Peer reviewers equally critique theory, method, and writing, with limited effect on the final content of accepted manuscripts.
The primary aims of peer review are to detect flaws and deficiencies in the design and interpretation of studies, and ensure the clarity and quality of their presentation. However, it has been questioned whether peer review fulfils this function. Studies have highlighted a stronger focus of reviewers on critiquing methodological aspects of studies and the quality of writing in biomedical sciences, with less focus on theoretical grounding. In contrast, reviewers in the social sciences appear more concerned with theoretical underpinnings. These studies also found the effect of peer review on manuscripts' content to be variable, but generally modest and positive. I qualitatively analysed 1430 peer reviewers' comments for a sample of 40 social science preprint-publication pairs to identify the key foci of reviewers' comments. I then quantified the effect of peer review on manuscripts by examining differences between the preprint and published versions using the normalised Levenshtein distance, cosine similarity, and word count ratios for titles, abstracts, document sections and full-texts. I also examined changes in references used between versions and linked changes to reviewers' comments. Reviewers' comments were nearly equally split between issues of methodology (30.7%), theory (30.0%), and writing quality (29.2%). Titles, abstracts, and the semantic content of documents remained similar, although publications were typically longer than preprints. Two-thirds of citations were unchanged, 20.9% were added during review and 13.1% were removed. These findings indicate reviewers equally attended to the theoretical and methodological details and communication style of manuscripts, although the effect on quantitative measures of the manuscripts was limited. The online version contains supplementary material available at 10.1007/s11192-022-04357-y.


Chronic disaster syndrome: Displacement, disaster capitalism, and the eviction of the poor from New Orleans.
Many New Orleans residents who were displaced in 2005 by Hurricanes Katrina and Rita and the subsequent levee failures and floods are still displaced. Living with long-term stress related to loss of family, community, jobs, and social security as well as the continuous struggle for a decent life in unsettled life circumstances, they manifest what we are calling "chronic disaster syndrome." The term refers not only to the physiological and psychological effects generated at the individual level by ongoing social disruption but also to the nexus of socioeconomic and political conditions that produce this situation as a long-term and intractable problem. Chronic disaster syndrome emerges from the convergence of three phenomena that create a nexus of displacement: long-term effects of personal trauma (including near loss of life and loss of family members, homes, jobs, community, financial security, and well-being); the social arrangements that enable the smooth functioning of what Naomi Klein calls "disaster capitalism," in which "disaster" is prolonged as a way of life; and the permanent displacement of the most vulnerable populations from the social landscape as a perceived remedy that actually exacerbates the syndrome.


Diagnosis of diffuse malignant infiltration of lung (lymphangitic carcinomatosis) by percutaneous fine-needle aspiration biopsy.
The diagnosis of diffuse malignant infiltration of lung is often made with certainty only by open lung biopsy or at autopsy. However, the clinical presentation and radiological examination are often sufficiently characteristic to suggest the diagnosis. Percutaneous fine-needle aspiration biopsy (PFNAB) has been reserved mainly for the diagnosis of focal lesions of lung and has been reported not to be useful in the diagnosis of diffuse lung disease, especially when the latter is mainly interstitial. We report 15 patients with radiologically diagnosed diffuse interstitial infiltration of lung, 13 of whom had lymphangitic carcinomatosis either on clinical follow-up, cytological or pathological examination. Cytology by percutaneous fine-needle aspiration biopsy was positive for malignant cells in 11 of the 13 patients. We propose that PFNAB be used early in investigation when the clinical and radiological findings suggest that a patient has diffuse malignant interstitial lung infiltration.


High risk of primary liver cancer in a cohort of 179 patients with Acute Hepatic Porphyria.
Previous studies have indicated a high risk of hepatocellular carcinoma in acute hepatic porphyrias. In this retrospective study we present the incidence of primary liver cancer and clinical characteristics in a cohort of 179 acute porphyria patients above the age of 50 years. Twenty-three cases with primary liver cancer were found either by a surveillance program or due to clinical suspicion. Standardized rate ratio was used to estimate the relative risk of primary liver cancer after indirect standardization. Survival data were calculated using the Kaplan-Meier method. The mean age at diagnosis was 69 years. Hepatocellular carcinoma was found in 19 patients while four patients had cholangiocarcinoma or a combination of the two. Four patients had underlying cirrhosis. Mean tumour size was 4.3 cm in the surveillance group and 10.3 cm in the non-surveillance group (p = 0.01). The overall relative risk of primary liver cancer was 86 above the age of 50: 150 for women and 37 for men. Mean survival time was 5.7 years. Acute hepatic porphyria carries a high risk of primary liver cancer above the age of 50 which warrants ultrasound surveillance. Sex distribution and frequency of cirrhosis differs from more common aetiologies of primary liver cancer.


Early gastric cancer in the province of Forlì: follow-up of 337 patients in a high risk region for gastric cancer.
Long-term clinical outcome was analysed in a series of 337 patients with early gastric cancer (EGC) at a median follow-up of 8 years. Tumours were classified according to the macroscopic and microscopic criteria proposed by the Japanese society of gastroenterological endoscopy (JSGE) and Lauren, respectively. Type of penetration (PEN) was classified according to Kodama. Overall survival rate was 92% at 5 years and 88% at 8 years and was significantly related to depth, type of penetration, lymph node status and tumour size. A significantly lower 5-year survival (p<0.05) was observed for patients with lymph node metastases and PEN A type EGC (55%) or for those with node-positive tumours and submucosal wall penetration (58%) than for the other pathologic subgroups. Therefore, these two subgroups should be considered as advanced gastric cancer patients from the prognostic point of view. Moreover, multivariate analysis by Cox regression model showed the degree of lymph node involvement and Kodama's type PEN A as the only independent prognostic factors.


Association between Term Equivalent Brain Magnetic Resonance Imaging and 2-Year Outcomes in Extremely Preterm Infants: A Report from the Preterm Erythropoietin Neuroprotection Trial Cohort.
To compare the term equivalent brain magnetic resonance imaging (MRI) findings between erythropoietin (Epo) treated and placebo control groups in infants 240/7-276/7 weeks of gestational age and to assess the associations between MRI findings and neurodevelopmental outcomes at 2 years corrected age. The association between brain abnormality scores and Bayley Scales of Infant Development, Third Edition at 2 years corrected age was explored in a subset of infants enrolled in the Preterm Erythropoietin Neuroprotection Trial. Potential risk factors for neurodevelopmental outcomes such as treatment assignment, recruitment site, gestational age, inpatient complications, and treatments were examined using generalized estimating equation models. One hundred ten infants were assigned to Epo and 110 to placebo groups. 27% of MRI scans were rated as normal, and 60%, 10%, and 2% were rated as having mild, moderate, or severe abnormality. Brain abnormality scores did not significantly differ between the treatment groups. Factors that increased the risk of higher brain injury scores included intubation; bronchopulmonary dysplasia; retinopathy of prematurity; opioid, benzodiazepine, or antibiotic treatment >7 days; and periventricular leukomalacia or severe intraventricular hemorrhage diagnosed on cranial ultrasound. Increased global brain abnormality and white matter injury scores at term equivalent were associated with reductions in cognitive, motor, and language abilities at 2 years of corrected age. Evidence of brain injury on brain MRIs obtained at term equivalent correlated with adverse neurodevelopmental outcomes as assessed by the Bayley Scales of Infant and Toddler Development, Third Edition at 2 years corrected age. Early Epo treatment had no effect on the MRI brain injury scores compared with the placebo group.


Advantages of voice reproduction and the development of a biomimetic self-regulating double-clack valve for a prosthesis of the larynx--a feasibility study.
The human larynx is a versatile organ. Main functions are phonation, protection and regulation of the air ways. Patients suffer severely from the diagnosis of a laryngeal carcinoma of the stages T3 and T4. In most cases this diagnosis will lead to a total laryngectomy, which is usually dissatisfying in the sense of postoperative rehabilitation. The postoperative consequences include the loss of the native voice, the loss of regular air ways via mouth and nose, sense of smell, and the inability to build up an abdominal pressure. In this paper we focus on the feasibility of a modular larynx prosthesis which enables the laryngectomee to talk with his native voice, to breathe via the regular air ways, and to build up abdominal pressure. In particular we will give insights for a postoperative solution - a modular prosthesis based on a biomimetic self-regulating double clack-valve and on a voice reconstruction module, a so called vocoder. The vocoder is a device to reproduce the natural human voice. Most important for the use is an additional device required to analyze, conserve and manage voice characteristics of the patient before surgery. The self-regulating double clack-valve is designed to build up an abdominal pressure e.g. to cough. Therefore, our valve-system is working in both directions - a two-way valve system. By bridging the gap of the regular air ways lost by laryngectomy, the sense of smell and taste are restored. In the following we will present details and characteristics of these two main components required for a modular prosthesis of the larynx in laryngectomees.


Charged pore-lining residues are required for normal channel kinetics in the eukaryotic mechanosensitive ion channel MSL1.
Mechanosensitive (MS) ion channels are widespread mechanisms for cellular mechanosensation that can be directly activated by increasing membrane tension. The well-studied MscS family of MS ion channels is found in bacteria, archaea, and plants. MscS-Like (MSL)1 is localized to the inner mitochondrial membrane of Arabidopsis thaliana, where it is required for normal mitochondrial responses to oxidative stress. Like Escherichia coli MscS, MSL1 has a pore-lining helix that is kinked. However, in MSL1 this kink is comprised of two charged pore-lining residues, R326 and D327. Using single-channel patch-clamp electrophysiology in E. coli, we show that altering the size and charge of R326 and D327 leads to dramatic changes in channel kinetics. Modest changes in gating pressure were also observed while no effects on channel rectification or conductance were detected. MSL1 channel variants had differing physiological function in E. coli hypoosmotic shock assays, without clear correlation between function and particular channel characteristics. Taken together, these results demonstrate that altering pore-lining residue charge and size disrupts normal channel state stability and gating transitions, and led us to propose the "sweet spot" model. In this model, the transition to the closed state is facilitated by attraction between R326 and D327 and repulsion between R326 residues of neighboring monomers. In the open state, expansion of the channel reduces inter-monomeric repulsion, rendering open state stability influenced mainly by attractive forces. This work provides insight into how unique charge-charge interactions can be combined with an otherwise conserved structural feature to help modulate MS channel function.


Psychiatric Care of the Post-September 11 Combat Veteran: A Review.
Post-September 11, 2001 combat veterans represent a growing cohort of patients with unique mental health needs, particularly around post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI). The United States (US) remains engaged in conflicts around the globe, so this patient cohort will continue to grow in number. With around 40% of American combat veterans from Iraq and Afghanistan seeking mental health care outside of the Veterans Affairs, understanding the psychiatric needs of the post-September 11 combat veteran is an important goal for all psychiatrists. These patients are relevant to consultation-liaison (C-L) psychiatrists because of their high comorbidity of conditions such as TBI, obstructive sleep apnea, insomnia, and chronic pain. This article reviews the current literature on mental health care for the post-September 11 combat veteran, emphasizing PTSD and TBI treatment, and culling evidence-based recommendations from randomized controlled trials of combat veterans. Emphasis is also placed on the Veterans Affairs/Department of Defense Clinical Practice Guidelines. The authors also bring unique clinical expertise of having served on active duty as psychiatrists for the US Army, including in a combat zone, and both currently work in a Veterans Affairs Iraq and Afghanistan combat veteran mental health clinic. This review outlines useful treatment approaches for PTSD and TBI and briefly covers the comorbid conditions of major depression, chronic pain, and substance use disorders. This review will prepare C-L psychiatrists to care for this challenging patient cohort.


Delayed light imaging for the early detection of plant stress.
Image-intensified photographs of delayed light emission (DLE) from soybean leaves exposed to sulfur dioxide showed evidence of the stress that developed during the exposure period. A comparison of DLE images taken during the fumigation with a conventional photograph taken 5 days later showed a clear correspondence between leaf areas that had the most diminished DLE intensity and those that showed the greatest visible injury. These results suggest that DLE imagery will be a useful tool in the investigation of the spatial distribution and temporal development of plant stress.


Polyamines may influence phytochelatin synthesis during Cd stress in rice.
Although the metabolism of phytochelatins and higher polyamines are linked with each other, the direct relationship between them under heavy metal stress has not yet been clarified. Two approaches were used to reveal the influence of polyamine content on cadmium stress responses, particularly with regard to phytochelatin synthesis: putrescine pre-treatment of rice plants followed by cadmium stress, and treatment with the putrescine synthesis inhibitor, 2-(difluoromethyl)ornithine combined with cadmium treatment. The results indicated that putrescine pre-treatment enhanced the adverse effect of cadmium, while the application of 2-(difluoromethyl)ornithine reduced it to a certain extent. These differences were associated with increased polyamine content, more intensive polyamine metabolism, but decreased thiol and phytochelatin contents. The gene expression level and enzyme activity of phytochelatin synthase also decreased in rice treated with putrescine prior to cadmium stress, compared to cadmium treatment alone. In contrast, the inhibition of putrescine synthesis during cadmium treatment resulted in higher gene expression level of phytochelatin synthase. The results suggest that polyamines may have a substantial influence on phytochelatin synthesis at several levels under cadmium stress in rice.


Wearable Technology to Support Early Child Language Experiences: What's Important to Parents and Clinicians?
Emerging research evidence has demonstrated the potential for digital tools, such as automated language processing technology, to support parent-child interactions. Making use of digital tools can aid measurement of parent interaction metrics, additionally, providing contingent feedback to parents based on their language metrics can facilitate positive changes in their everyday input to their young children. Product innovation aside, there is a distinct lack of understanding about how best to integrate real-world, user design needs and preferences to improve deployment of technologies into routine clinical interventions. The present study explored salient requirements of a wearable language tracking device from the users' perspectives. Mothers of young children and clinicians with experience working in paediatric settings completed a written questionnaire and rated the importance of specific functions and features of a child-worn, language tracking device on a 10-point Likert scale. There was strong rating consensus across the participants that comfort, reliability and the provision of clear and useful results were of greater importance. The need for the wearable language tracking device to 'blend in' with different types of clothing was rated as less important. The extended Unified Theory of Acceptance and Use of Technology (UTAUT2) model was employed as a framework for addressing these importance ratings in this population of interest. This study highlighted the need to consider user-focused service design. Addressing user's preferences could facilitate greater technology adoption which ultimately enriches the language experiences for young children.


Nephroscope-assisted single trocar peritoneal dialysis catheter insertion improves catheter survival compared with laparoscopic technique: Ten-year experience of a single center.
An ideal technique for peritoneal dialysis (PD) catheter insertion should provide a long-term functioning catheter until permanent renal replacement therapy becomes available. We developed a technique using the nephroscope-assisted single-trocar approach in 2011. In this study, we report the outcomes, learning curve analysis and cost-effectiveness analysisof the nephroscopic approach compared with the traditional laparoscopic approach. Between January 2005 and December 2020, we retrospectively reviewed 511 patients who received PD catheter insertions using the laparoscopic or nephroscopic approach. We compared the baseline characteristics of the patients, surgical outcomes, and complications of the two groups. We further analyzed the nephroscopic group to determine the cost-effectiveness analysis, learning curve and the complication frequency between the learning and mastery periods of the nephroscopic approach. A total of 208 patients underwent laparoscopic PD catheter insertion, whereas 303 patients received nephroscopic surgery. The median catheter survival in the nephroscopic group is significantly longer (43.1 vs. 60.5 months, p = 0.019). The incidence of peritonitis (29.3% vs.20.8%, p = 0.035) and exit site infection (12.5% vs. 6.6%, p = 0.019) were significantly lower in the nephroscopic group. The cost-effectiveness analysis showed a medical expense reduction of 16000 USD annually by using the nephroscopic technique. There was no difference in the frequency of surgical complications between the learning and mastery phases when examining the learning curve analysis for the nephroscopic technique. Compared with the traditional laparoscopic approach, the nephroscopic technique effectively prolonged catheter survival and reduces health care cost by reducing infectious complications. The low complication rate during the learning phase of surgery makes the procedure safe for patients and surgeons.


Validity of Simpson-Angus Scale (SAS) in a naturalistic schizophrenia population.
Simpson-Angus Scale (SAS) is an established instrument for neuroleptic-induced parkinsonism (NIP), but its statistical properties have been studied insufficiently. Some shortcomings concerning its content have been suggested as well. According to a recent report, the widely used SAS mean score cut-off value 0.3 of for NIP detection may be too low. Our aim was to evaluate SAS against DSM-IV diagnostic criteria for NIP and objective motor assessment (actometry). Ninety-nine chronic institutionalised schizophrenia patients were evaluated during the same interview by standardised actometric recording and SAS. The diagnosis of NIP was based on DSM-IV criteria. Internal consistency measured by Cronbach's alpha, convergence to actometry and the capacity for NIP case detection were assessed. Cronbach's alpha for the scale was 0.79. SAS discriminated between DSM-IV NIP and non-NIP patients. The actometric findings did not correlate with SAS. ROC-analysis yielded a good case detection power for SAS mean score. The optimal threshold value of SAS mean score was between 0.65 and 0.95, i.e. clearly higher than previously suggested threshold value. We conclude that SAS seems a reliable and valid instrument. The previously commonly used cut-off mean score of 0.3 has been too low resulting in low specificity, and we suggest a new cut-off value of 0.65, whereby specificity could be doubled without loosing sensitivity.


First human isolate of Hantavirus (Andes virus) in the Americas.
We isolated Andes virus (formal name: Andes virus [ANDV], a species in the genus Hantavirus), from serum of an asymptomatic 10-year-old Chilean boy who died 6 days later of hantavirus pulmonary syndrome (HPS). The serum was obtained 12 days after his grandmother died from HPS and 2 days before he became febrile. No hantavirus immunoglobulin (Ig) G or IgM antibodies were detected in the serum sample. After three blind passages, ANDV antigens were detected in Vero E6 cells by immunofluorescence assay and enzyme-linked immunosorbent assay, and ANDV RNA was detected by reverse transcription-polymerase chain reaction. A fragment of the virus genome showed 96.2% nucleotide identity with that of prototype ANDV. To our knowledge, this is the first isolation of any agent of hemorrhagic fever with HPS from a human and the first such isolation of hantavirus before symptoms of that syndrome or HPS began.


The Cognitive Assessment by Visual Election (CAVE): A pilot study to develop a cognitive assessment tool for people emerging from disorders of consciousness.
Instruments for assessing people with disorders of consciousness have been developed over the last 15 years, but there remains a dearth of suitable assessment paradigms for those who have emerged from disorders of consciousness. This paper presents a pilot study for the development of the Cognitive Assessment by Visual Election (CAVE), a short assessment designed to investigate a number of cognitive domains in very severely brain injured patients who are in or have emerged from minimally conscious states (EMCS). Reliability and validity data are presented. The challenge of determining neuropsychological profiles of EMCS patients is discussed, current published assessments are briefly reviewed and suggestions for a wider assessment framework are made.


MOF-Derived Ni/ZIF-8/ZnO Arrays on Carbon Fiber Cloth for Efficient Adsorption-Catalytic Oxidation.
The catalytic oxidation of toxic organic pollutants in water requires enhanced efficiency for commercial applications. A ZnO nanorod array grown on a carbon fiber cloth (CFC) serves as the zinc source to ensure that the Ni/ZIF-8/ZnO nanoreactor is constructed. The Ni/ZIF-8/ZnO/CFC nanoreactor efficiently activates peroxymonosulfate (PMS) for bisphenol A (BPA) degradation owing to its high density of active sites, high adsorbability, and dispersibility structure, which concentrates catalytic and adsorptive sites within a confined space. Experimental and theoretical calculations clearly show that the introduction of Ni is beneficial for improving the adsorption of BPA and the activation of PMS. The synergistic mechanism of BPA adsorption-PMS activation is also investigated, and the degradation pathway of BPA is examined. Moreover, a filter catalytic unit is constructed using Ni/ZIF-8/ZnO/CFC to achieve a continuous zero discharge of BPA, which is convenient for nanocatalyst recycling. This study aims to develop a new strategy for the removal of emerging organic pollutants from water using a system with strong adsorption and catalytic capabilities.


The Meaning of Inchoative se in Brazilian Portuguese: A Replication of Lundquist et al.'s (2016) Experiment.
In the well-known causative alternation, a verb appears either in a causative-transitive or in an inchoative-intransitive form. The inchoative form is marked with a reflexive clitic in some languages, such as Norwegian, but is unmarked in others, such as English. There are two main proposals to explain the alternation: a lexical-derivational account (a lexical rule is responsible for the demotion of the cause argument), and a syntactic-derivational one (in a type of reflexivization, the theme/patient is construed as responsible for causing the event). A third type of approach posits that the alternation emerges when a verb can be found in different constructions and no derivation is involved. Lundquist et al. (Glossa J Gen Linguist 1:1-30, 2016) put the first two approaches to experimental testing and found that while the decausativization approach is adequate for English, the reflexivization approach explains the Norwegian facts. The present experimental study investigates which proposal is adequate to explain the alternation in Brazilian Portuguese. Differently from both English and Norwegian, Brazilian Portuguese allows reflexive-marked and unmarked inchoatives with the same verb. In a replication of Lundquist et al.'s (Glossa J Gen Linguist 1:1-30, 2016) experiment, our results show that Brazilian Portuguese assigns distinct meanings to the two forms of the inchoative. We conclude that the reflexive pronoun se indicates that the change of state described in the inchoative sentence was caused by some entity, but not an agent. We then argue that a non-derivational approach explains the alternation, as a single verb occurs in distinct syntactic configurations, with distinct meaning implications.


The relationship of saccadic peak velocity to latency: evidence for a new prosaccadic abnormality in schizophrenia.
Antisaccades have not only longer latencies but also lower peak velocities than prosaccades. It is not known whether these latency and velocity differences are related. Studies of non-human primates suggest that prosaccade peak velocity declines as latency from target appearance increases. We examined whether a similar relationship between peak velocity and latency existed in human saccades, whether it accounted for the difference in peak velocity between antisaccades and prosaccades, and whether it was affected by schizophrenia, a condition that affects antisaccade performance. Sixteen control and 21 schizophrenia subjects performed prosaccade and antisaccade trials in the same test session. In both groups antisaccades had lower peak velocities than prosaccades. Latency did not influence the peak velocities of antisaccades in either subject group. At short latencies, the peak velocities of prosaccades were also similar in the two groups. However, while prosaccade peak velocities declined minimally with increasing latency in control subjects, those in the schizophrenia group declined significantly until they reached a value similar to antisaccade peak velocities. We conclude that, in normal subjects, the effect of latency on prosaccade peak velocity is minimal and cannot account for the lower velocity of antisaccades. In schizophrenia, we hypothesize that the latency-related decline in prosaccade peak velocity may reflect either an increased rate of decay of the effect of the transient visual signal at the saccadic goal, or a failure of the continuing presence of the target to sustain neural activity in the saccadic system.


Phylogenetic analysis of eastern equine encephalitis virus isolates from Florida.
Florida has the highest degree of endemicity for eastern equine encephalitis virus (EEEV) of any state in the United States and is the only state with year-round transmission of EEEV. To further understand the viral population dynamics in Florida, the genome sequence of six EEEV isolates from central Florida were determined. These data were used to identify the most polymorphic regions of the EEEV genome from viruses isolated in Florida. The sequence of these polymorphic regions was then determined for 18 additional Florida isolates collected in four geographically distinct regions over a 20-year period. Phylogenetic analyses of these data suggested a rough temporal association of the Florida isolates, but no clustering by region or by source of the isolate. Some clustering of northeastern isolates with Florida isolates was seen, providing support for the hypothesis that Florida serves as a reservoir for the periodic introduction of EEEV into the northeastern United States.


Identification of a common low density lipoprotein receptor mutation (R329X) in the south of England: complete linkage disequilibrium with an allele of microsatellite D19S394.
Familial hypercholesterolaemia is commonly caused by mutations in the low density lipoprotein receptor (LDLR) gene and more than 300 different mutations have been described worldwide. Some mutations occur at relatively higher frequency in certain populations, reflecting both chance and demography, most evident in founder populations. As part of a study of kindreds of 78 probands from Southampton and south west Hampshire, we identified the same mutation (R329X) in 9/78 (11.5%) probands. In all (100%) of these probands, length allele 259nt of the 17 allele microsatellite D19S394, sited approximately 250 kilobases telomeric and 5' to the LDLR gene, was observed, although in the general population this allele has a prevalence of only 16.1%. A simple diagnostic assay for R329X was constructed in conjunction with more detailed family studies. Both the R329X and linked D19S394 allele also cosegregated with the FH phenotype within each kindred. Although R329X involves a CpG site, it is highly likely that the families are identical by descent for R329X, we surmise with a common ancestor within 500 to 1000 years, although the mutation is not restricted to this geographical area. This relationship illustrates that the linkage disequilibrium of gene LDLR with marker D19S394 will enable rapid recognition using D19S394 genotype of possible common FH mutation(s) within a cohort of FH patients from a particular locality or ethnic group.


Temperature characteristics of surface micromachined MEMS-VCSEL with large tuning range.
Several Applications for tunable laser diodes have strict constraints in terms of overall power consumption. Furthermore, the implementation in harsh environments with large temperature fluctuations is necessary. Due to the constraint in power consumption, the application of active cooling might not be an option. For this reason we investigate the temperature characteristics of an electrically pumped MEMS-VCSEL with wide continuous wavelength tuning. For the first time, a mode hop free single mode (side mode suppression ratio (SMSR) > 40dB) tuning range of 45nm at 70°C is demonstrated with a MEMS-VCSEL. An increase of the tuning range from 85nm at 20°C to 92nm at 40°C is measured and explained. In contrast to fixed wavelength VCSEL, the investigated device shows a negative temperature induced wavelength shift of -4.5nmK(-1), which is caused by the MEMS-mirror. At 1560nm, the fibre-coupled optical output power is above 0.6mW over the entire temperature range between 20°C to 70°C and shows a maximum of > 3mW at 20°C.


Bone recycling in nasal septal reconstruction.
Septal reconstruction alone or together with rhinoplasty can be a very challenging operation. In situations where septal cartilage is used for grafting or is not enough, bony implants taken from the perpendicular plate of the ethmoid and vomer can be used as a filler material between the mucoperichondrial flaps to avoid from unwanted mucosal atrophy, flapping, and septal perforation. These bony implants can also be used for splinting the dorsal and/or caudal segment of the septal cartilage after reshaping by rongeurs. On rare occasions, they can even be used for subtotal reconstruction of the septum.


Long-Life Room-Temperature Sodium-Sulfur Batteries by Virtue of Transition-Metal-Nanocluster-Sulfur Interactions.
Room-temperature sodium-sulfur (RT-Na/S) batteries hold significant promise for large-scale application because of low cost of both sodium and sulfur. However, the dissolution of polysulfides into the electrolyte limits practical application. Now, the design and testing of a new class of sulfur hosts as transition-metal (Fe, Cu, and Ni) nanoclusters (ca. 1.2 nm) wreathed on hollow carbon nanospheres (S@M-HC) for RT-Na/S batteries is reported. A chemical couple between the metal nanoclusters and sulfur is hypothesized to assist in immobilization of sulfur and to enhance conductivity and activity. S@Fe-HC exhibited an unprecedented reversible capacity of 394 mAh g-1 despite 1000 cycles at 100 mA g-1 , together with a rate capability of 220 mAh g-1 at a high current density of 5 A g-1 . DFT calculations underscore that these metal nanoclusters serve as electrocatalysts to rapidly reduce Na2 S4 into short-chain sulfides and thereby obviate the shuttle effect.


Identifying risk factors for diabetes in first degree relatives of non-insulin dependent diabetic patients.
Glucose tolerance test data on 794 first-degree relatives of diabetics in pedigrees ascertained through non-insulin dependent diabetes mellitus from southeastern Michigan were used to identify risk factors for diabetes. The general risk factors, age and obesity, were important in predicting diabetes at initial visit, although the predicted risk curves were very different from males and females. In predicting diabetes at initial visit, the number of affected sibs contributed more to the logistic regression than did the number of affected parents. Among a group of 393 individuals who were followed up for a mean of eight years, the initial glucose tolerance test response was the best single predictor of being diabetic on follow-up. These results suggest there may be a strong within-generational component which influences both the quantitative test response and the risk to diabetes. This component may reflect environmental factors influencing glucose tolerance among sibs and, as such, should be considered when studying the genetics of diabetes.


[Experimental investigations of the propagation mechanism and the nerve regulatory mechanism of the interdigestive migrating electric complex in intestinal movement].
Segments and Thirty-Vella type loops of the small intestine of dogs were prepared, and the excitation propagation pattern of the interdigestive migrating electric complex (IMEC) was observed by electromyography. The nerve regulatory mechanism in intestinal movement was investigated. The results indicated that first, the frequency of the basic electric rhythm (BER) is controlled so that a downward gradient is formed from the upper to the lower intestine, but this gradient continues to be controlled by a two-dimensional control mechanism involving parietal factors and extrinsic nerves due to transection of the intestines and damage to the extrinsic nerves in the dominant region. However, propagation of the IMEC in the small intestine appeared to be regulated by a combination of the two-dimensional control mechanism involving extrinsic and parietal nerves corresponding to the BER control mechanism. It was clear that the propagation mechanism of IMEC is related to the BER frequency, and propagation of the IMEC is downward in accordance with the frequency gradient of BER.


Laboratory experience for teaching sensory physiology.
The major challenge in laboratory teaching is the application of abstract concepts in simple and direct practical lessons. However, students rarely have the opportunity to participate in a laboratory that combines practical learning with a realistic research experience. In the Bioengineering Department, we started an experiential laboratory physiology to teach graduated students some aspects of sensorial physiology and exposes them to laboratory skills in instrumentation and physiological measurements. Students were able to analyze and quantify the effects of activation of mechanoreceptors in multifiber afferent discharges using equipment that was not overly sophisticated. In consequence, this practical laboratory helps students to make connections with physiological concepts acquired in theoretical classes and to introduce them to electrophysiological research.


MR imaging of sodium in the human brain with a fast three-dimensional gradient-recalled-echo sequence at 4 T.
Sodium ions play a vital role in cellular homeostasis and electrochemical activity throughout the human body. However, the in vivo detection of sodium (23Na) with magnetic resonance (MR) techniques is hindered by the fast transverse relaxation, low tissue equivalent concentration, and small gyromagnetic ratio of sodium ions compared with protons (1H). The goals of this study were to acquire MR images of sodium in the whole human brain by using a fast three-dimensional gradient-recalled-echo sequence and to investigate the effect that restrictions on specific absorption ratio have on MR imaging of sodium at 4 T. A three-dimensional gradient-recalled-echo sequence with short echo time was developed for MR imaging of sodium. Slab encoding was removed and a hard excitation pulse was used. Five healthy human volunteers were examined in a whole-body MR imager with the use of a custom transmit-and-receive birdcage coil. Fields of view were selected to cover the entire brain: 38 x 38 cm in the axial plane, with 24 sections of 5.8 mm each or 12 sections of 1.1 cm each. The in-plane acquisition matrix was 64 x 128, and voxel size was 0.2 cm(3). Sodium in white matter was depicted with an acceptable signal-to-noise ratio of 20-25. The echo time, and hence the signal-to-noise ratio, was limited by the MR imager's maximum allowable gradient strength. To keep the specific absorption ratio below 3 W/kg (the limit established by the Food and Drug Administration), it was necessary to prolong the repetition time to 30 msec. The MR imaging protocol used in this study provided acceptable visualization of sodium in the whole brain in a tolerable total acquisition time of 15 minutes.


Factors Influencing Electrode Position and Bending of the Proximal Lead in Deep Brain Stimulation for Movement Disorders.
The introduction of intracranial air (ICA) during deep brain stimulation (DBS) surgery is thought to have a negative influence on targeting and clinical outcomes. To investigate ICA volumes following surgery and other patient-specific factors as potential variables influencing translocation of the DBS electrode and proximal lead bowing. High-resolution postoperative computed tomography scans (≤1.0 mm resolution in all directions) within 24 h following DBS surgery and 4-6 weeks of follow-up were acquired. A total of 50 DBS leads in 33 patients were available for analysis. DBS leads included Abbott/St. Jude Medical InfinityTM, Boston Scientific VerciseTM, and Medtronic 3389TM. Both ICA volume and anatomical target were significantly associated with measures of DBS electrode translocation. ICA volume and DBS lead model were found to be significant predictors of proximal lead bowing. Measures of proximal lead bowing and translocation along the electrode trajectory for the Medtronic 3389TM DBS lead were significantly larger than measures for the Abbott/St. Jude Medical InfinityTM and Boston Scientific VerciseTM DBS leads. The association between ICA volume and translocation of the DBS electrode is small in magnitude and not clinically relevant for DBS cases within a normal range of postoperative subdural air volumes. Differences in proximal lead bowing observed between DBS leads may reflect hardware engineering subtleties in the construction of DBS lead models.


Review on the Impact of Milk Oligosaccharides on the Brain and Neurocognitive Development in Early Life.
Milk Oligosaccharides (MOS), a group of complex carbohydrates found in human and bovine milk, have emerged as potential modulators of optimal brain development for early life. This review provides a comprehensive investigation of the impact of milk oligosaccharides on brain and neurocognitive development of early life by synthesizing current literature from preclinical models and human observational studies. The literature search was conducted in the PubMed search engine, and the inclusion eligibility was evaluated by three reviewers. Overall, we identified 26 articles for analysis. While the literature supports the crucial roles of fucosylated and sialylated milk oligosaccharides in learning, memory, executive functioning, and brain structural development, limitations were identified. In preclinical models, the supplementation of only the most abundant MOS might overlook the complexity of naturally occurring MOS compositions. Similarly, accurately quantifying MOS intake in human studies is challenging due to potential confounding effects such as formula feeding. Mechanistically, MOS is thought to impact neurodevelopment through modulation of the microbiota and enhancement of neuronal signaling. However, further advancement in our understanding necessitates clinical randomized-controlled trials to elucidate the specific mechanisms and long-term implications of milk oligosaccharides exposure. Understanding the interplay between milk oligosaccharides and cognition may contribute to early nutrition strategies for optimal cognitive outcomes in children.


Lymphovenous shunts in man.
Lymphovenous shunts have been detected in patients by lymphography with Ultrafluid Lipiodol. No shunts were found in patients with normal lymphatic systems. They were found in patients with lymphoedema, with lymph nodes involved by malignant disease, and in patients who had had surgical interruption of lymphatic pathways, either vessels or nodes. The total incidence of lymphovenous shunts in 700 lymphographic studies was 2.3%. The incidence in the various pathological groups was highest in those with obvious lymph node involvement.In certain situations, particularly primary lymphoedema, the role of a lymphovenous shunt appears favourable to prognosis. In other situations a deleterious effect may be produced.


Evaluation of a commercial ligase chain reaction kit (Abbott LCx) for direct detection of Mycobacterium tuberculosis in pulmonary and extrapulmonary specimens.
Direct detection of Mycobacterium tuberculosis by means of a commercial ligase chain reaction DNA amplification method (LCx M. tuberculosis; Abbott Diagnostics Division, Abbott Park, Ill.) was investigated with 511 (including 147 extrarespiratory) specimens collected from 358 patients. LCx results were compared with standard microbiological data, and conflicting cases were resolved according to the final clinical diagnosis. M. tuberculosis was detected in 45 of 358 subjects by means of the LCx test. The test was negative for all 30 specimens with mycobacteria other than M. tuberculosis. The sensitivity, specificity, and positive and negative predictive values for the LCx test, compared with culture results, were 93.90, 92.31, 70.00, and 98.75%, respectively; these values rose in resolved cases to 95.53, 99.25, 97.27, and 98.75%, respectively. With respiratory specimens, for which the LCx system is licensed, the sensitivity reached 98.97%. In patients with a final clinical diagnosis of tuberculosis the sensitivity of the LCx system was 89.36% compared to 82.98% for cultures and 78.72% for microscopy. We conclude that the LCx test is user friendly, rapid, fairly sensitive, and highly specific. It can also be effectively used on extrapulmonary specimens provided possible false-negative results are taken into account. However, the use of LCx test appears to be less appropriate for the monitoring of antituberculosis therapy, as the majority of samples from treated tuberculosis patients gave consistently positive results, despite the sterilization of cultures.


Description and optimization of a multiplex bead-based flow cytometry method (MBFCM) to characterize extracellular vesicles in serum samples from patients with hematological malignancies.
Extracellular Vesicles (EVs) are membranous vesicles produced by all cells under physiological and pathological conditions. In hematological malignancies, tumor-derived EVs might reprogram the bone marrow environment, suppress antileukemic immunity, mediate drug resistance and interfere with immunotherapies. EVs collected from the serum of leukemic samples might correlate with disease stage, drug-/immunological resistance, or might correlate with antileukemic immunity/immune response. Special EV surface protein patterns in serum have the potential as noninvasive biomarker candidates to distinguish several disease-related patterns ex vivo or in vivo. EVs were isolated from the serum of acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), chronic lymphoid leukemia (CLL) patients, and healthy volunteers. EVs were characterized by transmission electron microscopy and fluorescence nanoparticle tracking analysis, and EV surface protein profiles were analyzed by multiplex bead-based flow cytometry to identify tumor- or immune system-related EVs of AML, ALL, CLL, and healthy samples. Aiming to provide proof-of-concept evidence and methodology for the potential role of serum-derived EVs as biomarkers in leukemic versus healthy samples in this study, we hope to pave the way for future detection of promising biomarkers for imminent disease progression and the identification of potential targets to be used in a therapeutic strategy.


Androgens Mediate β-adrenergic Vasorelaxation Impairment Using Adenylyl Cyclase.
Cardiovascular disease development has been associated with sex differences, suggesting that sex hormones are implicated in vascular function and development of hypertension. Vascular tone comparison at different stages of rat growth represents a good model to study testosterone-related vascular response. We explored the role of testosterone in modulation of age-dependent impaired β-adrenergic vasodilation. The 3-week-old male Sprague-Dawley rats were sorted in 3-week-old rats without any manipulation and 3-week-old rats treated with testosterone. The 9-week-old rats were randomly grouped into 9-week-old rats without any manipulation (sham), 9-week-old rats that underwent gonadectomy (9-week-old castrated), and 9-week-old castrated treated with testosterone replacement therapy (9-week-old castrated + testosterone). Vascular relaxation was evaluated in aortic rings. β-adrenergic receptor protein expression, cyclic adenosine monophosphate production, testosterone levels, and adenylyl cyclase (AC) gene expression were assessed. Testosterone levels were low in 3-week-old and 9-week-old castrated rats compared with 9-week-old sham rats. Testosterone replacement raised these levels in 3-week-old and 9-week-old castrated rats similar to those of 9-week-old sham rats. SQ22536, the AC inhibitor, prevented isoproterenol-induced relaxation in aortic rings from 3-week-old and 9-week-old castrated rats. The β-adrenergic receptor protein expression was similar in all experimental groups. AC mRNA and protein expression and cyclic adenosine monophosphate levels were elevated in 3-week-old and 9-week-old castrated rats compared with 3-week-old + testosterone, 9-week-old sham, and 9-week-old castrated + testosterone rats. In conclusion, we demonstrated that age maturation was associated with vascular relaxation impairment. Variations in testosterone levels and reduced AC expression may be responsible for this altered vascular function.


Development and evaluation of a rapid multiplex-PCR based system for Mycobacterium tuberculosis diagnosis using sputum samples.
Global tuberculosis (TB) control and eradication is hampered by the unavailability of simple, rapid and affordable diagnostic tests deployable at low infrastructure microscopy centers. We have developed and evaluated the performance of a nucleic acid amplification test for detection of Mycobacterium tuberculosis (MTB), the NWU-TB test, in clinical sputum specimens from 306 patients with suspected pulmonary tuberculosis. The test involves sputum sample processing using a Lyser device within 7 min, followed by rapid multiplex-PCR on a fast thermal cycler within 25 min, and amplicon resolution on agarose gel electrophoresis. Samples were also examined for presence of MTB using smear microscopy, GeneXpert and MGIT culture. Results were assessed in comparison to a MGIT culture as gold standard. Of the 306 patients, 174 had a previous TB history or already on treatment, and 132 were TB naïve cases. The NWU-TB system was found to have an overall sensitivity and specificity of 80.8% (95% CI: 75-85.7) and 75.6% (95% CI: 64.9-84.4) respectively, in comparison to 85.3% (95% CI: 79.9-89.6) and 73.2% (95% CI: 62.2-82.4) respectively for GeneXpert; and 62.1% (95% CI: 55.3-68.4) and 56.1% (95% CI: 44.7-67) respectively for smear microscopy. The study has shown that the NWU-TB system allows detection of TB in less than two hours and can be utilized at low infrastructure sites to provide quick and accurate diagnosis at a very low cost.


Neonicotinoid insecticides: oxidative stress in planta and metallo-oxidase inhibition.
Neonicotinoids not only control insect pests but also sometimes independently alter plant growth and response to stress. We find that imidacloprid, thiacloprid, acetamiprid, thiamethoxam, and clothianidin but not nitenpyram and dinotefuran induce foliar lesions and peroxidative damage in soybean ( Glycine max ) seedlings assayed with the 3,3'-diaminobenzidine stain. The chloropyridinyl-carboxylic acid (COOH) but not the -carboxaldehyde (CHO) metabolites induce peroxidative damage but in a different pattern. Surprisingly, the chlorothiazolyl -CHO and -COOH metabolites induce chlorosis but no clear superimposable peroxidative damage or cell death. Four metallo-oxidases known to modulate reactive oxygen species were not sensitive in vitro to the parent neonicotinoid itself but were to several CHO and COOH metabolites and related compounds, with a sensitivity order of CHO > COOH and tyrosinase > xanthine oxidase and aldehyde oxidase > catalase. Although metallo-oxidase inhibition does not correlate overall with lesion formation, it may play an as yet unknown role in plant response to neonicotinoids.


Inequality of gender, age and disabilities due to leprosy and trends in a hyperendemic metropolis: Evidence from an eleven-year time series study in Central-West Brazil.
The present study aimed to investigate the epidemiological situation of leprosy (Hansen's Disease), in a hyperendemic metropolis in the Central-West region of Brazil. We studied trends over eleven years, both in the detection of the disease and in disabilities, analyzing disparities and/or differences regarding gender and age. This is an ecological time series study conducted in Cuiabá, capital of the state of Mato Grosso. The population consisted of patients diagnosed with leprosy between the years 2008 and 2018. The time series of leprosy cases was used, stratifying it according to gender (male and female), disability grade (G0D, G1D, G2D, and not evaluated) and age. The calendar adjustment technique was applied. For modeling the trends, the Seasonal-Trend decomposition procedure based on Loess (STL) was used. We identified 9.739 diagnosed cases, in which 58.37% were male and 87.55% aged between 15 and 59 years. Regarding detection according to gender, there was a decrease among women and an increase in men. The study shows an increasing trend in disabilities in both genders, which may be related to the delay in diagnosis. There was also an increasing number of cases that were not assessed for disability at the time of diagnosis, which denotes the quality of the services.


Ultrasonic wave speed measurement using the time-delay profile of rf-backscattered signals: simulation and experimental results.
Conventional methods determine the ultrasonic wave speed measuring the medium path length propagated by a pulsed wave and the corresponding time-of-flight. In this work, the wave speed is determined without the need of the path length. A transmit transducer sends a pulsed wave into the medium (wave speed constant along the beam axis) and the backscattered signal is collected by a hydrophone placed at two distinct positions near the transmitted beam. The time-delay profile, between gated windows of the two rf-signals received by the hydrophone, is determined using a cross-correlation method. Also, a theoretical time-delay profile is determined considering the wave speed as a parameter. The estimated wave speed is obtained upon minimization of the rms error between theoretical and experimental time-delay profiles. A PZT conically focused transmitting transducer with center frequency of 3.3 MHz, focal depth of 30 mm, and beam full width (-3 dB) of 2 mm at the focus was used together with a PZT hydrophone (0.8 mm of aperture). The method was applied to three phantoms (wave speed of 1220, 1540, and 1720 m/s) and, in vitro, to fresh bovine liver sample, immersed in a temperature-controlled water bath. The results present a relative speed error less than 3% when compared with the sound speed obtained by a conventional method.


Nucleophilic cycloaromatization of ynamide-terminated enediynes.
Introduction of a nitrogen atom at one of the acetylenic termini of 10-, 11-, 12-, and 13-membered benzannulated cyclic enediynes results in a complete suppression of the conventional radical Bergman reaction in favor of a polar cycloaromatization. The latter reaction is catalyzed by acids and proceeds via initial protonation of an ynamide fragment. The resulting ketenimmonium cation then cyclizes to produce naphthyl cation, which rapidly reacts with nucleophiles or undergoes Friedel-Crafts addition to aromatic compounds. In alcohols, addition of the nucleophilic solvent across the activated triple bond competes with the cyclization reaction. The ratio of cyclized to solvolysis products decreases with the increase in ring size.


GABAergic excitation after febrile seizures induces ectopic granule cells and adult epilepsy.
Temporal lobe epilepsy (TLE) is accompanied by an abnormal location of granule cells in the dentate gyrus. Using a rat model of complex febrile seizures, which are thought to be a precipitating insult of TLE later in life, we report that aberrant migration of neonatal-generated granule cells results in granule cell ectopia that persists into adulthood. Febrile seizures induced an upregulation of GABA(A) receptors (GABA(A)-Rs) in neonatally generated granule cells, and hyperactivation of excitatory GABA(A)-Rs caused a reversal in the direction of granule cell migration. This abnormal migration was prevented by RNAi-mediated knockdown of the Na(+)K(+)2Cl(-) co-transporter (NKCC1), which regulates the excitatory action of GABA. NKCC1 inhibition with bumetanide after febrile seizures rescued the granule cell ectopia, susceptibility to limbic seizures and development of epilepsy. Thus, this work identifies a previously unknown pathogenic role of excitatory GABA(A)-R signaling and highlights NKCC1 as a potential therapeutic target for preventing granule cell ectopia and the development of epilepsy after febrile seizures.


Clinical significance of D-dimer levels in refractory Mycoplasma pneumoniae pneumonia.
The levels of serum D-dimer (D-D) in children with Mycoplasma pneumoniae pneumonia (MPP) were assessed to explore the clinical significance of D-D levels in refractory MPP (RMPP). A total of 430 patients with MPP were enrolled between January 2015 and December 2015 and divided into a general MPP (GMPP) group (n = 306) and a RMPP group (n = 124). Clinical data, D-D level, white blood cell (WBC) count, proportion of neutrophils (N%), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), alanine transaminase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were compared between the two groups. Multivariate logistic regression was performed to identify independent predictors of RMPP. (1) Hospitalization time, preadmission fever duration, total fever duration, WBC, N %, CRP, LDH, ESR, ALT, AST, and D-D were significantly higher in the RMPP group than those in the GMPP group (all P < 0.05). (2) Correlation analysis showed that D-D was positively correlated with WBC, CRP, ESR, and LDH, and could be used to jointly evaluate the severity of the disease. (3) Multivariate logistic regression analysis identified preadmission fever duration, CRP, LDH and DD as independent risk factors for RMPP (all P < 0. 05). D-D had the highest predictive power for RMPP (P < 0.01). The D-D level also had a good ability to predict pleural effusion and liver injury (all P < 0.01). Serum D-D levels were significantly increased in patients with RMPP, indicating that excessive inflammatory response and vascular endothelial injury with prolonged duration existed in this patient population. Increased levels of serum D-D may be used as an early predictor of RMPP and the occurrence of complications. Our findings provide a theoretical basis for the early diagnosis of RMPP, early intervention and excessive inflammatory response in the pathogenesis of mycoplasma.


Reduction in acute gastroenteritis hospitalizations among US children after introduction of rotavirus vaccine: analysis of hospital discharge data from 18 US states.
In 2006, RotaTeq (RV5) was recommended for routine vaccination of United States (US) infants. We compared hospitalization rates for acute gastroenteritis among US children aged <5 years during pre-RV5 rotavirus seasons from 2000 through 2006 with those during the post-RV5 2007 and 2008 seasons. Using 100% hospital discharge data from 18 states, accounting for 49% of the US population, we calculated acute gastroenteritis hospitalization rates for children aged <5 years by rotavirus season, 8 age groups (0-2, 3-5, 6-11, 12-17, 18-23, 24-35, 36-47, and 48-59 months), and state. Compared with the median rate for the 2000-2006 rotavirus seasons (101.1 hospitalizations per 10,000 children), the rates for 2007 and 2008 (85.5 and 55.5 hospitalizations per 10,000 children) were 16% and 45% lower, respectively. Children aged 0-2 months had a 28% reduction, those aged 6-23 months had a reduction of 50%, and children aged 3-5 months and 24-59 months had reductions ranging between 42% and 45% during the 2008 rotavirus season, compared with the median rate for 2000-2006 rotavirus seasons. The introduction of the RV5 vaccine was associated with a dramatic reduction in hospitalizations for acute gastroenteritis among US children during the 2008 rotavirus season.


Can nausea and vomiting be treated with ginger extract?
Ginger (Zingiber officinale) is a spice traditionally used to treat indigestion, nausea and vomiting. Ginger extracts accelerate gastric emptying and stimulate gastric antral contractions. These effects are mainly due to the presence of gingerols and shogaols and their activity on cholinergic M receptors and serotonergic 5-HT and 5-HT receptors. Various researches on this subject have led to controversial results, due to the chemical instability of ginger extracts and particularly of gingerols, which are readily-oxidizable substances. A systematic review of double-blind, placebo-controlled, randomized studies highlighted the potential efficacy of ginger on the prevention and treatment of nausea and vomiting of various origins, even though additional controlled studies are needed. This review focuses on pregnancy-induced nausea and vomiting and on chemotherapy induced nausea, and hypothesizes a therapeutic role for ginger extracts in case of side effects, as an alternative to traditional prokinetic drugs such as domperidone, levosulpiride or metoclopramide.


Wikipedia network analysis of cancer interactions and world influence.
We apply the Google matrix algorithms for analysis of interactions and influence of 37 cancer types, 203 cancer drugs and 195 world countries using the network of 5 416 537 English Wikipedia articles with all their directed hyperlinks. The PageRank algorithm provides a ranking of cancers which has 60% and 70% overlaps with the top 10 deadliest cancers extracted from World Health Organization GLOBOCAN 2018 and Global Burden of Diseases Study 2017, respectively. The recently developed reduced Google matrix algorithm gives networks of interactions between cancers, drugs and countries taking into account all direct and indirect links between these selected 435 entities. These reduced networks allow to obtain sensitivity of countries to specific cancers and drugs. The strongest links between cancers and drugs are in good agreement with the approved medical prescriptions of specific drugs to specific cancers. We argue that this analysis of knowledge accumulated in Wikipedia provides useful complementary global information about interdependencies between cancers, drugs and world countries.


Hemolysis due to gram-negative urinary tract infection.
Twenty-four infants 8--62 days of age with urinary tract infection have presented with a chief complaint of jaundice. The bilirubin determinations have ranged from 6--48.2 mg/dl, with elevation of both the direct and indirect reacting bilirubin fractions except for the youngest infants (under 10 days old), where only indirect bilirubin elevation was present. The BUNs ranged from 18--153 mg/dl with general correlation to the bilirubin elevation. Hemolysis was documented in 21 infants. The infecting organisms were predominantly Escherichia coli (20 patients) of the low-number serotypes. We have been able to test 11 of the isolates and have found that all produced hemolysis on blood agar plates. Another interesting observation has been the reversal of the expected frequency of the A and B blood groups in our series. There is an excessive number of infants of blood group B with a paucity of blood group A; blood group O is as expected. The relationship of blood group type and E. coli infection and the presence or absence of jaundice needs to be explored in a larger group of infants.


Balancing Passive and Active Targeting to Different Tumor Compartments Using Riboflavin-Functionalized Polymeric Nanocarriers.
Riboflavin transporters (RFTs) and the riboflavin carrier protein (RCP) are highly upregulated in many tumor cells, tumor stem cells, and tumor neovasculature, which makes them attractive targets for nanomedicines. Addressing cells in different tumor compartments requires drug carriers, which are not only able to accumulate via the EPR effect but also to extravasate, target specific cell populations, and get internalized by cells. Reasoning that antibodies are among the most efficient targeting systems developed by nature, we consider their size (∼10-15 nm) to be ideal for balancing passive and active tumor targeting. Therefore, small, short-circulating (10 kDa, ∼7 nm, t1/2 ∼ 1 h) and larger, longer-circulating (40 kDa, ∼13 nm, t1/2 ∼ 13 h) riboflavin-targeted branched PEG polymers were synthesized, and their biodistribution and target site accumulation were evaluated in mice bearing angiogenic squamous cell carcinoma (A431) and desmoplastic prostate cancer (PC3) xenografts. The tumor accumulation of the 10 kDa PEG was characterized by rapid intercompartmental exchange and significantly improved upon active targeting with riboflavin (RF). The 40 kDa PEG accumulated in tumors four times more efficiently than the small polymer, but its accumulation did not profit from active RF-targeting. However, RF-targeting enhanced the cellular internalization in both tumor models and for both polymer sizes. Interestingly, the nanocarriers' cell-uptake in tumors was not directly correlated with the extent of accumulation. For example, in both tumor models the small RF-PEG accumulated much less strongly than the large passively targeted PEG but showed significantly higher intracellular amounts 24 h after iv administration. Additionally, the size of the polymer determined its preferential uptake by different tumor cell compartments: the 10 kDa RF-PEGs most efficiently targeted cancer cells, whereas the highest uptake of the 40 kDa RF-PEGs was observed in tumor-associated macrophages. These findings imply that drug carriers with sizes in the range of therapeutic antibodies show balanced properties with respect to passive accumulation, tissue penetration, and active targeting. Besides highlighting the potential of RF-mediated (cancer) cell targeting, we show that strong tumor accumulation does not automatically mean high cellular uptake and that the nanocarriers' size plays a critical role in cell- and compartment-specific drug targeting.


Behavior of an aerated submerged fixed-film reactor (ASFFR) under simultaneous organic and ammonium loading.
The performance of an aerated submerged fixed-film reactor (ASFFR) under simultaneous organic and ammonium loading and its effect on nitrification was studied. Organic loadings varied in the range of 1.93 to 5.29 g chemical oxygen demand (COD) m-2 d-1 and NH4-N loadings were in the range of 116 to 318 mg NH4-N m-2 d-1. Increments of loading rates were obtained both by increasing the flow rate and increasing the influent substrate in individual pilot runs. Results showed that with organic loading rates up to 3.97 g COD m-2 d-1, complete nitrification was achievable. Although high organic loading such as 5.29 g COD m-2 d-1 could cause nitrification to stop, shifting to lower organic loadings made nitrification start and set rapidly to its previous steady-state concentrations. Comparison of results showed that in the ASFFR, nitrification would be severely affected by an organic loading rate of 5.29 g COD m-2 d-1 by increasing either the flow or the influent substrate. It should be noted that the average value of dissolved oxygen was 3.4 mg L-1 with an air supply of 15 L min-1, and there was no indication of oxygen limitation. The results of this study show the flexibility of ASFFRs under changing organic loads. Furthermore, for achieving complete nitrification and optimum application of these reactors for protecting receiving water from the environmental hazards of ammonium, the maximum organic loading that would present complete nitrification should be considered.


Hypoxia ischemia results in blood brain barrier damage via AKT/GSK-3β/CREB pathway in neonatal rats.
Previous studies have showed that the permeability of blood brain barrier (BBB) increased after hypoxia ischemia (HI). The current research uncovered the mechanism of altered BBB permeability after hypoxic-ischemic brain damage (HIBD) through AKT/GSK-3β/CREB signaling pathway in neonatal rats. Firstly, Magnetic resonance imaging (MRI) combined with hematoxylin-eosin (H&E) staining was used to assess brain injury. Initial findings showed abnormal signals in T2-weighted imaging (T2WI) and diffusion weighted imaging (DWI). Changes also happened in the morphology of nerve cells. Subsequently, we found that BBB damage is manifested as leakage of immunoglobulin G (IgG) and destruction of BBB-related proteins and ultrastructure. Meanwhile, the levels of matrix metalloproteinase-9 (MMP-9) significantly increased at 24 h after HIBD compared to a series of time points. Additionally, immunohistochemical (IHC) staining combined with Western blot (WB) was used to verify the function of the AKT/GSK-3β/CREB signaling pathway in BBB damage after HI in neonatal rats. Results showed that less Claudin-5, ZO-1, p-AKT, p-GSK-3β and p-CREB, along with more MMP-9 protein expression were visible on the damaged side of the cerebral cortex in the HIBD group in contrast to the sham and HIBD + SC79 groups. Together, our findings demonstrated that HI in neonatal rats might upregulate the levels of MMP-9 protein and downregulate the levels of Claudin-5 and ZO-1 by inhibiting the AKT/GSK-3β/CREB pathway, thus disrupting the BBB, which in turn aggravates brain damage after HI in neonatal rats.


ASSOCIATION OF SOLUTE CARRIER ORGANIC ANION TRANSPORTER 1B1 GENE POLYMORPHISM WITH RESPONSE TO ATORVASTATIN AND ASSOCIATED MYOPATHY IN IRAQI DYSLIPIDEMIA PATIENTS.
Aim: The study aims to investigate the effect of solute carriers organic anions transporters 1B1 (SLCO1B1) gene polymorphisms rs4149056, rs2306283, rs55901008, and rs729559745 in a sample of patients with dyslipidemia, and relate it to atorvastatin response and associated myopathy. Materials and Methods: A cross sectional enrolled 200 patients both males and females of Arabic race, Iraqi nationality aged between 30-65 years. The patients were divided into two groups: Group 1 (Atorvastatin responders and tolerant), Group 2 (Atorvastatin non responder and intolerant). Blood samples collected from the patients for biochemical studies and analyzed statistically by Student T-test and Chi-square, and DNA extracted for polymerase chains reactions (PCR). Results: The results showed insignificant association P≥0.05 between the demographic characteristics of the study population with different genotypes, and significant difference P<0.05 in the biochemical parameters regarding (T-cholesterol, triglycerides, low density lipoproteins, and Creatine kinase-MM) when comparing the two groups. Odds ratio (OR) with confidence intervals CI (95%) used to evaluate the risk association to develop myopathy and poor response to atorvastatin therapy show relevant association for CC and CT genotype of rs4149056, while rs2306283 GG genotype show low association, also rs55901008 show low association for CC genotype, and moderate association for rs72559745 genotypes GG, AG. Conclusions: The mutant allele's genotypes of rs4149056, rs55901008, and rs72559745, and the wild allele genotype of rs2306283 show significant association with the development of poor response to atorvastatin and elevated the level of CK-MM plasma concentration.


Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study.
Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods. The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years). The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups. The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.


Prevention of cardiac allograft vasculopathy with Certican (everolimus): the Stanford University experience within the Certican Phase III clinical trial.
A large Phase III clinical trial with the novel proliferation signal inhibitor, Certican (everolimus), has shown this agent to be associated with lower rates of acute rejection, cardiac allograft vasculopathy (CAV) and cytomegalovirus (CMV) infection when compared with azathioprine (AZA) at 12 months post-transplant. Given that CAV is the main risk factor for mortality after the first year post-transplant, and that acute rejection and CMV infection play a key role in the development of this disease, the findings suggest that everolimus has an important role as part of the primary immunosuppression of this population. Consideration of the presentation and outcome of patients from Stanford University who were enrolled in the pivotal trial with everolimus in heart transplantation has highlighted the efficacy of everolimus in this setting. Analysis of the angiographic outcome data of these patients demonstrates that the efficacy of everolimus observed in the large, multicenter trial involving heart transplant patients was replicated in the findings of a single center. This finding is important for the interpretation of clinical trial data, offering reassurance that data from large trials are applicable to an individual center. The results from Stanford also reveal an important difference between everolimus and AZA with regard to intimal thickening and the incidence of abnormal left ventricular ejection fraction (LVEF), suggesting that everolimus may improve left ventricular function. Because abnormal LVEF has been associated with greater risk of vascular rejection and allograft vascular disease, use of everolimus could well improve long-term outcomes in heart transplant recipients.


[Experimental study on fas expression of spermatogenic cell in male rats induced by fluorine].
To research the effect of fluorine on the expression of Fas protein, then study the mechanism of male reproductive toxicity induced by fluoride on molecular level. Thirty Wistar male rats were divided into control group, low-dose group and high-dose group. The NaF dosage for every group were 0,2 and 4g/L. The content of NaF in testis was measured by using fluorine selective electrode. Changes of testosterone and Fas protein were observed using the methods of radioimmunoassay, in situ hybridization. In addition, we observed the quality of spermatozoa. The testis fluoride content of two fluorine treatment groups were higher than that of control group (P < 0.05), and had a dose-dependent effect. The level of testosterone, the number and the livability of the spermatozoon in fluorotic groups were lower than those of control rats (P < 0.05), and the above indexes decreased with the incrase of dosage. The expression of Fas in spermatogenic cells and the sperm aberration of each fluorotic group were higher than control group (P < 0.05), both of them increased with the increase of dosage. Fluorin could reduce the level of serum testosterone, then activated the Fas/FasL system, which caused damage to the reprodutive system.


Thermal tracking of sports players.
We present here a real-time tracking algorithm for thermal video from a sports game. Robust detection of people includes routines for handling occlusions and noise before tracking each detected person with a Kalman filter. This online tracking algorithm is compared with a state-of-the-art offline multi-target tracking algorithm. Experiments are performed on a manually annotated 2-minutes video sequence of a real soccer game. The Kalman filter shows a very promising result on this rather challenging sequence with a tracking accuracy above 70% and is superior compared with the offline tracking approach. Furthermore, the combined detection and tracking algorithm runs in real time at 33 fps, even with large image sizes of 1920 × 480 pixels.


Integrin engagement-induced inhibition of human myelopoiesis is mediated by proline-rich tyrosine kinase 2 gene products.
Hematopoietic progenitor proliferation and differentiation are inhibited by integrin engagement of fibronectin (FN). Focal adhesion kinases have been shown to mediate intracellular signaling from integrins, and we recently demonstrated that gene expression and pre-mRNA splicing of the focal adhesion kinase, PYK2, is abnormal in CD34(+) cells from chronic myelogenous leukemia (CML) patients. Here we investigated whether PYK2 gene products mediate integrin signaling in hematopoietic stem and progenitor cells. Cord blood CD34(+) cells were retrovirally transduced with vectors encoding Pyk2H, Pyk2, or the dominant negative-acting, kinase-deficient, C-terminal PYK2 fragment, PRNK, and myeloid proliferation and differentiation was assessed using colony-forming cell (CFC), long-term culture-initiating cell (LTC-IC), and liquid culture assays. CD34(+) cells overexpressing Pyk2H or Pyk2 generated 50% less colony-forming unit granulocyte/macrophage (CFU-GM) than eGFP-transduced controls. Although the number of CFC generated by PRNK-expressing cells was unchanged, LTC-IC were significantly reduced. Culture of CD34(+) cells on FN significantly reduced the generation of mature myeloid cells vs those cultured on BSA-coated wells, and could be overcome by addition of SCF. As is observed when integrins are engaged, overexpression of either Pyk2H or Pyk2 decreased committed myeloid progenitor proliferation and differentiation; however, SCF could not override this inhibition. Finally, as is observed when integrins are not engaged, PRNK-mediated inhibition of endogenous Pyk2H resulted in integrin-nonresponsive proliferation and differentiation of myeloid precursors and accelerated differentiation of primitive hematopoietic progenitors. These studies indicate that PYK2 gene products mediate integrin-induced signals that regulate myelopoiesis.


DNA release dynamics from bioreducible poly(amido amine) polyplexes.
The DNA release dynamics of bioreducible poly(amido amine) polyplexes were studied in real time by atomic force microscopy (AFM). DNA release is triggered by a depolymerization of high-molecular-weight polycations into low-molecular-weight oligocations that occurs by means of the thiol and disulfide exchange reaction mechanism. AFM images were captured in a simulated physiological reducing environment that used dithiothreitol. Distinctive stages of disassembly are common among various polyplexes that have different disulfide content, molecular weight, and polymer architecture, while the DNA release rate depends upon the disulfide content. In the first stage, polyplexes evolve from metastable structures into the more stable toroid structure upon the depolymerization. In the second stage, toroids either aggregate or fuse into larger toroids. In the last stage, DNA wormlike chains and loops are held by a central compact core. The results confirm the prospect of bioreducible poly(amido amine)s as controlled DNA delivery vectors. The study offers new physical insights into the DNA release pathway including intermediate structures that have a high degree of structural heterogeneity and disassembly induced particle growth. The study identifies disassembly induced colloidal and morphological instability as an important issue to be addressed.


Precatheterization Use of P2Y12 Inhibitors in Non-ST-Elevation Myocardial Infarction Patients Undergoing Early Cardiac Catheterization and In-Hospital Coronary Artery Bypass Grafting: Insights From the National Cardiovascular Data Registry®.
Current guidelines recommend early P2Y12 inhibitor administration in non-ST-elevation myocardial infarction, but it is unclear if precatheterization use is associated with longer delays to coronary artery bypass grafting (CABG) or higher risk of post-CABG bleeding and transfusion. This study examines the patterns and outcomes of precatheterization P2Y12 inhibitor use in non-ST-elevation myocardial infarction patients who undergo CABG. Retrospective analysis was done of 20 304 non-ST-elevation myocardial infarction patients in the ACTION (Acute Coronary Treatment and Intervention Outcomes Network) Registry (2009-2014) who underwent catheterization within 24 hours of admission and CABG during the index hospitalization. Using inverse probability-weighted propensity adjustment, we compared time from catheterization to CABG, post-CABG bleeding, and transfusion rates between patients who did and did not receive precatheterization P2Y12 inhibitors. Among study patients, 32.9% received a precatheterization P2Y12 inhibitor (of these, 2.2% were given ticagrelor and 3.7% prasugrel). Time from catheterization to CABG was longer among patients who received precatheterization P2Y12 inhibitor (median 69.9 hours [25th, 75th percentiles 28.2, 115.8] versus 43.5 hours [21.0, 71.8], P<0.0001), longer for patients treated with prasugrel (median 114.4 hours [66.5, 155.5]) or ticagrelor (90.4 hours [48.7, 124.5]) compared with clopidogrel (69.3 [27.5, 114.6], P<0.0001). Precatheterization P2Y12 inhibitor use was associated with a higher risk of post-CABG major bleeding (75.7% versus 73.4%, adjusted odds ratio 1.33, 95% confidence interval 1.22-1.45, P<0.0001) and transfusion (47.6% versus 35.7%, adjusted odds ratio 1.51, 95% confidence interval 1.41-1.62, P<0001); these relationships did not differ among patients treated with clopidogrel, prasugrel, or ticagrelor. Precatheterization P2Y12 inhibitor use occurs commonly among non-ST-elevation myocardial infarction patients who undergo early catheterization and in-hospital CABG. Despite longer delays to surgery, the majority of pretreated patients proceed to CABG <3 days postcatheterization. Precatheterization P2Y12 inhibitor use is associated with higher risks of postoperative bleeding and transfusion.


Spectrophotometry and chromatography analyses combined with chemometrics tools to differentiate green coffee beans into special or traditional.
Green coffee is the hulled coffee bean, rich in chemical compounds indicative of quality before roasting, making the classification special or traditional. This work aimed to determine compounds in green coffee beans and find the differentiation of green coffee beans into special or traditional ones through chemometrics. For that, the levels of phenolic compounds, reducing, nonreducing, and total sugars were quantified by spectrophotometry: caffeine, trigonelline, 5-hydroxymethylfurfural (5-HMF), 3-hydroxybenzoic, 4-hydroxybenzoic, chlorogenic, caffeic, and nicotinic acids (NAs) by high-performance liquid chromatography-UV-Vis; acetaldehyde, acetone, methanol, ethanol, and isoamyl by HS-GC-FID. Principal component analysis (PCA) was used to differentiate green coffee beans through the levels obtained in spectrophotometric and chromatographic analyses. Statistically, the contents of total phenolic compounds, caffeine, nonreducing sugars, total sugars, NA, 5-HMF, acetaldehyde, ethanol, and ethanol/methanol showed significant differences. The PCA made it possible to classify green coffee beans into special and traditional, in addition to understanding the attributes that influenced the differentiation between coffees. In addition, it was possible to classify green coffee beans into special and traditional, either using all parameters evaluated or only using spectrophotometric analyses. In this way, some advantages allow classification without using a trained and experienced evaluator as their previous experience can influence the results due to their expertise in a certain type of coffee, in addition to being faster and cheaper, especially regarding spectrophotometric analyses.


A case study of the impact of a dietitian in the multi-disciplinary team within primary care: a service evaluation.
Expanding the primary care workforce to alleviate general practitioner (GP) workload, improve access and improve quality of care is a current UK strategy. Evidence suggests dietitians can improve patient outcomes and make cost savings. The present study aimed to evaluate a dietitian working as an expert generalist and first contact practitioner (FCP) in a general practice multi-disciplinary team (MDT) to provide appropriate care to patients and reduce GP workload. A dietitian was employed for 6 months at 0.6 full-time equivalents in a group of general practices in Devon, UK. Data were collected on the referral source, patient satisfaction, health outcomes and changes in prescribing data for all patients seen by the dietitian. Focus groups and interviews provided data to understand the experience of introducing a dietitian into the team. This model of service delivery showed the dietitian acting as an expert generalist, a FCP and able to educate the MDT. A range of professionals within the MDT referred patients with a wide range of diagnoses (both paediatric and adults) and the dietitian acted as a FCP for 29% of patients. Saving were made for the optimisation of medicine management. The dietitian can improve patient-centred care for several patient groups; enhance learning for staff around nutrition and dietary issues; and contribute to more efficient working and cost savings around prescription of nutritional products. This was an evaluation of one service and further research is needed to understand the value dietitians can contribute and the factors supporting effective and efficient working in this context.


The molecular basis for cross-reacting material-positive hemophilia A due to missense mutations within the A2-domain of factor VIII.
Factor VIII (FVIII) is the protein defective in the bleeding disorder hemophilia A. Approximately 5% of hemophilia A patients have normal amounts of a dysfunctional FVIII protein and are termed cross-reacting material (CRM)-positive. The majority of genetic alterations that result in CRM-positive hemophilia A are missense mutations within the A2-domain. To determine the mechanistic basis of the genetic defects within the A2-domain for FVIII function we constructed six mutations within the FVIII cDNA that were previously found in five CRM-positive hemophilia A patients (R527W, S558F, I566T, V634A, and V634M) and one CRM-reduced hemophilia A patient (DeltaF652/3). The specific activity for each mutant secreted into the conditioned medium from transiently transfected COS-1 cells correlated with published data for the patients plasma-derived FVIII, confirming the basis of the genetic defect. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of immunoprecipitated FVIII protein radiolabeled in COS-1 cells showed that all CRM-positive mutant proteins were synthesized and secreted into the medium at rates similar to wild-type FVIII. The majority of the DeltaF652/3 mutant was defective in secretion and was degraded within the cell. All mutant FVIII proteins were susceptible to thrombin cleavage, and the A2-domain fragment from the I566T mutant had a reduced mobility because of use of an introduced potential N-linked glycosylation site that was confirmed by N-glycanase digestion. To evaluate interaction of FVIII with factor IXa, we performed an inhibition assay using a synthetic peptide corresponding to FVIII residues 558 to 565, previously shown to be a factor IXa interaction site. The concentration of peptide required for 50% inhibition of FVIII activity (IC50) was reduced for the I566T (800 mumol/L) and the S558F (960 mumol/L) mutants compared with wild-type FVIII (> 2,000 mumol/L). N-glycanase digestion increased I566T mutant FVIII activity and increased its IC50 for the peptide (1,400 mumol/L). In comparison to S558F, a more conservative mutant (S558A) had a sixfold increased specific activity that also correlated with an increased IC50 for the peptide. These results provided support that the defects in the I566T and S558F FVIII molecules are caused by steric hindrance for interaction with factor IXa.


Effects of Trecadrine, a beta3-adrenergic agonist, on leptin secretion, glucose and lipid metabolism in isolated rat adipocytes.
Leptin, a hormone produced in adipocytes, is a key signal in the regulation of food intake and energy expenditure. Beta-adrenergic agonists have been shown to inhibit leptin gene expression and leptin secretion. The mechanisms underlying the inhibitory effects of beta-adrenergic agonists have not been established. In this study, we examined the effects of Trecadrine, a novel beta3-adrenergic agonist, on basal and insulin-stimulated leptin secretion in isolated rat adipocytes. Because insulin-stimulated glucose metabolism is an important regulator of leptin expression and secretion by the adipocytes, the effects of Trecadrine on indices of adipocyte metabolism were also examined. Isolated adipocytes were incubated with Trecadrine (10(-8)-10(-4) M) in the absence or presence of insulin (1.6 nM). Leptin secretion, glucose utilization, lactate production, glucose incorporation into CO(2) and triglyceride, as well as lipolysis (glycerol release) were determined. Trecadrine induced a concentration-dependent inhibition of basal leptin secretion. Trecadrine also decreased insulin-stimulated leptin secretion; however, the effect was not as pronounced as in the absence of insulin. Treatment of adipocytes with Trecadrine increased basal glucose utilization and produced a further increase in insulin-stimulated glucose utilization. Basal lactate production was also increased by Trecadrine; however, the proportion (percentage) of glucose carbon released as lactate was unaffected. In the presence of insulin, absolute lactate production was unaffected by Trecadrine at 96 h. However, the percentage of glucose carbon released as lactate was significantly decreased by insulin treatment, and was further decreased by the co-treatment with Trecadrine. Trecadrine induced a dose-dependent increase of the absolute amount of glucose incorporated into triglyceride. However, the percentage of glucose utilized that was incorporated into triglyceride was unaffected by Trecadrine. Trecadrine did not modify the proportion of glucose utilized that was oxidized to CO(2). Trecadrine increased glycerol release after 96 h of treatment. Glycerol release was negatively correlated with leptin secretion. These results suggest that alterations of glucose metabolism are not directly involved in the effects of beta3-adrenergic agonists to inhibit leptin expression and secretion. The inverse relationship between leptin secretion and the increase of glycerol levels, which is an index of the activation of cAMP-dependent protein kinases, suggests that activation of the cAMP signaling pathway mediates the inhibitory effects of Trecadrine on leptin gene expression and secretion.


The effect of bronchodilator drugs on breath-holding capability in asthma.
A method of assessing the relationship between maximum voluntary breath-holding time (BHT) and the partial pressure of end-tidal carbon dioxide (PETCO2) during hyperoxic carbon dioxide rebreathing is described. The resulting index is referred to as the breath-holding capability (BHC). BHC and the maximum rate of early inspiratory pressure fall at the mouth while breathing oxygen at rest (RHdP/dtmax) were measured in normal and asthmatic subjects before and after treatment with nebulized solutions of salbutamol and ipratropium bromide. BHC was low in asthmatics when their airflow resistance was high and rose when the airflow resistance fell as the result of treatment; RHdp/dtmax was high in the asthmatics before treatment and fell after bronchodilator drugs were administered. The fall in respiratory drive which followed bronchodilatation in the asthmatic subjects cannot be solely explained in terms of the resulting fall in viscous and elastic work of breathing. Vagal afferent signals arising in the airways might play a part in modifying respiratory drive in such circumstances.


Hydrogenase in Rhizobium japonicum Increases Nitrogen Fixation by Nodulated Soybeans.
Some Rhizobium strains synthesize a unidirectional hydrogenase system in legume nodule bacteroids; this system participates in the recycling of hydrogen that otherwise would be lost as a by-product of the nitrogen fixation process. Soybeans inoculated with Rhizobium japonicum strains that synthesized the hydrogenase system fixed significantly more nitrogen and produced greater yields than plants inoculated with strains lacking hydrogen-uptake capacity. Rhizobium strains used as inocula for legumes should have the capability to synthesize the hydrogenase system as one of their desirable characteristics.


Intrathecal Actions of the Cannabis Constituents Δ(9)-Tetrahydrocannabinol and Cannabidiol in a Mouse Neuropathic Pain Model.
(1) Background: The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), synergistically reduce allodynia in various animal models of neuropathic pain. Unfortunately, THC-containing drugs also produce substantial side-effects when administered systemically. We examined the effectiveness of targeted spinal delivery of these cannabis constituents, alone and in combination. (2) Methods: The effect of acute intrathecal drug delivery on allodynia and common cannabinoid-like side-effects was examined in a mouse chronic constriction injury (CCI) model of neuropathic pain. (3) Results: intrathecal THC and CBD produced dose-dependent reductions in mechanical and cold allodynia. In a 1:1 combination, they synergistically reduced mechanical and cold allodynia, with a two-fold increase in potency compared to their predicted additive effect. Neither THC, CBD nor combination THC:CBD produced any cannabis-like side-effects at equivalent doses. The anti-allodynic effects of THC were abolished and partly reduced by cannabinoid CB1 and CB2 receptor antagonists AM281 and AM630, respectively. The anti-allodynic effects of CBD were partly reduced by AM630. (4) Conclusions: these findings indicate that intrathecal THC and CBD, individually and in combination, could provide a safe and effective treatment for nerve injury induced neuropathic pain.


A matching algorithm to address imbalances in study populations: application to the National Institute of Neurological Diseases and Stroke Recombinant Tissue Plasminogen Activator acute stroke trial.
Outcome from stroke is highly dependent on baseline conditions. Patients with stroke have a wide range of severities, ages, and etiologies and it has proven difficult to achieve randomization of key variables in clinical trials. We present a new post hoc approach to achieve balance among selected variables. To illustrate the approach, we rebalanced the National Institute of Neurological Diseases and Stroke Recombinant Tissue Plasminogen Activator trial, in which the contribution of baseline imbalances continues to be debated. We selected baseline stroke severity (National Institutes of Health Stroke Scale), age, and glucose as matching criteria. The closest matched placebo and treated subjects were identified based on nearness to each other in 3-dimensional Euclidean space. Matching was performed within the quintiles of National Institutes of Health Stroke Scale that have been previously used to assess balance. Subjects who could not be matched were eliminated. Outcomes were assessed using the original specified National Institute of Neurological Diseases and Stroke trial measures. We successfully matched the 2 arms resulting in nearly identical baseline characteristics and distribution among quintiles. Despite fewer subjects after outlier elimination, the primary outcome measures remained significantly improved. After rebalancing, the magnitude of benefit was reduced by 13% to 23%. Benefit was apparent mostly in the large vessel occlusion subtype. This study demonstrated the feasibility of rebalancing individual subjects within a randomized trial. After rebalancing and outlier elimination, recombinant tissue plasminogen activator continued to demonstrate improved outcome. That the apparent treatment effect was reduced suggests that imbalances contributed to the magnitude of the original National Institute of Neurological Diseases and Stroke outcomes. This method could in theory be applied to any data set to find matched subjects for outcome or other analyses.


ImmunoDB: a web based tool to analyze preclinical data.
Often researchers find it difficult to interpret and correlate the results obtained from several experiments thus the development of a system that would allow storage, display and data analysis would be very useful. A web based interface is presented that allows people from a laboratory to submit the collected data and to compare results within different experiments. The interface was designed to be user-friendly and to be a basis of a flexible tool for performing analysis in an intuitive manner.


Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors.
The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. However, because of a similarly essential role for the host proteasome, the key property of any antiproteasome therapeutic is selectivity. Several parasite-specific proteasome inhibitors have recently been reported, however, their selectivity must be improved to enable clinical development. Here we describe screening of diverse libraries of non-natural synthetic fluorogenic substrates to identify determinants at multiple positions on the substrate that produce enhanced selectivity. We find that selection of an optimal electrophilic "warhead" is essential to enable high selectivity that is driven by the peptide binding elements on the inhibitor. We also find that host cell toxicity is dictated by the extent of coinhibition of the human β2 and β5 subunits. Using this information, we identify compounds with over 3 orders of magnitude selectivity for the parasite enzyme. Optimization of the pharmacological properties resulted in molecules that retained high potency and selectivity, were soluble, sufficiently metabolically stable and orally bioavailable. These molecules are highly synergistic with ART and can clear parasites in a mouse model of infection, making them promising leads as antimalarial drugs.