and MRIs. Being able to share information is one of the goals of the future. Today's computer technology has helped a great deal to allow orthopaedic surgeons from around the world to consult on a difficult case or to become a part of a large database. Obtaining the results from a method of treatment using a multicentric information study can be done on a regular basis. In the future, computers will help us to retrieve information from patients' clinical history directly from a hospital database or by portable memory cards that will carry every radiograph or video from previous surgeries.


Virus-Like Particles Presenting the FGF-2 Protein or Identified Antigenic Peptides Promoted Antitumor Immune Responses in Mice.
Fibroblast growth factor (FGF)-2 is overexpressed in various tumor tissues. It affects tumor cell proliferation, invasion and survival, promotes tumor angiogenesis and is tightly involved in the development of systemic and local immunosuppressive tumor mechanisms. This study aimed to develop an effective vaccine against FGF-2 and to investigate the effects of anti-FGF-2 immunization on tumor growth and antitumor immune responses. A set of thirteen synthesized overlapping peptides covering all possible linear B-cell epitopes of murine FGF-2 and a recombinant FGF-2 protein were conjugated to virus-like particles (VLPs) of recombinant hepatitis B core antigen (HBcAg). The VLPs were immunized through a preventive or therapeutic strategy in a TC-1 or 4T1 grafted tumor model. Immunization with FGF-2 peptides or full-length protein-coupled VLPs produced FGF-2-specific antibodies with a high titer. Peptide 12, which is located in the heparin-binding site of FGF-2, or protein-conjugated VLPs presented the most significant effects on the suppression of TC-1 tumor growth. The levels of IFN-γ-expressing splenocytes and serum IFN-γ were significantly elevated; further, the immune effector cells CD8+ IFN-γ+ cytotoxic T lymphocytes (CTLs) and CD4+ IFN-γ+ Th1 cells were significantly increased, whereas the immunosuppressive cells CD4+ CD25+ FOXP3+ Treg cells and Gr-1+ CD11b+ myeloid-derived suppressor cells (MDSCs) were decreased in the immunized mice. In addition, VLP immunization significantly suppressed tumor vascularization and promoted tumor cell apoptosis. In mice bearing 4T1 breast tumor, preventive immunization with FGF-2-conjugated VLPs suppressed tumor growth and lung metastasis, and increased effector cell responses. Active immunization against FGF-2 is a new possible strategy for tumor immunotherapy.


Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What's behind Neuro-RACopathies.
Rho family guanosine triphosphatases (GTPases) regulate cellular signaling and cytoskeletal dynamics, playing a pivotal role in cell adhesion, migration, and cell cycle progression. The Rac subfamily of Rho GTPases consists of three highly homologous proteins, Rac 1-3. The proper function of Rac1 and Rac3, and their correct interaction with guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs) are crucial for neural development. Pathogenic variants affecting these delicate biological processes are implicated in different medical conditions in humans, primarily neurodevelopmental disorders (NDDs). In addition to a direct deleterious effect produced by genetic variants in the RAC genes, a dysregulated GTPase activity resulting from an abnormal function of GEFs and GAPs has been involved in the pathogenesis of distinctive emerging conditions. In this study, we reviewed the current pertinent literature on Rac-related disorders with a primary neurological involvement, providing an overview of the current knowledge on the pathophysiological mechanisms involved in the neuro-RACopathies.


Healthy kids vids: Development and acceptability of narrative healthy lifestyle videos and text messages for parents of young children from socioeconomically disadvantaged populations.
Dietary intake and physical activity behaviours of many Australian children are not meeting recommendations, particularly for those living in socioeconomically disadvantaged circumstances. This study aimed to design and assess the feasibility and acceptability of a suite of narrative videos and text messages focused on healthy eating and physical activity behaviours appropriate for parents of young children from socioeconomically disadvantaged backgrounds. Parents of 1-5-year-old children (n = 6) were recruited to develop a suite of 12 narrative videos on healthy eating and physical activity behaviours, underpinned by theory. Twelve complementary text messages were subsequently developed. A different group of parents (n = 16) recruited from socioeconomically disadvantaged areas reviewed the videos and text messages over 6 weeks and provided feedback via surveys and qualitative interviews (n = 13). There was a high level of engagement with and acceptability of the videos and text message content. Participants found the videos easy to access and they liked the narrative style. Screen time videos and text messages relating to screen time, play and physical activity, role modelling and fussy eating were most useful. Narrative style healthy eating, physical activity and screen time videos and complementary text messages were highly acceptable to the sample of parents of 1-5-year-old children from socioeconomically disadvantaged areas recruited from the Illawarra Shoalhaven region of NSW, Australia. SO WHAT?: Short narrative style videos and text messages are an easy to process and acceptable method of delivering healthy lifestyle promotion content to parents.


Myeloma: making sense of a complex blood cancer.
Myeloma is a challenging blood cancer characterized by bone destruction, hypercalcaemia, renal insufficiency and anaemia. Although myeloma remains incurable, recent advancements in treatments have resulted in significant improvements in morbidity. The use of immunomodulatory drugs-thalidomide, lenalidomide, pomalidomide (in clinical trials)-and the proteasome inhibitor, bortezomib, in conjunction with conventional chemotherapy and supportive therapies, have resulted in a significant shift in approaches to treatment and an improvement in patients' quality of life. Nurses must remain up-to-date with current treatments for myeloma and their related side-effects. In addition, nurses play a key role in the coordination of a multidisciplinary approach to care for myeloma patients.


Working Under the Gun: A Theoretical Analysis of Stressors Associated With the Re-negotiation of Norms and Control of Work Tasks During COVID-19.
The COVID-19 pandemic has led many of the world's nations to impose numerous preventive and mitigative measures to increase social distance, including various forms of home isolation and quarantine. A central premise for the current paper is that the COVID-19 situation is likely to constitute a massive re-negotiation of social and organizational norms, which may lead to psychological distress at the individual, family and interpersonal level. Virtually overnight, people have to re-define what is expected and deemed appropriate by a given group member in a certain social setting. This goes for all kinds of general social interaction, such as societal, even multinational medical demands on social distancing. Simultaneously it also goes for a sudden, gargantuan re-division of labor in a complex global system. We provide a theoretical analysis of the potential consequences of re-negotiation of norms from the perspective of four sets of psychological theory: Theory of professions; organizational strategic crisis responses; the job-demands-resources model; and theories addressing the interplay between norm violations and psychological distance. From these theories we derive three suggestions that the discussion centers around: (1) The COVID-19 situation leads to a massive re-negotiation of norms related to work, (2) The COVID-19 situation diffuses the demarcation between the various professional arenas and the private sphere, and this diffusion enhances the stress associated with norm conflict, and (3) Norm conflicts are enhanced by digitalization. Our discussion centers on potential stressors associated with the renegotiation of norms, and also includes a few suggestions for practice. For each theoretical suggestion, we give examples of how the suggestion may manifest itself with respect to (a) the work task, (b) the individual's relationship to their leader and/or organization, and (c) interpersonal relationships. We finally point to some theoretical and applied implications.


Central nervous system demyelinating disease protection by the human commensal Bacteroides fragilis depends on polysaccharide A expression.
The importance of gut commensal bacteria in maintaining immune homeostasis is increasingly understood. We recently described that alteration of the gut microflora can affect a population of Foxp3(+)T(reg) cells that regulate demyelination in experimental autoimmune encephalomyelitis (EAE), the experimental model of human multiple sclerosis. We now extend our previous observations on the role of commensal bacteria in CNS demyelination, and we demonstrate that Bacteroides fragilis producing a bacterial capsular polysaccharide Ag can protect against EAE. Recolonization with wild type B. fragilis maintained resistance to EAE, whereas reconstitution with polysaccharide A-deficient B. fragilis restored EAE susceptibility. Enhanced numbers of Foxp3(+)T(reg) cells in the cervical lymph nodes were observed after intestinal recolonization with either strain of B. fragilis. Ex vivo, CD4(+)T cells obtained from mice reconstituted with wild type B. fragilis had significantly enhanced rates of conversion into IL-10-producing Foxp3(+)T(reg) cells and offered greater protection against disease. Our results suggest an important role for commensal bacterial Ags, in particular B. fragilis expressing polysaccharide A, in protecting against CNS demyelination in EAE and perhaps human multiple sclerosis.


DDAVP-induced correction of prolonged bleeding time in patients with congenital platelet function defects.
In 37 patients with prolonged bleeding time, where thrombocytopenia, von Willebrand's disease or deficiency of other coagulation factors could be excluded, we have evaluated the effect of a DDAVP-infusion (0.2 ug/kg) together with tranexamic acid (10 mg/kg). Patients with acquired impairment of primary hemostasis were not included, except two cases where this could have been a contributing factor. The bleeding time was completely normalized in 27 cases and partially corrected in three more patients. The predominant feature among those, who did not respond, was a pattern compatible with thrombasthenia or cyclooxygenase deficiency, as assessed by platelet aggregation studies. Among the patients, in whom DDAVP was effective, this drug was thereafter successfully used as an alternative to blood products in 8 cases during and after surgery or delivery.


Pharmacodynamics and safety of pantoprazole in neonates, preterm infants, and infants aged 1 through 11 months with a clinical diagnosis of gastroesophageal reflux disease.
Limited data on proton pump inhibitors in infants led regulatory agencies to request sponsors to conduct pediatric studies. To determine the pharmacodynamic response to pantoprazole in infants with GERD to aid the dose selection for an efficacy study. In two open-label studies, neonates and preterm infants (study 1, ~1.2 mg/kg [high dose]) and infants 1 through 11 months (study 2, ~0.6 [low dose] or ~1.2 mg/kg [high dose]) received once-daily pantoprazole. Twenty-four-hour dual-electrode pH-metry parameters were compared between predose and steady state (≥5 days) (two-sided paired t test). Treatment was administered for ≤6 weeks. In studies 1 and 2, 21 and 24 patients, respectively, were enrolled for pharmacodynamic evaluation. The high dose provided similar responses in the two studies and improved these parameters significantly: mean gastric pH and percent time gastric pH > 4 increased (p < 0.05 both studies), normalized area under the curve (AUC) of gastric H(+) activity decreased (p < 0.05 study 2), and normalized AUC of esophageal H(+) activity decreased (p < 0.05 both studies). The AUC of esophageal pH < 4 decreased. Normalized AUC of esophageal H(+) activity decreased (p < 0.05 both studies), indicating refluxate pH increased, although this was not reflected in any change in mean esophageal pH or reflux index. The normalized AUC of esophageal H(+) activity was a more sensitive measure of changes in esophageal pH. In neonates, preterm infants, and infants aged 1 through 11 months, pantoprazole (high dose) improved pH-metry parameters after ≥5 consecutive daily doses, and was generally well tolerated for ≤6 weeks.


Balanced trafficking between the ER and the Golgi apparatus increases protein secretion in yeast.
The yeast Saccharomyces cerevisiae is widely used as a cell factory to produce recombinant proteins. However, S. cerevisiae naturally secretes only a few proteins, such as invertase and the mating alpha factor, and its secretory capacity is limited. It has been reported that engineering protein anterograde trafficking from the endoplasmic reticulum to the Golgi apparatus by the moderate overexpression of SEC16 could increase recombinant protein secretion in S. cerevisiae. In this study, the retrograde trafficking in a strain with moderate overexpression of SEC16 was engineered by overexpression of ADP-ribosylation factor GTP activating proteins, Gcs1p and Glo3p, which are involved in the process of COPI-coated vesicle formation. Engineering the retrograde trafficking increased the secretion of α-amylase but did not induce production of reactive oxygen species. An expanded ER membrane was detected in both the GCS1 and GLO3 overexpression strains. Physiological characterizations during batch fermentation showed that GLO3 overexpression had better effect on recombinant protein secretion than GCS1 overexpression. Additionally, the GLO3 overexpression strain had higher secretion of two other recombinant proteins, endoglucanase I from Trichoderma reesei and glucan-1,4-α-glucosidase from Rhizopus oryzae, indicating overexpression of GLO3 in a SEC16 moderate overexpression strain might be a general strategy for improving production of secreted proteins by yeast.


Morphologic design of nanostructures for enhanced antimicrobial activity.
Despite significant progress in synthetic polymer chemistry and in control over tuning the structures and morphologies of nanoparticles, studies on morphologic design of nanomaterials for the purpose of optimizing antimicrobial activity have yielded mixed results. When designing antimicrobial materials, it is important to consider two distinctly different modes and mechanisms of activity-those that involve direct interactions with bacterial cells, and those that promote the entry of nanomaterials into infected host cells to gain access to intracellular pathogens. Antibacterial activity of nanoparticles may involve direct interactions with organisms and/or release of antibacterial cargo, and these activities depend on attractive interactions and contact areas between particles and bacterial or host cell surfaces, local curvature and dynamics of the particles, all of which are functions of nanoparticle shape. Bacteria may exist as spheres, rods, helices, or even in uncommon shapes (e.g., box- and star-shaped) and, furthermore, may transform into other morphologies along their lifespan. For bacteria that invade host cells, multivalent interactions are involved and are dependent upon bacterial size and shape. Therefore, mimicking bacterial shapes has been hypothesized to impact intracellular delivery of antimicrobial nanostructures. Indeed, designing complementarities between the shapes of microorganisms with nanoparticle platforms that are designed for antimicrobial delivery offers interesting new perspectives toward future nanomedicines. Some studies have reported improved antimicrobial activities with spherical shapes compared to non-spherical constructs, whereas other studies have reported higher activity for non-spherical structures (e.g., rod, discoid, cylinder, etc.). The shapes of nano- and microparticles have also been shown to impact their rates and extents of uptake by mammalian cells (macrophages, epithelial cells, and others). However, in most of these studies, nanoparticle morphology was not intentionally designed to mimic specific bacterial shape. Herein, the morphologic designs of nanoparticles that possess antimicrobial activities per se and those designed to deliver antimicrobial agent cargoes are reviewed. Furthermore, hypotheses beyond shape dependence and additional factors that help to explain apparent discrepancies among studies are highlighted.


Macrophage retinoblastoma deficiency leads to enhanced atherosclerosis development in ApoE-deficient mice.
The cellular composition of an atherosclerotic lesion is determined by cell infiltration, proliferation, and apoptosis. The tumor suppressor gene retinoblastoma (Rb) has been shown to regulate both cell proliferation and cell death in many cell types. To study the role of macrophage Rb in the development of atherosclerosis, we used apoE-deficient mice with a macrophage-restricted deletion of Rb (Rb(del) mice) and control littermates (Rb(fl) mice). After 12 wk feeding a cholesterol-rich diet, the Rb(del) mice showed a 51% increase in atherosclerotic lesion area with a 39% increase in the relative number of advanced lesions. Atherosclerotic lesions showed a 13% decrease in relative macrophage area and a 46% increase in relative smooth muscle cell area, reflecting the more advanced state of the lesions. The increase in atherosclerosis was independent of in vitro macrophage modified lipoprotein uptake or cytokine production. Whereas macrophage-restricted Rb deletion did not affect lesional macrophage apoptosis, a clear 2.6-fold increase in lesional macrophage proliferation was observed. These studies demonstrate that macrophage Rb is a suppressing factor in the progression of atherosclerosis by reducing macrophage proliferation.


Crosslinking-guided geometry of a complete CXC receptor-chemokine complex and the basis of chemokine subfamily selectivity.
Chemokines and their receptors are orchestrators of cell migration in humans. Because dysregulation of the receptor-chemokine system leads to inflammation and cancer, both chemokines and receptors are highly sought therapeutic targets. Yet one of the barriers for their therapeutic targeting is the limited understanding of the structural principles behind receptor-chemokine recognition and selectivity. The existing structures do not include CXC subfamily complexes and lack information about the receptor distal N-termini, despite the importance of the latter in signaling, regulation, and bias. Here, we report the discovery of the geometry of the complex between full-length CXCR4, a prototypical CXC receptor and driver of cancer metastasis, and its endogenous ligand CXCL12. By comprehensive disulfide cross-linking, we establish the existence and the structure of a novel interface between the CXCR4 distal N-terminus and CXCL12 β1-strand, while also recapitulating earlier findings from nuclear magnetic resonance, modeling and crystallography of homologous receptors. A cross-linking-informed high-resolution model of the CXCR4-CXCL12 complex pinpoints the interaction determinants and reveals the occupancy of the receptor major subpocket by the CXCL12 proximal N terminus. This newly found positioning of the chemokine proximal N-terminus provides a structural explanation of CXC receptor-chemokine selectivity against other subfamilies. Our findings challenge the traditional two-site understanding of receptor-chemokine recognition, suggest the possibility of new affinity and signaling determinants, and fill a critical void on the structural map of an important class of therapeutic targets. These results will aid the rational design of selective chemokine-receptor targeting small molecules and biologics with novel pharmacology.


Transient visual field loss secondary to migraine.
Migraine is responsible for a variety of monocular and binocular transient visual field phenomena. These disturbances can mimic symptoms of serious neurologic disease. This paper presents three cases of transient migrainous vision loss and highlights current knowledge regarding migraine. Conditions to be considered in the differential diagnosis of transient field loss are also reviewed.


Tykes and bikes: injuries associated with bicycle-towed child trailers and bicycle-mounted child seats.
To describe the incidence, type, and severity of injuries related to the use of bicycle-towed trailers for transporting children and to compare them with injuries associated with the use of child seats mounted on adult bicycles. A retrospective analysis of data from the National Electronic Injury Surveillance System of the US Consumer Product Safety Commission for 1990 to 1998. There were 49 injuries to children during the 9-year study period (estimated 2338 injuries; 95% confidence interval [CI], 1121-3555): 6 were associated with the use of bicycle-towed trailers (an estimated 322 injuries; 95% CI, 158-486) and 43 were related to the use of bicycle-mounted child seats (an estimated 2015 injuries; 95% CI, 988-3042). The mean age of injured children was 2.4 years and 51% were male. A collision with a motor vehicle accounted for 2 (33%) of the injuries associated with bicycle-towed trailers; 3 (50%) of the injuries were the result of falls. A motor vehicle was involved in 4 injuries (9%) related to the use of bicycle-mounted child seats (Fisher exact test, P<.13 vs bicycle-towed trailers); 31 (72%) were the result of falls (Fisher exact test, P<.26 vs bicycle-towed trailers). Contact with a bicycle wheel or spokes was the mechanism of 1 injury associated with the use of a bicycle-towed trailer (17%) and the mechanism for 8 (19%) of the injuries associated with the use of a bicycle-mounted child seat (Fisher exact test, P<.69). The head or face was the most common site of injury, accounting for 5 (83%) injuries among those riding in bicycle-towed trailers and 21 (49%) injuries among children in bicycle-mounted child seats (Fisher exact test, P<.12). All 6 children injured in bicycle-towed trailers had contusions/ abrasions or lacerations; 22 (51%) children injured using bicycle-mounted child seats had contusions/abrasions or lacerations and 9 (21%) had fractures. Two children (33%) injured in bicycle-towed trailers and 2 (5%) injured in bicycle-mounted child seats were admitted to the hospital (Fisher exact test, P<.06). When compared with bicycle-mounted child seats, there were fewer reported injuries to children associated with the use of bicycle-towed trailers. Motor vehicle involvement and need for hospital admission were similar among injured children in both groups, and the head or face was the most common site of injury. These data imply that ongoing surveillance efforts to identify injuries associated with use of bicycle-towed child trailers are warranted and that bicycle helmets should be worn by children riding in bicycle-towed child trailers and in bicycle-mounted child seats.


Survey of Southern Wisconsin Needle Exchange Clients Regarding Opioid Overdose and Naloxone Use.
Factors surrounding opioid overdose and naloxone use must be explored from the user perspective in order to more effectively combat the current opioid crisis. AIDS Resource Center of Wisconsin needle exchange clients were surveyed regarding overdose victim demographics, interventions, experience with naloxone, and overdose outcomes. Most respondents (102/108, 94.4%) reported either experiencing or witnessing an overdose. While naloxone was often used (64/102, 62.7%), other recommended interventions, such as calling 911 (44/102, 43.1%) and rescue breathing (31/102, 30.4%) often were not. Potential legal consequences were cited as a major barrier for contacting emergency medical services (42.3%). There appears to be a need for education and/or policy change to facilitate appropriate overdose prevention and use of emergency medical services in the setting of opioid overdose.


Cytokinome profile evaluation in patients with hepatitis C virus infection.
The ''omics sciences'' (genomics, transcriptomics, proteomics) are often used to study living organisms as a whole system by evaluating the complex expression patterns of genes, miRNA, proteins, and metabolites. This study aimed, through bioinformatics and systems biology, to decipher the cytokinome profile in the evolution of inflammatory processes leading to cancer. The cytokinome was defined as the totality of cytokines and their interactions in and around biological cells. The system biology approach would provide a better understanding of the complex interaction network of cytokines, especially in cancer patients. Acquired knowledge would enable health providers with tools to evaluate disease onset through progression as well as identifying innovative therapeutic strategies. Understanding the role each cytokine plays in the metabolic network is of great importance. This paper reviews our group's ''omics'' work. In particular, it addresses the role cytokines play in liver disease in six different scenarios. The first is the role the cytokines play in chronic inflammatory diseases and cancers. The second is the significance of the cytokinome profile. The third is the role of liver cirrhosis as an inflammatory disease. The fourth is the comparison of cytokine levels evaluated in patients with chronic hepatitis C virus (HCV) or with HCV-related cirrhosis. The fifth is the comparison of cytokine levels evaluated in patients with HCV-related cirrhosis in the presence and absence of type 2 diabetes. And lastly, we present a comparison of cytokine levels evaluated in patients with HCV-related cirrhosis in the presence and absence of hepatocellular carcinoma.


Buccal Midazolam Compared With Rectal Diazepam Reduces Seizure Duration in Children in the Outpatient Setting.
Seizures are very common in children. They frequently happen in outpatient settings, in the presence of caregivers who are not always trained in their management. First-line rescue therapy is based on benzodiazepine, historically diazepam. Recent studies have investigated the use of other benzodiazepines in the treatment of acute seizures. The aims of this study were to evaluate the management of pediatric seizures carried out by parents or caregivers in an outpatient setting and to evaluate the differences in terms of immediate management and subsequent outcome when comparing the use of rectal diazepam versus buccal midazolam. In this retrospective study, medical records of children consulting for seizures at the Robert Debré Pediatric Emergency Department of Paris, France, over 18 months were analyzed to evaluate seizure characteristics, management by caregivers, received treatments, and the admission rate. Five hundred ninety-four patients resulted eligible for the study. The interview was completed for 135 children who presented a further episode of seizure after inclusion. In the subgroup of children receiving buccal midazolam, compared with the subgroup receiving intrarectal diazepam, seizure duration was significantly shorter (10.3 vs 48.4 minutes, P = 0.0004), and the risk of a status epilepticus decreased (1 vs 11, P = 0.0008). The admission rate was not different between the 2 subgroups. Based on our results, buccal midazolam seems to have some advantages compared with rectal diazepam in terms of feasibility in an outpatient setting and in terms of reduced seizure duration.


"Sexual" behavior in parthenogenetic lizards (Cnemidophorus).
All-female, parthenogenetic species afford a unique test of hypotheses regarding the nature and evolution of sexuality. Basic data on the behavior of parthenogens are lacking, however. We have discovered, from observations of captive Cnemidophorus uniparens, C. velox, and C. tesselatus, behavior patterns remarkably similar to the courtship and copulatory behavior of closely related sexual species. Briefly, in separately housed pairs, one lizard was repeatedly seen to mount and ride its cagemate and appose the cloacal regions. Dissection or palpation revealed that, in each instance, the courted animal was reproductively active, having ovaries containing large, preovulatory follicles, while the courting animal was either reproductively inactive or postovulatory, having ovaries containing only small, undeveloped follicles. These observations are significant for the questions they raise. For example, is this behavior a nonfunctional vestige of the species' ancestry, or is this behavior necessary for successful reproduction in the species (e.g., by priming reproductive neuroendocrine mechanisms as has been demonstrated in sexual species)?


Low Homoarginine Levels in the Prognosis of Patients With Acute Chest Pain.
The endogenous amino acid homoarginine predicts mortality in cerebro- and cardiovascular disease. The objective was to explore whether homoarginine is associated with atrial fibrillation (AF) and outcome in patients with acute chest pain. One thousand six hundred forty-nine patients with acute chest pain were consecutively enrolled in this study, of whom 589 were diagnosed acute coronary syndrome (ACS). On admission, plasma concentrations of homoarginine as well as brain natriuretic peptide (BNP), and high-sensitivity assayed troponin I (hsTnI) were determined along with electrocardiography (ECG) variables. During a median follow-up of 183 days, 60 major adverse cardiovascular events (MACEs; 3.8%), including all-cause death, myocardial infarction, or stroke, were registered in the overall study population and 43 MACEs (7.5%) in the ACS subgroup. Adjusted multivariable Cox regression analyses revealed that an increase of 1 SD of plasma log-transformed homoarginine (0.37) was associated with a hazard reduction of 26% (hazard ratio [HR], 0.74; 95% CI, 0.57-0.96) for incident MACE and likewise of 35% (HR, 0.65; 95% CI, 0.49-0.88) in ACS patients. In Kaplan-Meier survival curves, homoarginine was predictive for patients with high-sensitivity assayed troponin I (hsTnI) above 27 ng/L (P<0.05). Last, homoarginine was inversely associated with QTc duration (P<0.001) and prevalent AF (OR, 0.83; 95% CI, 0.71-0.95). Low plasma homoarginine was identified as a risk marker for incident MACEs in patients with acute chest pain, in particular, in those with elevated hsTnI. Impaired homoarginine was associated with prevalent AF. Further studies are needed to investigate the link to AF and evaluate homoarginine as a therapeutic option for these patients.


Disassociating Lung Mechanics and Oxygenation in Pediatric Acute Respiratory Distress Syndrome.
Both oxygenation and peak inspiratory pressure are associated with mortality in pediatric acute respiratory distress syndrome. Since oxygenation and respiratory mechanics are linked, it is difficult to identify which variables, pressure or oxygenation, are independently associated with outcome. We aimed to determine whether respiratory mechanics (peak inspiratory pressure, positive end-expiratory pressure, ΔP [PIP minus PEEP], tidal volume, dynamic compliance [Cdyn]) or oxygenation (PaO2/FIO2) was associated with mortality. Prospective, observational, cohort study. University affiliated PICU. Mechanically ventilated children with acute respiratory distress syndrome (Berlin). None. Peak inspiratory pressure, positive end-expiratory pressure, ΔP, tidal volume, Cdyn, and PaO2/FIO2 were collected at acute respiratory distress syndrome onset and at 24 hours in 352 children between 2011 and 2016. At acute respiratory distress syndrome onset, neither mechanical variables nor PaO2/FIO2 were associated with mortality. At 24 hours, peak inspiratory pressure, positive end-expiratory pressure, ΔP were higher, and Cdyn and PaO2/FIO2 lower, in nonsurvivors. In multivariable logistic regression, PaO2/FIO2 at 24 hours and ΔPaO2/FIO2 (change in PaO2/FIO2 over the first 24 hr) were associated with mortality, whereas pressure variables were not. Both oxygenation and pressure variables were associated with duration of ventilation in multivariable competing risk regression. Improvements in oxygenation, but not in respiratory mechanics, were associated with lower mortality in pediatric acute respiratory distress syndrome. Future trials of mechanical ventilation in children should focus on oxygenation (higher PaO2/FIO2) rather than lower peak inspiratory pressure or ΔP, as oxygenation was more consistently associated with outcome.