Hydroperoxides in plasma are reduced by intensified insulin treatment. A randomized controlled study of IDDM patients with microalbuminuria.
An association between reactive oxygen species and diabetic micro- and macrovascular complications has been proposed. In the present study, we have examined the effect of an improved blood glucose control on plasma levels of hydroperoxides in patients with IDDM. Subjects included 30 young IDDM patients with microalbuminuria who were randomized to receive either continuous subcutaneous insulin infusion (CSII) by a portable insulin pump (n = 15) or conventional insulin treatment (CIT) (n = 15) for 24 months. Plasma levels of hydroperoxides were measured by the ferrous oxidation with Xylenol Orange, version 2 (FOX2) assay. This method measures total lipid hydroperoxides and, unlike other methods, does not suffer from extraction losses. The mean HbA1c level was lower in the CSII group at the end of the study than in the CIT group: (mean [95% CI]) 8.6 (8.1-9.1) vs. 9.6 (9.0-10.3)%, respectively (P < 0.002). The level of plasma hydroperoxides was very similar at the start of the study but was significantly lower in the CSII group compared with the CIT group at the end of the study: 2.9 (2.1-3.7) vs. 4.3 (3.2-5.4) mumol/l, respectively (P < 0.02). In the CSII group, hydroperoxides were reduced by 31% from baseline (P < 0.001), whereas there was no change in levels of hydroperoxides in the CIT group. Mean hydroperoxide levels correlated with mean HbA1c during the study (r = 0.39, P < 0.04). Hydroperoxide levels were associated with the levels of microalbuminuria (r = 0.45, P < 0.02). This study provides support for the hypothesis that hyperglycemia is an important factor in the generation of hydroperoxides, and, thus, reactive oxygen species, in the circulation of IDDM patients.


An Overview of Golgi Membrane-Associated Degradation (GOMED) and Its Detection Methods.
Autophagy is a cellular mechanism that utilizes lysosomes to degrade its own components and is performed using Atg5 and other molecules originating from the endoplasmic reticulum membrane. On the other hand, we identified an alternative type of autophagy, namely, Golgi membrane-associated degradation (GOMED), which also utilizes lysosomes to degrade its own components, but does not use Atg5 originating from the Golgi membranes. The GOMED pathway involves Ulk1, Wipi3, Rab9, and other molecules, and plays crucial roles in a wide range of biological phenomena, such as the regulation of insulin secretion and neuronal maintenance. We here describe the overview of GOMED, methods to detect autophagy and GOMED, and to distinguish GOMED from autophagy.


[Metabolic effects of succinic and nicotinic acids in emotional pain stress].
In experiments on rats it was shown that administration of succinic and nicotinic acids in doses of 30 and 4 mg/kg for 5 days elevated pyruvic acid level and changed catecholamine balance in tissues of the aorta and heart. The administration of the drugs to rats with current-induced stress partially eliminated unfavourable shifts in carbohydrate metabolism and catecholamine balance in the aortic and cardiac tissues. Succinic acid had more pronounced metabolic activity.


Evaluation of toxicity of two pesticides: flucycloxuron and diflubenzuron on a cellular model, Paramecium sp.
The effect of two pesticides, the diflubenzuron (DFB) and the Flucycloxuron (FCX) has been studied on a cellular model: Paramecium sp., a ciliated protiste. The treatment with the DFB in the concentrations of 10 and 20 microg/ml reduces the growth of this protiste appreciably. The survey of the respiratory metabolism by the polarography technique (Oxygen electrode) shows a sensitive inhibition of the oxygen consumption by the studied protiste. In the case of the FCX, the treatment with the two concentrations (10 and 20 microg/ml) reveals an inhibition of the ciliated protiste growth; however, this pesticide inhibits the respiratory metabolism of ciliated protiste. This effect is a lot more marked with the FCX that with the DFB. The coloration with neutral red showed a perturbation in cuticle level, translated by the penetration quantity of the color in treated cells, especially at 20 microg/ml of FCX.


The design of clinical graft studies.
This paper contains certain proposals for future graft studies. Graft failure should be defined as any occlusion of the graft. Time should be measured from the end of operation to the first occlusion of the graft. The results should be analysed by the Kaplan-Meier estimator, and patency rates should be compared by the log-rank test or Gehan's test. It is stressed that scientifically valid data can only be obtained in prospective, randomized trials.


Aspirin and immunotherapy: a Faustian bargain?
Fibrinogen-like protein 1 (FGL1) has been associated with improved survival in hepatocellular carcinoma (HCC). However, recent evidence suggests that FGL1 may bind to surface receptors on lymphocytes and induce immune senescence. In this issue of the JCI, Lin and co-authors show that FGL1 may be acetylated by aspirin and targeted for degradation, which is associated with increased antitumor immunity and improved survival. Similar findings were obtained with inhibitors of sirtuin 2 (SIRT2), a histone deacetylase. These findings expand our current understanding of the role of FGL1 in cancer and provide an impetus for the evaluation of alternative immunotherapy combinations in HCC.


Global convergence in leaf respiration from estimates of thermal acclimation across time and space.
Recent compilations of experimental and observational data have documented global temperature-dependent patterns of variation in leaf dark respiration (R), but it remains unclear whether local adjustments in respiration over time (through thermal acclimation) are consistent with the patterns in R found across geographical temperature gradients. We integrated results from two global empirical syntheses into a simple temperature-dependent respiration framework to compare the measured effects of respiration acclimation-over-time and variation-across-space to one another, and to a null model in which acclimation is ignored. Using these models, we projected the influence of thermal acclimation on: seasonal variation in R; spatial variation in mean annual R across a global temperature gradient; and future increases in R under climate change. The measured strength of acclimation-over-time produces differences in annual R across spatial temperature gradients that agree well with global variation-across-space. Our models further project that acclimation effects could potentially halve increases in R (compared with the null model) as the climate warms over the 21st Century. Convergence in global temperature-dependent patterns of R indicates that physiological adjustments arising from thermal acclimation are capable of explaining observed variation in leaf respiration at ambient growth temperatures across the globe.


Critical review of norovirus surrogates in food safety research: rationale for considering volunteer studies.
The inability to propagate human norovirus (NoV) or to clearly differentiate infectious from noninfectious virus particles has led to the use of surrogate viruses, like feline calicivirus (FCV) and murine norovirus-1 (MNV), which are propagatable in cell culture. The use of surrogates is predicated on the assumption that they generally mimic the viruses they represent; however, studies are proving this concept invalid. In direct comparisons between FCV and MNV, their susceptibility to temperatures, environmental and food processing conditions, and disinfectants are dramatically different. Differences have also been noted between the inactivation of NoV and its surrogates, thus questioning the validity of surrogates. Considerable research funding is provided globally each year to conduct surrogate studies on NoVs; however, there is little demonstrated benefit derived from these studies in regard to the development of virus inactivation techniques or food processing strategies. Human challenge studies are needed to determine which processing techniques are effective in reducing NoVs in foods. A major obstacle to clinical trials on NoVs is the perception that such trials are too costly and risky, but in reality, there is far more cost and risk in allowing millions of unsuspecting consumers to contract NoV illness each year, when practical interventions are only a few volunteer studies away. A number of clinical trials have been conducted, providing important insights into NoV inactivation. A shift in research priorities from surrogate research to volunteer studies is essential if we are to identify realistic, practical, and scientifically valid processing approaches to improve food safety.


Low frequency of mismatch repair deficiency in gallbladder cancer.
DNA mismatch repair (MMR) deficiency is a major pathway of genomic instability in cancer. It leads to the accumulation of numerous mutations predominantly at microsatellite sequences, a phenotype known as microsatellite instability (MSI). MSI tumors have a distinct clinical behavior and commonly respond well to immune checkpoint blockade, irrespective of their origin. Data about the prevalence of MSI among gallbladder cancer (GBC) have been conflicting. We here analyzed a well-characterized cohort of 69 Western-world GBCs. We analyzed the mononucleotide MSI marker panel consisting of BAT25, BAT26, and CAT25 to determine the prevalence of MMR deficiency-induced MSI. MSI was detected in 1/69 (1.4%) of analyzed GBCs. The detected MSI GBC had a classical histomorphology, i.e. of acinar/tubular/glandular pancreatobiliary phenotype, and showed nuclear expression of all four MMR proteins MLH1, MSH2, MSH6, and PMS2. The MSI GBC patient showed a prolonged overall survival, despite having a high tumor stage at diagnosis. The patient had no known background or family history indicative of Lynch syndrome. Even though the overall number of MSI tumors is low in GBC, the potentially therapeutic benefit of checkpoint blockade in the respective patients may justify MSI analysis of GBC.


Antimicrobial resistance determinants of Escherichia coli isolates recovered from some rivers in Osun State, South-Western Nigeria: Implications for public health.
The inevitable development of resistance has sunk the great success achieved in the discovery of antimicrobial agents and dashed the hope of man in the recovery from infections and illnesses, as diseases and disease agents that were once thought to be controlled by antimicrobials are now re-emerging in new leagues resistance to therapy. A total of 300 PCR confirmed Escherichia coli isolates recovered from different river sources in Osun State, Nigeria were evaluated for their antibiogram profiling by the disc diffusion method and the resistant isolates were further profiled for their genotypic antimicrobial resistance determinants by polymerase chain reaction assays. Among the 20 antimicrobials selected from 10 families, resistance among sulfonamides, β-lactams and tetracyclines were found to be most frequent than phenicols and aminoglycosides with a noticeable increase in the number of multi-drug resistance ranging from three to nine antimicrobials. A total of 19 resistance determinants were assessed with their prevalence and distributions obtained as follows; [sulfonamides sulI (8%), sulII (41%)], [β-lactams; ampC 22%; blaTEM, (21%), and blaZ (18%),], [tetracyclines tetA (24%), tetB (23%), tetC (18%), tetD (78%), tetK (15%), and tetM, (10%)], [phenicols; catI (37%), catII (28%), and cmIA1 (19%)] and [aminoglycosides; aacC2 (8%), aphA1 (80%), aphA2 (80%), aadA (79%) and strA (38%)]. The Pearson chi-square exact test revealed many strong significant associations among ampC, blaTEM, blaZ and tetA genes with some determinants screened. The findings signify high increase in the prevalence of multidrug resistant E. coli isolates and resistance determinants indicating increased public health risks associated with the ingestion of waters from untreated sources. Hence, a necessity for safe water supply, provision of proper sanitation facilities and good surveillance programmes to monitor antimicrobial resistance patterns in water bodies.


Epidemiology of the post-polio syndrome.
A late-onset syndrome, consisting of muscle weakness, muscle pain, and unaccustomed fatigue, has been reported with increasing frequency among former poliomyelitis patients. A population-based cohort of poliomyelitis patients from Allegheny County, Pennsylvania, was traced and surveyed to estimate the prevalence and incidence and to identify determinants of the post-polio syndrome. A questionnaire validated in clinical examinations of 40 cohort members was used in the survey. The prevalence of the post-polio syndrome was 28.5% of all paralytic cases (95% confidence interval 24.4-32.6). The risk of post-polio syndrome was significantly higher among patients who sustained substantial permanent impairment after polio and among females. The incidence did not vary with age at acute onset, acute severity, or level of physical activity after recovery. The strongest determinant of post-polio syndrome onset was the length of the interval following the acute illness, with incidence peaking at 30-34 years. Of all cases of post-polio syndrome, 79% reported no major change in impairment status since onset. This study demonstrates that poliomyelitis patients are not equally susceptible to post-polio syndrome within the interval of 30-40 years after the original illness. For syndrome cases, the onset was associated with new neuromuscular symptoms and functional changes but not with major new impairment.


Helical Foldamers Incorporating Photoswitchable Residues for Light-Mediated Modulation of Conformational Preference.
An E unsaturated fumaramide linkage may be introduced into Aib peptide foldamer structures by standard coupling methods and photoisomerized to its Z (maleamide) isomer by irradiation with UV light. As a result of the photoisomerization, a new hydrogen-bonded contact becomes possible between the peptide domains located on either side of the unsaturated linkage. Using the fumaramide/maleamide linker to couple a chiral and an achiral fragment allows the change in hydrogen bond network to communicate a conformational preference, inducing a screw sense preference in the achiral domain of the maleamide-linked foldamers that is absent from the fumaramides. Evidence for the induced screw sense preference is provided by NMR and CD, and also by the turning on by light of the diastereoselectivity of a peptide chain extension reaction. The fumaramide/maleamide linker thus acts as a "conformational photodiode" that conducts stereochemical information as a result of irradiation by UV light.


A death pheromone, oleic acid, triggers hygienic behavior in honey bees (Apis mellifera L.).
Eusocial insects live in teeming societies with thousands of their kin. In this crowded environment, workers combat disease by removing or burying their dead or diseased nestmates. For honey bees, we found that hygienic brood-removal behavior is triggered by two odorants - β-ocimene and oleic acid - which are released from brood upon freeze-killing. β-ocimene is a co-opted pheromone that normally signals larval food-begging, whereas oleic acid is a conserved necromone across arthropod taxa. Interestingly, the odorant blend can induce hygienic behavior more consistently than either odorant alone. We suggest that the volatile β-ocimene flags hygienic workers' attention, while oleic acid is the death cue, triggering removal. Bees with high hygienicity detect and remove brood with these odorants faster than bees with low hygienicity, and both molecules are strong ligands for hygienic behavior-associated odorant binding proteins (OBP16 and OBP18). Odorants that induce low levels of hygienic behavior, however, are weak ligands for these OBPs. We are therefore beginning to paint a picture of the molecular mechanism behind this complex behavior, using odorants associated with freeze-killed brood as a model.


Proteomic and Biological Analysis of the Effects of Metformin Senomorphics on the Mesenchymal Stromal Cells.
Senotherapeutics are new drugs that can modulate senescence phenomena within tissues and reduce the onset of age-related pathologies. Senotherapeutics are divided into senolytics and senomorphics. The senolytics selectively kill senescent cells, while the senomorphics delay or block the onset of senescence. Metformin has been used to treat diabetes for several decades. Recently, it has been proposed that metformin may have anti-aging properties as it prevents DNA damage and inflammation. We evaluated the senomorphic effect of 6 weeks of therapeutic metformin treatment on the biology of human adipose mesenchymal stromal cells (MSCs). The study was combined with a proteome analysis of changes occurring in MSCs' intracellular and secretome protein composition in order to identify molecular pathways associated with the observed biological phenomena. The metformin reduced the replicative senescence and cell death phenomena associated with prolonged in vitro cultivation. The continuous metformin supplementation delayed and/or reduced the impairment of MSC functions as evidenced by the presence of three specific pathways in metformin-treated samples: 1) the alpha-adrenergic signaling, which contributes to regulation of MSCs physiological secretory activity, 2) the signaling pathway associated with MSCs detoxification activity, and 3) the aspartate degradation pathway for optimal energy production. The senomorphic function of metformin seemed related to its reactive oxygen species (ROS) scavenging activity. In metformin-treated samples, the CEBPA, TP53 and USF1 transcription factors appeared to be involved in the regulation of several factors (SOD1, SOD2, CAT, GLRX, GSTP1) blocking ROS.


Structure, dynamics and phase separation of measles virus RNA replication machinery.
The measles virus replication complex represents a potentially important, but as yet relatively unexplored target for viral inhibition. Little is known about the molecular mechanisms that underpin replication and transcription in paramyxoviruses. In recent years it has become clear that conformational dynamics play an important role in paramyxoviral replication, and that a complete understanding of the viral cycle requires a description of the structural plasticity of the different components. Here, we review recent progress in this direction, covering the dynamics of the nucleocapsid assembly process, high resolution structure and dynamics of protein:RNA interactions, and the investigation of the role of intrinsic conformational disorder in pre-assembly nucleoprotein/phosphoprotein complexes. Finally, we discuss the role of viral factories in the form of phase-separated membraneless organelles formed by measles virus phospho and nucleoproteins that promote the assembly of nucleocapsid structures.


Fire reduces parasite load in a Mediterranean lizard.
Wildfires are a natural disturbance in many ecosystems. However, their effect on biotic interactions has been poorly studied. Fire consumes the vegetation and the litter layer where many parasites spend part of their life cycles. We hypothesize that wildfires reduce habitat availability for parasites with consequent potential benefits for hosts. We tested this for the lizard Psammodromus algirus and its ectoparasites in a Mediterranean ecosystem. We predicted that lizards in recently burned areas would have lower parasite load (cleaning effect) than those in unburned areas and that this phenomenon implies that lizards spending their entire lives in postfire conditions experience a lower level of parasitism than those living in unburned areas. We compared the ectoparasite load of lizards between eight paired burned/unburned sites, including recent (less than 1 year postfire) and older fires (2-4 years). We found that lizards' ectoparasites prevalence was drastically reduced in recently burned areas. Likewise, lizards in older burned areas showed less evidence of past parasitic infections. Fire disrupted the host-parasite interaction, providing the opportunity for lizards to avoid the negative effects of ectoparasites. Our results suggest that wildfires probably fulfil a role in controlling vector-borne diseases and pathogens, and highlight ecological effects of wildfires that have been overlooked.


Beta-thalassemia major complicated by intracranial hemorrhage and critical illness polyneuropathy.
Intracranial hemorrhage (ICH) is rarely seen in patients with thalassemia. A seven-year-old male, known case of beta-thalassemia major, on irregular packed cell transfusions (elsewhere) and non-compliant with chelation therapy, presented with congestive cardiac failure (Hb-3 gm/dl). He received three packed red cell transfusions over 7 days (cumulative volume 40 cc/kg). On the 9th day, he developed projectile vomiting and two episodes of generalized tonic-clonic convulsions with altered sensorium. He had exaggerated deep tendon reflexes and extensor plantars. CT-scan of brain revealed bilateral acute frontal hematoma with diffuse subarachnoid hemorrhage (frontal and parietal). Coagulation profile was normal. CT-angiography of brain showed diffuse focal areas of reduced caliber of anterior cerebral, middle cerebral, and basilar and internal carotid arteries (likely to be a spasmodic reaction to subarachnoid hemorrhage). He required mechanical ventilation for 4 days and conservative management for the hemorrhage. However, on the 18th day, he developed one episode of generalized tonic-clonic convulsion and his sensorium deteriorated further (without any new ICH) and required repeat mechanical ventilation for 12 days. On the 28th day, he was noticed to have quadriplegia (while on a ventilator). Nerve conduction study (42nd day) revealed severe motor axonal neuropathy (suggesting critical illness polyneuropathy). He improved with physiotherapy and could sit upright and speak sentences at discharge (59th day). The child recovered completely after 3 months. It is wise not to transfuse more than 20 cc/kg of packed red cell volume during each admission and not more than once in a week (exception being congestive cardiac failure) for thalassemia patients.


On/off porosity switching and post-assembly modifications of Cu4L4 metal-organic polyhedra.
Synthetic porous materials composed of metal-organic polyhedra (MOPs) have found application in topical areas such as gas storage, separation and catalysis. Control over their physical properties (e.g. porosity) has typically been achieved through ligand design or judicious choice of metal ions. Here, we demonstrate pore-size control and on/off porosity in Cu4L4 MOPs by exploiting their structural non-rigidity. We report an aldehyde-functionalised MOP (1) that can be isolated in five distinct solvatomorphs, each exhibiting different structural flexibility. When soaked in MeOH, two of these solvatomorphs undergo a rapid transformation to a thermodynamically favoured phase, whilst in acetone they template the crystallisation of an entirely new crystal packing. We support these findings by single and powder X-ray diffraction and rationalise the observed phase transformations by lattice energy calculations. Of the five solvatomorphs, three can be obtained as solvent-exchanged pseudo-polymorphs with distinct porosities in their activated form (SABET = 35-455 m2 g-1). Further control over the crystal packing of MOPs is achieved through covalent post-assembly modifications, which promote the crystallisation of isoreticular 2-D sheet-like structures.


Reconstruction of parasacral hernia with acellular human dermis graft.
Parasacral hernias are defects through the pelvic floor which occur as the result of sacral resection. These defects are often large, and are frequently the result of treatment for sacral malignancies. This report documents the case of a 71-year-old woman who underwent radical coccygectomy and partial sacrectomy for a chordoma and subsequently presented 1 year later with a large parasacral hernia. The defect was repaired using an acellular human dermis graft with a gluteus maximus muscle-advancement flap overlay. This article summarizes the current literature of this challenging clinical problem, and examines the use of acellular human dermis in the repair of complex hernias.


Learning psychology as a challenging process towards development as well as "studies as usual": a thematic analysis of medical students' reflective writing.
Reflective writing in medical training has been shown to be most effective when combined with some form of personal meeting or dialog. During a course in medical psychology for medical students, reflective texts were followed up by an individual personal talk with a teacher from the course. Thematic analysis of the texts revealed four separate sub-themes: 1) the course has enabled me and the class to develop, which is good albeit arduous; 2) understanding myself is a resource in understanding people as well as knowing psychology; 3) the course provided me with new, purely intellectual skills as well as eye-openers; and 4) the receiving teacher is an integral part of my reflective writing. The main theme, capturing the students' writing process, concluded that students perceive the course as "Learning psychology as a challenging process towards development" as well as "studies as usual". Ethical, psychological, and pedagogical aspects are discussed in the paper.


Public support in England for raising the price of cigarettes to fund tobacco control activities.
Increasing the price of cigarettes reduces consumption, with a global price elasticity of approximately -0.4. In the UK where the cost of cigarettes is already relatively high, there is an issue surrounding public acceptance of further price rises ahead of the inflation rate. Previous research suggests that price increases may be supported where funds are dedicated to tobacco control. This study assessed public support in England for such a policy. A cross-sectional household survey was conducted in England between August 2008 and January 2009. A representative sample of 8736 respondents aged 16+, of whom 1900 (22%) were cigarette smokers at the time of the survey, was recruited. The primary outcome measure was support for a 20p (4%) price increase on a pack of cigarettes with proceeds going to fund tobacco control activities. 6216 participants (71%), including half (47%) of current cigarette smokers, indicated that they would support a 20p price increase if funds were dedicated to tobacco control activities. Levels of support among smokers were similar across the social gradient and gender. Younger smokers were more likely to support the increase. Smokers who smoked 0-10 cigarettes per day were more supportive of the increase than heavier smokers. There is broad public support for raising the cost of cigarettes with funds being used for tobacco control activities. The absence of a social gradient among smokers concurs with other research showing that more disadvantaged smokers are as engaged with tobacco control objectives as more affluent smokers.


Autoinhibition of Mint1 adaptor protein regulates amyloid precursor protein binding and processing.
Mint adaptor proteins bind to the amyloid precursor protein (APP) and regulate APP processing associated with Alzheimer's disease; however, the molecular mechanisms underlying Mint regulation in APP binding and processing remain unclear. Biochemical, biophysical, and cellular experiments now show that the Mint1 phosphotyrosine binding (PTB) domain that binds to APP is intramolecularly inhibited by the adjacent C-terminal linker region. The crystal structure of a C-terminally extended Mint1 PTB fragment reveals that the linker region forms a short α-helix that folds back onto the PTB domain and sterically hinders APP binding. This intramolecular interaction is disrupted by mutation of Tyr633 within the Mint1 autoinhibitory helix leading to enhanced APP binding and β-amyloid production. Our findings suggest that an autoinhibitory mechanism in Mint1 is important for regulating APP processing and may provide novel therapies for Alzheimer's disease.


A prospective randomized controlled multicenter trial comparing antibiotic therapy with appendectomy in the treatment of uncomplicated acute appendicitis (APPAC trial).
Although the standard treatment of acute appendicitis (AA) consists of an early appendectomy, there has recently been both an interest and an increase in the use of antibiotic therapy as the primary treatment for uncomplicated AA. However, the use of antibiotic therapy in the treatment of uncomplicated AA is still controversial. The APPAC trial is a randomized prospective controlled, open label, non-inferiority multicenter trial designed to compare antibiotic therapy (ertapenem) with emergency appendectomy in the treatment of uncomplicated AA. The primary endpoint of the study is the success of the randomized treatment. In the antibiotic treatment arm successful treatment is defined as being discharged from the hospital without the need for surgical intervention and no recurrent appendicitis during a minimum follow-up of one-year (treatment efficacy). Treatment efficacy in the operative treatment arm is defined as successful appendectomy evaluated to be 100%. Secondary endpoints are post-intervention complications, overall morbidity and mortality, the length of hospital stay and sick leave, treatment costs and pain scores (VAS, visual analoque scale). A maximum of 610 adult patients (aged 18-60 years) with a CT scan confirmed uncomplicated AA will be enrolled from six hospitals and randomized by a closed envelope method in a 1:1 ratio either to undergo emergency appendectomy or to receive ertapenem (1 g per day) for three days continued by oral levofloxacin (500 mg per day) plus metronidazole (1.5 g per day) for seven days. Follow-up by a telephone interview will be at 1 week, 2 months and 1, 3, 5 and 10 years; the primary and secondary endpoints of the trial will be evaluated at each time point. The APPAC trial aims to provide level I evidence to support the hypothesis that approximately 75-85% of patients with uncomplicated AA can be treated with effective antibiotic therapy avoiding unnecessary appendectomies and the related operative morbidity, also resulting in major cost savings.


Locomotion outcome in hemiplegic patients with middle cerebral artery infarction: the difference between right- and left-sided lesions.
This study was performed to analyze the locomotion outcome of hemiplegic patients with stroke and to explore the factors influencing it. A total of 247 patients (mean age 65.6 +/- 10.5 years) admitted to our hospital for rehabilitation were included in the study. Their cardinal neurologic sign was hemiplegia caused by infarction in the middle cerebral artery as a result of a first stroke. When rehabilitation programs were completed, the final motor outcome was evaluated and compared between patients with right and left hemispheric infarct. In addition, the following items were analyzed: size, location, and subtype of the infarct; hemispatial neglect and aphasia; cerebral blood flow (CBF); and periventricular lucency on computed tomography scan. (1) There was a negative relationship between the infarct size and the locomotion outcome. The difference in locomotion outcome was not significant between the patients with infarction of the perforating arteries and those of the cortical arteries. No significant difference in the locomotion outcome was found between the patients with an atherothrombotic or cardioembolic infarction. (2) In spite of the existence of hemispatial neglect or aphasia, the patients with a right-sided infarction were significantly inferior to patients with a left-sided one in locomotion outcome, except for those with a large infarction. (3) In patients with infarction in the territory of the perforating arteries, there was a negative relationship between the area of decreased CBF or periventricular lucency and the locomotion outcome. When the area of decreased CBF on the homolateral hemisphere involving the infarction extended to less than or equal to two cerebral lobes, the locomotion outcome was significantly worse in the patients with a right-sided infarction. Overall, for the patients with middle cerebral artery infarction, the locomotion outcome was poorer in patients with a right hemispheric infarction than a left-sided one, except in the case of a large infarction.


Deficient recovery response and adaptive feedback potential in dynamic gait stability in unilateral peripheral vestibular disorder patients.
Unilateral peripheral vestibular disorder (UPVD) causes deficient locomotor responses to novel environments due to a lack of accurate vestibular sensory information, increasing fall risk. This study aimed to examine recovery response (stability recovery actions) and adaptive feedback potential in dynamic stability of UPVD-patients and healthy control subjects during perturbed walking. 17 UPVD-patients (>6 months since onset) and 17 matched healthy control participants walked on a treadmill and were subjected to eight unexpected perturbations during the swing phase of the right leg. For each perturbation, the margin of stability (MS; state of body's centre of mass in relation to the base of support), was determined at touchdown of the perturbed leg and during the following six recovery steps. The first perturbation caused a reduced MS at touchdown for the perturbed leg compared to baseline, indicating an unstable position, with controls requiring five recovery steps to return to MS baseline and UPVD-patients not returning to baseline level within the analyzed six recovery steps. By the eighth perturbation, control subjects needed two steps, and UPVD-patients required three recovery steps, both thereby improving their recovery response with practice. However, MS at touchdown of the perturbed leg increased only for the controls after repeated perturbations, indicating adaptive feedback-driven locomotor improvements for the controls, but not for the UPVD-patients. We concluded that UPVD-patients have a diminished ability to control dynamic gait stability during unexpected perturbations, increasing their fall risk, and that vestibular dysfunction may inhibit the neuromotor system adapting the reactive motor response to perturbations.


The Work Environment Impact Scale - Self-Rating (WEIS-SR) evaluated in primary health care in Sweden.
To develop a self-report alternative to the Work Environment Impact Scale (WEIS). First the novel instrument was used and evaluated by ten occupational therapists and 45~clients in primary health care. Then the instrument was used by 26~clients who participated in a rehabilitation programme in another primary health care district. The instrument was investigated in two steps. First content validity and utility were investigated through a questionnaire addressed to occupational therapists and their clients respectively. The response distribution was calculated by frequencies. Internal consistency was investigated. In the second step, a revised version of the instrument was investigated for test-retest reliability and internal consistency. The test-retest reliability was calculated by weighted kappa. The internal consistency of the WEIS-SR was calculated by means of Cronbach's alpha. In step one the content validity was good to moderately good, the utility was good, and the internal consistency was satisfactory (0.72). In step two the internal consistency was good (0.88/0.89) and the test-retest reliability was mostly good to moderate (0.35-0.78, median 0.61). The instrument will be further investigated in other populations and take into consideration additional psychometric properties such as sensitivity to change, predictive validity, and concurrent validity.


Intraoperative airway obstruction in a Duchenne muscular dystrophy patient.
To report a complication of airway obstruction during spinal deformity correction surgery in Duchenne muscular dystrophy (DMD) patient, due to lordoscoliosis, airway malacia, and prone surgical positioning, which was rectified by changing the position of the patient and surgery was successfully completed. A 15-year-old boy was diagnosed with DMD and admitted for surgical treatment of thoracolumbar scoliosis. The patient's preoperative Cobb's angle was 79° and the kyphotic angle was -19°. During the initial period of surgery, while in the prone position, peak inspiratory pressure (PIP) suddenly increased from 20-21 to 38-41 cmH2O, wheezing sounds were heard on auscultation of both lungs, and his blood pressure began to fall. Under suspicion of airway problem, intraoperative fiberoptic bronchoscopy was performed which confirmed airway obstruction. Attributing patient's prone position as the cause of airway obstruction, the surgical position of the patient was changed from prone to semi-lateral. After this change, the PIP stabilized to within normal limits (20-23 cmH2O). The surgical correction was successfully completed with a posterior-only pedicle screw by the free-hand technique, with the patient in the semi-lateral position for the rest of surgery. Lordoscoliosis and airway malacia in a patient with DMD can lead to occlusion of the tracheobronchial lumen when the patient is in the prone position. Changing the patient's position from prone to semi-lateral can be of help to reverse this airway obstruction and complete the surgery. Pedicular screw insertion can be safely and effectively carried out in this position using free-hand technique.


Effectiveness, tolerability, and safety of subcutaneous methotrexate in early rheumatoid arthritis: A retrospective analysis of real-world data from the St. Gallen cohort.
Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment. Recently updated recommendations by the European League Against Rheumatism (EULAR) show MTX as an important part of the first-line strategy in patients with active RA. The study presented here aimed to assess the clinical effectiveness and tolerability of subcutaneous (SC) MTX among patients with RA. Patients with RA who were naïve at baseline to both conventional and biologic disease-modifying antirheumatic drugs, fulfilled the American College of Rheumatology/EULAR 2010 criteria, and had one or more follow-up visits were selected through sequential chart review for analysis of retrospective data. Patients received SC MTX at varying doses (10-25mg per week). The primary end point was a change in the Disease Activity Score including 28 joints (DAS28); secondary end points included time to employment of the first biologic agent and cumulative MTX doses. Overall, 70 patients were in follow-up for a mean of 1.8 years after initiating SC MTX treatment. During this time, 37 (53%) remained on SC MTX without any biologics (MTX-only) and 33 (47%) required the addition of a biologic therapy (MTX-biol). Biologic therapy was required after a mean ± SD of 387 ± 404 days. Mean weekly MTX doses were 17.4mg for patients in the MTX-only group and 19.1mg for patients in the MTX-biol group. Mean baseline DAS28 were similar for patients in the MTX-biol and MTX-only groups (4.9 and 4.7, respectively). Both low disease activity state (LDAS) and remission were achieved by slightly fewer patients in the MTX-biol than MTX-only groups (LDAS, 78.8% vs 81.1%; remission, 69.7% vs 75.7%). Over the full course of the study period, SC MTX was discontinued in 32 patients (46%). Among those who discontinued, the most common reasons were gastrointestinal discomfort (n = 7), lack of efficacy (n = 7), and disease remission (n = 3). Severe infections occurred in 3 patients in the MTX-biol group and 3 patients in the MTX-only group. SC MTX is a safe and effective treatment option for patients with RA. SC MTX resulted in high rates of remission and LDAS in early disease, over prolonged periods of time, it, therefore, may extend the time before patients require initiation of biologic therapy.


Effects of osmotic gradients on water and solute transport: in vivo studies in rat duodenum and ileum.
We examined effects of luminal osmolality on net water and solute movements in rat duodenum and ileum. Solutions of sodium chloride (permeating solute) or mannitol (nonpermeating solute) at hypo-, iso-, or hyperosmotic concentrations were recirculated through in situ segments. Luminal osmolality increased towards that of plasma with hyposmotic solutions of both solutes. With isosmotic solutions, luminal osmolality did not change with sodium chloride, but increased with mannitol. With hyperosmotic solutions, luminal osmolality always decreased toward that of plasma with sodium chloride; with mannitol, however, decreases were significant only when initial concentrations were above 400 mosmol/kg. The decrease in osmolality of hyperosmotic sodium chloride resulted from sodium absorption and water secretion. Thus, both hypo- and hyperosmotic solutions of sodium chloride adjusted toward isomolality with plasma by the usual mechanisms of water and solute movement. With mannitol, however, osmotic adjustment of hypertonic luminal contents was restricted or even absent due to movement of sodium down its concentration gradient and reduced hydraulic conductivity of the gut.


A randomized controlled trial of surgery vs steroid injection for carpal tunnel syndrome.
Decompressive surgery and steroid injection are widely used forms of treatment for carpal tunnel syndrome (CTS) but there is no consensus on their effectiveness in comparison to each other. The authors evaluated the efficacy of surgery vs steroid injection in relieving symptoms in patients with CTS. The authors conducted a randomized, single blind, controlled trial. Fifty patients with electrophysiologically confirmed idiopathic CTS were randomized and assigned to open carpal tunnel release (25 patients) or to a single injection of steroid (25 patients). Patients were followed up at 6 and 20 weeks. The primary outcome was symptom relief in terms of the Global Symptom Score (GSS), which rates symptoms on a scale of 0 (no symptoms) to 50 (most severe). Nerve conduction studies and grip strength measurements were used as secondary outcome assessments. At 20 weeks after randomization, patients who underwent surgery had greater symptomatic improvement than those who were injected. The mean improvement in GSS after 20 weeks was 24.2 (SD 11.0) in the surgery group vs 8.7 (SD 13.0) in the injection group (p < 0.001); surgical decompression also resulted in greater improvement in median nerve distal motor latencies and sensory nerve conduction velocity. Mean grip strength in the surgical group was reduced by 1.7 kg (SD 5.1) compared with a gain of 2.4 kg (SD 5.5) in the injection group. Compared with steroid injection, open carpal tunnel release resulted in better symptomatic and neurophysiologic outcome but not grip strength in patients with idiopathic carpal tunnel syndrome over a 20-week period.


Highly improved specificity for hybridization-based microRNA detection by controlled surface dissociation.
Poor specificity has been a lingering problem in many microRNA profiling methods, particularly surface hybridization-based methods such as microarrays. Here, we carefully investigated surface hybridization and dissociation processes of a number of sequentially similar microRNAs against nucleic acid capture probes. Single-base mismatched microRNAs were similarly hybridized to a complementary DNA capture probe and thereby poorly discriminated during conventional stringent hybridization. Interestingly, however, mismatched microRNAs showed significantly faster dissociation from the probe than the perfectly matched microRNA. Systematic analysis of various washing conditions clearly demonstrated that extremely high specificity can be obtained by releasing non-specific microRNAs from assay surfaces during a stringent and controlled dissociation step. For instance, compared with stringent hybridization, surface dissociation control provided up to 6-fold better specificity for Let-7a detection than for other Let-7 family microRNAs. In addition, a synthetically introduced single-base mismatch on miR206 was almost completely discriminated by optimized surface dissociation of captured microRNAs, while this mismatch was barely distinguished from target miR206 during stringent hybridization. Furthermore, a single dissociation condition was successfully used to simultaneously measure four different microRNAs with extremely high specificity using melting temperature-equalized capture probes. The present study on selective dissociation of surface bound microRNAs can be easily applied to various hybridization based detection methods for improved specificity.


A population-based serologic survey of immunity to tetanus in the United States.
Vaccination rates are frequently considered a surrogate measure of protection. To provide more accurate estimates, serum levels of antibody against tetanus were measured as part of the third National Health and Nutrition Examination Survey (NHANES III), which studied a representative sample of the civilian, noninstitutionalized population of the United States. We measured tetanus antitoxin using a solid-phase enzyme immunoassay in serum samples from 10,618 persons six years of age and older who were examined during phase 1 of NHANES III in 1988 to 1991. Overall, 69.7 percent of Americans six years of age and older had protective levels of tetanus antibodies (> 0.15 IU per milliliter). The rate decreased from 87.7 percent among those 6 to 11 years of age to 27.8 percent among those 70 years of age or older. Among children 6 to 16 years of age, 82.2 percent had protective levels of tetanus antibodies, with little variation according to race or ethnicity. More men than women were immune (79.0 percent vs. 62.4 percent). Mexican Americans had a significantly lower rate of immunity (57.9 percent, P < 0.05) than either non-Hispanic whites (72.7 percent) or non-Hispanic blacks (68.1 percent). Those with a history of military service, higher levels of education, or incomes above the poverty level were more likely to have protective antibody levels. Although the prevalence of immunity declined rapidly starting at the age of 40 years, most of the 107 cases of tetanus (with 20 deaths) reported in 1989 and 1990 occurred in persons 60 years of age or older. Despite the fact that effective vaccines against tetanus have been available since the 1940s, many Americans do not have immunity to tetanus, and the rates are lowest among the elderly. There is an excellent correlation between vaccination rates (96 percent) and immunity (96 percent) among six-year-olds. However, antibody levels decline over time, and one fifth of older children (10 to 16 years of age) do not have protective antibody levels.


Water deprivation upregulates angiotensin II receptors in rat anterior pituitary.
Angiotensin II (ANG II) receptors were quantitated in pituitary glands of individual male Long Evans rats by autoradiography after incubation of 8-microns thick pituitary sections with 125I-[Sar1]ANG II. Rat anterior pituitary had a single class of high-affinity saturable ANG II receptors with a Bmax of 1,360 +/- 109 fmol/mg protein and a Ka of 0.510 +/- 0.03 X 10(9) M-1. Five days of water deprivation produced a marked increase in the number of anterior pituitary ANG II receptors (Bmax: 2,428 +/- 233 fmol/mg protein, a 79% increase, P less than 0.001) and a decrease in affinity for the ligand (Ka: 0.337 +/- 0.01 10(9) M-1, a 34% decrease, P less than 0.05). Our results suggest a role for anterior pituitary ANG II receptors in the regulation of fluid and electrolyte metabolism in the rat.


Identification of genes differentially expressed during interaction of resistant and susceptible apple cultivars (Malus x domestica) with Erwinia amylovora.
The necrogenic enterobacterium, Erwinia amylovora is the causal agent of the fire blight (FB) disease in many Rosaceae species, including apple and pear. During the infection process, the bacteria induce an oxidative stress response with kinetics similar to those induced in an incompatible bacteria-plant interaction. No resistance mechanism to E. amylovora in host plants has yet been characterized, recent work has identified some molecular events which occur in resistant and/or susceptible host interaction with E. amylovora: In order to understand the mechanisms that characterize responses to FB, differentially expressed genes were identified by cDNA-AFLP analysis in resistant and susceptible apple genotypes after inoculation with E. amylovora. cDNA were isolated from M.26 (susceptible) and G.41 (resistant) apple tissues collected 2 h and 48 h after challenge with a virulent E. amylovora strain or mock (buffer) inoculated. To identify differentially expressed transcripts, electrophoretic banding patterns were obtained from cDNAs. In the AFLP experiments, M.26 and G.41 showed different patterns of expression, including genes specifically induced, not induced, or repressed by E. amylovora. In total, 190 ESTs differentially expressed between M.26 and G.41 were identified using 42 pairs of AFLP primers. cDNA-AFLP analysis of global EST expression in a resistant and a susceptible apple genotype identified different major classes of genes. EST sequencing data showed that genes linked to resistance, encoding proteins involved in recognition, signaling, defense and apoptosis, were modulated by E. amylovora in its host plant. The expression time course of some of these ESTs selected via a bioinformatic analysis has been characterized. These data are being used to develop hypotheses of resistance or susceptibility mechanisms in Malus to E. amylovora and provide an initial categorization of genes possibly involved in recognition events, early signaling responses the subsequent development of resistance or susceptibility. These data also provided potential candidates for improving apple resistance to fire blight either by marker-assisted selection or genetic engineering.


Carbon sequestration and climate change mitigation using macroalgae: a state of knowledge review.
The conservation, restoration, and improved management of terrestrial forests significantly contributes to mitigate climate change and its impacts, as well as providing numerous co-benefits. The pressing need to reduce emissions and increase carbon removal from the atmosphere is now also leading to the development of natural climate solutions in the ocean. Interest in the carbon sequestration potential of underwater macroalgal forests is growing rapidly among policy, conservation, and corporate sectors. Yet, our understanding of whether carbon sequestration from macroalgal forests can lead to tangible climate change mitigation remains severely limited, hampering their inclusion in international policy or carbon finance frameworks. Here, we examine the results of over 180 publications to synthesise evidence regarding macroalgal forest carbon sequestration potential. We show that research efforts on macroalgae carbon sequestration are heavily skewed towards particulate organic carbon (POC) pathways (77% of data publications), and that carbon fixation is the most studied flux (55%). Fluxes leading directly to carbon sequestration (e.g. carbon export or burial in marine sediments) remain poorly resolved, likely hindering regional or country-level assessments of carbon sequestration potential, which are only available from 17 of the 150 countries where macroalgal forests occur. To solve this issue, we present a framework to categorize coastlines according to their carbon sequestration potential. Finally, we review the multiple avenues through which this sequestration can translate into climate change mitigation capacity, which largely depends on whether management interventions can increase carbon removal above a natural baseline or avoid further carbon emissions. We find that conservation, restoration and afforestation interventions on macroalgal forests can potentially lead to carbon removal in the order of 10's of Tg C globally. Although this is lower than current estimates of natural sequestration value of all macroalgal habitats (61-268 Tg C year-1 ), it suggests that macroalgal forests could add to the total mitigation potential of coastal blue carbon ecosystems, and offer valuable mitigation opportunities in polar and temperate areas where blue carbon mitigation is currently low. Operationalizing that potential will necessitate the development of models that reliably estimate the proportion of production sequestered, improvements in macroalgae carbon fingerprinting techniques, and a rethinking of carbon accounting methodologies. The ocean provides major opportunities to mitigate and adapt to climate change, and the largest coastal vegetated habitat on Earth should not be ignored simply because it does not fit into existing frameworks.


Venous Congestion and Systemic Hypoperfusion in Cardiorenal Syndrome: Two Sides of the Same Coin.
A wide range of comorbidities play a pivotal role in worsening outcomes and increasing mortality risk in patients with heart failure (HF). Among them, renal dysfunction has been recognized as a highly prevalent prognostic variable, with a strong impact on prognosis, length of hospital stay and need for intensive care. In this context, recent evidence has pointed out the relevance of both systemic hypoperfusion and venous congestion on the imbalance of renal function as well as on the conditioning the pathophysiological crosstalk between heart and kidneys through a wide range of haemodynamic and biochemical pathways. This narrative review aims to investigate the intricate interplay between impaired systemic perfusion and venous congestion in cardiorenal syndrome, as well as their haemodynamic and biochemical implications for renal damage in HF.


The roles and responsibilities of physicians in Pre-Hospital Emergency Medical Services: A Caribbean perspective.
A Pre-hospital Emergency Medical Service (PHEMS) is a vital component of a country's health service because it provides early medical care to critically ill and injured persons in the field There is evidence to show that early care reduces mortality and morbidity and offers the patient the best chance of survival and improved quality of life. Caribbean territories have been developing their PHEMS as part of a programme of health sector reform. In a study of PHEMS in 12 Caribbean countries, the Pan American Health Organization reported that there were no clear guidelines with respect to the roles and responsibilities of the physician in PHEMS in the majority of countries. In fact, a few countries had services where there was no direct physician involvement. We present a brief review of the internationally recognized roles and responsibilities of physicians in PHEMS, and make recommendations with particular reference to the Caribbean. We suggest that there is a need for direct and active involvement of physicians in the development of PHEMS because the Emergency Medical Technician is recognized as an extension of the physician in the field and is supposed to be protected by the physician's licence to deliver medical care.


Radiation-induced cell death: importance of lysosomal destabilization.
The mechanisms involved in radiation-induced cellular injury and death remain incompletely understood. In addition to the direct formation of highly reactive hydroxyl radicals (HO*) by radiolysis of water, oxidative stress events in the cytoplasm due to formation of H2O2 may also be important. Since the major pool of low-mass redox-active intracellular iron seems to reside within lysosomes, arising from the continuous intralysosomal autophagocytotic degradation of ferruginous materials, formation of H2O2 inside and outside these organelles may cause lysosomal labilization with release to the cytosol of lytic enzymes and low-mass iron. If of limited magnitude, such release may induce 'reparative autophagocytosis', causing additional accumulation of redox-active iron within the lysosomal compartment. We have used radio-resistant histiocytic lymphoma (J774) cells to assess the importance of intralysosomal iron and lysosomal rupture in radiation-induced cellular injury. We found that a 40 Gy radiation dose increased the 'loose' iron content of the (still viable) cells approx. 5-fold when assayed 24 h later. Cytochemical staining revealed that most redox-active iron was within the lysosomes. The increase of intralysosomal iron was associated with 'reparative autophagocytosis', and sensitized cells to lysosomal rupture and consequent apoptotic/necrotic death following a second, much lower dose of radiation (20 Gy) 24 h after the first one. A high-molecular-mass derivative of desferrioxamine, which specifically localizes intralysosomally following endocytic uptake, added to the culture medium before either the first or the second dose of radiation, stabilized lysosomes and largely prevented cell death. These observations may provide a biological rationale for fractionated radiation.


[Range of neuromuscular involvement in 47 patients infected with the human immunodeficiency virus].
Over a 30 month period, 47 out of 749 patients infected with the human immunodeficiency virus had various neuromuscular symptoms. Based on clinical and electrophysiological data, 47% had distal symmetric polyneuropathy, 11% chronic inflammatory demyelinating polyneuropathy (CIDP), 8.5% toxic neuropathy related to 2-3-dideoxyinosine (DDI), 8.5% cranial neuropathy, 8.5% mononeuropathy multiplex or isolated focal neuropathy, 8.5% progressive lumbosacral polyradiculopathy, and 8.5% myopathy. Half of the patients exhibited previous or concomitant signs of central nervous system involvement and 18 patients died during the study period. CIDP and cranial neuropathies usually appeared early in the course of the disease and consequently showed neurological improvement. Nerve conduction studies of DDI related toxic neuropathies showed distal axono-myelinic sensitivo-motor neuropathy, differing from CIDP by the absence of a conduction block. Distal symmetric polyneuropathies, frequent in the advanced systemic illness, do not systematically require an extended workup, but more unusual peripheral neuropathies which might be treatable necessitate further investigations (electromyography, radiology, serological blood tests; protein chemistry and routine workup of the cerebrospinal fluid). For example, progressive lumbosacral polyradiculopathies responded to early treatment, with a better outcome in one case of herpetic origin than in another case due to cytomegalovirus infection. Our observations suggest that myopathies in HIV infected patients should first be tackled by temporary interruption of virostatic medication, followed by muscle biopsy if the symptoms persist.


The Compassion Club: A New Proposal for Transformation of Tobacco Retail.
One major assumption in the current tobacco industry is the distribution of tobacco products through a system of commercial for-profit retail. However, other models of distribution that do not rely on this mechanism exist. In this review, we examine the potential of a nonprofit Compassion Club model and discuss how the current existence of independent vape stores might provide the infrastructure to allow the transformation of tobacco distribution. Compassion Clubs exist internationally with different levels of regulation and legality and have generally been focused on the distribution of illegal drugs or hard-to-access pharmaceuticals. They provide access to drugs for existing users, limit access by novices, limit negative impacts from illicit markets, and provide social support focused on reducing harms associated with drug use. With decreasing prevalence of tobacco use in many countries and growing interest in a tobacco endgame, a Compassion Club model of distribution could help transition tobacco away from the model of commercial widely available distribution. More work is needed to develop the regulations and policies that might guide a compassion club model. Compassion clubs are a model for the distribution of psychoactive substances that are focused on harm reduction and social support rather than profit. There has been little discussion about the possibility that this promising model could be applied to help transform the tobacco industry. Many independent vape stores already demonstrate aspects of the compassion club model that could be used to support a transition.


Cytochrome P450s and cytochrome P450 reductase in the olfactory organ of the cotton leafworm Spodoptera littoralis.
Cytochrome P450 enzymes (P450s) are involved in many physiological functions in insects, such as the metabolism of signal molecules, adaptation to host plants and insecticide resistance. Several P450s have been reported in the olfactory organs of insects, the antennae, and have been proposed to play a role in odorant processing and/or xenobiotic metabolism. Despite recent transcriptomic analyses in several species, the diversity of antennal P450s in insects has not yet been investigated. Here, we report the identification of 37 putative P450s expressed in the antennae of the pest moth Spodoptera littoralis, as well as the characterization of a redox partner, cytochrome P450 reductase (CPR). Phylogenetic analysis revealed that S. littoralis P450s belong to four clades defined by their conservation with vertebrate P450s and their cellular localization. Interestingly, the CYP3 and CYP4 clans, which have been described to be mainly involved in the metabolism of plant compounds and xenobiotics, were largely predominant. More surprisingly, two P450s related to ecdysteroid metabolism were also identified. Expression patterns in adult and larval tissues were studied. Eight P450s appeared to be specific to the chemosensory organs, ie the antennae and proboscis, suggesting a specific role in odorant and tastant processing. Moreover, exposure of males to a plant odorant down-regulated the transcript level of CPR, revealing for the first time the regulation of this gene by odorants within insect antennae. This work suggests that the antennae of insects are a key site for P450-mediated metabolism of a large range of exogenous and endogenous molecules.


Combining network modeling and gene expression microarray analysis to explore the dynamics of Th1 and Th2 cell regulation.
Two T helper (Th) cell subsets, namely Th1 and Th2 cells, play an important role in inflammatory diseases. The two subsets are thought to counter-regulate each other, and alterations in their balance result in different diseases. This paradigm has been challenged by recent clinical and experimental data. Because of the large number of genes involved in regulating Th1 and Th2 cells, assessment of this paradigm by modeling or experiments is difficult. Novel algorithms based on formal methods now permit the analysis of large gene regulatory networks. By combining these algorithms with in silico knockouts and gene expression microarray data from human T cells, we examined if the results were compatible with a counter-regulatory role of Th1 and Th2 cells. We constructed a directed network model of genes regulating Th1 and Th2 cells through text mining and manual curation. We identified four attractors in the network, three of which included genes that corresponded to Th0, Th1 and Th2 cells. The fourth attractor contained a mixture of Th1 and Th2 genes. We found that neither in silico knockouts of the Th1 and Th2 attractor genes nor gene expression microarray data from patients with immunological disorders and healthy subjects supported a counter-regulatory role of Th1 and Th2 cells. By combining network modeling with transcriptomic data analysis and in silico knockouts, we have devised a practical way to help unravel complex regulatory network topology and to increase our understanding of how network actions may differ in health and disease.


Inhibitory effect of isavuconazole, ketoconazole, and voriconazole on the pharmacokinetics of methadone in vivo and in vitro.
The aim of this study was to investigate the possible effect of orally administered isavuconazole, ketoconazole, or voriconazole on the pharmacokinetics of methadone in rats. Twenty Sprague-Dawley (SD) rats were divided randomly into four groups: Group A (control), group B (5 mg/kg isavuconazole), group C (5 mg/kg ketoconazole), and group D (5 mg/kg voriconazole). A single dose of methadone was administrated half an hour later. Methadone in plasma concentrations and its metabolite EDDP in microsomes were determined by ultra-high-performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS), and pharmacokinetic parameters were calculated by DAS version 3.0. The Cmax of methadone in groups C and D increased to 2.7-fold and 5-fold, respectively. While AUC increased in three groups and group D increased the most. Also, isavuconazole, ketoconazole, and voriconazole showed inhibitory effect on human and rat microsomes. The inhibition ratios of isavuconazole, ketoconazole, and voriconazole in rat liver microsome were 97.87%, 96.74% and 78.9%, respectively (p < 0.01), while in human liver microsome, inhibition ratios were 86.97%, 96.46%, and 53.11%, respectively. And the IC50 for inhibition activity of isavuconazole, ketoconazole, and voriconazole in rat microsomes were 7.76 μM, 8.33 μM, and 4.45 μM, respectively. Our study indicated that taking methadone combine with ketoconazole, isavuconazole, or voriconazole could reduce the metabolism rate of methadone and prolong the pharmacological effects in vivo and in vitro.


Increase in serotonin precursor levels reinstates the context memory during reconsolidation.
In the present study, we tested possible ways of modification of the context long-term memory using the reconsolidation as a tool. Recently, using a depletion of the serotonin content, it was shown that the reinforcing neurotransmitter serotonin is necessary for successful repeated reconsolidation of context memory in terrestrial snails Helix lucorum (Balaban et al. in Sci Rep 6:36933, 2016), and in the present study, we investigated effects of serotonin increase in memory maintenance by injection of the serotonin precursor 5-hydroxytryptophan (5-HTP). We studied reinstatement of the context memory after its impairment during reconsolidation with a protein synthesis blocker anisomycin (ANI) or with a specific inhibitor of protein-kinase Mζ (ZIP). It was observed that applications of 5-HTP alone, known to increase the release of serotonin, or reactivation of memory alone did not restore the ZIP- or ANI-impaired context memory, while combination of the 5-HTP + reactivation of memory effectively reinstated the context memory. The data obtained confirmed the assumption that serotonin/reinforcing transmitter is a part of successful reconsolidation necessary for memory maintenance, demonstrated possible ways of long-term memory regulation during the reconsolidation process.


Chronic wasting disease in bank voles: characterisation of the shortest incubation time model for prion diseases.
In order to assess the susceptibility of bank voles to chronic wasting disease (CWD), we inoculated voles carrying isoleucine or methionine at codon 109 (Bv109I and Bv109M, respectively) with CWD isolates from elk, mule deer and white-tailed deer. Efficient transmission rate (100%) was observed with mean survival times ranging from 156 to 281 days post inoculation. Subsequent passages in Bv109I allowed us to isolate from all CWD sources the same vole-adapted CWD strain (Bv(109I)CWD), typified by unprecedented short incubation times of 25-28 days and survival times of ∼35 days. Neuropathological and molecular characterisation of Bv(109I)CWD showed that the classical features of mammalian prion diseases were all recapitulated in less than one month after intracerebral inoculation. Bv(109I)CWD was characterised by a mild and discrete distribution of spongiosis and relatively low levels of protease-resistant PrP(Sc) (PrP(res)) in the same brain regions. Despite the low PrP(res) levels and the short time lapse available for its accumulation, end-point titration revealed that brains from terminally-ill voles contained up to 10(8,4) i.c. ID50 infectious units per gram. Bv(109I)CWD was efficiently replicated by protein misfolding cyclic amplification (PMCA) and the infectivity faithfully generated in vitro, as demonstrated by the preservation of the peculiar Bv(109I)CWD strain features on re-isolation in Bv109I. Overall, we provide evidence that the same CWD strain was isolated in Bv109I from the three-cervid species. Bv(109I)CWD showed unique characteristics of "virulence", low PrP(res) accumulation and high infectivity, thus providing exceptional opportunities to improve basic knowledge of the relationship between PrP(Sc), neurodegeneration and infectivity.


"When You Move You Have Fun": Perceived Barriers, and Facilitators of Physical Activity From a Child's Perspective.
In Northern Ireland (NI), many children do not meet the recommended levels of physical activity (PA). To reduce the prevalence of physical inactivity and associated health conditions, it is important to understand the influences on children's PA, which in turn has the potential to inform future intervention design. The purpose of this formative study was to examine the current views, barriers, facilitators, experiences, and perceptions of children in relation to PA in the classroom, school, and home environments, and to assess the acceptability of components for a school-based intervention. Write and draw tasks and semi-structured focus groups (n = 10) were conducted with 50 children aged 7-9 years (22 boys, 28 girls) from six primary schools. Focus groups were recorded, transcribed, and analyzed thematically. Pen profiles were constructed from the transcripts in a deductive manner and represent key emergent themes. Results indicated that children's perception and knowledge of PA was mainly structured and sport-based, while some referred to fun, play and health. Fun, social support and outdoor activity were identified as key facilitators. Barriers included parental restrictions, lack of time and space in the different environments. The acceptability of intervention components was examined, children recognized the potential benefits of additional movement in the classroom, but opinions differed on the sit-to-stand desks. Findings contribute to a more detailed understanding of children's perceptions of context specific PA, the barriers they face, in addition to factors that support them to lead a physically active lifestyle, which may inform future PA promotion strategies.


Sugar convertibility in the parasitoid Cotesia glomerata (Hymenoptera: Braconidae).
Lack of suitable sugar sources for adult parasitic wasps is an important cause of failure in biological control programs, but the metabolic constraints of sugar feeding are poorly understood. Here we investigated the suitability of 11 naturally occurring sugars as energy sources for the parasitoid Cotesia glomerata (L.) (Hymenoptera: Braconidae). By feeding energy-deprived individuals with given quantities of a 40% (w:w) sugar solution, we assessed recovery time and lifespan after feeding. More than 50% of the wasps recovered within 20 min, and at least 80% within 60 min after uptake of one of the monosaccharides fructose or glucose, the disaccharide sucrose, or the trisaccharide melezitose. Between 40 to 80% of the test insects recovered within an hour after intake of maltose, raffinose, galactose, or mannose. Less than 25% recovered within 1 h after uptake of melibiose, trehalose, rhamnose, or water (control). Parasitoids obtained the highest lifespan benefits after intake of glucose, fructose, sucrose, or melezitose, indicating and confirming their convertibility as an energy source for C. glomerata. In contrast, no lifespan increase was found after consumption of rhamnose and trehalose. The differences in recovery time and lifespan are discussed in terms of parasitoid enzyme activity and metabolic processes.


Search for Supersymmetry with a Compressed Mass Spectrum in Events with a Soft τ Lepton, a Highly Energetic Jet, and Large Missing Transverse Momentum in Proton-Proton Collisions at sqrt[s]=13 TeV.
The first search for supersymmetry in events with an experimental signature of one soft, hadronically decaying τ lepton, one energetic jet from initial-state radiation, and large transverse momentum imbalance is presented. These event signatures are consistent with direct or indirect production of scalar τ leptons (τ[over ˜]) in supersymmetric models that exhibit coannihilation between the τ[over ˜] and the lightest neutralino (χ[over ˜]_{1}^{0}), and that could generate the observed relic density of dark matter. The data correspond to an integrated luminosity of 77.2 fb^{-1} of proton-proton collisions at sqrt[s]=13 TeV collected with the CMS detector at the LHC in 2016 and 2017. The results are interpreted in a supersymmetric scenario with a small mass difference (Δm) between the chargino (χ[over ˜]_{1}^{±}) or next-to-lightest neutralino (χ[over ˜]_{2}^{0}), and the χ[over ˜]_{1}^{0}. The mass of the τ[over ˜] is assumed to be the average of the χ[over ˜]_{1}^{±} and χ[over ˜]_{1}^{0} masses. The data are consistent with standard model background predictions. Upper limits at 95% confidence level are set on the sum of the χ[over ˜]_{1}^{±}, χ[over ˜]_{2}^{0}, and τ[over ˜] production cross sections for Δm(χ[over ˜]_{1}^{±},χ[over ˜]_{1}^{0})=50 GeV, resulting in a lower limit of 290 GeV on the mass of the χ[over ˜]_{1}^{±}, which is the most stringent to date and surpasses the bounds from the LEP experiments.


Conversion of atrial fibrillation to sinus rhythm and rate control by digoxin in comparison to placebo.
A randomized, double-blind study with a high dose of digoxin administered intravenously for conversion of atrial fibrillation (not due to haemodynamic alternations) to sinus rhythm, and for rate control in converters and non-converters was set up. Outcome measures were conversion within 12 h; time to conversion; early rate control; and stable slowing within 12 h. We studied 40 patients with recent onset (< 1 week) atrial fibrillation; controls received saline intravenously, the other patients digoxin 1.25 mg. One patient converted before digoxin administration. Conversion occurred in 9/19 patients on digoxin and in 8/20 on placebo (ns). The mean time to conversion tended to be shorter only for digoxin. Two late conversions on placebo were observed within 24 h. Heart rate during atrial fibrillation decreased after 30 min for converters and non-converters (P < 0.05). For all patients on digoxin, heart rate after 30 min was lower compared to baseline (P < 0.002) and to placebo (P < 0.02). Persistent, stable slowing occurred only in 3/10 non-converters on digoxin (P < 0.05), and two patients developed bradyarrhythmias. QTc was shortened immediately after conversion in all patients. Converters had baseline characteristics similar to those of non-converters. Intravenous digoxin offers no substantial advantages over placebo in recent onset atrial fibrillation with respect to conversion, and provides weak rate control.


Serotonin activates phospholipase D in rat mesangial cells.
We tested the hypothesis that serotonin activates phospholipase D (PLD) in cultured rat mesangial cells. The formation of phosphatidylethanol (PET) in ethanol was used as a measure of PLD activity. Serotonin [5-hydroxytryptamine (5-HT)] stimulated PET production, with an initial 10-fold increase in PET content within 15-30 s, followed by a decrease in PET to values only sixfold above baseline at 45-60 s. Thereafter, the values increased again at 5 min to a plateau 10-fold above baseline. The decrease in PET values, following the initial increase, was due to metabolism of PET, possibly by a phosphatidic acid phosphohydrolase, which led to a 76% decrease in PET within 1 h. Inhibition of phosphohydrolase with propranolol increased the phosphatidic acid and decreased the 1,2-diacylglycerol (DAG) content of 5-HT-stimulated cells. Finally, exogenous PLD induced mesangial cell proliferation as well as increases in phosphatidic acid, PET, and DAG. We conclude that phosphatidic acid contributes to DAG formation in mesangial cells. Furthermore, we suggest that PLD is involved in 5-HT-mediated mesangial cell proliferation.


Change in ATP and ADP content of fasting and feeding planarians (Polycelis nigra).
The ATP and ADP content of planarians subjected to starvation for two weeks followed by feeding for the same period was investigated. The ATP and ADP content during fasting increased and then, after feeding, returned to normal. The ATP/ADP ratio varied in the same way, which is consistent with the view that the adenylic nucleotide pool is implicated in the regulation of the energy metabolism of the organism.


Heat Stress Biomarker Amino Acids and Neuropeptide Afford Thermotolerance in Chicks.
With global warming, heat stress is becoming a pressing concern worldwide. In chickens, heat stress reduces food intake and growth, and increases body temperature and stress responses. Although it is believed that young chicks do not experience heat stress as they need a higher ambient temperature to survive, our series of studies in young chicks showed that they are sensitive to heat stress. This review summarizes current knowledge on amino acid metabolisms during heat stress, with special emphasis on the hypothermic functions of l-citrulline (l-Cit) and l-leucine (l-Leu), and the functions of neuropeptide Y (NPY) in terms of body temperature and heat stress regulation in chicks. Amino acid metabolism is severely affected by heat stress. For example, prolonged heat stress reduces plasma l-Cit in chicks and l-Leu in the brain and liver of embryos. l-Cit and l-Leu supplementation affords thermotolerance in young chicks. NPY expression is increased in the brains of heat-exposed chicks. NPY has a hypothermic action under control thermoneutral temperature and heat stress in chicks. The NPY-sub-receptor Y5 is a partial mediator of the hypothermic action of NPY. Further, NPY stimulates brain dopamine concentrations and acts as an anti-stress agent in heat-exposed fasted, but not fed chicks. In conclusion, young chicks can serve as a model animal for the study of heat stress in chickens. l-Cit, l-Leu, and NPY were identified as biomarkers of heat stress, with the potential to afford thermotolerance in chicks.


A versatile platform for creating a comprehensive UAS-ORFeome library in Drosophila.
Overexpression screens are used to explore gene functions in Drosophila, but this strategy suffers from the lack of comprehensive and systematic fly strain collections and efficient methods for generating such collections. Here, we present a strategy that could be used efficiently to generate large numbers of transgenic Drosophila strains, and a collection of 1149 UAS-ORF fly lines that were created with the site-specific ΦC31 integrase method. For this collection, we used a set of 655 genes that were cloned as two variants, either as an open reading frame (ORF) with a native stop codon or with a C-terminal 3xHA tag. To streamline the procedure for transgenic fly generation, we demonstrate the utility of injecting pools of plasmids into embryos, each plasmid containing a randomised sequence (barcode) that serves as a unique identifier for plasmids and, subsequently, fly strains. We also developed a swapping technique that facilitates the rapid exchange of promoters and epitope tags in vivo, expanding the versatility of the ORF collection. The work described here serves as the basis of a systematic library of Gal4/UAS-regulated transgenes.


Neuroleptic Malignant Syndrome Associated With Metoclopramide Use in a Boy: Case Report and Review of the Literature.
Neuroleptic malignant syndrome (NMS), an idiosyncratic reaction comprising muscular rigidity, altered level of consciousness, and autonomic dysfunction, is a rare but serious medical condition. It is most commonly precipitated by major tranquilizers such as butyrophenones, phenothiazines, and thioxanthines. Metoclopramide, a chlorbenzamide derivative with antidopaminergic properties, is widely used to treat nausea and emesis. We describe the first reported case of a boy who developed NMS in association with the use of this drug. A 13-year-old boy presented to the emergency department with a history of hyperthermia (42.6°C) and altered level of consciousness. He had recently had acute gastroenteritis and had been treated with metoclopramide 10 mg three times a day for 2 days. Vital signs were notable for hypotension, and physical examination revealed altered mental status with muscle rigidity. Laboratory testing revealed metabolic acidosis and increased prothrombin and partial thromboplastin times. He was actively cooled and received 3 rapid boluses, totaling 60 mL/kg, of isotonic crystalloids, for more than 20 minutes. Sepsis workup revealed no evidence of bacterial infection. He subsequently recovered fully and was discharged home with pediatric follow-up. This case represents the first description of NMS in association with metoclopramide in a healthy boy. It demonstrates the importance of considering this diagnosis early in the course of disease in patients with muscular rigidity, altered level of consciousness and autonomic dysfunction, and the need to rapidly respond to the physiological aberrations.


The genome sequence of Rickettsia prowazekii and the origin of mitochondria.
We describe here the complete genome sequence (1,111,523 base pairs) of the obligate intracellular parasite Rickettsia prowazekii, the causative agent of epidemic typhus. This genome contains 834 protein-coding genes. The functional profiles of these genes show similarities to those of mitochondrial genes: no genes required for anaerobic glycolysis are found in either R. prowazekii or mitochondrial genomes, but a complete set of genes encoding components of the tricarboxylic acid cycle and the respiratory-chain complex is found in R. prowazekii. In effect, ATP production in Rickettsia is the same as that in mitochondria. Many genes involved in the biosynthesis and regulation of biosynthesis of amino acids and nucleosides in free-living bacteria are absent from R. prowazekii and mitochondria. Such genes seem to have been replaced by homologues in the nuclear (host) genome. The R. prowazekii genome contains the highest proportion of non-coding DNA (24%) detected so far in a microbial genome. Such non-coding sequences may be degraded remnants of 'neutralized' genes that await elimination from the genome. Phylogenetic analyses indicate that R. prowazekii is more closely related to mitochondria than is any other microbe studied so far.


Aortic root replacement through right anterolateral thoracotomy.
A 59-year-old woman had undergone total arch replacement, followed by the mediastinal omental flap installation because of postoperative mediastinitis. One year later, she was diagnosed with annuloaortic ectasia with mitral regurgitation and underwent aortic root replacement (modified Bentall procedure) plus mitral valve annuloplasty through the right anterolateral thoracotomy. Her postoperative course was uneventful. The approach could be an alternative for the aortic root replacement in patients with previous median sternal wound complications.


Periungual Eccrine Poroma Masquerading as Ingrown Toenails A Case Report with Dermoscopic Findings.
Eccrine poroma is a rare benign adnexal neoplasm originating from a portion of the intraepidermal eccrine sweat gland duct and the acrosyringium. Typically, the lesions are asymptomatic, slow-growing nodules, which may be found in any sweat gland-bearing area. Multiple red lacunae, glomerular vessels, hairpin vessels, flower- and leaf-like vascular patterns, a polymorphic vascular pattern, globule/lacunae-like structures, a frog egg-like appearance, and comedo-like openings have been defined as characteristic dermoscopic patterns of the disease. We report a case of eccrine poroma in an unusual periungual and subungual location mimicking ingrown toenails. The dermoscopic findings of the lesions were compatible with those of eccrine poromas located in areas other than the periungual area. Recurrence was observed after the first excisional biopsy. There was no recurrence 10 months after the second surgical intervention, and near-complete regrowth of the nail plate was achieved. Eccrine poroma should be considered as a differential diagnosis in the presence of slow-growing, erythematous, painful, hemorrhagic papular lesions located in the periungual area in conjunction with a prediagnosis of ingrown toenails and malignant processes.


Educational differences in psychological distress? Results from a population-based sample of men and women in Sweden in 2012.
Mental health problems are more frequent in socially disadvantaged groups, but the results vary between different studies, different populations and different measures of mental health. This paper investigated the association between educational level, economic difficulties and psychological distress in men and women in Sweden. The study population included 24 510 respondents aged 25-74 years who responded to a survey questionnaire in Mid-Sweden in 2012 (response rate 53%). Psychological distress was measured with the 12-item version of the General Health Questionnaire, and multivariate logistic regression models were used in statistical analyses, adjusting for age, employment status and social support. The prevalence of psychological distress was higher in women (16.4%) than in men (11.3%; p<0.001). Persons with low and medium educational level had a lower risk of psychological distress than persons with high educational level after adjustment for confounders. Economic difficulties had a strong association with psychological distress (OR 2.80 (95% CI 2.39 to 3.27) and OR 2.40 (95% CI 2.12 to 3.71) in men and women, respectively) after adjustment for confounders. We found a strong association between economic difficulties and psychological distress in this study, but no inverse association between educational level and psychological distress. On the contrary, persons with high education had more psychological distress than persons with low and medium education when age, employment status and social support were taken into account. The findings were similar in men and women.


Prognosis in anoxic and traumatic coma.
This article presents a systematic review of the prognostic factors in coma caused by hypoxia and anoxia, and traumatic head injury. In the case of anoxic coma, poor prognosis can be determined very accurately at the bedside by the lack of brainstem reflexes assessed at day three post-insult. Electroencephalogram (EEG) and evoked potentials (i.e., auditory and somatosensory) detect additional patients with poor prognosis. Clinical examination is not as helpful in the case of traumatic coma. Evoked potentials performed within the first week detect approximately half of patients with a poor prognosis. EEG adds only a small amount of prognostic information.


A novel method for estimating the strength of positive mating preference by similarity in the wild.
Mating preference can be a driver of sexual selection and assortative mating and is, therefore, a key element in evolutionary dynamics. Positive mating preference by similarity is the tendency for the choosy individual to select a mate which possesses a similar variant of a trait. Such preference can be modelled using Gaussian-like mathematical functions that describe the strength of preference, but such functions cannot be applied to empirical data collected from the field. As a result, traditionally, mating preference is indirectly estimated by the degree of assortative mating (using Pearson's correlation coefficient, r) in wild captured mating pairs. Unfortunately, r and similar coefficients are often biased due to the fact that different variants of a given trait are nonrandomly distributed in the wild, and pooling of mating pairs from such heterogeneous samples may lead to "false-positive" results, termed "the scale-of-choice effect" (SCE). Here we provide two new estimators of mating preference (Crough and Cscaled) derived from Gaussian-like functions which can be applied to empirical data. Computer simulations demonstrated that r coefficient showed robust estimations properties of mating preference but it was severely affected by SCE, Crough showed reasonable estimation properties and it was little affected by SCE, while Cscaled showed the best properties at infinite sample sizes and it was not affected by SCE but failed at biological sample sizes. We recommend using Crough combined with the r coefficient to infer mating preference in future empirical studies.


Cardiac output and sympathetic vasoconstrictor responses during upright tilt to presyncope in healthy humans.
Syncope is a common clinical condition occurring even in healthy people without manifest cardiovascular disease. The purpose of this study was to determine the role of cardiac output and sympathetic vasoconstriction in neurally mediated (pre)syncope. Twenty-five subjects (age 15–51) with no history of recurrent syncope but who had presyncope during 60 deg upright tilt were studied; 10 matched controls who completed 45 min tilting were analysed retrospectively. Beat-to-beat haemodynamics (Modelflow), muscle sympathetic nerve activity (MSNA) and sympathetic baroreflex sensitivity (MSNA–diastolic pressure relation) were measured. MSNA, haemodynamic responses and baroreflex sensitivity during early tilting were not different between presyncopal subjects and controls. Hypotension was mediated by a drop in cardiac output in all presyncopal subjects, accompanied by a decrease in total peripheral resistance in 16 of them (64%, group A). In the other 9 subjects, total peripheral resistance was well maintained even at presyncope (36%, group B). Cardiac output was smaller (3.26 ± 0.34 (SEM) vs. 5.02 ± 0.40 l min(−1), P = 0.01), while total peripheral resistance was greater (1327 ± 117 vs. 903 ± 80 dyn s cm(−5), P < 0.01) in group B than group A at presyncope. The steeper fall in cardiac output in group B was due to a drop in heart rate. MSNA decreased rapidly at presyncope after the onset of hypotension. Thus, a moderate fall in cardiac output with coincident vasodilatation or a marked fall in cardiac output with no changes in peripheral vascular resistance may contribute to (pre)syncope. However, an intrinsic impairment of vasomotor responsiveness and sympathetic baroreflex function is not the cause of neurally mediated (pre)syncope in this population.


Cross-Feeding of Lactate Between Streptococcus lactis and Bacteroides sp. Isolated from Termite Hindguts.
Streptococcus lactis and Bacteroides sp., isolated from hindguts of Reticulitermes flavipes termites, were grown anaerobically in monoculture and coculture. When grown in a glucose medium, S. lactis monoculture produced lactate as the major fermentation product, with small amounts of formate, acetate, ethanol, and CO(2). In coculture, glucose was completely consumed during growth of S. lactis. Lactate, produced by S. lactis, then supported much of the growth of Bacteroides and was fermented to propionate, acetate, and CO(2). Small amounts of succinate were formed during growth of Bacteroides in the coculture, but little change in the formate or ethanol concentration was observed. Monoculture growth of Bacteroides in a tryptone-yeast extract medium revealed that incorporation of 20 to 40 mM lactate increased cell yields and production of organic acids. However, initial lactate concentrations greater than 40 mM suppressed not only growth of Bacteroides but also acidic product formation. Results suggest that cross-feeding of lactate between streptococci and bacteroides constitutes one aspect of the overall hindgut fermentation in termites.


Intracavity parametric generation of nanosecond terahertz radiation using quasi-phase-matching.
We report the use of quasi-phase-matching techniques based on periodically-poled MgO:LiNbO(3) for the generation of nanosecond duration pulses of terahertz radiation in intracavity optical parametric oscillators. Multiple idler-waves are generated with temporal studies indicating that the initiating process is the expected parametric down-conversion, but followed by cascaded difference frequency generation. A number of grating geometries have been explored, revealing the presence of dual solutions for the quasi-phase-matching process in the general case. Choice of grating parameters so as to minimize oscillation threshold while simultaneously ensuring effective extraction of the THz radiation is considered.


The epidemiology of postpartum malaria: a systematic review.
Pregnant women are more susceptible to malaria than their non-pregnant counterparts. Less is known about the risk of malaria in the postpartum period. The epidemiology of postpartum malaria was systematically reviewed. Eleven articles fitted the inclusion criteria. Of the 10 studies that compared malaria data from the postpartum period with pregnancy data, nine studies suggested that the risk for malaria infection decreased after delivery. All three studies that compared postpartum data with non-pregnant non-postpartum women concluded that the risk did not return to pre-pregnancy levels immediately after delivery. The results of this review have to be carefully interpreted, as the majority of studies were not designed to study postpartum malaria, and there was large variability in study designs and reported outcomes. Current evidence suggests an effort should be made to detect and radically cure malaria during pregnancy so that women do not enter the postpartum period with residual parasites.


Cascade coupling/cyclization process to N-substituted 1,3-dihydrobenzimidazol-2-ones.
Assembly of N-substituted 1,3-dihydrobenzimidazol-2-ones is achieved starting from methyl o-haloarylcarbamates via a CuI/amino acid catalyzed coupling with amines and subsequent condensative cyclization. A number of functional groups are tolerated by these reaction conditions, including vinyl, nitro, carboxylate, amide, ester, ketone, and silyl ether groups.


Palladin mutation causes familial pancreatic cancer and suggests a new cancer mechanism.
Pancreatic cancer is a deadly disease. Discovery of the mutated genes that cause the inherited form(s) of the disease may shed light on the mechanism(s) of oncogenesis. Previously we isolated a susceptibility locus for familial pancreatic cancer to chromosome location 4q32-34. In this study, our goal was to discover the identity of the familial pancreatic cancer gene on 4q32 and determine the function of that gene. A customized microarray of the candidate chromosomal region affecting pancreatic cancer susceptibility revealed the greatest expression change in palladin (PALLD), a gene that encodes a component of the cytoskeleton that controls cell shape and motility. A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) in a highly conserved region tracked with all affected family members and was absent in the non-affected members. The mutational change is not a known single nucleotide polymorphism. Palladin RNA, measured by quantitative RT-PCR, was overexpressed in the tissues from precancerous dysplasia and pancreatic adenocarcinoma in both familial and sporadic disease. Transfection of wild-type and P239S mutant palladin gene constructs into HeLa cells revealed a clear phenotypic effect: cells expressing P239S palladin exhibited cytoskeletal changes, abnormal actin bundle assembly, and an increased ability to migrate. These observations suggest that the presence of an abnormal palladin gene in familial pancreatic cancer and the overexpression of palladin protein in sporadic pancreatic cancer cause cytoskeletal changes in pancreatic cancer and may be responsible for or contribute to the tumor's strong invasive and migratory abilities.


Identification and Characterization of a Novel Palmitoyl Acyltransferase as a Druggable Rheostat of Dynamic Palmitoylome in L. donovani.
Palmitoylation has been recently identified as an important post-translational rheostat for controlling protein function in eukaryotes. However, the molecular machinery underlying palmitoylation remains unclear in the neglected tropical parasite, Leishmania donovani. Herein, we have identified a catalog of 20 novel palmitoyl acyltransferases (PATs) and characterized the promastigote-specific PAT (LdPAT4) containing the canonical Asp-His-His-Cys (DHHC) domain. Immunofluorescence analysis using in-house generated LdPAT4-specific antibody demonstrated distinct expression of LdPAT4 in the flagellar pocket of promastigotes. Using metabolic labeling-coupled click chemistry method, the functionality of this recombinant enzyme could be authenticated in E. coli strain expressing LdPAT4-DHHC domain. This was evident by the cellular uptake of palmitic acid analogs, which could be successfully inhibited by 2-BMP, a PAT-specific inhibitor. Using CSS-Palm based in-silico proteomic analysis, we could predict up to 23 palmitoylated sites per protein in the promastigotes, and further identify distinctive palmitoylated protein clusters involved in microtubule assembly, flagella motility and vesicular trafficking. To highlight, proteins such as Flagellar Member proteins (FLAM1, FLAM5), Intraflagellar Transport proteins (IFT88), and flagellar motor assembly proteins including the Dynein family were found to be enriched. Furthermore, analysis of global palmitoylation in promastigotes using Acyl-biotin exchange purification identified a set of S-palmitoylated proteins overlapping with the in-silico proteomics data. The attenuation of palmitoylation using 2-BMP demonstrated several phenotypic alterations in the promastigotes including distorted morphology, reduced motility (flagellar loss or slow flagellar beating), and inefficient invasion of promastigotes to host macrophages. These analyses confirm the essential role of palmitoylation in promastigotes. In summary, the findings suggest that LdPAT4 acts as a functional acyltransferase that can regulate palmitoylation of proteins involved in parasite motility and invasion, thus, can serve as a potential target for designing chemotherapeutics in Visceral Leishmaniasis.