Neonatal Injury Alters Sensory Input and Synaptic Plasticity in GABAergic Interneurons of the Adult Mouse Dorsal Horn.
Neonatal tissue injury disrupts the balance between primary afferent-evoked excitation and inhibition onto adult spinal projection neurons. However, whether this reflects cell-type-specific alterations at synapses onto ascending projection neurons, or rather is indicative of global changes in synaptic signaling across the mature superficial dorsal horn (SDH), remains unknown. Therefore the present study investigated the effects of neonatal surgical injury on primary afferent synaptic input to adult mouse SDH interneurons using in vitro patch-clamp techniques. Hindpaw incision at postnatal day (P)3 significantly diminished total primary afferent-evoked glutamatergic drive to adult Gad67-GFP and non-GFP neurons, and reduced their firing in response to sensory input, in both males and females. Early tissue damage also shaped the relative prevalence of monosynaptic A- versus C-fiber-mediated input to mature GABAergic neurons, with an increased prevalence of Aβ- and Aδ-fiber input observed in neonatally-incised mice compared with naive littermate controls. Paired presynaptic and postsynaptic stimulation at an interval that exclusively produced spike timing-dependent long-term potentiation (t-LTP) in projection neurons predominantly evoked NMDAR-dependent long-term depression in naive Gad67-GFP interneurons. Meanwhile, P3 tissue damage enhanced the likelihood of t-LTP generation at sensory synapses onto the mature GABAergic population, and increased the contribution of Ca2+-permeable AMPARs to the overall glutamatergic response. Collectively, the results indicate that neonatal injury suppresses sensory drive to multiple subpopulations of interneurons in the adult SDH, which likely represents one mechanism contributing to reduced feedforward inhibition of ascending projection neurons, and the priming of developing pain pathways, following early life trauma.SIGNIFICANCE STATEMENT Mounting clinical and preclinical evidence suggests that neonatal tissue damage can result in long-term changes in nociceptive processing within the CNS. Although recent work has demonstrated that early life injury weakens the ability of sensory afferents to evoke feedforward inhibition of adult spinal projection neurons, the underlying circuit mechanisms remain poorly understood. Here we demonstrate that neonatal surgical injury leads to persistent deficits in primary afferent drive to both GABAergic and presumed glutamatergic neurons in the mature superficial dorsal horn (SDH), and modifies activity-dependent plasticity at sensory synapses onto the GABAergic population. The functional denervation of spinal interneurons within the mature SDH may contribute to the "priming" of developing pain pathways following early life injury.


Favorable outcome in a fetus with an early-onset extensive cystic hygroma colli and intralesional hemorrhage.
We present a rare occurrence of an early-onset extensive cystic hygroma colli with intralesional hemorrhage and a favorable outcome. A 23-year-old primigravida woman was referred for management of a left isolated extensive cystic hygroma colli at 22 weeks' gestation. Amniocentesis revealed a 46, XY karyotype. Ultrasound-guidance in utero paracentesis was performed weekly or fortnightly from 22 to 36 gestational weeks. The aspirated fluid was chocolate-colored and contained abundant lymphocytes, erythrocytes, and protein. Despite multiple aspirations, the fetal cystic hygroma colli increased in size from 5.2x4.2 cm at 22 weeks' gestation to 9x9.7 cm at 36 weeks' gestation. The woman underwent cesarean section at 36 week's gestation and a-2808 g neonate was born with a 10x6 cm left neck mass, which did not impair spontaneous normal respiration. At the age of 4 days, the neonate underwent simple excision of the cystic hygroma, which was confined to the anterior superficial neck. The neonate was discharged 4 days after operation in good condition. In the present case, in utero paracentesis did not prevent the progressive growth of an early-onset extensive cystic hygroma colli with intralesional hemorrhage. However, lack of extension of the lesion into the surrounding structures and successful postnatal surgery contributed to the favorable outcome of this patient.


Alvimopan for recovery of bowel function after radical cystectomy.
Alvimopan is used in abdominal surgery to reduce postoperative ileus in patients undergoing small bowel resections with primary anastomosis. The role and efficacy of alvimopan in patients undergoing radical cystectomy with urinary diversion is not well understood. To assess the effects of alvimopan in the context of enhanced recovery pathways compared to enhanced recovery pathways alone for perioperative bowel dysfunction in patients undergoing radical cystectomy. The terms alvimopan and cystectomy were used to search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase. We also reviewed abstracts from the past four years (2013 to 2016) of the American Urologic Association, Society of Urologic Oncology, and American Society of Clinical Oncology Genitourinary Cancers. We searched for randomized controlled trials that compared alvimopan to placebo. This study was based on a published protocol. We performed a comprehensive search of multiple databases including CENTRAL in the Cochrane Library, MEDLINE, Embase, LILACS, Web of Science, Scopus and Biosis, which we last updated on 6 February 2017. We also searched abstract proceedings for major relevant meetings (2013 to 2016), databases of the grey literature, trial registries, citations of relevant reviews and contacted clinical experts and the drug manufacturer.Two independent reviewers screened the literature in two stages (title and abstract, full-text) using Covidence software. Two independent reviewers assessed the risk of bias on a 'per outcome' basis using the Cochrane 'Risk of bias; tool and rated the quality of evidence according to GRADE. Results of the single eligible trial were reported in a 'Summary of findings' table based on an intention-to-treat analysis. Based on a single trial and moderate-quality evidence, alvimopan reduced the time to reach a composite endpoint of tolerance of solid food and documented bowel movements (hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.41 to 2.23). This represents 165 more patients (109 more to 207 more) per 1000 meeting this endpoint within 10 days of surgery. Based on moderate-quality evidence, alvimopan reduced the time to hospital discharge (HR 1.67, 95% CI 1.38 to 2.01). This represents 138 more patients (82 more to 198 more) per 1000 being discharged within 10 days of surgery. Also based on moderate-quality evidence, alvimopan was associated with a reduced risk of major adverse events (risk ratio (RR) 0.28, 95% CI 0.18 to 0.44) representing 355 fewer patients (404 fewer to 276 fewer) with major adverse events per 1000. We downgraded this outcome for indirectness as it included adverse events that we did not consider major.In terms of secondary outcomes, alvimopan did not appear to alter the rate of readmission (RR 0.89, 95% CI 0.59 to 1.33), change the rate of any cardiovascular event (RR 0.54, 95% CI 0.27 to 1.05) or alter the mean narcotic pain medication use (mean difference 0, 95% CI 14.08 fewer to 14.08 more morphine equivalents). The quality of evidence was moderate for all three outcomes. Based on high-quality evidence, alvimopan reduced the rate of nasogastric tube replacement (RR 0.31, 95% CI 0.16 to 0.59). We did not find evidence for the drug's impact on rates of parenteral nutrition. All outcomes were short term and limited to a 30-day time horizon.Based on the existence of only one trial, we were unable to perform any subgroup or sensitivity analyses. In patients undergoing radical cystectomy and urinary diversion, the use of alvimopan administered as part of an enhanced recovery pathway for a limited duration (up to 15 doses for up to seven days) probably reduces the time to tolerance of solid food, time to hospital discharge and rates of major adverse events. Readmission rates, rates of cardiovascular events and narcotic pain requirements are probably similar. The need for reinsertion of nasogastric tubes is reduced. We found no evidence for the impact on rates of parenteral nutrition within 30 postoperative days.


Sediment controls dynamic behavior of a Cordilleran Ice Stream at the Last Glacial Maximum.
The uncertain response of marine terminating outlet glaciers to climate change at time scales beyond short-term observation limits models of future sea level rise. At temperate tidewater margins, abundant subglacial meltwater forms morainal banks (marine shoals) or ice-contact deltas that reduce water depth, stabilizing grounding lines and slowing or reversing glacial retreat. Here we present a radiocarbon-dated record from Integrated Ocean Drilling Program (IODP) Site U1421 that tracks the terminus of the largest Alaskan Cordilleran Ice Sheet outlet glacier during Last Glacial Maximum climate transitions. Sedimentation rates, ice-rafted debris, and microfossil and biogeochemical proxies, show repeated abrupt collapses and slow advances typical of the tidewater glacier cycle observed in modern systems. When global sea level rise exceeded the local rate of bank building, the cycle of readvances stopped leading to irreversible retreat. These results support theory that suggests sediment dynamics can control tidewater terminus position on an open shelf under temperate conditions delaying climate-driven retreat.


Effect of Oryza sativa extract on the progression of airway inflammation and remodeling in an experimental animal model of asthma.
Airway inflammation and remodeling in chronic asthma are characterized by airway eosinophilia, hyperplasia of smooth muscle and goblet cells, and subepithelial fibrosis. The present study was undertaken to evaluate the effects of DA-9201, an ethanolic extract of black rice (Oryza sativa L.), on airway inflammation and remodeling in a murine model of chronic asthma. BALB/c mice sensitized to ovalbumin (OVA) were chronically challenged with aerosolized OVA for 6 weeks. DA-9201 (30, 100, or 300 mg/kg) or dexamethasone (3 mg/kg) was orally administered during the last 4 and 2 weeks, respectively. Airway inflammation, lung pathology by histomorphometry and immunohistochemistry, IgE level and Th2 cytokines were evaluated. The OVA-treated mice showed extensive eosinophilia, chronic inflammatory responses and characteristics of airway remodeling including subepithelial fibrosis, smooth muscle hypertrophy, and goblet cell hyperplasia. As compared to the OVA-treated control group, treatment with DA-9201 resulted in significant reductions in the accumulation of eosinophils in peribronchial areas, chronic pulmonary inflammation and progression of airway remodeling. Furthermore, DA-9201 significantly reduced total serum and BALF IgE levels and Th2 cytokines. These results indicate that DA-9201 may play an important role in attenuating the progressing of airway inflammation and remodeling and suggest the potential benefits of DA-9201 in prevention or treatment of asthma.


Interferon alpha in the treatment of polycythemia vera.
Interferon alpha (IFN) inhibits the growth of the abnormal clone in patients with myeloproliferative disorders, leading to a reduction of the clinical and laboratory signs of the pathologic myeloproliferation. The therapeutic efficacy of IFN in polycythemia vera (PV) is demonstrated by the summarized treatment results of 279 patients participating in 16 prospective nonrandomized studies and in three case reports. The initial IFN dose ranged from 3 to 35 million IU/week. In 82% of the patients the frequency of phlebotomies was reduced. In 50% a complete remission was achieved, defined as a stable hematocrit of 45% without concomitant phlebotomies. Reduction of splenomegaly was seen in 77% and control of pruritus in 81% of the patients. The median observation time of the studies was 13 months (ranging from 3 to 84 months). Individual cases were followed for up to 126 months. In 21% of the patients IFN was terminated, owing mostly to side effects. The selective suppression of the malignant clone by IFN was demonstrated by the induction of cytogenetic remissions in sporadic cases with a chromosomal marker and by the observation of unmaintained remissions that lasted up to 4.8 years. IFN has no known mutagenic or teratogenic effects. The data presently available demonstrate that IFN is an effective alternative to the present forms of treatment in PV. Controlled prospective studies are essential to clarify whether the favorable biologic properties are also reflected by a benefit in clinical course and survival, and whether IFN may reduce the rates of acute leukemia and myelofibrosis. A randomized study that compares IFN and hydroxyurea in patients with PV has recently been initiated by the Suddeutsche Hamoblastosegruppe (SHG) in Germany.


Neuropeptide W: an anorectic peptide regulated by leptin and metabolic state.
Neuropeptide W (NPW) is an anorectic peptide produced in the brain. Here, we showed that NPW was present in several hypothalamic nuclei, including the paraventricular hypothalamic nucleus, ventromedial hypothalamic nucleus, lateral hypothalamus, and hypothalamic arcuate nucleus. NPW expression was significantly up-regulated in leptin-deficient ob/ob and leptin receptor-deficient db/db mice. The increase in NPW expression in ob/ob mice was abrogated to control levels after leptin replacement. Leptin induced suppressors of cytokine signaling-3 after phosphorylation of signal transducer and activator of transcription-3 in NPW-expressing neurons. In addition, we demonstrated that NPW reduces feeding via the melanocortin-4-receptor signaling pathway. We also showed that NPW activates proopiomelanocortin and inhibits neuropeptide Y neurons using loose-patch extracellular recording of these neurons identified by promoter-driven green fluorescent protein expression. This study indicates that NPW may play an important role in the regulation of feeding and energy metabolism under the conditions of leptin insufficiency.


Insulin induction of Xenopus laevis oocyte maturation is inhibited by monoclonal antibody against p21 ras proteins.
Microinjection of transforming p21 ras protein induces maturation of Xenopus laevis oocytes, and the induction is blocked by coinjection of monoclonal antibody (Y13-259) against p21 ras proteins. Similar to other inducing agents, the effect of p21 ras protein is mediated via the appearance of maturation or meiosis-promoting factor activity. In addition, the neutralizing antibody markedly reduces oocyte maturation after insulin induction, whereas it fails to inhibit progesterone induction. Our results suggest that insulin induces maturation of oocytes via a different pathway than that of steroidal agents. The induction by insulin is ras dependent, and the action of ras may be directed at the steps before meiosis-promoting factor autocatalytic activation. These results suggest a role of p21 ras protein in the events associated with amphibian oocyte maturation.


Addition of nitric oxide through nitric oxide-paracetamol enhances healing rat achilles tendon.
Nitric oxide is an important messenger molecule in many physiological processes. The addition of NO via NO-flurbiprofen enhances the material properties of healing tendon, however, flurbiprofen has a detrimental effect on healing. We asked if NO delivered by a cyclooxygenase 3 inhibitor (paracetamol/acetaminophen) would enhance healing in a rat Achilles tendon healing model. Rats were injected subcutaneously daily with NO-paracetamol, paracetamol or vehicle from two days before surgery to the day of tissue harvesting. Paracetamol had no effect on tendon healing compared with vehicle alone. NO-paracetamol did not change the failure load, but did decrease the water content, enhance the collagen content, reduce the cross-sectional area and improve the ultimate stress of healing tendon compared with paracetamol and vehicle. The collagen organization of the healing tendon in the NO-paracetamol group, as determined by polarized light microscopy, was enhanced. Our data suggests NO-paracetamol increases the total collagen content and enhances organization while decreasing the cross-sectional area of healing rat Achilles tendon and is consistent with human clinical trials where NO has improved the symptoms and signs of tendinopathy.


Structural pattern in central uplifts of cryptoexplosion structures as typified by sierra madera.
The pattern of deformation in central uplifts of Sierra Madera and other well-known cryptoexplosion structures indicates that inward as well as upward movement of strata formed the uplifts. This kind of movement is incompatible with structures not of impact origin with which they have been compared. The structural style of cryptoexplosion structures, together with features that suggest shock deformation, supports the belief that they are the eroded roots of impact craters.


Characteristics and management of diabetic patients hospitalized for myocardial infarction in France.
The objective of this study was to compare the management of diabetic and non-diabetic patients before, during and after hospitalization for myocardial infarction (MI). Hospital admissions for MI in France from January to June 2006 were obtained from the national hospital-discharge database and merged with data on medications, 6 months before and after hospitalization of patients covered by the general health insurance scheme. Diabetic patients were identified by having at least two refunds for antidiabetic medications 6 months before the index hospitalization. Results comparing diabetic and non-diabetic patients were adjusted for age and gender. Of the 14,007 patients included in the study, 2545 were diabetic (18.2%). Before hospital admission, diabetic patients more frequently received secondary cardiovascular preventative medications (12.7% vs 4.2%; P<0.0001) and stent implants (4.2% vs 2.2%; P<0.0001) than did non-diabetic patients. During hospitalization and the following month, angioplasty (56.1% vs 61.7%; P=0.0001) and stent implantation (53.3% vs 59.3%; P<0.0001) were less frequently performed in diabetic patients and only coronary angiography was done in similar proportions of diabetic and non-diabetic patients (16.7% vs 15.2%). In addition, during the 6 months after hospitalization, diabetic vs non-diabetic patients had more admissions for cardiovascular reasons (36.9% vs 29.5%; P<0.0001) and were prescribed more secondary preventative medications (65.9% vs 61.7%; P<0.0001). They were also more frequently treated with insulin only (19.6% 6 months before vs 27.2% 6 months after) or oral antidiabetic drugs (14.6% vs 19.7%, respectively) than were non-diabetics. French diabetic patients subsequent to MI undergo fewer angioplasty procedures than do non-diabetic patients. After the acute stage, secondary preventative medications are used more often, with a marked rise in the use of insulin.


Functional characterisation of an intron retaining K(+) transporter of barley reveals intron-mediated alternate splicing.
Intron retention in transcripts and the presence of 5' and 3' splice sites within these introns mediate alternate splicing, which is widely observed in animals and plants. Here, functional characterisation of the K(+) transporter, HvHKT2;1, with stably retained introns from barley (Hordeum vulgare) in yeast (Saccharomyces cerevisiae), and transcript profiling in yeast and transgenic tobacco (Nicotiana tabacum) is presented. Expression of intron-retaining HvHKT2;1 cDNA (HvHKT2;1-i) in trk1, trk2 yeast strain defective in K(+) uptake restored growth in medium containing hygromycin in the presence of different concentrations of K(+) and mediated hypersensitivity to Na(+) . HvHKT2;1-i produces multiple transcripts via alternate splicing of two regular introns and three exons in different compositions. HKT isoforms with retained introns and exon skipping variants were detected in relative expression analysis of (i) HvHKT2;1-i in barley under native conditions, (ii) in transgenic tobacco plants constitutively expressing HvHKT2;1-i, and (iii) in trk1, trk2 yeast expressing HvHKT2;1-i under control of an inducible promoter. Mixed proportions of three HKT transcripts: HvHKT2;1-e (first exon region), HvHKT2;1-i1 (first intron) and HvHKT2;1-i2 (second intron) were observed. The variation in transcript accumulation in response to changing K(+) and Na(+) concentrations was observed in both heterologous and plant systems. These findings suggest a link between intron-retaining transcripts and different splice variants to ion homeostasis, and their possible role in salt stress.


The responses of mitochondrial proteome in rat liver to the consumption of moderate ethanol: the possible roles of aldo-keto reductases.
A large body of evidence supports the view that mitochondria are a primary target of alcohol stress. Changes in mitochondrial proteins due to moderate ethanol intake, however, have not been broadly and accurately estimated. For this study, rats were fed low doses of ethanol and the mitochondria were isolated from heart, kidney, and liver, using ultracentrifugation with Nycodenz density gradient. The mitochondrial proteins were well resolved upon two-dimensional electrophoresis (2DE), and the alcohol-responsive 2DE spots were identified by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF/TOF MS). Compared with the control group, the proteins extracted from liver mitochondria of ethanol-fed rats exhibited the significant changes on 2DE images, whereas the 2DE images obtained from the kidney and the heart mitochondria remained almost unchanged by ethanol feeding. Significantly, over 50% of the alcohol-responsive proteins in liver mitochondria were members of aldo-keto reductase family (AKR), which were usually present in cytoplasm. The organelle distributions of AKR proteins in liver mitochondria were further confirmed by Western blot analysis as well as by confocal microscopy. In addition, translocations of AKR were examined in the CHANG cell line, which was cultured with and without ethanol. The results of Western blot strongly suggested that the abundances of AKR proteins in the mitochondria were greatly reduced by the presence of ethanol in culture medium. The results of this study show that, even with moderate ethanol feeding, the mitochondrial proteome in rat liver was more sensitive to alcohol stress than that of either the kidney or the heart. The translocation of AKR proteins may be involved in the detoxification of liver cells.


Paeonol attenuates cigarette smoke-induced lung inflammation by inhibiting ROS-sensitive inflammatory signaling.
Cigarette smoking causes persistent lung inflammation that is mainly regulated by redox-sensitive pathways. We have previously reported that cigarette smoke (CS) activates reactive oxygen species- (ROS-) sensitive mitogen-activated protein kinases (MAPKs)/nuclear factor-κB (NF-κB) signaling leading to induction of lung inflammation. Paeonol, the main phenolic compound present in the Chinese herb Paeonia suffruticosa, has antioxidant and anti-inflammatory properties. However, whether paeonol has similar beneficial effects against CS-induced lung inflammation remains unclear. Using a murine model, we showed that chronic CS exposure for 4 weeks caused pulmonary inflammatory infiltration, increased lung vascular permeability, elevated lung levels of chemokines, cytokines, and 4-hydroxynonenal (an oxidative stress biomarker), and induced lung inflammation; all of these CS-induced events were suppressed by chronic treatment with paeonol. Using human bronchial epithelial cells (HBECs), we demonstrated that cigarette smoke extract (CSE) sequentially increased extracellular and intracellular levels of ROS, activated the MAPKs/NF-κB signaling, and induced interleukin-8 (IL-8); all these CSE-induced events were inhibited by paeonol pretreatment. Our findings suggest a novel role for paeonol in alleviating the oxidative stress and lung inflammation induced by chronic CS exposure in vivo and in suppressing CSE-induced IL-8 in vitro via its antioxidant function and an inhibition of the MAPKs/NF-κB signaling.


Neurofibroma of the pinna.
Neurofibromas are relatively common lesions of the nervous system, but only a few cases involving the pinna have been reported. The emphasis in most of these reports was on the cosmetic deformity; functional impairment in the form of hearing loss has been mentioned in only a few reports. We report a case of pinnal neurofibroma in which the primary complaint was otitis externa; hearing loss and cosmetic deformity were also present. Surgical excision resulted in an excellent functional and cosmetic outcome. This case demonstrates that neurofibroma of the pinna in the area of the external meatus can produce functional as well as cosmetic impairment, and surgery can produce a very satisfactory result.


Absorption kinetics and action profiles of intermediate acting human insulins.
The effects of the currently available intermediate acting human insulins on plasma insulin levels and action profiles, assessed by the euglycaemic clamp technique for a period of 8 hr following the administration, were studied in 8 healthy volunteers. The amount of insulin administered was 0.33 IU/kg body wt., using the NPH-insulins Humulin NPH, Insulatard Human, and Protaphane HM and the zinc insulins Monotard-HM and Humulin Zinc. After administration of NPH-insulins an earlier rise of plasma insulin levels was observed, reaching a plateau after about 3 hr, whereas after injection of zinc insulins the plasma insulin levels only gradually increased during at least the first 5-6 hr after administration. Glucose requirements followed a more or less similar pattern, although within the NPH-insulins Protaphane-HM lagged slightly behind during the first 2 hr when compared to Humulin NPH. We conclude therefore, that human NPH-insulins show a faster action profile as compared to human zinc insulins. This difference should be taken into account when switching over from one insulin to another.


Determining frequency of genes of CTX-M and CTX-M-15 of producing Enterobacteriaceae of isolated extended-spectrum beta-lactamases from clinical samples of patients referred to training hospitals of Medical Sciences University, Khorramabad, Iran.
The purpose of conducting this research was evaluation of the frequency of extended-spectrum beta-lactamases (ESBLs) in separated Enterobacteriaceae isolates from clinical samples in Khorramabad city and determination of their antimicrobial resistance pattern. In this study, 240 isolates belonging to Enterobacteriaceae family were collected in time duration between March and June in 2014. The isolates were identified by standard biochemical tests. Producing isolates of enzymes of ESBLs were identified by combined disc method and based on the Clinical and Laboratory Standards Institute criterion, and then, frequency of genes of blaCTX-M and blaCTX-M-15 in positive phenotypic isolates was determined using polymerase chain reaction method. In the present research, the most frequency was, respectively, belonged to Escherichia coli with 76%, Klebsiella pneumoniae - 16.2%, Citrobacter freundii - 5.4%, Proteus mirabilis - 1.6%, and Enterobacter - 0.83%. The obtained results from determining the antibiotic sensitivity pattern in the separated isolates showed that the maximum resistance of different isolates was related to antibiotics of ampicillin 88% while the minimum antibiotic resistance of isolates was related to the amikacin antibiotic with resistance value of 2.5%. The obtained results from the combined disc phenotypic method in the present research showed that from 240 Enterobacteriaceae isolates, 59% was generators of ESBLs. In addition, 85% of positive phenotype Enterobacteriacea had genes of blaCTX-M-15 and blaCTX-M that totally formed 50.4% of all separated bacteria from the clinical samples. The obtained results from the present research showed that the prevalence of ESBL enzymes and antibiotic resistance to ESBLs is high among the separated Enterobacteriaceae isolates from the clinical samples in Khorramabad city. Hence, policies of prescription of antibiotics and infection control in hospitals should be reviewed.


A heteroleptic bis(tridentate)ruthenium(II) polypyridine complex with improved photophysical properties and integrated functionalizability.
The synthesis and photophysical properties of a ruthenium(II) complex bearing an electron-accepting 2,2';6',2''-terpyridine ligand and an electron-donating N,N'-dimethyl-N,N'-dipyridin-2-ylpyridine-2,6-diamine (ddpd) ligand are presented. The heteroleptic complex is easily prepared isomerically pure and features intense low-energy metal-to-ligand charge-transfer (MLCT) absorption bands and intense room temperature (3)MLCT emission with a long (3)MLCT lifetime. The favorable photophysical properties are due to the strong ligand field imposed by the ddpd ligand.


In vitro metabolic stability of exendin-4: pharmacokinetics and identification of cleavage products.
The aim of this study was to investigate the metabolic stability and cleavage sites of exendin-4 in rat tissue homogenates, as well as to identify the types of proteases involved in exendin-4 degradation. The stability of exendin-4 in kidney and liver homogenates from rats was evaluated using liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) with gradient elution. Furthermore, we used a combination of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and LC-ESI-MS/MS to identify the structures of the major degradation products of exendin-4, and peptidase inhibitors were used to characterize exendin-4 degradation in rat liver and kidney homogenates and to identify the proteases involved in exendin-4 metabolism. Exendin-4 had a half-life of 7.8 and 100.9 min in the kidney and liver homogenate, respectively. The enzymes most likely to be involved in the degradation of exendin-4 were aminopeptidases, serineproteases, and metalloproteases. Exendin-4(15-39) and exendin-4(16-39) were the predominant direct exendin-4 metabolites in the kidney, and the main product of exendin-4 metabolism in the liver was exendin-4(12-39). Our results indicated that the metabolism of exendin-4 involved an initial endoproteolytic cleavage and subsequent exoproteolytic digestion. The degradation of exendin-4 in the kidney and liver homogenates followed distinct patterns, and the primary cleavage sites of exendin-4 degradation in rat kidney homogenates were located after AA-14, and -15, whereas those in rat liver homogenates were located after AA-11.


Think global, act local: medical students contextualize global health education.
There is considerable heterogeneity in the extent to which global health education is emphasized in undergraduate medical curricula. Here, we performed an exploratory analysis to test the hypothesis that exposure to global health education may influence the attitudes of medical students toward the treatment of local vulnerable patient populations. All pre-clerkship students at an urban Canadian university were invited to attend a voluntary global health education session on challenges in treating human immunodeficiency virus (HIV) in the developing world. Those who attended as well as those who did not completed pre- and post-session surveys measuring willingness to treat patients with HIV and related attitudes. A repeated measure analysis of variance (ANOVA) was performed to assess the effect of the intervention on attitudes toward locally affected populations. A total of 201 (81.4%) and 143 (58.3%) students completed the pre- and post-session surveys, respectively. Students who scored their willingness to treat patients with HIV within highest 10% of the scale on the pre-session survey were excluded from the analysis to account for a ceiling effect. On repeated measure ANOVA, willingness to treat local patients with HIV increased significantly following the session (P < 0.01). Students intending to attend the session also reported a greater propensity to treat patients with HIV than those who did not (P = 0.03). In this exploratory study, we find that following exposure to a global health lecture on the challenges of HIV in the developing world, students possessed more favorable attitudes toward the treatment of marginalized local patient populations, a finding that may be exploited in undergraduate and continuing medical education.


G-Protein biased opioid agonists: 3-hydroxy-N-phenethyl-5-phenylmorphans with three-carbon chain substituents at C9.
A series of compounds have been synthesized with a variety of substituents based on a three-carbon chain at the C9-position of 3-hydroxy-N-phenethyl-5-phenylmorphan (3-(2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol). Three of these were found to be μ-opioid receptor agonists in the inhibition of forskolin-induced cAMP accumulation assay and they did not recruit β-arrestin at all in the PathHunter assay and in the Tango assay. Compound 12 (3-((1S,5R,9R)-2-phenethyl-9-propyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), 13 (3-((1S,5R,9R)-9-((E)-3-hydroxyprop-1-en-1-yl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol), and 15a (3-((1S,5R,9R)-9-(2-hydroxypropyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-5-yl)phenol) were partial μ-agonists. Two of them had moderate efficacies (E MAX ca. 65%) and one had lower efficacy, and they were ca. 5, 3, and 4 times more potent, respectively, than morphine in vitro. Computer simulations were carried out to provide a molecular basis for the high bias ratios of the C9-substituted 5-phenylmorphans toward G-protein activation.


Analysis of emergency physician data can pay off.
A hospital's emergency physician billing procedures and fee schedules may not have kept pace with changes in the make-up of emergency room personnel. Revisions require thorough analysis of coding procedures, payer and patient data, Medicare rates, and breakdowns of collections. A successful analysis may yield improved collections, increased physician compensation, and separate billing by emergency physicians.


Association analysis of SSR markers with phenology, grain, and Stover-yield related traits in pearl millet (Pennisetum glaucum (L.) R. Br.).
Pearl millet is a staple food crop for millions of people living in the arid and semi-arid tropics. Molecular markers have been used to identify genomic regions linked to traits of interest by conventional QTL mapping and association analysis. Phenotypic recurrent selection is known to increase frequencies of favorable alleles and decrease those unfavorable for the traits under selection. This study was undertaken (i) to quantify the response to recurrent selection for phenotypic traits during breeding of the pearl millet open-pollinated cultivar "CO (Cu) 9" and its four immediate progenitor populations and (ii) to assess the ability of simple sequence repeat (SSR) marker alleles to identify genomic regions linked to grain and stover yield-related traits in these populations by association analysis. A total of 159 SSR alleles were detected across 34 selected single-copy SSR loci. SSR marker data revealed presence of subpopulations. Association analysis identified genomic regions associated with flowering time located on linkage group (LG) 6 and plant height on LG4, LG6, and LG7. Marker alleles on LG6 were associated with stover yield, and those on LG7 were associated with grain yield. Findings of this study would give an opportunity to develop marker-assisted recurrent selection (MARS) or marker-assisted population improvement (MAPI) strategies to increase the rate of gain for pearl millet populations undergoing recurrent selection.


Enhancing System Acceptance through User-Centred Design: Integrating Patient Generated Wellness Data.
Gestational diabetes mellitus (GDM) is a condition that appears during pregnancy and is expected to be a temporary one. While patients are encouraged to manage it themselves, research findings indicate that GDM may negatively affect the foetus; in addition, there is an increased risk of women with GDM subsequently developing Type 2 diabetes. To alleviate the risks, women with GDM are advised to maintain a record of their diet and blood glucose levels and to attend regular clinical reviews. Rather than using a paper diary, women with GDM can maintain a record of their blood glucose level readings and other relevant data using a wellness mobile application (app). However, such apps are developed for general use and may not meet the specific needs of clinical staff (physicians, dietitians, obstetricians and midwives) involved in managing GDM; for example, an app may record glucose readings but not the details of a meal taken before or after the glucose reading. Second, the apps do not permanently store the data generated by the patient and do not support the transfer of these data to a clinical system or information portal. The mobile health (mHealth) system designed and developed in this research allows one to integrate different types of user generated wellness data into a centralised database. A user-centered design (UCD) approach informed by the technology acceptance model (TAM) was adopted. This paper investigates and evaluates the effectiveness of the approach with regard to facilitating system acceptance and future adoption through an early focus on enhancing system usefulness and ease of use. The functional system requirements of the proposed system were refined through a series of interviews with the perspective of clinical users; ease-of-use and usability issues were resolved through 'think aloud' sessions with clinicians and GDM patients.


Isolation and characterization of staphylocoagulase chymotryptic fragment. Localization of the procoagulant- and prothrombin-binding domain of this protein.
Several strains of Staphylococcus aureus secrete a protein, staphylocoagulase, that binds stoichiometrically to human prothrombin, resulting in a coagulant complex designated staphylothrombin. In the present study, staphylocoagulase was digested with alpha-chymotrypsin and the resulting fragments were isolated by gel filtration. One fragment (Mr 43,000) exhibited a high affinity for human prothrombin (Kd = 1.7 X 10(-9) M), which is comparable to the affinity observed using intact staphylocoagulase (Kd = 4.6 X 10(-10) M). A complex of the Mr 43,000 fragment and prothrombin possessed both clotting and amidase activity essentially identical to that observed in a complex of intact staphylocoagulase and prothrombin. A second fragment (Mr 30,000) exhibited weaker affinity for prothrombin (Kd = 1.2 X 10(-7) M). While clotting activity was not observed with a complex of this fragment and prothrombin, it nonetheless possessed a weak amidase activity. A third fragment (Mr 20,000) was found to bind to prothrombin, but the resultant complex did not exhibit clotting or amidase activity. Amino-terminal sequence analyses of these staphylocoagulase fragments revealed that the Mr 43,000 fragment constitutes the amino-terminal portion of staphylocoagulase and also contains the Mr 30,000 and 20,000 fragments. Moreover, the amino-terminal sequence of the Mr 20,000 fragment was identical to that observed for the Mr 30,000 fragment. From these results, we conclude that the functional region of staphylocoagulase for binding and activation of human prothrombin is localized in the amino-terminal region of the intact bacterial protein.


A Novel Electrospun Nanofiber System with PEGylated Paclitaxel Nanocrystals enhancing the Transmucus Permeability and in Situ Retention for an Efficient Cervicovaginal Cancer Therapy.
Overcoming the vaginal barrier to achieve sufficient drug penetration and retention is a huge obstacle for drug delivery in chemotherapeutics for cervical cancer. In this study, we investigate the feasibility of a novel composite nanocrystal/nanofiber system for improving the transmucus penetration and, thus, enhancing retention and drug delivery to the lesion of a cervicovaginal tumor. Herein, paclitaxel (PTX) was sequentially formulated in the form of nanocrystals, coated with polydopamine (PDA), and modified with PEG. The nanocrystals (NCs@PDA-PEG) were creatively fabricated to create a composite nanofibrous membrane (NCs@PDA-PEG NFs) by using an electrospinning technique. The morphology, size distribution, drug loading, encapsulation efficiency, X-ray powder diffraction (XRD), Fourier transform infrared (FTIR) spectra, in vitro release, in vivo vaginal retention, apoptosis index, anti-tumor efficacy in a murine cervicovaginal tumor model, and local irritation were characterized. The NCs@PDA-PEG were formulated in a cube-like shape with an average size of 385.6 ± 35.47 nm; they were dispersed in electrospun nanofibers, and the drug loading was 7.94%. The XRD curves indicated that the phase state of PTX changed after the creation of the nanocrystals. The FTIR spectra showed that the drug and the excipients were compatible with each other. In vitro delivery showed that the dissolution of PTX in the electrospun nanofibers was significantly faster than that when using bulk PTX. Compared with the PTX NC NFs, the NC@PDA-PEG NFs exhibited prolonged vaginal residence, superior transmucus penetration, minimal mucosal irritation, and significant tumor inhibition efficacy after the intravaginal administration of the NFs in tumor-bearing mice. In conclusion, by acting as novel pharmaceutical repositories, NCs@PDA-PEG NFs can be promising candidates for non-invasive local treatment, leading to efficient tumor inhibition in cervicovaginal cancer.


Langerhans cells are critical in the development of atopic dermatitis-like inflammation and symptoms in mice.
Genetic or vitamin D3-induced overexpression of thymic stromal lymphopoietin (TSLP) by keratinocytes results in an atopic dermatitis (AD)-like inflammatory phenotype in mice echoing the discovery of high TSLP expression in epidermis from AD patients. Although skin dendritic cells (DC) are suspected to be involved in AD, direct evidence of a pathogenetic role for skin DC in TSLP-induced skin inflammation has not yet been demonstrated. In a mouse model of AD, i.e. mice treated with the low-calcemic vitamin D3 analogue, MC903, we show that epidermal Langerhans cells (LC)-depleted mice treated with MC903 do neither develop AD-like inflammation nor increased serum IgE as compared to vitamin D3 analogue-treated control mice. Accordingly, we show that, in mice treated with MC903 or in K14-TSLP transgenic mice, expression of maturation markers by LC is increased whereas maturation of dermal DC is not altered. Moreover, only LC are responsible for the polarization of naïve CD4(+) T cells to a Th2 phenotype, i.e. decrease in interferon-gamma and increase in interleukin (IL)-13 production by CD4(+) T cells. This effect of LC on T-lymphocytes does not require OX40-L/CD134 and is mediated by a concomitant down-regulation of IL-12 and CD70. Although it was previously stated that TSLP up-regulates the production of thymus and activation-regulated chemokine (TARC)/chemokine (C-C motif) ligand 17 (CCL17) and macrophage-derived chemokine (MDC)/CCL22 by human LC in vitro, our work shows that production of these Th2- cell attracting chemokines is increased only in keratinocytes in response to TSLP overexpression. These results demonstrate that LC are required for the development of AD in mouse models of AD involving epidermal TSLP overexpression.


Gonococcal endocarditis with initially negative blood cultures.
This case of gonococcal endocarditis in a young man highlights the recognized capacity of Neisseria gonorrhoeae to destroy an infected valve, and illustrates that emergency valve replacement in the presence of congestive heart failure may be life-saving. The utility of the echocardiogram and the reportedly low yield of positive blood cultures in this disease are represented.


Complications of arthroscopy of the hip.
Although arthroscopy of the hip is being carried out increasingly, little is known about the rate of associated complications. We describe a prospective study of 640 consecutive procedures in which a consistent technique was used. The overall complication rate was 1.6%. Complications, none of which was major or long-term, included transient palsy of the sciatic and femoral nerves, perineal injury, bleeding from the portal wounds, trochanteric bursitis and intra-articular breakage of the instrument. We believe that it is possible to undertake this operation safely using the technique described.


S-layer positive motile aeromonads isolated from channel catfish.
Motile aeromonads are ubiquitous aquatic bacteria that can cause motile aeromonad septicemia (MAS), a disease which affects channel catfish and can produce significant economic loss. Motile aeromonads isolated from commercially-raised channel catfish were screened for production of S-layer protein in order to evaluate its potential role in natural epizootics. The S-layer protein was produced by 14 of 24 (58%) isolates from epizootics evaluated in this study. Concomitant infections with other internal pathogens were detected in 10 of the 24 cases used in this study, and only one of those 10 isolates (10%) produced the S-layer protein. When Aeromonas sp. was the only internal pathogen diagnosed, 13 of 14 (93%) isolates produced the S-layer protein.


Soybean plant stage and population growth of soybean aphid.
The soybean aphid, Aphis glycines Matsumura, is a newly invasive species of aphid in North America. Previous studies disagree as to whether soybean, Glycine max (L.) Merr., plant stage has an impact on aphid intrinsic rate of increase. Therefore, the growth rate of soybean aphids on soybean plants of different stages was examined at two different scales in the field. A planting date experiment was used to measure the population growth of soybean aphids on plants of different stages. Clip-cages were used to measure life history characteristics of individual aphids on plants of different stages. No differences were found in the population growth or dynamics of soybean aphids in the planting date experiment. The life history characteristics of individual aphids also showed no significant difference when feeding on different growth stages of soybean plants. The impact of these findings on soybean aphid management is discussed and the possible reasons why the results differ from previous estimates of the aphid growth-plant stage relationship are considered.


The relationships between employment, clinical status, and psychiatric hospitalisation in patients with schizophrenia receiving either IPS or a conventional vocational rehabilitation programme.
Positive relationships between employment and clinical status have been found in several studies. However, an unequivocal interpretation of these relationships is difficult on the basis of common statistical methods. In this analysis, a structural equation model approach for longitudinal data was applied to identify the direction of statistical relationships between hours worked, clinical status and days in psychiatric hospital in 312 persons with schizophrenia who participated in a multi-centre randomised controlled trial comparing the effectiveness of Individual Placement and Support (IPS) with conventional vocational services in six study settings across Europe. Data were analysed by an autoregressive cross-lagged effects model, an autoregressive cross-lagged model with random intercepts and an autoregressive latent trajectory model. Comparison of model fit parameters suggested the autoregressive cross-lagged effects model to be the best approach for the given data structure. All models indicated that patients who received an IPS intervention spent more hours in competitive employment and, due to indirect positive effects of employment on clinical status, spent fewer days in psychiatric hospitals than patients who received conventional vocational training. Results support the hypothesis that the IPS intervention has positive effects not only on vocational but also on clinical outcomes in patients with schizophrenia.


Rescue of the first alphanucleorhabdovirus entirely from cloned complementary DNA: An efficient vector for systemic expression of foreign genes in maize and insect vectors.
Recent reverse genetics technologies have enabled genetic manipulation of plant negative-strand RNA virus (NSR) genomes. Here, we report construction of an infectious clone for the maize-infecting Alphanucleorhabdovirus maydis, the first efficient NSR vector for maize. The full-length infectious clone was established using agrobacterium-mediated delivery of full-length maize mosaic virus (MMV) antigenomic RNA and the viral core proteins (nucleoprotein N, phosphoprotein P, and RNA-directed RNA polymerase L) required for viral transcription and replication into Nicotiana benthamiana. Insertion of intron 2 ST-LS1 into the viral L gene increased stability of the infectious clone in Escherichia coli and Agrobacterium tumefaciens. To monitor virus infection in vivo, a green fluorescent protein (GFP) gene was inserted in between the N and P gene junctions to generate recombinant MMV-GFP. Complementary DNA (cDNA) clones of MMV-wild type (WT) and MMV-GFP replicated in single cells of agroinfiltrated N. benthamiana. Uniform systemic infection and high GFP expression were observed in maize inoculated with extracts of the infiltrated N. benthamiana leaves. Insect vectors supported virus infection when inoculated via feeding on infected maize or microinjection. Both MMV-WT and MMV-GFP were efficiently transmitted to maize by planthopper vectors. The GFP reporter gene was stable in the virus genome and expression remained high over three cycles of transmission in plants and insects. The MMV infectious clone will be a versatile tool for expression of proteins of interest in maize and cross-kingdom studies of virus replication in plant and insect hosts.


Nesidioblastosis in children.
Three cases in which seizure disorder was first noticed were examined in the last seven years; low fasting glucose and high serum insulin levels then led to the diagnosis of severe hypoglycemia secondary to nesidioblastosis. Hypoglycemic episodes were uncontrolled by frequent oral feedings and intravenous administration of dextrose, glucagon, and diazoxide. Within three weeks after diagnosis, all three patients underwent subtotal pancreatectomy; all three survived and have been followed-up for two to seven years. Two remain euglycemic and have no evidence of CNS damage. The third has occasional fasting hypoglycemia that is treated with diazoxide; he continues to have a seizure disorder and is mentally retarded. Neonatal hypoglycemia secondary to hyperinsulinism requires prompt recognition and aggressive treatment to avoid irreversible CNS damage. Subtotal pancreatectomy safely and effectively restores the euglycemic state.


ARF the integrator: linking NF-kappaB, p53 and checkpoint kinases.
The ARF tumor suppressor initiates the cellular response to aberrant oncogene activation through binding to and inhibiting the activity of Hdm2/Mdm2, the inhibitor of p53. However, many pathways also active in the cell will oppose p53 function if left unchecked. An example of this, is the RelA (p65) NF-kappaB subunit. Frequently activated by oncogenes, RelA is a potent inducer of anti-apoptotic gene expression, which has the potential to inhibit the pro-apoptotic functions of p53. We have recently discovered that by inducing the activity of the checkpoint kinases ATR and Chk1, ARF neutralises this opposing pathway. ARF-induced Chk1 phosphorylates RelA on threonine 505, a residue in its transactivation domain, thus inhibiting NF-kappaB's ability to stimulate anti-apoptotic gene expression. Furthermore, ARF-induced ATR is required for efficient induction and activation of p53. We propose that this pathway will target other proteins with pro-proliferative or anti-apoptotic functions. Therefore, through this mechanism, ARF can integrate the cellular response to an oncogene, thus maximising the effectiveness of the p53 tumor suppressor pathway.


A reduction approach for fuzzy rule bases of fuzzy controllers.
In this paper, a new approach to reducing the number of rules in a given fuzzy rule base of a fuzzy controller is presented. The fuzzy mechanism of the fuzzy controller under consideration consists of the product-sum inference, singleton output consequents and centroid defuzzification. The output consequents in the cells of the rule table are collected and represented as an output consequent matrix. The feature of the output consequent matrix is extracted by the singular values of the matrix. The output consequent matrix is reasonably approximated with a dominant consequent matrix. Also, the elements of the dominant consequent matrix is determined to minimize the approximation error function. Then the size of the dominant consequent matrix (the size of the fuzzy rule base) is reduced through the rule combination approach. The scaling factors for the fuzzy controller with the reduced rule table are adjusted to have the control system satisfy the performance indices. The effectiveness of the proposed approach is shown using simulation and experimental results.


The treatment of infectious disease with a medical device: results of a clinical trial of ultraviolet blood irradiation (UVBI) in patients with hepatitis C infection.
Prior to the advent of therapies with sustained virological response rates of 94%, this study was conducted for the US Food and Drug Administration (FDA) to assess the safety and efficacy of ultraviolet blood irradiation (UVBI) for the treatment of hepatitis C virus (HCV) infection. Nine patients received 15 UVBI treatments over the course of 22 weeks with the AVIcure Hemo-modulator, which was modified from the original Knott Hemo-irradiator. The patients' viral loads and liver function tests were obtained periodically during the study and analyzed during the course of the trial. At the end of the study, the overall mean reduction in HCV viral load was 21.5% (p = 0.023); on day 140, direct bilirubin declined by 41.1% (p=0.0059), aspartate aminotransferase declined by 15.2% (p=0.0069), and alanine aminotransferase declined by 19.3% (p=0.0031). The nadir of the mean and median viral load occurred on day 259, and it corresponded to a mean viral load reduction of 44.9% (p=0.0048). During the course of the study, three patients had a greater than 0.5 log reduction in viral load (patient 1, 0.56 log reduction on day 259; patient 4, 0.69 log reduction at the end of the study; patient 11, 0.91 log reduction on day 259). Two patients showed marked improvement in their concurrent psoriasis at the conclusion of the trial. In this study, UVBI was safe and had a beneficial effect in the treatment of HCV. This device should be studied for use in psoriasis and in infectious diseases that have few treatment options. This article describes a prospective, controlled, phase II clinical trial submitted to the FDA of this device used for the treatment of HCV infection (Investigational Device Exemption (IDE) #G030242).


An evolutionary model for the insect vitellins.
Insects can be divided into three groups based on the sizes of the polypeptide constituents of their vitellogenins and vitellins. In order to determine the relationships between these groups, antisera to the vitellins of seven insects from six taxonomic orders were used to assess immunological cross-reactivity. Antigenic relatedness was observed only between vitellins from species within the same family. Amino acid compositional data for vitellins from nine species were used to assess homology by difference matrices. The S delta Q values were similar for both intra-order and inter-order comparisons and strongly suggested relatedness. The S delta n comparisons supported the immunological data that indicated that the vitellins were evolving rapidly. For most insect vitellins there are two distinct size classes of polypeptides that seem to be derived from a single asymmetric proteolytic cleavage of a precursor. We propose a model that suggests that the different size polypeptides represent distinct domains and that in the evolution of the vitellogenin genes of the Diptera and Hymenoptera there has been domain elimination.


Pressure-flow characteristics of /m/ and /p/ production in speakers without cleft palate: developmental findings.
The purpose of this study was to describe the pressure-flow characteristics of a large sample of speakers without cleft palate ranging in age from early childhood to young adulthood. Speakers consisted of 223 children, teens, and adults without cleft palate categorized into five age groups: 6 through 8 years, 9 through 10, 11 through 12, 13 through 16, and 18 through 37 years. Speakers produced the syllables /mi/, /pi/, and /p/¿/, the word "hamper," and the sentence "Peep into the hamper." The pressure-flow method was used to determine oral air pressure, nasal airflow, and estimates of velopharyngeal (VP) orifice size associated with /ml and /p/ production. Descriptive statistics were computed for each age group and speech sample. Analysis of variance (ANOVA) procedures were used to determine the effects of age, sex, and production level (word versus sentence) on the aerodynamic variables. ANOVA procedures indicated significant main effects (p < .01) of age on most of the aerodynamic variables during production of /m/ and /p/. No significant main effects or interactions involving sex were found for any variable. Regardless of age, approximately 95% to 99% of the speakers exhibited airtight VP closure during /p/ at syllable level, depending upon the selected nasal airflow criterion. ANOVA procedures also indicated significant main effects of production level (word versus sentence) on each of the aerodynamic variables during the /mp/ sequence. These effects appeared to be related to speaking rate. The study suggests that speakers without cleft palate exhibit essentially complete VP closure during production of oral pressure consonants in isolated syllables, and developmental aspects of speech aerodynamics be considered during pressure-flow testing.


Brain opioid receptors in the hibernating bat, Myotis lucifugus: modification by low temperature and comparison with rat, mouse and hamster.
Several studies have provided evidence that brain opioid peptides may be involved in the control of the hibernation cycle. We have now examined the influence of hibernation on central opioid receptors. We have characterized the receptor binding properties of [3H]-naloxone in slices of the cerebral cortex and hypothalamus of the bat Myotis lucifugus. These receptors possess those characteristics expected of an opioid site namely high affinity, stereospecificity and saturability. Under normal incubation conditions (30 degrees C) we observed no effect of hibernation on [3H]-naloxone binding. However, when binding assays were performed at temperatures corresponding to the appropriate body temperature (e.g., 4 degrees C for hibernation) we detected a significant low temperature-induced increase in hypothalamic binding. Similar experiments in rat, mouse and hamster revealed that [3H]-naloxone binding was also increased at 4 degrees C when compared to 30 degrees C. This was true in hypothalamus and cortex. Additional studies in the rat demonstrated that the opioid receptor is of higher affinity at low temperatures. The behavioural and neurochemical consequences of this change in the opioid receptor, and whether this might be involved in the regulation of hibernation, remain to be studied.


Enhancement of GABAergic tonic currents by midazolam and noradrenaline in rat substantia gelatinosa neurons in vitro.
Substantia gelatinosa of the spinal dorsal horn is crucial for transmission and modification of noxious stimuli. Previous studies have demonstrated that intrathecal midazolam, a benzodiazepine agonist, enhanced perioperative analgesia. Not only synaptic but also extrasynaptic inhibitory currents contribute to modification of noxious stimuli. Thus, the effects of midazolam on extrasynaptic gamma-aminobutyric acid (GABA) type A receptors in substantia gelatinosa neurons and interaction with noradrenaline, a transmitter of the descending inhibitory systems, were investigated. Using whole cell patch-clamp technique in the adult rat spinal cord slices, extrasynaptic GABAergic currents were recorded in substantia gelatinosa neurons in the presence of gabazine (1 microm), which blocked synaptic GABAergic currents, and then midazolam (5 microm) and noradrenaline (20 microm) were applied. Bath application of midazolam induced tonic outward currents in the presence of gabazine. Although the decay time of synaptic current was prolonged, neither frequency nor amplitude was affected by midazolam. In contrast, the application of noradrenaline markedly increased both frequency and amplitude of synaptic currents with a slight enhancement of tonic currents. Coapplication of noradrenaline and midazolam markedly increased tonic currents, and the increase was much greater than the sum of currents induced by noradrenaline and midazolam. Midazolam had much larger effects on extrasynaptic GABA type A receptors than the synaptic receptors, suggesting a role of the enhancement of GABAergic extrasynaptic currents in the midazolam-induced analgesia. Because noradrenaline is shown to increase extrasynaptic GABA concentration, simultaneous administration of noradrenaline and midazolam may enhance the increased GABA action by midazolam, thereby resulting in an increase in tonic extrasynaptic currents.


Comparative study of lumboperitoneal shunt versus ventriculoperitoneal shunt in post meningitis communicating hydrocephalus in children.
Managing post meningitis hydrocephalus in children is a herculean task for the treating pediatric surgeon or neurosurgeon because of the morbidity associated with the disease per se and the complications of shunt surgery. By this study, the effectiveness of lumboperitoneal (LP) shunt and ventriculoperitoneal (VP) shunt in cases of post meningitis communicating hydrocephalus was assessed in children. This was a retrospective analysis of the records of children admitted in our institute between December 2005 and March 2008. Only children with post meningitis communicating hydrocephalus who underwent either LP or VP with a minimum follow-up period of 36 months were included in the study. Children with non-communicating hydrocephalus or hydrocephalus due to another etiology were excluded. Investigations were included plain brain computed tomography scan, air encephalography and X-ray skull. Medium pressure Chabbra shunt with slit valves was used in all cases of VP and LP shunt. A comparative analysis of the outcome was carried out between the two groups. There were 66 males and 24 females (M: F 2.7:1. The average age at presentation was 40.3 months. LP shunt was performed in 37 while VP shunt in 53 cases Complication rate in the LP and VP shunt was 15% and 29% respectively with non-obstructed complications higher in VP group when compared to LP group. Obstructed complication rate was similar in both groups. Due to less morbidity and ease of placement, LP shunt can be an alternative to VP shunt in cases of communicating hydrocephalus in children, which has more non-obstructed complication rates as compared to LP shunt.


Unsupervised Learning Composite Network to Reduce Training Cost of Deep Learning Model for Colorectal Cancer Diagnosis.
Deep learning facilitates complex medical data analysis and is increasingly being explored in colorectal cancer diagnostics. However, the training cost of the deep learning model limits its real-world medical utility. In this study, we present a composite network that combines deep learning and unsupervised K-means clustering algorithm (RK-net) for automatic processing of medical images. RK-net was more efficient in image refinement compared with manual screening and annotation. The training of a deep learning model for colorectal cancer diagnosis was accelerated by two times with utilization of RK-net-processed images. Better performance was observed in training loss and accuracy achievement as well. RK-net could be useful to refine medical images of the ever-expanding quantity and assist in subsequent construction of the artificial intelligence model.


Cervical spine trauma.
Cervical spine trauma is a common problem with a wide range of severity from minor ligamentous injury to frank osteo-ligamentous instability with spinal cord injury. The emergent evaluation of patients at risk relies on standardized clinical and radiographic protocols to identify injuries; elucidate associated pathology; classify injuries; and predict instability, treatment and outcomes. The unique anatomy of each region of the cervical spine demands a review of each segment individually. This article examines both upper cervical spine injuries, as well as subaxial spine trauma. The purpose of this article is to provide a review of the broad topic of cervical spine trauma with reference to the classic literature, as well as to summarize all recently available literature on each topic. IDENTIFICATION OF REFERENCES FOR INCLUSION: A Pubmed and Ovid search was performed for each topic in the review to identify recently published articles relevant to the review. In addition prior reviews and classic references were evaluated individually for inclusion of classic papers, classifications and previously unidentified references.


Development of two-kidney Goldblatt hypertension in rats under dietary sodium restriction.
In Sprague-Dawley rats with unilateral renal artery stenosis and an intact contralateral kidney, administration of a low-sodium diet did not prevent the development of hypertension. Despite an elevated blood pressure, hyponatremia, marked activation of the renin-angiotensin system, and increased hematocrit values, only 10% of the rats showed lesions of malignant hypertension. Systolic blood pressures of one- and two-kidney sham-operated rats fed a low-sodium diet were significantly higher than that of normotensive controls fed a normal diet. Uninephrectomy did not reduce plasma renin activity. The low-sodium diet increased plasma renin activity to about the same level in one- and two-kidney normotensive rats. However, the increase in plasma renin activity elicited by dietary sodium restriction was markedly less in one-kidney Goldblatt hypertension. Systolic blood pressure reached similar levels in one- and two-kidney Goldblatt hypertensive rats fed a low-sodium diet. These data indicate that a decrease in sodium intake does not prevent the development of two-kidney Goldblatt hypertension.


Simulation-based reconstruction of global bird migration over the past 50,000 years.
Migration is a widespread response of birds to seasonally varying climates. As seasonality is particularly pronounced during interglacial periods, this raises the question of the significance of bird migration during past periods with different patterns of seasonality. Here, we apply a mechanistic model to climate reconstructions to simulate the past 50,000 years of bird migration worldwide, a period encompassing the transition between the last glacial period and the current interglacial. Our results indicate that bird migration was also a prevalent phenomenon during the last ice age, almost as much as today, suggesting that it has been continually important throughout the glacial cycles of recent Earth history. We find however regional variations, with increasing migratory activity in the Americas, which is not mirrored in the Old World. These results highlight the strong flexibility of the global bird migration system and offer a baseline in the context of on-going anthropogenic climate change.


Induced Radioactivity in Lead Shielding at the National Synchrotron Light Source.
The National Synchrotron Light Source (NSLS) at Brookhaven National Laboratory was shut down in September 2014. Lead bricks used as radiological shadow shielding within the accelerator were exposed to stray radiation fields during normal operations. The FLUKA code, a fully integrated Monte Carlo simulation package for the interaction and transport of particles and nuclei in matter, was used to estimate induced radioactivity in this shielding and stainless steel beam pipe from known beam losses. The FLUKA output was processed using MICROSHIELD® to estimate on-contact exposure rates with individually exposed bricks to help design and optimize the radiological survey process. This entire process can be modeled using FLUKA, but use of MICROSHIELD® as a secondary method was chosen because of the project's resource constraints. Due to the compressed schedule and lack of shielding configuration data, simple FLUKA models were developed. FLUKA activity estimates for stainless steel were compared with sampling data to validate results, which show that simple FLUKA models and irradiation geometries can be used to predict radioactivity inventories accurately in exposed materials. During decommissioning 0.1% of the lead bricks were found to have measurable levels of induced radioactivity. Post-processing with MICROSHIELD® provides an acceptable secondary method of estimating residual exposure rates.


Regulation of postocclusive hyperemia by endogenously synthesized prostaglandins in the dog heart.
Experiments were performed to evaluate the role of prostaglandin synthesis in the regulation of coronary blood flow in dog hearts. The left main coronary artery was cannulated and flow measured both in otherwise intact animals and in canine heart-lung preparations. Prostaglandin E was measured by radioimmunoassay. Reactive hyperemia (flow after occlusion release) was induced by coronary occlusion for 10, 15, and 20 s and was 39 plus or minus 13 (mean plus or minus SEM), 66 plus or minus 21, and 82 plus or minus 24 ml, respectively. Indomethacin, an inhibitor of prostaglandin synthetase, reduced reactive hyperemia at 10, 15, and 20 s to 15 plus or minus 5, 33 plus or minus 11, and 47 plus or minus 17 ml, respectively (P smaller than 0.05). Meclofenamate, a different prostaglandin synthetase inhibitor, gave similar results. In a second group of five dogs, prostaglandin production of the heart was examined in response to 20-s occlusions. There was a significant increase in prostaglandin production from a basal level of 18.6 plus or minus 4.9 mg/min to 35.3 plus or minus 5.8 ng/min after occlusion of the coronary artery for 20 s (P smaller than 0.05). After indomethacin, this increase in prostaglandin production was not observed and reactive hyperemia was significantly reduced. Thus, prostaglandin synthesis appears to be important to modulating canine coronary blood flow in response to brief periods of coronary occlusion.


[Effects of different electrofusion parameters on activation and early development of mouse embryos reconstructed by cumulus cell nuclear transfer].
To study the effects of different parameters for electrofusion on the activation and early development of mouse embryos reconstructed by cumulus cell nuclear transfer, and explore optimal parameters for electrofusion. A C57BL/6j mouse cumulus cell nucleus 10-12 mm in diameter was inserted into the perivitelline space of an enucleated oocyte. The fusion of donor-recipient pairs was induced with different parameters for electrofusion (with variation in electric field intensity, pulse duration and pulse times). Successful formation of the reconstructed embryos from donor-recipient pairs and the reconstructed embryos developing into the early embryonic stages (2-cell, 4-8-cell and morula stages) were observed and counted. The electric field intensity and pulse duration allowed variation during electrofusion within the range of 1 000-2 000 kV/cm and 40-160 ms, respectively. The donor-recipient pairs fused at very low rate when the parameters were below the allowed ranges, and disintegration or even death might occur when the parameters were above the ranges. Within these allowed ranges, variation of the electrofusion parameters did not produce significant impact on the ratio of the reconstructed embryos in 2-cell, 4-8-cell or morula stages (P<0.05). In addition, we suggested that pulse times be limited to 1-2. Optimal parameters for electrofusion are crucial for the fusion of donor-recipient pairs and the activation of the reconstructed embryo.


Circulating Tumor DNA Assays in Clinical Cancer Research.
The importance of circulating free DNA (cfDNA) in cancer clinical research was recognized in 1994 when a mutated RAS gene fragment was detected in a patient's blood sample. Up to 1% of the total circulating DNA in patients with cancer is circulating tumor DNA (ctDNA) that originates from tumor cells. As ctDNA is rapidly cleared from the blood stream and can be obtained by minimally invasive methods, it can be used as a dynamic cancer biomarker for cancer early detection, diagnosis, and treatment monitoring. Despite the potential for clinical use, few ctDNA assays have been cleared or approved by the US Food and Drug Administration. As tools for clinical and translational research, current ctDNA assays face some challenges, and more research is needed to advance use of these assays. On September 29-30, 2016, the Division of Cancer Treatment and Diagnosis at the National Cancer Institute convened a workshop entitled "Circulating Tumor DNA Assays in Clinical Cancer Research" to garner input from industry experts, academia, and government research and regulatory agencies to understand and promote the translation of ctDNA assays to clinical research, with potential to advance to use in clinical practice. This Commentary presents the topics of the workshop covered in the presentations and points made in the discussions that followed: 1) background on ctDNA, 2) potential clinical utility of ctDNA assays, 3) assay technology, 4) assay clinical and analytical validation, and 5) industry perspectives. Additional relevant information that has come to light since the workshop has been included.


Development and psychometric properties of the Inner Strength Scale.
Four dimensions of inner strength were previously identified in a meta-theoretical analysis: firmness, creativity, connectedness, and flexibility. The aim of this study was to develop an Inner Strength Scale (ISS) based on those four dimensions and to evaluate its psychometric properties. An initial version of ISS was distributed for validation purpose with the Rosenberg Self-Esteem Scale, the resilience scale, and the sense of Coherence Scale. A convenience sample of 391 adults, aged 19-90 years participated. Principal component analysis (PCA) and confirmatory factor analysis (CFA) were used in the process of exploring, evaluating, and reducing the 63-item ISS to the 20-item ISS. Cronbach's alpha and test-retest were used to measure reliability. CFA showed satisfactory goodness-of-fit for the 20-item ISS. The analysis supported a fourfactor solution explaining 51% of the variance. Cronbach's alpha on the 20-item ISS was 0.86, and the test-retest showed stability over time (r=0.79). The ISS was found to be a valid and reliable instrument for capturing a multifaceted understanding of inner strength. Further tests of psychometric properties of the ISS will be performed in forthcoming studies.


Non-Hodgkin's Lymphoma Presenting as Isolated Peritoneal Lymphomatosis: A Case Report and Literature Review.
Peritoneal lymphomatosis is extremely rare and associated with poor prognosis. Most practitioners only pay more attention to peritoneal carcinomatosis. However, peritoneal lymphomatosis can be neglected and misdiagnosed. We report a teenager with 10 days of abdominal distension and pain accompanied by computed tomography scan suggesting diffuse thickening of the peritoneum and omentum and abdominopelvic effusion. Tuberculous peritonitis and peritoneal carcinomatosis were initially suspected. However, it was finally confirmed as non-Hodgkin's B-cell lymphoma by omentum biopsies. He achieved complete remission after chemotherapy and autologous stem cell transplantation. But unfortunately, he suffered a relapse and died 10 months after diagnosis. Following a review of the literature, it can be concluded that the discovery of lymphomatosis in peritoneum is a rare finding. Lymphoma should be considered in the differential diagnosis of unexplained peritoneal thickening on computed tomography, and this case emphasizes the importance of early pathological diagnosis to make sure that the right treatment can be started opportunely.


Putrid gums and 'dead men's cloaths': James Lind aboard the Salisbury.
18th century sailors often suffered from scurvy. In 1747 James Lind conducted his classic experiments aboard the Salisbury, in which he cured scurvy with oranges and lemons. The Royal Navy did not introduce citrus rations until 1795. The original ship's papers allow the circumstances of the experiment to be reconstructed. The relevant patrol began in March 1747, and Lind's experiment began after 8 weeks at sea. The muster roll records almost no sickness aboard until the ship returned to Plymouth in June. This is at odds with Lind's account and suggests an antisickness official culture, which may have contributed to the neglect of his work.


Injury of the renal microvascular endothelium alters barrier function after ischemia.
The role of renal microvascular endothelial cell injury in the pathophysiology of ischemic acute renal failure (ARF) remains largely unknown. No consistent morphological alterations have been ascribed to the endothelium of the renal microvasculature as a result of ischemia-reperfusion injury. Therefore, the purpose of this study was to examine biochemical markers of endothelial injury and morphological changes in the renal microvascular endothelium in a rodent model of ischemic ARF. Circulating von Willebrand factor (vWF) was measured as a marker of endothelial injury. Twenty-four hours after ischemia, circulating vWF peaked at 124% over baseline values (P = 0.001). The FVB-TIE2/GFP mouse was utilized to localize morphological changes in the renal microvascular endothelium. Immediately after ischemia, there was a marked increase in F-actin aggregates in the basal and basolateral aspect of renal microvascular endothelial cells in the corticomedullary junction. After 24 h of reperfusion, the pattern of F-actin staining was more similar to that observed under physiological conditions. In addition, alterations in the integrity of the adherens junctions of the renal microvasculature, as demonstrated by loss of localization in vascular endothelial cadherin immunostaining, were observed after 24 h of reperfusion. This observation temporally correlated with the greatest extent of permeability defect in the renal microvasculature as identified using fluorescent dextrans and two-photon intravital imaging. Taken together, these findings indicate that renal vascular endothelial injury occurs in ischemic ARF and may play an important role in the pathophysiology of ischemic ARF.


An evidence-based narrative review of the emergency department evaluation and management of rhabdomyolysis.
Rhabdomyolysis is a medical condition caused by muscle breakdown leading to potential renal damage. This can result in significant morbidity and mortality if not rapidly identified and treated. This article provides an evidence-based narrative review of the diagnosis and management of rhabdomyolysis, with focused updates for the emergency clinician. Rhabdomyolysis is caused by the breakdown of muscle cells leading to the release of numerous intracellular molecules, including potassium, calcium, phosphate, uric acid, and creatinine kinase. There are a number of potential etiologies, including exertion, extreme temperature changes, ischemia, infections, immobility, drugs, toxins, endocrine causes, autoimmune reactions, trauma, or genetic conditions. Findings can include myalgias, muscle weakness, or dark-colored urine, but more often include non-specific symptoms. The diagnosis is often determined with an elevated creatinine kinase greater than five times the upper-limit of normal. Severe disease may result in renal failure, electrolyte derangements, liver disease, compartment syndrome, and disseminated intravascular coagulation. Treatment includes addressing the underlying etiology, as well as aggressive intravenous hydration with a goal urine output of 300 mL/h. Bicarbonate, mannitol, and loop diuretics do not possess strong evidence for improved outcomes. Renal replacement therapy should be determined on a case-by-case basis. Most patients are admitted, though some may be appropriate for discharge. Rhabdomyolysis is a potentially dangerous medical condition requiring rapid diagnosis and management that may result in significant complications if not appropriately identified and treated. Emergency clinician knowledge of this condition is essential for appropriate management.


Photodissociation dynamics of ClCN at different wavelengths.
The photodissociation dynamics of small molecules in the gas and condensed phase is an important source of information for better characterizing intermolecular interactions. Herein, classical molecular dynamics simulations with provisions to follow reactive processes between different electronic states are used to probe the wavelength dependence of product state distributions after laser excitation of ClCN. It is found that the maximum of the rotational excitation distribution P(j) of the CN product shifts to lower j-values with increasing wavelength and the width of the distribution narrows. Both observations are in accord with earlier experiments and provide improvements over previous theoretical treatments of the process with the same interaction potentials. For the reaction in a water droplet, strong quenching of rotational excitation is found.


Selective depletion of dopamine in the goldfish pituitary caused by domperidone.
The effects of the dopamine type-2 receptor (D-2) antagonist domperidone on pituitary and brain amine concentrations and serum gonadotropin levels in the goldfish were investigated. Domperidone caused a long-lasting, dose-dependent depletion of dopamine in the goldfish pituitary. Pituitary concentrations of 5-hydroxytryptamine (5HT) were unaffected by domperidone treatment. Concentrations of noradenaline, dopamine, and 5HT in the hypothalamus and telencephalon were also unaffected by domperidone treatment. In contrast to the goldfish, dopamine levels in both mouse pituitary and hypothalamus were unaffected by domperidone treatment. The depletion of dopamine was observed in both sexually regressed and recrudescent, male and female fish, but elevation of serum gonadotropin levels in response to domperidone treatment occurred only in sexually recrudescent fish. Treatment of sexually recrudescent fish with the D-2 antagonists pimozide, (-)-sulpiride and eticlopride and the dopamine type-1 (D-1) antagonists SKF 83566 and SCH 23390 failed to elicit a depletion of pituitary dopamine or elevation of serum gonadotropin. Treatment of sexually recrudescent fish with domperidone, alpha-methyl-p-tyrosine or carbidopa elicited comparable depletions of pituitary dopamine and elevations of serum gonadotropin. The results suggest that in addition to D-2 receptor antagonist activity, domperidone has some other neuropharmacological action on dopaminergic neurones in the goldfish pituitary.


PM10 and Pseudomonas aeruginosa: effects on corneal epithelium.
In vivo data indicate that mouse corneas exposed to PM10 showed early perforation and thinning after infection with Pseudomonas aeruginosa. To understand the mechanisms underlying this finding, we tested the effects of PM10 and the mitochondria targeted anti-oxidant SKQ1 in immortalized human corneal epithelial cells (HCET) that were challenged with Pseudomonas aeruginosa strain 19660. Mouse corneas were infected with strain 19660 after a 2 week whole-body exposure to PM10 or control air and assessed by clinical scores, slit lamp photography and western blot. HCET were exposed to 100μg/ml PM10 for 24h before challenge with strain 19660 (MOI 20). A subset of cells were pre-treated with 50nM SKQ1 for 1h before PM10 exposure. Phase contrast microscopy was used to study cell morphology, cell viability was measured by an MTT assay, and ROS by DCFH-DA. Levels of pro-inflammatory markers and anti-oxidant enzymes were evaluated by RT-PCR, western blot and ELISA. Reduced glutathione (GSH) and malondialdehyde (MDA) levels were evaluated by assay kits. In vivo, whole body exposure to PM10 vs. control air exposed mouse corneas showed early perforation and/or corneal thinning at 3 days post infection, accompanied by increased TNF-α and decreased SOD2 protein levels. In vitro, PM10 induced a dose dependent reduction in cell viability of HCET and significantly increased mRNA levels of pro-inflammatory molecules compared to control. Exposure to PM10 before bacterial challenge further amplified the reduction in cell viability and GSH levels. Furthermore, PM10 exposure also exacerbated the increase in MDA and ROS levels and phase contrast microscopy revealed more rounded cells after strain 19660 challenge. PM10 exposure also further increased the mRNA and protein levels of pro-inflammatory molecules, while anti-inflammatory IL-10 was decreased. SKQ1 reversed the rounded cell morphology observed by phase contrast microscopy, increased levels of MDA, ROS and pro-inflammatory molecules, and restored IL-10. PM10 induces decreased cell viability, oxidative stress and inflammation in HCET and has an additive effect upon bacterial challenge. SKQ1 protects against oxidative stress and inflammation induced by PM10 after bacterial challenge by reversing these effects. The findings provide insight into mechanisms underlying early perforation and thinning observed in infected corneas of PM10 exposed mice.


Physics-Driven Deep Learning for Computational Magnetic Resonance Imaging: Combining physics and machine learning for improved medical imaging.
Physics-driven deep learning methods have emerged as a powerful tool for computational magnetic resonance imaging (MRI) problems, pushing reconstruction performance to new limits. This article provides an overview of the recent developments in incorporating physics information into learning-based MRI reconstruction. We consider inverse problems with both linear and non-linear forward models for computational MRI, and review the classical approaches for solving these. We then focus on physics-driven deep learning approaches, covering physics-driven loss functions, plug-and-play methods, generative models, and unrolled networks. We highlight domain-specific challenges such as real- and complex-valued building blocks of neural networks, and translational applications in MRI with linear and non-linear forward models. Finally, we discuss common issues and open challenges, and draw connections to the importance of physics-driven learning when combined with other downstream tasks in the medical imaging pipeline.


Sex differences in renal transporters: assessment and functional consequences.
Mammalian kidneys are specialized to maintain fluid and electrolyte homeostasis. The epithelial transport processes along the renal tubule that match output to input have long been the subject of experimental and theoretical study. However, emerging data have identified a new dimension of investigation: sex. Like most tissues, the structure and function of the kidney is regulated by sex hormones and chromosomes. Available data demonstrate sex differences in the abundance of kidney solute and electrolyte transporters, establishing that renal tubular organization and operation are distinctly different in females and males. Newer studies have provided insights into the physiological consequences of these sex differences. Computational simulations predict that sex differences in transporter abundance are likely driven to optimize reproduction, enabling adaptive responses to the nutritional requirements of serial pregnancies and lactation - normal life-cycle changes that challenge the ability of renal transporters to maintain fluid and electrolyte homeostasis. Later in life, females may also undergo menopause, which is associated with changes in disease risk. Although numerous knowledge gaps remain, ongoing studies will provide further insights into the sex-specific mechanisms of sodium, potassium, acid-base and volume physiology throughout the life cycle, which may lead to therapeutic opportunities.


Pulmonary vs nonpulmonary sepsis and mortality in acute lung injury.
Acute lung injury (ALI) is a frequent complication of sepsis. It is unclear if a pulmonary vs nonpulmonary source of sepsis affects mortality in patients with sepsis-induced ALI. Two hundred eighty-eight consecutive patients with sepsis-induced ALI from 14 ICUs at four hospitals in Baltimore, MD were prospectively classified as having a pulmonary vs nonpulmonary source of sepsis. Multiple logistic regression was conducted to evaluate the independent association of a pulmonary vs nonpulmonary source of sepsis with inpatient mortality. In an unadjusted analysis, in-hospital mortality was lower for pulmonary vs nonpulmonary source of sepsis (42% vs 66%, p < 0.0001). Patients with pulmonary sepsis had lower acute physiology and chronic health evaluation (APACHE) II and sequential organ failure assessment (SOFA) scores, shorter ICU stays prior to the development of ALI, and higher lung injury scores. In the adjusted analysis, several factors were predictive of mortality: age (odds ratio [OR], 1.03; 95% confidence interval [CI], 1.01 to 1.06), Charlson comorbidity index (OR, 1.15; 95% CI, 1.02 to 1.30), ICU length of stay prior to ALI diagnosis (OR, 1.19; 95% CI, 1.01 to 1.39), APACHE II score (OR, 1.07; 95% CI, 1.03 to 1.12), lung injury score (OR, 1.64; 95% CI, 1.11 to 2.43), SOFA score (OR, 1.15; 95% CI, 1.06 to 1.26), and cumulative fluid balance in the first 7 days after ALI diagnosis (OR, 1.06; 95% CI, 1.03 to 1.10). A pulmonary vs nonpulmonary source of sepsis was not independently associated with mortality (OR, 0.72; 95% CI, 0.38 to 1.35). Although lower mortality was observed for ALI patients with a pulmonary vs nonpulmonary source of sepsis, this finding is likely due to a lower severity of illness in those with pulmonary sepsis. Pulmonary vs nonpulmonary source of sepsis was not independently predictive of mortality for patients with ALI.


Modern Medical Consequences of the Ancient Evolution of a Long, Flexible Lumbar Spine.
Modern human bipedality is unique and requires lumbar lordosis, whereas chimpanzees, our closest relatives, have short lumbar spines rendering them incapable of lordosis. To facilitate lordosis, humans have longer lumbar spines, greater lumbosacral angle, dorsally wedged lumbar vertebral bodies, and lumbar zygapophyseal joints with both increasingly coronal orientation and further caudal interfacet distances. These features limit modern lower lumbar spine and lumbosacral joint ailments, albeit imperfectly. The more coronal zygapophyseal orientation limits spondylolisthesis, while increasing interfacet distance may limit spondylolysis. Common back pain, particularly in people who are obese or pregnant, may result from increased lumbar lordosis, causing additional mass transfer through the zygapophyseal joints rather than vertebral bodies. Reduction in lumbar lordosis, such as in flatback syndrome from decreased lumbosacral angle, can also cause back pain. Human lumbar lordosis is necessary for placing the trunk atop the pelvis and presents a balancing act not required of our closest primate relatives.


Importance of genetic factors influencing the metabolism of foreign compounds.
Gene differences may alter an individual's response to foreign compounds by affecting their absorption, binding, distribution, excretion, biotransformation, or drug-drug interactions. Genetic differences in the metabolism of xenobiotics among inbred strains of various laboratory animals and model systems are reviewed. The inbred mouse has been studied most extensively. Genetic differences in toxicity are shown to be caused by various environmental pollutants in several inbred strains of mice and in siblings of the (C57BL/6N)(DBA/2N)F1 X DBA/2N backcross, in which the phenotypes "aromatic hydrocarbon responsiveness" or "nonresponsiveness" had been predetermined. This trait of "responsiveness"--which refers to the capacity for induction of cytochrome P1450 and numerous monooxygenase activities by certain aromatic compounds--segregates almost exclusively as a single gene among offspring of this backcross. All nonresponsive mice ingesting benzo/a/pyrene (about 125 mg/kg per day) die within 4 weeks, whereas the survival of responsive mice receiving the chemical orally is not significantly different from that of control mice; the apparent cause of early death in these experiments in toxic depression of the bone marrow. The life span of animals exposed to certain environmental pollutants can therefore be markedly influenced by a single gene or a very small number of genes. The same genetic trait can be either beneficial or detrimental to the animal, depending on whether detoxification or metabolic potentiation occurs. There also may exist genetic differences in man's susceptibility to toxicity or cancer caused by the numerous foreign compounds in his environment.


Lead accumulation and tolerance of Moso bamboo (Phyllostachys pubescens) seedlings: applications of phytoremediation.
A hydroponics experiment was aimed at identifying the lead (Pb) tolerance and phytoremediation potential of Moso bamboo (Phyllostachys pubescens) seedlings grown under different Pb treatments. Experimental results indicated that at the highest Pb concentration (400 μmol/L), the growth of bamboo seedlings was inhibited and Pb concentrations in leaves, stems, and roots reached the maximum of 148.8, 482.2, and 4282.8 mg/kg, respectively. Scanning electron microscopy revealed that the excessive Pb caused decreased stomatal opening, formation of abundant inclusions in roots, and just a few inclusions in stems. The ultrastructural analysis using transmission electron microscopy revealed that the addition of excessive Pb caused abnormally shaped chloroplasts, disappearance of endoplasmic reticulum, shrinkage of nucleus and nucleolus, and loss of thylakoid membranes. Although ultrastructural analysis revealed some internal damage, even the plants exposed to 400 µmol/L Pb survived and no visual Pb toxicity symptoms such as necrosis and chlorosis were observed in these plants. Even at the highest Pb treatment, no significant difference was observed for the dry weight of stem compared with controls. It is suggested that use of Moso bamboo as an experimental material provides a new perspective for remediation of heavy metal contaminated soil owing to its high metal tolerance and greater biomass.


Antimicrobial resistance profiles of Listeria monocytogenes isolated from chicken meat in Fukuoka, Japan.
In this study, the antimicrobial resistance profiles of L. monocytogenes isolated from chicken meat in Fukuoka in 2017 were compared with the isolates of 2012. A total of 85 and 50 chicken meat samples, including different body parts, were collected from different supermarkets in Fukuoka in 2012 and 2017, respectively. Detection, isolation, identification, and characterization of L. monocytogenes were performed according to the conventional methods. Forty-five among 85 samples (53%) were positive for L. monocytogenes in 2012, while 12 among 50 samples in 2017 (24%) tested positive. One hundred fifty-three and 29 L. monocytogenes strains were isolated in 2012 and 2017, respectively. The serotypes of isolates in 2012 were 1/2a (21.5%), 1/2b (73.9%), 1/2c (1.5%), and 4b/4e (3.1%). In contrast, the 2017 isolates showed 1/2a (48.3%) and 1/2b (51.7%) serotypes. While all isolates in 2012 were positive for hlyA (listeriolysin O) in the PCR assay with hlyA primer set 7, only 17 hlyA positive isolates were seen in 2017. Moreover, 75 isolates with different ribotypes in 2012 and 29 isolates in 2017, respectively, were tested for antimicrobial susceptibility by broth microdilution for 18 different antimicrobial agents. Most of the 2012 and 2017 isolates displayed antimicrobial susceptibility. However, among the 2012 and 2017 isolates, 98.7% and 100% of the isolates were resistant to cefoxitin, 57.3% and 95.7% to fosfomycin, 72.0% and 82.6% to oxacillin, 8.0% and 17.4% to clindamycin, respectively. In addition, 2.7% of the isolates in 2012 were resistant to flomoxef and 4.3% of the isolates in 2017 to linezolid. Multidrug resistance (MDR) to 3 or more antimicrobials was observed in 35/75 (46.7%) isolates of 2012 and 19/23 (82.6%) in 2017. Detection of antimicrobial resistance (AMR) genes by PCR showed that the resistant isolates of 2012 were positive for mecA (96.3%) and ermC (83.3%), whereas the resistant isolates in 2017 screened positive for mecA (94.7%) and mefA (25.0%). Other cfxA, ermA, ermB, fosA, fosB, and fosC genes were absent in the PCR assay for any of the isolates. This study investigated for the first time the change in the L. monocytogenes contamination of chicken meat and antibiotic resistance of the isolated L. monocytogenes strains in Fukuoka, Japan, in the course of 5 years. Although the contamination rate of L. monocytogenes in 2017 was found to be lower than that in 2012, AMR of the isolates in 2017 was higher.


Fatty acid composition transport and metabolism in doxorubicin-sensitive and-resistant rat glioblastoma cells.
We have studied the lipid composition and the acyl group composition, transport, and metabolism of doxorubicin-sensitive and -resistant rat glioblastoma cells in monolayer cultures (C6 clone). No difference in lipid composition was evidenced; the acyl group composition was, in contrast, highly modified in resistant cells, and these modifications appeared progressively during the acquisition of the resistance. Resistant cells were characterized by a decrease of n-9 eicosatrienoic acid and by a 2-3-fold increase of the proportions of the polyunsaturated fatty acids of the n-6 and n-3 families, especially arachidonic acid and n-3 docosahexaenoic acid. These differences were probably due to a 2-fold increase of the uptake of fatty acids by resistant cells as compared to sensitive cells, this increase allowing the suppression of an essential fatty acid deficiency. Only small changes in the transformations of 16 and 18-carbon atoms' fatty acids to higher analogues were evidenced. A small reduction of the desaturation of stearic acid to oleic acid and of linoleic acid to arachidonic acid was the main characteristic of resistant cells; these differences can be explained as a consequence of the suppression of the essential fatty acid deficiency.