Pharmacological and biochemical characterization of cholecystokinin/gastrin receptors in developing rat pancreas. Age-related expression of distinct receptor glycoforms.
Cholecystokinin/gastrin receptors in the pancreas of newborn (3-day-old) rats are of type A, as in control mature rats, revealed by pharmacological analysis of specific 125I-Bolton-Hunter-reagent-labelled [Thr34,Ahx37]cholecystokinin(31-39) (Ahx, aminohexanoic acid) binding. Also, by 1 day post-partum, pancreatic cholecystokinin receptors were shown to be coupled to guanine-nucleotide-binding regulatory (G) proteins. Scatchard analysis of 125I-Bolton-Hunter-reagent-labelled [Thr34,Ahx37]cholecystokinin(31-39) binding to pancreatic membranes from rats at different times after birth showed a slight increase in the binding capacity of cholecystokinin receptors between days 3 and 14 and a sixfold increase in 21-day-old rats, with no change in receptor affinity during development. SDS/PAGE analysis of pancreatic membranes affinity labelled with the photoactivable ligand 125I-[2-(p-azidosalicylamido)-1,3'-dithiopropionate]-labelled [Thr34,Ahx37]cholecystokinin-(31-39) identified cholecystokinin receptors of 100-135 kDa in 3-day-old rats, 96-130 kDa in 7-day-old rats, 90-125 kDa in 10-day-old rats and 85-100 kDa in 14-day-old and 21-day-old rats, as found in control adult rats. Endo-beta-N-acetylglucosaminidase F treatment yielded a core protein of 42 kDa in all developmental stages. These findings are consistent with an age-related postnatal expression of distinct glycoforms of pancreatic cholecystokinin receptors. Furthermore, it was observed that the period 2-3 weeks after birth, characterized by stabilization of the mass of the cholecystokinin receptor, precedes the dramatic increase in the receptor number.


The analytic bilinear discrimination of single-trial EEG signals in rapid image triage.
The linear discriminant analysis (LDA) method is a classical and commonly utilized technique for dimensionality reduction and classification in brain-computer interface (BCI) systems. Being a first-order discriminator, LDA is usually preceded by the feature extraction of electroencephalogram (EEG) signals, as multi-density EEG data are of second order. In this study, an analytic bilinear classification method which inherits and extends LDA is proposed. This method considers 2-dimentional EEG signals as the feature input and performs classification using the optimized complex-valued bilinear projections. Without being transformed into frequency domain, the complex-valued bilinear projections essentially spatially and temporally modulate the phases and magnitudes of slow event-related potentials (ERPs) elicited by distinct brain states in the sense that they become more separable. The results show that the proposed method has demonstrated its discriminating capability in the development of a rapid image triage (RIT) system, which is a challenging variant of BCIs due to the fast presentation speed and consequently overlapping of ERPs.


Comparison of carvedilol and metoprolol on serum lipid concentration in diabetic hypertensive patients.
Vasoconstricting beta-blocker use is associated with a reduction in HDL cholesterol, higher triglyceride, total cholesterol and LDL cholesterol levels, whereas carvedilol, a vasodilating beta-blocker, has not been associated with these effects. To compare in a randomized, double-blind study, the effects of the beta 1-blocker metoprolol tartrate with the combined alpha 1, beta-blocker carvedilol on serum lipid concentrations. A prospective randomized, double-blind, parallel-group trial compared the effects of carvedilol and metoprolol on total cholesterol, triglycerides, calculated LDL, HDL and non-HDL cholesterol levels at baseline and after 5 months of therapy as a secondary objective in the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensive (GEMINI) study. In this study, 1235 participants with type 2 diabetes and hypertension who were receiving renin-angiotensin system blockers were randomized either to carvedilol, receiving 6.25-25 mg twice daily, or to metoprolol tartrate, receiving 50-200 mg twice daily. If needed, hydrochlorothiazide and a dihydropyridine calcium channel blocker were added to achieve blood pressure goals. In the metoprolol tartrate group, triglycerides and non-HDL cholesterol increased and both the LDL and the HDL cholesterol levels decreased. In the carvedilol group, total LDL and HDL cholesterol decreased, non-HDL cholesterol was unchanged and triglycerides increased. Comparing the carvedilol and metoprolol tartrate groups, there was no statistically significant difference in LDL and HDL cholesterol levels, but there was a significantly greater decreases with carvedilol in total cholesterol [-2.9%, 95% confidence interval (CI) -4.60 to -1.15, p < 0.001], triglycerides (-9.8%, 95% CI -13.7, -5.75%, p < 0.001) and non-HDL cholesterol (-4.03%, 95% CI -6.3 to -1.8, p < 0.0006). At the end of the study, significantly more participants in the metoprolol tartrate group had had initiation of statin therapy or the statin dose increased than those in the carvedilol group (11 vs. 32%, p = 0.04). In patients with type 2 diabetes currently receiving a renin-angiotensin blocker, compared with metoprolol tartrate, the addition of carvedilol for blood pressure control resulted in a significant decrease in triglyceride, total cholesterol and non-HDL cholesterol levels. The use of metoprolol resulted in a significantly greater rate of initiation of statin therapy or an increase in the dose of existing statin therapy when compared with carvedilol utilization.


Effects of an injectable functionalized self-assembling nanopeptide hydrogel on angiogenesis and neurogenesis for regeneration of the central nervous system.
Brain injury is a devastating medical condition and represents a major health problem. Tissue and organ reconstruction have been regarded as promising therapeutic strategies. Here, we propose a regenerative methodology focusing on the provision of functionalized nanopeptide scaffolds to facilitate angiogenesis and neurogenesis at the brain injury site. The peptide RADA16-SVVYGLR undergoes self-assembly to construct an interconnected network with intertwining nanofibers, and can be controlled to display various physicochemical properties by the adjustment of microenvironmental factors such as pH and ion concentration. Such scaffolds can support endothelial cells to form tube-like structures and neural stem cells to survive and proliferate. In an in vivo zebrafish brain injury model, sprouting angiogenesis and developmental neurogenesis were achieved, and functional recovery of the severed optic tectum was enhanced in RADA16-SVVYGLR hydrogel-implanted zebrafish. This nanopeptide hydrogel was non-toxic to zebrafish embryos during early developmental stages. This angiogenic self-assembling peptide hydrogel had programmable physical properties, good biocompatibility, and regenerative ability for functional recovery in the injured brain. We suggest that functionalized self-assembling peptides encapsulated with neural stem cells or used alone could be an attractive and effective therapeutic modality for brain injury and diseases (e.g., trauma, stroke, tumor, degenerative neurological disorders, etc.).


Caloric restriction delays cardiac ageing in rats: role of mitochondria.
We tested whether long-term caloric restriction (CR) corrects pre-existing manifestations of cardiac ageing in rats. The age-specific effects of CR (-40%, 6 months) on mortality, left ventricular (LV) function, mitochondrial function, oxidative damage, and apoptosis were analysed in young (6 + 6 months) and senescent rats (24 + 6 months). CR in senescent rats significantly reduced mortality. LV and cardiomyocyte hypertrophy were reduced together with the mRNA expression and plasma concentrations of overload indicators BNP/ANP. Mitochondrial function was improved, resulting in lower oxidative damage and apoptotic activation. In particular, the pro-apoptotic Bcl-xS/Bcl-xL isoform pattern, mitochondrial translocation of Bax, release of cytochrome C into cytosol, and caspase-9 activation were reduced in comparison to age-matched rats on the control diet. However, CR resulted only in minor changes in young rats. Serum obtained from old control or CR rats was used for in vitro experiments. H9C2 cardiomyoblasts and adult rat ventricular cardiomyocytes preconditioned with CR serum demonstrated a low Bcl-xS/Bcl-xL ratio. H9C2 cells were resistant against H(2)O(2)-mediated loss of mitochondrial membrane potential, apoptosis activation, and reduced cell viability. Thus, beneficial effects of CR are mediated through circulating factors and can be mimicked with CR serum. However, this protection critically depended on a high Bcl-xL protein expression as seen after siRNA-mediated Bcl-xL knockdown. CR is cardioprotective in senescent myocardium by correcting pre-existing mitochondrial dysfunction and apoptotic activation and by preventing deterioration in LV function. Therefore, interventions that mimic these effects of CR may represent an additional therapeutic option for the aged or failing heart.


In vitro and in vivo effects of suppressor of cytokine signalling 7 knockdown in breast cancer: the influence on cellular response to hepatocyte growth factor.
Suppressor of cytokine signaling 7 (SOCS7) is a member of the SOCS family and is known to interact with phospholipase Cγ-1 (PLCγ-1), a key downstream mediator of the hepatocyte growth factor (HGF)/C-MET axis. Here, we report our observations of the effect of knocking down SOCS7 gene on the behaviour of breast cancer cells both in vitro and in vivo and to elucidate whether this involves HGF/C-MET pathway using the PLCγ-1 blocker U73122. MCF7 and MDA-MB-231 breast cancer cells were transfected with anti-SOCS7 ribozymal transgene, to create sublines with SOCS7 knockdown. The in vitro growth and migration of the cells were evaluated in basic conditions and with HGF and U73122 treatment using growth assays, scratch-wound, and electrical cell impedance sensing (ECIS) migration assays. MCF7 and MDA-MB-231 in vivo tumour xenograft growth were also studied. Basal in vitro growth and migration of both cellular lines and the in vivo MCF7 xenograft growth were significantly enhanced with SOCS7 knockdown. In vitro HGF treatment has further influenced the growth and migration when SOCS7 gene was knocked-down in both cellular lines (P < 0.05). PLCγ-1 pharmacological inhibition of the HGF/C-MET cascade during their in vitro growth and migration seemed to only occur when SOCS7 gene was knocked down. We report a unique regulatory role for SOCS7 in controlling the malignant behaviour of breast cancer lines MCF7 and MDA-MB-231 in vitro and the MCF7 tumour xenografts in vivo. We also report a regulatory role for SOCS7 during the in vitro HGF-induced growth and migration in these cells as HGF treatment and SOCS7 loss have synergistically enhanced these functions. This SOCS7 knockdown-attributed effect could be due to a precise anti-PLCγ-1 role.


The spectrin-based membrane skeleton as a membrane protein-sorting machine.
Normal cell function is dependent on the existence of membrane compartments that have unique populations of membrane proteins. Sorting of membrane proteins forms the basis for the biogenesis of distinct membrane compartments. There are many examples of membrane protein-sorting events in cells, but the molecular machinery involved is poorly understood. We discuss characteristics of a putative membrane protein-sorting machine and show that the spectrin-based membrane skeleton conforms to these characteristics. The spectrin-based membrane skeleton is a submembranous, spatially limited, two-dimensional lattice that binds a subset of membrane proteins. These properties allow the membrane skeleton to facilitate the formation of distinct membrane domains and thus reveal its potential as a membrane protein-sorting machine.


Molecular profiling of ovine prion diseases by using thermolysin-resistant PrPSc and endogenous C2 PrP fragments.
Disease-associated PrP fragments produced upon in vitro or in vivo proteolysis can provide significant insight into the causal strain of prion disease. Here we describe a novel molecular strain typing assay that used thermolysin digestion of caudal medulla samples to produce PrPres signatures on Western blots that readily distinguished experimental sheep bovine spongiform encephalopathy (BSE) from classical scrapie. Furthermore, the accumulation of such PrPres species within the cerebellum also appeared to be dependent upon the transmissible spongiform encephalopathy (TSE) strain, allowing discrimination between two experimental strains of scrapie and grouping of natural scrapie isolates into two profiles. The occurrence of endogenously produced PrP fragments, namely, glycosylated and unglycosylated C2, within different central nervous system (CNS) regions is also described; this is the first detailed description of such scrapie-associated fragments within a natural host. The advent of C2 fragments within defined CNS regions, compared between BSE and scrapie cases and also between two experimental scrapie strains, appeared to be largely dependent upon the TSE strain. The combined analyses of C2 fragments and thermolysin-resistant PrP species within caudal medulla, cerebellum, and spinal cord samples allowed natural scrapie isolates to be separated into four distinct molecular profiles: most isolates produced C2 and PrPres in all CNS regions, a second group lacked detectable cerebellar C2 fragments, one isolate lacked both cerebellar PrPres and C2, and a further isolate lacked detectable C2 within all three CNS regions and also lacked cerebellar PrPres. This CNS region-specific deposition of disease-associated PrP species may reflect the natural heterogeneity of scrapie strains in the sheep population in the United Kingdom.


Molecular basis for functional switching of GFP by two disparate non-native post-translational modifications of a phenyl azide reaction handle.
Through the genetic incorporation of a single phenyl azide group into superfolder GFP (sfGFP) at residue 148 we provide a molecular description of how this highly versatile chemical handle can be used to positively switch protein function in vitro and in vivo via either photochemistry or bioconjugation. Replacement of H148 with p-azido-l-phenylalanine (azF) blue shifts the major excitation peak ∼90 nm by disrupting the H-bond and proton transfer network that defines the chromophore charged state. Bioorthogonal click modification with a simple dibenzylcyclooctyne or UV irradiation shifts the neutral-anionic chromophore equilibrium, switching fluorescence to the optimal ∼490 nm excitation. Click modification also improved quantum yield over both the unmodified and original protein. Crystal structures of both the click modified and photochemically converted forms show that functional switching is due to local conformational changes that optimise the interaction networks surrounding the chromophore. Crystal structure and mass spectrometry studies of the irradiated protein suggest that the phenyl azide converts to a dehydroazepine and/or an azepinone. Thus, protein embedded phenyl azides can be used beyond simple photocrosslinkers and passive conjugation handles, and mimic many natural post-translational modifications: modulation though changes in interaction networks.


On the complexity of triggering evolutionary radiations.
Recent developments in phylogenetic methods have made it possible to reconstruct evolutionary radiations from extant taxa, but identifying the triggers of radiations is still problematic. Here, we propose a conceptual framework to explore the role of variables that may impact radiations. We classify the variables into extrinsic conditions vs intrinsic traits, whether they provide background conditions, trigger the radiation, or modulate the radiation. We used three clades representing angiosperm phylogenetic and structural diversity (Ericaceae, Fagales and Poales) as test groups. We located radiation events, selected variables potentially associated with diversification, and inferred the temporal sequences of evolution. We found 13 shifts in diversification regimes in the three clades. We classified the associated variables, and determined whether they originated before the relevant radiation (backgrounds), originated simultaneously with the radiations (triggers), or evolved later (modulators). By applying this conceptual framework, we establish that radiations require both extrinsic conditions and intrinsic traits, but that the sequence of these is not important. We also show that diversification drivers can be detected by being more variable within a radiation than conserved traits that only allow occupation of a new habitat. This framework facilitates exploration of the causative factors of evolutionary radiations.


The effect of non-surgical weight loss interventions on urinary incontinence in overweight women: a systematic review and meta-analysis.
Although the aetiology of urinary incontinence can be multifactorial, in some cases weight loss could be considered as a part of the therapeutic approach for urinary incontinence in people who are overweight. The objective of this study was to review and meta-analyse the effect of non-surgical weight loss interventions on urinary incontinence in overweight women. Web of Science, PubMed, Pedro, SPORTDiscus and Cochrane were systematically searched for clinical trials that met the a priori set criteria. Data of women who participated in non-surgical weight loss interventions (diet, exercise, medication or a combination) were included in the meta-analysis. After removing duplicates, 62 articles remained for screening on title, abstract and full text. Six articles (totalling 2,352 subjects in the intervention groups) were included for meta-analysis. The mean change in urinary incontinence (reported as frequency or quantity, depending on the study) after a non-surgical weight loss intervention, expressed as standardized effect size and corrected for small sample sizes (Hedges' g), was -0.30 (95%CI = -0.47 to -0.12). This systematic review and meta-analysis shows evidence that a non-surgical weight loss intervention has the potential to improve urinary incontinence and should be considered part of standard practice in the management of urinary incontinence in overweight women.


Dissociable roles for cortical and subcortical structures in memory retrieval and acquisition.
The relationship between anterograde and retrograde amnesia remains unclear. Previous data from both clinical neuropsychology and monkey lesion studies suggest that damage to discrete subcortical structures leads to a relatively greater degree of anterograde than retrograde amnesia, whereas damage to discrete regions of cortex leads to the opposite pattern of impairments. Nevertheless, damage to the medial diencephalon in humans is associated with both retrograde and anterograde amnesia. In the present study, we sought to reconcile this by assessing retention as well as subsequent relearning and new postoperative learning. Rhesus monkeys learned 300 unique scene discriminations preoperatively, and retention was assessed in a preoperative and postoperative one-trial retrieval test. Combined bilateral subcortical lesions to the magnocellular mediodorsal thalamus and fornix impaired postoperative retention of the preoperatively acquired information. In addition, subsequent relearning and new postoperative learning were also impaired. This contrasts with the effects of a discrete lesion to just one of these structures, after which retention is intact in both cases. Discrete bilateral ablations to the entorhinal cortex impaired retention but had no effect on new learning. Combined with previous work from our laboratory, these results support the hypothesis that subcortical damage has a relatively greater effect on new learning, and cortical damage has a relatively greater effect on retention. Furthermore, the results demonstrate that retrograde amnesia occurs as a result of subcortical damage only if it is widespread, leading to an extensive disruption of cortical functioning. Damage of this nature may account for dense amnesia.


The "vagal ansa": a source of complication in vagus nerve stimulation.
A 16-year-old boy underwent vagus nerve stimulation for treatment-resistant multifocal epilepsy. During intraoperative system diagnostics, vigorous contraction of the ipsilateral sternomastoid muscle was observed. On re-exploration, a thin nerve fiber passing from the vagus to the sternomastoid was found hooked up in the upper electrode. Detailed inspection revealed an abnormal course of the superior root of the ansa cervicalis, which descended down as a single nerve trunk with the vagus and separated to join the inferior root. The authors discuss the variation in the course of the ansa cervicalis and how this could be a reason for postoperative neck muscle contractions.


Pervasive Endosymbiont Arsenophonus Plays a Key Role in the Transmission of Cotton Leaf Curl Virus Vectored by Asia II-1 Genetic Group of Bemisia tabaci.
Insects often coevolved with their mutualistic partners such as gut endosymbionts, which play a key in the physiology of host. Studies on such interactions between Bemisia tabaci and its primary and secondary endosymbionts have gained importance due to their indispensable roles in the biology of this insect. Present study reports the predominance of two secondary endosymbionts, Arsenophonus and Cardinium in the Asia II-1 genetic group of whitefly and elucidates their role in the transmission of its vectored Cotton leaf curl virus. Selective elimination of endosymbionts was optimized using serial concentration of ampicillin, chloramphenicol, kanamycin, tetracycline, and rifampicin administered to viruliferous whiteflies through sucrose diet. Primary endosymbiont, Portiera was unresponsive to all the antibiotics, however, rifampicin and tetracycline at 90 μg/ml selectively eliminated Arsenophonus from the whitefly. Elimination of Arsenophonus resulted in significant decrease in virus titer from viruliferous whitefly, further the CLCuV transmission efficiency of these whiteflies was significantly reduced compared to the control flies. Secondary endosymbiont, Cardinium could not be eliminated completely even with higher concentrations of antibiotics. Based on the findings, Arsenophonus plays a key role in the retention and transmission of CLCuV in the Asia II-1 genetic group of B. tabaci, while the role of Cardinium could not be established due to its unresponsiveness to antibiotics.


Observing the development of the temporomandibular joint in embryonic and post-natal mice using various staining methods.
The temporomandibular joint (TMJ) is a specialized synovial joint that is essential for the movement and function of the mammalian jaw. The TMJ develops from two mesenchymal condensations, and is composed of the glenoid fossa that originates from the otic capsule by intramembranous ossification, the mandibular condyle of the temporal bone and a fibrocartilagenous articular disc derived from a secondary cartilaginous joint by endochondral ossification. However, the development of the TMJ remains unclear. In the present study, the formation and development of the mouse TMJ was investigated between embryonic day 13.5 and post-natal day 180 in order to elucidate the morphological and molecular alterations that occur during this period. TMJ formation appeared to proceed in three stages: Initiation or blastema stage; growth and cavitation stage; and the maturation or completion stage. In order to investigate the activity of certain transcription factors on TMJ formation and development, the expression of extracellular matrix (ECM), sex determining region Y-box 9, runt-related transcription factor 2, Indian hedgehog homolog, Osterix, collagen I, collagen II, aggrecan, total matrix metalloproteinase (MMP), MMP-9 and MMP-13 were detected in the TMJ using in situ and/or immunohistochemistry. The results indicate that the transcription factors, ECM and MMP serve critical functions in the formation and development of the mouse TMJ. In summary, the development of the mouse TMJ was investigated, and the molecular regulation of mouse TMJ formation was partially characterized. The results of the present study may aid the systematic understanding of the physiological processes underlying TMJ formation and development in mice.


Guidelines for clinical diagnosis and treatment of osteonecrosis of the femoral head in adults (2019 version).
Osteonecrosis of the femoral head (ONFH) is a common and refractory disease in orthopaedic clinics. The number of patients with ONFH is increasing worldwide every year. There are an estimated 8.12 million patients with nontraumatic osteonecrosis in China alone. Treatment of nontraumatic osteonecrosis has always been a clinical challenge for orthopaedic surgeons. To further standardize diagnosis and treatment of ONFH, these guidelines provide not only basic diagnosis, treatment, and evaluation systems for ONFH but also expert advice and standards in many aspects, including epidemiology, aetiology, diagnostic criteria, pathological staging, prevention and treatment options, and postoperative rehabilitation. The aetiological factors of ONFH can currently be divided into two major categories: traumatic and nontraumatic; however, the specific pathological mechanism of ONFH is not completely clear. Currently, the staging system of ONFH formulated by the Association Research Circulation Osseous is widely used in clinical practice. Based on the changes in the intraosseous blood supply at different stages, the corresponding nonsurgical and surgical treatments are recommended, and when there are risk factors for possible ONFH, certain preventive measures to avoid the occurrence of osteonecrosis are recommended. These guidelines provide brief classification criteria and treatment regimen for osteonecrosis. Specification of the aetiology, treatment plan based on comprehensive consideration of the different stages of osteonecrosis, hip function, age, and occupation of the patients are important steps in diagnosis and developing treatment strategies. New advances in the epidemiology, etiology, pathophysiology, imaging, diagnosis and treatment of ONFH have been renewed in this revision. This guideline can be used for reference by orthopedic professionals and researchers, and for standardized diagnosis and treatment management under the clinical guidance, which is conducive to the prevention, treatment and further research of ONFH, improving the diagnosis and treatment level, making patients' symptoms under good control, and improving their quality of life.


A decision guideline for emergency department utilization of noncontrast head computed tomography in HIV-infected patients.
To determine which neurologic signs or symptoms are predictive of new focal lesions on head CT in HIV-infected patients. Prospective study with convenience sample enrollment of HIV-infected patients who presented to a large inner-city university-based ED over an 11-month period. Patients were assessed using a standardized neurologic evaluation to ascertain whether they had developed new or changed neurologic signs or symptoms. Patients with any new or changed neurologic findings had a head CT scan in the ED. The association between individual complaints or findings and new focal lesions on head CT was assessed by univariate analysis, and sensitivity, specificity, and positive predictive values were calculated. Stepwise logistic regression analysis was then carried out to estimate the relative risk for those variables independently associated with new focal lesions on CT scans. A decision guideline was developed incorporating those variables. One hundred ten patients were identified as having new or changed neurologic signs or symptoms and had a head CT done in the ED. Twenty-seven patients (24%) had focal lesions on head CT, of which 19 (18%) were identified as new focal lesions; eight of these (7%) demonstrated a mass effect. Clinical findings most strongly associated with new focal findings on head CT were: 1) new seizure, relative risk (RR) = 73.5, 95% CI = 6.2 to 873.0; 2) depressed or altered orientation, RR = 39.1, 95% CI = 4.6 to 330.0; and 3) headache, different in quality, RR = 27.0, 95% CI = 3.2 to 230.1. Use of these three findings as a screen for ordering head CT in the ED would have identified 95% (18/19) of the patients with new focal intracranial lesions, and resulted in a 53% reduction in the number of head CTs ordered in the ED. Inclusion of one additional parameter (prolonged headache, > or =3 days), would have resulted in identification of 100% of all new focal lesions, with a 37% reduction in the number of head CTs ordered. Among those patients with new focal findings, 74% required emergent management (i.e., seizure control, IV antibiotics, IV steroids or surgery). The most common intracranial lesion among patients with CD4 counts less than 200 cells/microL was toxoplasmosis, while cerebrovascular accidents (ischemic or hemorrhagic) were most common in those with CD4 counts greater than 200 cells/microL. Specific clinical signs and symptoms were associated with the presence of new intracranial lesions in a group of HIV-infected patients who presented to the ED with neurologic complaints. These clinical findings can be incorporated into guidelines for determining the need for emergent head CT. Validation and widespread application of these guidelines could result in limiting the use of emergent neuroimaging to a more well-defined HIV-infected patient population.


A compact X-Band ODNP spectrometer towards hyperpolarized 1H spectroscopy.
The demand for compact benchtop NMR systems that can resolve chemical shift differences in the ppm to sub-ppm range is growing. However due to material and size restrictions these magnets are limited in field strength and thus in signal intensity and quality. The implementation of standard hyperpolarization techniques is a next step in an effort to boost the signal. Here we present a compact Overhauser Dynamic Nuclear Polarization (ODNP) setup with a permanent magnet that can resolve 1H chemical shift differences in the ppm range. The assembly of the setup and its components are described in detail, and the functionality of the setup is demonstrated experimentally with ODNP enhanced relaxation measurements yielding a maximal enhancement of -140 for an aqueous 4-hydroxy-TEMPO solution. Additionally, 1H spectroscopic resolution and significant enhancements are demonstrated on acetic acid as a solvent.


Renin/prorenin receptor, (P)RR, in end-organ damage: current issues in 2007.
We present a critical review on emerging concepts on the role of (pro)renin receptor, (P)RR, in diabetic and hypertensive nephropathy. Discovery of nonproteolytic activation of prorenin by the receptor led to nontoxic peptidic prorenin receptor blocker. The receptor blocker permitted long-term in vivo studies on the role of (P)RR in diabetic and hypertensive end-organ damage. Chronic infusion of receptor blocker prevented streptozotocin diabetic nephropathy and attenuated hypertensive cardiomyopathy and nephropathy. In support of these results, transgenic rats overexpressing the receptor nonselectively developed renal glomerulopathy with aging without elevating blood glucose or blood pressures. It indicated that the receptor overexpression alone is sufficient for end-organ damage, and diabetes mellitus and hypertension induce the end-organ damage by increasing (P)RR expression. We propose that (P)RR is a pivotal link between pathogenesis of diabetes mellitus and end-organ damage. (P)RR seems to activate this mechanism largely by activating receptor signals rather than by local angiotensin II. We realized that (P)RR blocker is a competitive inhibitor against prorenin, and its efficiency depends on ambient concentration of prorenin and renin. Optimization of the condition will be necessary to maximize the inhibitory and therapeutic effects.


Early decompressive craniectomy for severe penetrating and closed head injury during wartime.
Decompressive craniectomy has defined this era of damage-control wartime neurosurgery. Injuries that in previous conflicts were treated in an expectant manner are now aggressively decompressed at the far-forward Combat Support Hospital and transferred to Walter Reed Army Medical Center (WRAMC) and National Naval Medical Center (NNMC) in Bethesda for definitive care. The purpose of this paper is to examine the baseline characteristics of those injured warriors who received decompressive craniectomies. The importance of this procedure will be emphasized and guidance provided to current and future neurosurgeons deployed in theater. The authors retrospectively searched a database for all soldiers injured in Operations Iraqi Freedom and Enduring Freedom between April 2003 and October 2008 at WRAMC and NNMC. Criteria for inclusion in this study included either a closed or penetrating head injury suffered during combat operations in either Iraq or Afghanistan with subsequent neurosurgical evaluation at NNMC or WRAMC. Exclusion criteria included all cases in which primary demographic data could not be verified. Primary outcome data included the type and mechanism of injury, Glasgow Coma Scale (GCS) score and injury severity score (ISS) at admission, and Glasgow Outcome Scale (GOS) score at discharge, 6 months, and 1-2 years. Four hundred eight patients presented with head injury during the study period. In this population, a total of 188 decompressive craniectomies were performed (154 for penetrating head injury, 22 for closed head injury, and 12 for unknown injury mechanism). Patients who underwent decompressive craniectomies in the combat theater had significantly lower initial GCS scores (7.7 +/- 4.2 vs 10.8 +/- 4.0, p < 0.05) and higher ISSs (32.5 +/- 9.4 vs 26.8 +/- 11.8, p < 0.05) than those who did not. When comparing the GOS scores at hospital discharge, 6 months, and 1-2 years after discharge, those receiving decompressive craniectomies had significantly lower scores (3.0 +/- 0.9 vs 3.7 +/- 0.9, 3.5 +/- 1.2 vs 4.0 +/- 1.0, and 3.7 +/- 1.2 vs 4.4 +/- 0.9, respectively) than those who did not undergo decompressive craniectomies. That said, intragroup analysis indicated consistent improvement for those with craniectomy with time, allowing them, on average, to participate in and improve from rehabilitation (p < 0.05). Overall, 83% of those for whom follow-up data are available achieved a 1-year GOS score of greater than 3. This study of the provision of early decompressive craniectomy in a military population that sustained severe penetrating and closed head injuries represents one of the largest to date in both the civilian and military literature. The findings suggest that patients who undergo decompressive craniectomy had worse injuries than those receiving craniotomy and, while not achieving the same outcomes as those with a lesser injury, did improve with time. The authors recommend hemicraniectomy for damage control to protect patients from the effects of brain swelling during the long overseas transport to their definitive care, and it should be conducted with foresight concerning future complications and reconstructive surgical procedures.


Dispersal capacity predicts both population genetic structure and species richness in reef fishes.
Dispersal is a fundamental species characteristic that should directly affect both rates of gene flow among spatially distributed populations and opportunities for speciation. Yet no single trait associated with dispersal has been demonstrated to affect both micro- and macroevolutionary patterns of diversity across a diverse biological assemblage. Here, we examine patterns of genetic differentiation and species richness in reef fishes, an assemblage of over 7,000 species comprising approximately one-third of the extant bony fishes and over one-tenth of living vertebrates. In reef fishes, dispersal occurs primarily during a planktonic larval stage. There are two major reproductive and parental investment syndromes among reef fishes, and the differences between them have implications for dispersal: (1) benthic guarding fishes lay negatively buoyant eggs, typically guarded by the male parent, and from these eggs hatch large, strongly swimming larvae; in contrast, (2) pelagic spawning fishes release small floating eggs directly into the water column, which drift unprotected before small weakly swimming larvae hatch. Using phylogenetic comparative methods, we show that benthic guarders have significantly greater population structure than pelagic spawners and additionally that taxonomic families of benthic guarders are more species rich than families of pelagic spawners. Our findings provide a compelling case for the continuity between micro- and macroevolutionary processes of biological diversification and underscore the importance of dispersal-related traits in influencing the mode and tempo of evolution.


Psychological and behavioural responses to COVID-19: a China-Britain comparison.
Despite the burgeoning literature on COVID-19, there has been little cross-national work on the correlates of mental health or its association with pandemic behaviours. We considered psychological distress, quarantine status, social distancing and self-medication in China and the UK. We conducted online surveys in China (N=1135) and the UK (N=1293), beginning in March 2020. Participants indicated demographics, whether they were in quarantine, relationship status, social distancing, use of vitamins/traditional medicines and completed the K6 scale of psychological distress. 19.1% of the respondents in China were at risk of severe mental illness (SMI: 95% CI 16.9% to 21.6%) and 16.6% (95% CI 14.6% to 18.8%) in the UK. Risk of SMI was among those in quarantine (OR 11.18 (95% CI 4.08 to 30.62); p=0.001) and in younger respondents (OR 2.61 (95% CI 1.01 to 6.79); p=0.048) although the latter effect was significant only in the UK. Risk of SMI was positively associated with self-medication (βs=0.17, p=0.001) and negatively with social distancing in China (country×SMI β=0.51, p=0.001), with further interactions for age and sex (social distancing), age, marital status and quarantine (self-medication). Across the countries, quarantine was associated with poorer mental health, while greater psychological distress was associated with greater self-medication rate. Future work should explore further cross-national variations in psychological health and behaviours during pandemics.


Understanding the role of eco-evolutionary feedbacks in host-parasite coevolution.
It is widely recognised that eco-evolutionary feedbacks can have important implications for evolution. However, many models of host-parasite coevolution omit eco-evolutionary feedbacks for the sake of simplicity, typically by assuming the population sizes of both species are constant. It is often difficult to determine whether the results of these models are qualitatively robust if eco-evolutionary feedbacks are included. Here, by allowing interspecific encounter probabilities to depend on population densities without otherwise varying the structure of the models, we provide a simple method that can test whether eco-evolutionary feedbacks per se affect evolutionary outcomes. Applying this approach to explicit genetic and quantitative trait models from the literature, our framework shows that qualitative changes to the outcome can be directly attributable to eco-evolutionary feedbacks. For example, shifting the dynamics between stable monomorphism or polymorphism and cycling, as well as changing the nature of the cycles. Our approach, which can be readily applied to many different models of host-parasite coevolution, offers a straightforward method for testing whether eco-evolutionary feedbacks qualitatively change coevolutionary outcomes.


Central pressor action of neurotensin in conscious rats.
The effects of neurotensin upon blood pressure in conscious rats were examined after intracerebroventricular (i.v.t.) or intravenous (i.v.) administration of this peptide. Whereas i.v. injected neurotensin (0.1-2.0 microgram/kg) was depressor, i.v.t. injected neurotensin (1 microgram and above) was pressor. Peripheral depressor responses could not be repeated in the same animal due to tachyphylaxis, but central pressor responses were repeatable without reduction in magnitude, showing that the two effects were separate entities. Thyrotropin-releasing hormone (TRH), which is reported to be a potent neurotensin antagonist, completely abolished the neurotensin depressor response, and attenuated the central pressor action. TRH did not alter the central pressor effect of another peptide, angiotensin II (AII). The potent AII receptor antagonist saralasin, while abolishing the central pressor effect of AII, was completely without effect upon the neurotensin-induced pressor response. These results indicate that i.v.t. injected neurotensin and AII stimulate a rise in blood pressure via different receptors. The alpha-adrenergic antagonists phentolamine, prazosin, or yohimbine (injected i.v.t.) involvement of the sympathetic nervous system in this response. These results are discussed in relation to the central pressor actions of other neuropeptides.


The clinical characteristics of gastroesophageal reflux disease in patients with laryngeal symptoms who are referred to gastroenterology.
The prevalence of gastroesophageal reflux disease (GERD) has increased recently in Asia-Pacific countries. However, little is known about its prevalence and clinical characteristics in GERD patients with atypical symptoms in Asia. The aim of this study was to investigate the clinical characteristics of GERD in patients who had laryngeal symptoms in Korea. Data were gathered retrospectively from patients who presented with atypical symptoms, such as throat discomfort, globus pharyngeus, hoarseness, and chronic cough. They underwent a 24-hour ambulatory intraesophageal pH monitoring and filled in a validated reflux questionnaire. Overall, 128 patients (36 men and 92 women) with laryngeal symptoms were included. Of these 128, 43 patients (34%) had erosive esophagitis or pathological reflux from 24-hour ambulatory pH monitoring, and 24 (19%) had a positive Bernstein test or positive symptom index from 24-hour pH monitoring. Sixty-one patients (48%) had no evidence of reflux esophagitis on upper endoscopy and pathological acid reflux on 24-hour pH monitoring. Fifty-six patients (44%) had weekly heartburn or regurgitation. Typical symptoms and dyspepsia were significantly more common in patients with GERD who had laryngeal symptoms than non-GERD. Fifty-two percent of patients had laryngeal symptoms that were associated with GERD. The presence of typical reflux symptoms and dyspepsia are risk factors for GERD in patients who present with laryngeal symptoms.


Physiological mechanisms of vascular response induced by shear stress and effect of exercise in systemic and placental circulation.
Physiological vascular function regulation is essential for cardiovascular health and depends on adequate control of molecular mechanisms triggered by endothelial cells in response to mechanical and chemical stimuli induced by blood flow. Endothelial dysfunction is one of the main risk factors of cardiovascular pathology, where the imbalance between the synthesis of vasodilator and vasoconstrictor molecules is common in the development of vascular disorders in systemic and placental circulation. In the placenta, an organ without autonomic innervations, the local control of vascular tone is critical for maintenance of fetal growth and mechanisms that underlie shear stress response induced by blood flow are essential during pregnancy. In this field, shear stress induced by moderate exercise is one of the most important mechanisms to improve vascular function through nitric oxide synthesis and stimulation of mechanical response of endothelial cells triggered by ion channels, caveolae, endothelial NO synthase, and vascular endothelial growth factor, among others. The demand for oxygen and nutrients by tissues and organs, especially in placentation and pregnancy, determines blood flow parameters, and physiological adaptations of vascular beds for covering metabolic requirements. In this regard, moderate exercise versus sedentarism shows potential benefits for improving vascular function associated with the enhancement of molecular mechanisms induced by shear stress. In this review, we collect evidence about molecular bases of physiological response to shear stress in order to highlight the relevance of moderate exercise-training for vascular health in adult and fetal life.


Mechanism of entry into the cytosol of poliovirus type 1: requirement for low pH.
The effect of a number of drugs and culture conditions on the entry into cells of a strain of poliovirus 1 (Brunende) was tested. The cells were exposed in the dark to light-sensitive, neutral red-containing virus, in the presence of the drug to be tested. Then the cells were exposed to light, transferred to normal medium, and incubated overnight. Cytopathogenic effect was measured as inhibition of [3H]leucine incorporation. Compounds that dissipate proton gradients across membranes, like monensin, protonophores, and amines, and compounds that inhibit the acidification process, such as N,N'-dicyclohexylcarbodiimide (DCCD) and tributyltin, inhibited the entry of virus, but not virus binding. This was also the case with metabolic inhibitors that deplete cells for ATP. The same compounds also inhibited the cell-induced alteration of the virus particles. When cells with surface-bound virus were exposed to low pH, the virus entered efficiently, even in the presence of monensin and DCCD. The results indicate that acidification somehow facilitates the entry of the virus RNA into the cytosol and that under normal conditions the entry occurs from intracellular acidic vesicles.


The ETS family member Tel antagonizes the Fli-1 phenotype in hematopoietic cells.
The ETS family member Tel is rearranged in human leukemia of both myeloid and lymphoid origin while the ETS member Fli-1 is insertionally activated in Friend erythroleukemia in mice and is translocated to the EWS locus in Ewing's sarcoma. In previous studies we demonstrated that Tel binds to Fli-1 and blocks transactivation of megakaryocytic promoters by Fli-1. In this study we demonstrate that expression of Fli-1 in the leukemia cell line K562 induces a megakaryocytic phenotype and the expression of the platelet markers GPIX, GP1balpha, and GPIIb. Introduction of Tel blocked the megakaryocytic phenotype induced by Fli-1, suggesting a biological correlation to the biochemical interaction of Tel and Fli-1 reported previously.


Antagonistic effect of amiloride on alpha-2 adrenoceptor-mediated pigment aggregation: pharmacological heterogeneity between B-HT 920 and noradrenaline.
Pigment aggregation in melanophores from the cuckoo wrasse (Labrus ossifagus L.) has previously been shown to be mediated by alpha-2 adrenoceptors. In the present investigation, the effect of amiloride on pigment aggregation induced by noradrenaline and B-HT 920 was studied. Amiloride caused a parallel shift to the right in concentration-response curves for 5-allyl-2-amino-5,6,7,8-tetrahydrothiazolo-[4,5-d]azepine-dihyd roc hloride: (B-HT 920), with no change in the maximal response, indicating simple competitive inhibition. Subsequent Schild plot analysis gave a straight line with a slope of almost unity (0.95) and a KB of 5 x 10(-6) M. In contrast to the effect of amiloride on B-HT 920-induced pigment aggregation, only a very high concentration of amiloride (1 x 10(3) M) inhibited the corresponding effect of noradrenaline. Na+/H+ exchange has been suggested as a possible mechanism for alpha-2 adrenoceptors, and the amiloride analogs 5-(N,N-dimethyl)amiloride and 5-(N,N-hexamethylene)amiloride are known to be more specific than amiloride itself in this respect. However, these analogs inhibited the effect of B-HT 920 significantly less effectively than amiloride. Furthermore, manipulating the extracellular pH between 6.8 and 7.8 did not affect the concentration response curves of B-HT 920. Neither did the prostanoid pathway inhibitors, quinacrine or indomethacin, inhibit the pigment-aggregating effect of B-HT 920. The present results suggest that amiloride competes with B-HT 920 as receptor antagonist, and that Na+/H+ exchange is insignificant for the alpha-2 adrenoceptor-stimulated pigment aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)


Therapeutic effects of iNOS inhibition against vitiligo in an animal model.
Nitric oxide (NO) is involved in several biological processes, but its role in human melanogenesis and vitiligo need further studies. Previous studies revealed that exposure to UVA and UVB were capable of the inducing nitric oxide production in keratinocytes and melanocytes through the activation of constitutive nitric oxide synthase, whereas inducible nitric oxide synthase overexpression has been reported to play an important role in hyperpigmentary disorders. The aim of this study was to evaluate iNOS inhibitor aminoguanidine (AG) as a therapeutic agent in our mouse model of vitiligo. In this study, male C57BL/6J Ler-vit/vit mice were purchased to evaluate the effect of iNOS inhibitor (aminoguanidine) (50 and 100 mg/kg) and L-arginine (100 mg/kg) in a mouse model of vitiligo induced by monobenzone 40%. Moreover, we used phototherapy device to treat the mice with NBUVB as a gold standard.The findings revealed that monobenzone was capable of inducing depigmentation after 6 weeks. However, aminoguanidine in combination with monobenzone was decrease the effect of monobenzone, while L-arginine play a key role in promoting the effect of monobenzone (P<0.001). Based on the phototherapy, the efficacy of phototherapy significantly increased by adding L-arginine (P<0.05). Taken together, we suggest that iNOS inhibitor can be a novel treatment for the prevention and treatment of vitiligo by combination of NBUVB therapy, furthermore; NO agents like L-arginine could also increase the effectiveness of phototherapy. Taken together, this pilot study showed significant repigmentation of vitiligous lesions treated with iNOS inhibitor plus NBUVB therapy, where other aspect including expression of an inducible iNOS, NO and TNF levels remained to be evaluated in mice model.


Effects of washing fiddler crabs (Uca pugnax) following an oil spill.
An oil spill on 2 January 1990 in New Jersey resulted in premature emergence of fiddler crabs Uca pugnax from their underground burrows. Live fiddler crabs that emerged on the surface were collected and behavioral changes were compared between those that were washed with freshwater and those that were not washed. Locomotion, aggression, balance, and burrowing behavior were examined. Unwashed crabs improved significantly on only one of twelve behavioral tests, while washed crabs improved in four tests relating to movement, defensive behavior, and burrowing. The washed crabs showed the greater improvement on ten of twelve tests while unwashed crabs showed greater improvement for two tests. Washed crabs also showed greater improvement in their ability to find and to construct their own burrows. These experiments indicate that oil removal improves the behavioral performance of crabs, and suggests that under some circumstances the immediate flushing of salt marsh creeks by uncontaminated tidal waters may decrease behavioral effects on crabs.


Guidance for the core content of a Curriculum in Special Care Dentistry at the undergraduate level.
Given the rapidly changing demography of populations worldwide, dental professionals of the future need to be able to meet the challenge posed by the evolving landscape in health care needs. Leading institutions are now embedding teaching and learning in special care dentistry (SCD) within their curricula, to provide students with the knowledge, skills and attitudes to meet the oral health needs of vulnerable groups within their communities. The International Association for Disability and Oral Health (iADH) has initiated the development of undergraduate curriculum guidance in SCD through a consensus process. The curriculum in SCD is defined in statements of learning outcomes with many of the skills being transferable across the undergraduate course. This curriculum includes examples of teaching and assessment, designed to enhance critical thinking in relation to SCD and to promote positive attitudes towards disability and diversity. The learning outcomes are designed to be readily adapted to conform to the generic profiles and competencies, already identified in undergraduate frameworks by global educational associations, as well as meeting the requirements of professional regulatory bodies worldwide. Suggestions for teaching and learning are not intended to be prescriptive; rather, they act as a signpost to possible routes to student learning. Ideally, this will require that students have a sufficiently diverse patient case mix during their undergraduate studies, to achieve the required levels of confidence and competence by the time they graduate. Clinical care competencies in SCD emphasise the need for learners to broaden their theoretical knowledge and understanding through practical experience in providing care for people with special health care needs. It is crucial to the development of equitable dental services for all members of a community, that these learning outcomes are embedded into evolving curricula but most importantly, that they are evaluated and refined in a dynamic way with shared learning for all teachers.


Results supporting calculated wall correction factors for cavity chambers.
Thick walled cavity ionization chambers are used by primary standard laboratories as primary air kerma standards in 137Cs and 60Co gamma-rays. Application of the cavity theory requires correction for the effects of photon attenuation and scattering in the chamber walls. For more than a decade there have been intensive discussions about the validity of wall correction factors determined by more traditional extrapolation methods versus those calculated by Monte Carlo methods. For existing primary standards the alternative methods lead to results that differ by up to 50% of the correction itself. This report presents both experimental and theoretical results which strongly support the validity of calculated wall correction factors. Moreover, it is demonstrated that, in selected cases, the application of a linear extrapolation method leads to errors in the determination of the air kerma reaching up to 13%.


High frequency of integrase Q148R minority variants in HIV-infected patients naive of integrase inhibitors.
Integrase positions 148 and 155 represent main determinants of resistance to integrase inhibitors. We assessed the prevalence of minority variants harboring such mutations in integrase-naive HIV-infected patients. Two groups of patients were studied: 40 heavily antiretroviral-experienced patients, initiating a raltegravir-based therapy and 51 antiretroviral-naive patients. Allele-specific real-time PCR (AS-PCR) systems, developed for Q148H, Q148R and N155H mutations, were performed at baseline for antiretroviral-experienced patients. Samples from antiretroviral-naive patients were tested with the Q148R AS-PCR assay. The limits of detection of AS-PCR systems were 0.10, 0.10 and 0.05% for Q148H, Q148R and N155H mutations, respectively. AS-PCR systems were successful in 79 of 91 samples. In antiretroviral-experienced patients, Q148R minority variants were frequently detected (26/32 patients, 81%) at low-level frequency (median = 0.40%), whereas no minority variants exhibiting Q148H or N155H mutation were found. Twenty-four of 26 patients exhibiting Q148R variants were virological responders but four of them displayed a delayed virological response occurring between W18 and W36. Two patients exhibited virological failure under raltegravir, both harboring Q148R minority variants at baseline. However, we did not find any association between the presence of Q148R minority variants and an increased risk of virological failure. Q148R minority variants were also found in 86% of antiretroviral-naive patients, a prevalence significantly higher than that of K103N minority variants (26%). Q148R variants were frequently detected, always at low-level, in antiretroviral-experienced and naive patients. Although their presence was not consistently associated with virological failure, their impact on long-term viral suppression needs to be further investigated.


A learning skills course for the 1st year medical students: an experience at a Saudi medical school.
Every year nearly 1,500 students enter into medical program after passing high school and national aptitude exams. However, many students experience frustration, failure, and psychological morbidities like stress, depression, and anxiety because they are not aware of their learning styles or do not have effective learning skills and strategies. The College of Medicine of Al-Imam Muhammad ibn Saud Islamic University has adopted the outcome based, community oriented, Spiral Curriculum. Although the curriculum is innovative, on the other hand, it is very demanding. The purpose of this paper is to share educational structure and evaluation results of the course on effective learning and study skills for the 1st year medical students. To prepare our students in order to cope with this demanding but promising curriculum, we conducted an effective and comprehensive learning skills course for 16 weeks in the first semester of year 1 in the medical program. Performance of each student was assessed and the course evaluation was done by students at the end of the course. The attendance of the students throughout the course was over 90%. The average performance of students in the summative assessment was 78% and the course was generally liked by the students. Students overall had a positive attitude toward the learning skills course. Majority of the students showed interest in attending the sessions regularly and realized the significance of this course to improve their learning skills.


Sexual risk behaviors among adolescents in Port-au-Prince, Haiti.
Engagement in sexual activity among Haitian youth is increasing. The present cross-sectional study examined the independent correlates of sexual risk behaviors among 200 (108 male/92 female) 13-18 year-old adolescents in Port-au-Prince, Haiti using face-to-face interviews. The majority (60.0 %) had engaged in sexual intercourse. Multivariate modeling found males to be 3.52 times more likely to have had sex, 5.42 times more likely to report sexual debut before age 14, 9.75 times more likely to have >1 sexual partner, and 3.33 times more likely to not have used a condom during last sex. Adolescents living with parents, grandparents, aunts or uncles were less likely to report having unprotected sex compared with those without adult family members in the home (AOR range 0.26-0.51). The high prevalence of risky sex among males and the protective influence of stable family cohesiveness have important implications for HIV prevention efforts.


An internalist view on the value of life and some tricky cases relevant to it.
If we understand death as the irreversible loss of the good life, we can give meaning to the idea that for suffering patients in the end stage of their illness, life may become an evil and death no longer a threat. Life may lose its good already in the living person. But what does the good of life consist in, then? I defend an internalist view according to which the goodness of life is intrinsically related to the attitudes, concerns, interests and experiences of the person who is leading the life. This results in the contention that the core of what we understand as the value of the person's life is to be identified with what makes life go well for the person living the particular life. This internalist view does not presuppose (or imply) hedonism or mentalism, nor does it pose an experience requirement. Something may be good for you, because it is valuable as seen from your authentic viewpoint, even if you do not actually experience this goodness, or think otherwise because you are mistaken about your own well-being. To test this position, and the authenticity-requirement it includes, I discuss three cases of patients who are persistent in denying that in their life any value is left and who contend that death is not worse than further living. Internalism acknowledges that in the life of these patients there may be 'functionings' and 'beings' that are worthwhile, where the test of value is at least partially independent of subjective assessment. Still, internalism claims that something truly valuable can only contribute to the good of one's life of it has positive meaning as seen from the attitudinal viewpoint that identifies oneself.


Comparison of the sensitivity of strains of Salmonella enterica serovar Typhimurium in the detection of mutagenicity induced by nitroarenes.
The use of strains of Salmonella enterica serovar Typhimurium with different metabolic capacities can indicate the class or classes of compounds present in an environmental sample and enable the diagnosis of the mutagenic activity of these pollutants adsorbed on particulate matter (PM) in the air. In the present study, the sensitivity of Salmonella strains TA98NR, TA98/1,8-DNP₆, YG1021, and YG1024 to detect nitro compounds adsorbed on samples of PM 2.5 was compared from three sites in Rio de Janeiro city. Samples were collected using a high-volume sampler at three sites: one with light traffic and two with heavy traffic. The assays were performed in the presence of 10-50 μg/ plate organic extracts with and without exogenous metabolization. The YG1021 and YG1024 strains showed the highest rev/m(3) values, confirming their enhanced sensitivity. As YG1024 also demonstrated sensitivity to nitro and amino compounds, we suggest its use in research into environmental contamination.


Identification of Potential Inhibitors Targeting GTPase-Kirsten RAt Sarcoma Virus (K-Ras) Driven Cancers via E-Pharmacophore-Based Virtual Screening and Drug Repurposing Approach.
Mutations in the K-Ras gene are among the most frequent genetic alterations in various cancers, and inhibiting RAS signaling has shown promising results in treating solid tumors. However, finding effective drugs that can bind to the RAS protein remains challenging. This drove us to explore new compounds that could inhibit tumor growth, particularly in cancers that harbor K-Ras mutations. Our study used bioinformatic techniques such as E-pharmacophore virtual screening, molecular simulation, principal component analysis (PCA), extra precision (XP) docking, and ADMET analyses to identify potential inhibitors for K-Ras mutants G12C and G12D. In our study, we discovered that inhibitors such as afatinib, osimertinib, and hydroxychloroquine strongly inhibit the G12C mutant. Similarly, hydroxyzine, zuclopenthixol, fluphenazine, and doxapram were potent inhibitors for the G12D mutant. Notably, all six of these molecules exhibit a high binding affinity for the H95 cryptic groove present in the mutant structure. These molecules exhibited a unique affinity mechanism at the molecular level, which was further enhanced by hydrophobic interactions. Molecular simulations and PCA revealed the formation of stable complexes within switch regions I and II. This was particularly evident in three complexes: G12C-osimertinib, G12D-fluphenazine, and G12D-zuclopenthixol. Despite the dynamic nature of switches I and II in K-Ras, the interaction of inhibitors remained stable. According to QikProp results, the properties and descriptors of the selected molecules fell within an acceptable range compared to sotorasib. We have successfully identified potential inhibitors of the K-Ras protein, laying the groundwork for the development of targeted therapies for cancers driven by K-Ras mutations.


Midarm muscle circumference, physical performance and mortality: results from the aging and longevity study in the Sirente geographic area (ilSIRENTE study).
Sarcopenia has been indicated as a reliable marker of frailty and poor prognosis among the oldest individuals. We evaluated the relationship between midarm muscle circumference (MAMC) and physical performance, muscle strength, functional status and survival in persons aged 80 years or older. Data are from the baseline evaluation of the Aging and Longevity Study in the Sirente Geographic Area (ilSIRENTE Study) (n = 357). MAMC was calculated taking into account the mid upper arm circumference and the triceps skinfold thickness of the right arm. Physical performance was assessed using the physical performance battery score, which is based on three timed tests: 4-m walking speed test, the balance test and the chair stand test. Analyses of covariance were performed to evaluate the relationship between different MAMC levels and physical function. Cox proportional regression models were used to estimate crude and adjusted hazard ratios and 95% confidence intervals of death by MAMC levels. After adjustment for potential confounders - which included age, gender, living alone, sensory impairments (hearing and vision), body mass index, albumin and cholesterol - physical performance and function (which were measured using the 4-m walking speed test, the Short Physical Performance Battery score, the hand grip strength), improved significantly as MAMC increased. Compared with those in the low MAMC tertile, subjects in the high MAMC tertile had a lower risk of death (adjusted hazard ratio (HR) 0.45; 95% Confidence Interval (CI) 0.23-0.87). The present study suggests that among community-dwelling old-old subjects muscle mass may be positively related to functional performance and survival.


Characterization of MicroRNA expression profiles in the ovarian tissue of goats during the sexual maturity period.
The ovary is an important reproductive organ in mammals, and its development directly affects the sexual maturity and reproductive capacity of individuals. MicroRNAs (miRNAs) are recognized as regulators of reproductive physiological processes in various animals and have been shown to regulate ovarian development through typical targeting and translational repression. However, little is known about the regulatory role of miRNAs in ovarian tissue development during sexual maturity in goats. To comprehensively profile the different physiological stages of sexual maturation in goats, we performed small-RNA sequencing of ovarian tissue samples collected at four specific time points (1 day after birth (D1), 2 months old (M2), 4 months old (M4), and 6 months old (M6)). In addition, we used ELISAs to measure serum levels of reproductive hormones to study their temporal changes. The results showed that serum levels of gonadotropin-releasing hormone, follicle-stimulating hormone, luteinizing hormone, oestradiol, progesterone, oxytocin, and prolactin were lower in goats at the D1 stage than at the other three developmental stages (P < 0.05). The secretion patterns of these seven hormones show a similar trend, with hormone levels reaching their peaks at 4 months of age. A total of 667 miRNAs were detected in 20 libraries, and 254 differentially expressed miRNAs and 3 groups of miRNA clusters that had unique expression patterns were identified (|log2-fold change|> 1, FDR < 0.05) in the 6 comparison groups. RT‒qPCR was employed to confirm that the expression pattern of the 15 selected miRNAs was consistent with the Illumina sequencing results. Gene ontology analyses revealed significant enrichment of GO terms such as cell proliferation regulation, epithelial cell development, and amino acid transport, as well as important signaling pathways including the MAPK signaling pathway, the PI3K-Akt signaling pathway, and the oestrogen signaling pathway. Further miRNA‒mRNA regulation network analysis revealed that 8 differentially expressed miRNAs (chi-miR-1343, chi-miR-328-3p, chi-miR-877-3p, chi-miR-296-3p, chi-miR-128-5p, chi-miR-331-3p, chi-miR-342-5p and chi-miR-34a) have important regulatory roles in ovarian cell proliferation, hormone secretion and metabolism-related biological processes. Overall, our study investigated the changes in serum hormone and miRNA levels in the ovaries. These data provide a valuable resource for understanding the molecular regulatory mechanisms of miRNAs in ovarian tissue during the sexual maturity period in goats.


Compatible instrumentation for intraoperative MRI: expanding resources.
Steadfast progress has been made from biopsy to surgery with interventional MRI (iMRI). Such image-guided interventions require specialized instrumentation due to the unusual elements of the MR environment. Suppliers/manufacturers of MR-compatible instrumentation were few in 1994, but now there are more than 50. We present fundamental issues of MR compatibility and a list of known suppliers/manufacturers.


Conservation of RNA chaperone activity of the human La-related proteins 4, 6 and 7.
The La module is a conserved tandem arrangement of a La motif and RNA recognition motif whose function has been best characterized in genuine La proteins. The best-characterized substrates of La proteins are pre-tRNAs, and previous work using tRNA mediated suppression in Schizosaccharomyces pombe has demonstrated that yeast and human La enhance the maturation of these using two distinguishable activities: UUU-3'OH-dependent trailer binding/protection and a UUU-3'OH independent activity related to RNA chaperone function. The La module has also been identified in several conserved families of La-related proteins (LARPs) that engage other RNAs, but their mode of RNA binding and function(s) are not well understood. We demonstrate that the La modules of the human LARPs 4, 6 and 7 are also active in tRNA-mediated suppression, even in the absence of stable UUU-3'OH trailer protection. Rather, the capacity of these to enhance pre-tRNA maturation is associated with RNA chaperone function, which we demonstrate to be a conserved activity for each hLARP in vitro. Our work reveals insight into the mechanisms by which La module containing proteins discriminate RNA targets and demonstrates that RNA chaperone activity is a conserved function across representative members of the La motif-containing superfamily.


[Diathesis and predisposition. A molecular reappraisal of the mode of reacting].
The identification of the causes of important infectious and hereditary diseases became scientifically clear in the last years of the nineteenth century and in the first years of the twentieth. Through many centuries, the lack of etiologic knowledge regarding diseases has extraordinarily enhanced the value of the concept of predisposition so that "diathesis" helped to "explain" many forms of morbidity. Several discoveries as to the real "causes" of diseases, however, led to a critical downgrading of its value. But in-depth knowledge regarding the proteins controlled by genes of the "major histocompatibility complex" (MHC, HLA) in man was followed, a few years later, by the demonstration of the fact that carriers of particular alleles are exposed to higher risks of contracting certain diseases than non-carriers of these molecules. A new key for interpretation-this time, a genetic and molecular one-was thus offered for the concept of "predisposition". Actually, man's HLA-associated molecular individuality induces and causes an extraordinarily personal way of reacting to various stimuli. An obvious consequence of this is not only that man, having become aware of his "molecular uniqueness" (which is significantly HLA-related), can view himself as a "biological Ego" but, most of all, that some of his predispositions towards becoming ill may be ascribed to some of his individual molecular characterizations. Thus, the onset and the course of many diseases would be viewed as the effect of a given "way of reacting". This could be recognized as the true essence of diathesis, 18 centuries after Galen.


Congenital generalized infantile myofibromatosis and neonatal hemochromatosis. An autopsy case report.
An autopsy case of congenital infantile myofibromatosis and neonatal hemochromatosis is reported. A thirty-six-hour-old baby girl had multiple subcutaneous nodules in addition to multiple visceral involvement of heart, lungs, pharynx, larynx, stomach, small bowel, large bowel, pancreas, kidneys, spleen, thyroid, adrenal glands, lymph nodes, peripheral nerves, meninges and soft tissues. In these tumoral nodules, three types of histological patterns were observed: 1-hemangiopericytoma-like, 2-mixed, and 3-pure spindle cell. Tumor cells were immunohistochemically positive for actin, and negative for desmin, muscle-specific antigen, and estrogen, related protein. The histological and immunohistochemical findings of the case suggested that a close relationship may exist between infantile myofibromatosis and infantile hemangiopericytoma. In addition to infantile myofibromatosis, neonatal hemochromatosis characterized by iron deposition in parenchymatous organs such as liver, pancreas, lungs, thyroid, and adrenal glands was another important characteristic of the case.


[Comparative analysis of the histological variants of renal cell cancer].
85 cases of renal-cell carcinoma are studied histologically, cytologically and electron-microscopically. Morphological variant was determined according to the classification of N. A. Krayevsky et al. Histological and cytological variants of renal-cell carcinoma, differences of the degree of their differentiation are shown. Electron-microscopically the cell types characteristic of clear-cell and granular-cell variants of a different degree of differentiation are distinguished. Similarity of cell ultrastructure in granular-cell, sarcoma-like and glandular tumour variants is found. The ultrastructural features of nephrocytes and renal tubules in the form of the accumulation of microvilli, cytoplasmic membrane invaginations, desmosomes, basal membrane fragments which are seen as the markers of the tumour organospecificity were preserved in all variants of renal-cell carcinoma studied.


[Outcome of untreated lung cancer].
The study was concerned with postdiagnostic survival time in 933 cases of unresected lung cancer. The course of the disease was found to be in correlation with patient's age as well as stage, clinico-anatomical type and morphological pattern of tumor.


[Kinetics of the inactivation of tetrodotoxin-sensitive sodium channels in the spinal ganglion neurons of rats].
The assessment of TTX-sensitive sodium transmembrane ionic current induced by depolarizing shifts in the MP performed in neurons of isolated dorsal root ganglion of adult rats revealed that the kinetics of the inactivation of TTX-sensitive sodium channels was more complicated than suggested by Hodgkin and Huxley for gating devices, the behaviour of the inactivation system following at least two exponential kinetics.


A MEIG1/PACRG complex in the manchette is essential for building the sperm flagella.
A key event in the process of spermiogenesis is the formation of the flagella, which enables sperm to reach eggs for fertilization. Yeast two-hybrid studies revealed that meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) interact, and that sperm-associated antigen 16, which encodes an axoneme central apparatus protein, is also a binding partner of MEIG1. In spermatocytes of wild-type mice, MEIG1 is expressed in the whole germ cell bodies, but the protein migrates to the manchette, a unique structure at the base of elongating spermatid that directs formation of the flagella. In the elongating spermatids of wild-type mice, PACRG colocalizes with α-tubulin, a marker for the manchette, whereas this localization was not changed in the few remaining elongating spermatids of Meig1-deficient mice. In addition, MEIG1 no longer localizes to the manchette in the remaining elongating spermatids of Pacrg-deficient mice, indicating that PACRG recruits MEIG1 to the manchette. PACRG is not stable in mammalian cells, but can be stabilized by MEIG1 or by inhibition of proteasome function. SPAG16L is present in the spermatocyte cytoplasm of wild-type mice, and in the manchette of elongating spermatids, but in the Meig1 or Pacrg-deficient mice, SPAG16L no longer localizes to the manchette. By contrast, MEIG1 and PACRG are still present in the manchette of Spag16L-deficient mice, indicating that SPAG16L is a downstream partner of these two proteins. Together, our studies demonstrate that MEIG1/PACRG forms a complex in the manchette and that this complex is necessary to transport cargos, such as SPAG16L, to build the sperm flagella.


Reticulate representation of evolutionary and functional relationships between phage genomes.
Bacteriophage genomes show pervasive mosaicism, indicating the importance of horizontal gene exchange in their evolution. Phage genomes represent unique combinations of modules, each of them with a different phylogenetic history. The traditional classification, based on a variety of criteria such as nucleic acid type (single/double-stranded DNA/RNA), morphology, and host range, appeared inconsistent with sequence analyses. With the genomic era, an ever increasing number of sequenced phages cannot be classified, in part due to a lack of morphological information and in part to the intrinsic incapability of tree-based methods to efficiently deal with mosaicism. This problem led some virologists to call for a moratorium on the creation of additional taxa in the order Caudovirales, in order to let virologists discuss classification schemes that might better suit phage evolution. In this context, we propose a framework for a reticulate classification of phages based on gene content. Starting from gene families, we built a weighted graph, where nodes represent phages and edges represent phage-phage similarities in terms of shared genes. We then apply various measures of graph topology to analyze the resulting graph. Most double-stranded DNA phages are found in a single component. The values of the clustering coefficient and closeness distinguish temperate from virulent phages, whereas chimeric phages are characterized by a high betweenness coefficient. We apply a 2-step clustering method to this graph to generate a reticulate classification of phages: Each phage is associated with a membership vector, which quantitatively characterizes its membership to the set of clusters. Furthermore, we cluster genes based on their "phylogenetic profiles" to define "evolutionary cohesive modules." In virulent phages, evolutionary modules span several functional categories, whereas in temperate phages they correspond better to functional modules. Moreover, despite the fact that modules only cover a fraction of all phage genes, phage groups can be distinguished by their different combination of modules, serving the bases for a higher level reticulate classification. These 2 classification schemes provide an automatic and dynamic way of representing the relationships within the phage population and can be extended to include newly sequenced phage genomes, as well as other types of genetic elements.


Finite-Time Passivity of Adaptive Coupled Neural Networks With Undirected and Directed Topologies.
In this paper, the finite-time passivity (FTP) problem for two classes of coupled neural networks (CNNs) with adaptive coupling weights is discussed. By selecting appropriate adaptive laws and controllers, several FTP conditions are given for CNNs with undirected and directed topologies. Furthermore, some finite-time synchronization conditions are also established by employing the FTP of the CNNs. At last, two numeral examples are used to check the correctness of the obtained criteria.


Hourly Origin-Destination Matrix Estimation Using Intelligent Transportation Systems Data and Deep Learning.
Predicting the travel demand plays an indispensable role in urban transportation planning. Data collection methods for estimating the origin-destination (OD) demand matrix are being extensively shifted from traditional survey techniques to the pre-collected data from intelligent transportation systems (ITSs). This shift is partly due to the high cost of conducting traditional surveys and partly due to the diversity of scattered data produced by ITSs and the opportunity to derive extra benefits out of this big data. This study attempts to predict the OD matrix of Tehran metropolis using a set of ITS data, including the data extracted from automatic number plate recognition (ANPR) cameras, smart fare cards, loop detectors at intersections, global positioning systems (GPS) of navigation software, socio-economic and demographic characteristics as well as land-use features of zones. For this purpose, five models based on machine learning (ML) techniques are developed for training and test. In evaluating the performance of the models, the statistical methods show that the convolutional neural network (CNN) leads to the best performance in terms of accuracy in predicting the OD matrix and has the lowest error in terms of root mean square error (RMSE) and mean absolute percentage error (MAPE). Moreover, the predicted OD matrix was structurally compared with the ground truth matrix, and the CNN model also shows the highest structural similarity with the ground truth OD matrix in the presented case.


Saffron (Crocus sativus L.): As an Antidepressant.
Saffron, Crocus sativus (Iridaceae), is a perennial herb, which earned its popularity as both medicine and spice. It is an inhabitant of different mountainous regions of Asia Minor to Greece, Western Asia, Egypt, and India. The benefits of saffron as an antidepressant are well-documented. Almost 150 volatile and nonvolatile compounds are obtained from the chemical analysis of this plant. Fewer than 50 constituents elucidated and identified so far showed phytochemical characteristics. The major bioactive compounds identified are safranal, crocin, and picrocrocin, which are responsible for its aroma as well as its bitter taste. This review is an attempt to encompass the methods of analysis and pharmacodynamic and pharmacokinetic properties of saffron followed by its efficacious and safe potential.


Sphingolipid Synthesis Inhibition by Myriocin Administration Enhances Lipid Consumption and Ameliorates Lipid Response to Myocardial Ischemia Reperfusion Injury.
Myocardial infarct requires prompt thrombolytic therapy or primary percutaneous coronary intervention to limit the extent of necrosis, but reperfusion creates additional damage. Along with reperfusion, a maladaptive remodeling phase might occur and it is often associated with inflammation, oxidative stress, as well as a reduced ability to recover metabolism homeostasis. Infarcted individuals can exhibit reduced lipid turnover and their accumulation in cardiomyocytes, which is linked to a deregulation of peroxisome proliferator activated receptors (PPARs), controlling fatty acids metabolism, energy production, and the anti-inflammatory response. We previously demonstrated that Myriocin can be effectively used as post-conditioning therapeutic to limit ischemia/reperfusion-induced inflammation, oxidative stress, and infarct size, in a murine model. In this follow-up study, we demonstrate that Myriocin has a critical regulatory role in cardiac remodeling and energy production, by up-regulating the transcriptional factor EB, PPARs nuclear receptors and genes involved in fatty acids metabolism, such as VLDL receptor, Fatp1, CD36, Fabp3, Cpts, and mitochondrial FA dehydrogenases. The overall effects are represented by an increased β-oxidation, together with an improved electron transport chain and energy production. The potent immunomodulatory and metabolism regulatory effects of Myriocin elicit the molecule as a promising pharmacological tool for post-conditioning therapy of myocardial ischemia/reperfusion injury.


Evidence-Based Quality Improvement (EBQI) in the pre-implementation phase: key steps and activities.
Evidence-Based Quality Improvement (EBQI) involves researchers and local partners working collaboratively to support the uptake of an evidence-based intervention (EBI). To date, EBQI has not been consistently included in community-engaged dissemination and implementation literature. The purpose of this paper is to illustrate the steps, activities, and outputs of EBQI in the pre-implementation phase. The research team applied comparative case study methods to describe key steps, activities, and outputs of EBQI across seven projects. Our approach included: (1) specification of research questions, (2) selection of cases, (3) construction of a case codebook, (4) coding of cases using the codebook, and (5) comparison of cases. The cases selected included five distinct settings (e.g., correction facilities, community pharmacies), seven EBIs (e.g., nutrition promotion curriculum, cognitive processing therapy) and five unique lead authors. Case examples include both community-embedded and clinically-oriented projects. Key steps in the EBQI process included: (1) forming a local team of partners and experts, (2) prioritizing implementation determinants based on existing literature/data, (3) selecting strategies and/or adaptations in the context of key determinants, (4) specifying selected strategies/adaptations, and (5) refining strategies/adaptations. Examples of activities are included to illustrate how each step was achieved. Outputs included prioritized determinants, EBI adaptations, and implementation strategies. A primary contribution of our comparative case study is the delineation of various steps and activities of EBQI, which may contribute to the replicability of the EBQI process across other implementation research projects.


Biomolecular Phase Separation: From Molecular Driving Forces to Macroscopic Properties.
Biological phase separation is known to be important for cellular organization, which has recently been extended to a new class of biomolecules that form liquid-like droplets coexisting with the surrounding cellular or extracellular environment. These droplets are termed membraneless organelles, as they lack a dividing lipid membrane, and are formed through liquid-liquid phase separation (LLPS). Elucidating the molecular determinants of phase separation is a critical challenge for the field, as we are still at the early stages of understanding how cells may promote and regulate functions that are driven by LLPS. In this review, we discuss the role that disorder, perturbations to molecular interactions resulting from sequence, posttranslational modifications, and various regulatory stimuli play on protein LLPS, with a particular focus on insights that may be obtained from simulation and theory. We finally discuss how these molecular driving forces alter multicomponent phase separation and selectivity.


Ultrastructural analysis of spermiogenesis in Iguana iguana (Reptilia: Sauria: Iguanidae).
Spermiogenesis in the lizard, Iguana iguana, was studied by transmission and scanning electron microscopy. During this process, structures such as the acrosomal complex in the spermatid head and the axonemal complex in the mid and principal pieces of the flagellum are formed. The nuclear content is initially compacted into thick, longitudinal chromatin filaments. Nuclear shape is determined by further compaction and by the manchette, a layer of microtubules surrounding the head. The acrosomal complex originates from Golgi vesicles and the interaction between the proacrosomal vesicle and the nucleus. The midpiece consists of a pair of centrioles, surrounded by a fibrous sheath and rings of simple and modified mitochondria. The centrioles sustain the axoneme that appears at the end of the midpiece. The axoneme extends throughout the principal piece of the flagellum with the 9 + 2 pattern, still surrounded by the fibrous sheath. In the endpiece, the axoneme continues, surrounded only by the plasma membrane. In the lumen of seminiferous tubules, immature spermatozoa retain abundant residual cytoplasm.


Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial.
Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3-25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in all patients who received one or more doses of the study drug. The trial is registered with ClinicalTrials.gov, number NCT01302600. The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and -1·82 for placebo (treatment difference 2·00 points, 96% CI -0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. AFM Téléthon and Trophos SA.


Neural signatures of co-occurring reading and mathematical difficulties.
Impaired abilities in multiple domains is common in children with learning difficulties. Co-occurrence of low reading and mathematical abilities (LRLM) appears in almost every second child with learning difficulties. However, little is known regarding the neural bases of this combination. Leveraging a unique and tightly controlled sample including children with LRLM, isolated low reading ability (LR), and isolated low mathematical ability (LM), we uncover a distinct neural signature in children with co-occurring low reading and mathematical abilities differentiable from LR and LM. Specifically, we show that LRLM is neuroanatomically distinct from both LR and LM based on reduced cortical folding of the right parahippocampal gyrus, a medial temporal lobe region implicated in visual associative learning. LRLM children were further distinguished from LR and LM by patterns of intrinsic functional connectivity between parahippocampal gyrus and brain circuitry underlying reading and numerical quantity processing. Our results critically inform cognitive and neural models of LRLM by implicating aberrations in both domain-specific and domain-general brain regions involved in reading and mathematics. More generally, our results provide the first evidence for distinct multimodal neural signatures associated with LRLM, and suggest that this population displays an independent phenotype of learning difficulty that cannot be explained simply as a combination of isolated low reading and mathematical abilities.


Decoding the functional roles of cationic side chains of the major antimicrobial region of human cathelicidin LL-37.
Human cathelicidin LL-37 is a critical cationic antimicrobial peptide for host defense against infection, immune modulation, and wound healing. This article elucidates the functional roles of the cationic side chains of the major antimicrobial region of LL-37, corresponding to residues 17 to 32 (designated GF-17). Antimicrobial assays, killing kinetics studies, and vesicle leakage experiments all indicate that a conversion of lysines to arginines affected the ability of the peptide to kill the Gram-positive Staphylococcus aureus strain USA300. Alanine scanning experiments show that S. aureus is less sensitive than Escherichia coli to a single cationic residue mutation of GF-17. Among the five cationic residues, R23 appears to be somewhat important in killing S. aureus. However, R23 and K25 of GF-17 are of prime importance in killing the Gram-negative organism E. coli. In particular, R23 is essential for (i) rapid recognition, (ii) permeation of the E. coli outer membrane, (iii) clustering of anionic lipids in a membrane system mimicking the E. coli inner membrane, and (iv) membrane disruption. Bacterial aggregation (i.e., rapid recognition via charge neutralization) is the first step of the peptide action. Structurally, R23 is located in the interface (i.e., the first action layer), a situation ideal for the interactions listed above. In contrast, residues K18, R19, and R29 are on the hydrophilic surface of the amphipathic helix and play only a secondary role. Mapping of the functional spectrum of cationic residues of GF-17 provides a solid basis for engineering bacterium-specific antimicrobials using this highly potent template.


Influenza vaccination during pregnancy: a qualitative study of the knowledge, attitudes, beliefs, and practices of general practitioners in Central and South-Western Sydney.
Pregnant women have an increased risk of influenza complications. Influenza vaccination during pregnancy is safe and effective, however coverage in Australia is less than 40%. Pregnant women who receive a recommendation for influenza vaccination from a health care provider are more likely to receive it, however the perspectives of Australian general practitioners has not previously been reported. The aim of the study was to investigate the knowledge, attitudes, beliefs, and practices of general practitioners practicing in South-Western Sydney, Australia towards influenza vaccination during pregnancy. A qualitative descriptive study was conducted, with semi-structured interviews completed with seventeen general practitioners in October 2012. A thematic analysis was undertaken by four researchers, and transcripts were analysed using N-Vivo software according to agreed codes. One-third of the general practitioners interviewed did not consider influenza during pregnancy to be a serious risk for the mother or the baby. The majority of the general practitioners were aware of the government recommendations for influenza vaccination during pregnancy, but few general practitioners were confident of their knowledge about the vaccine and most felt they needed more information. More than half the general practitioners had significant concerns about the safety of influenza vaccination during pregnancy. Their practices in the provision of the vaccine were related to their perception of risk of influenza during pregnancy and their confidence about the safety of the vaccine. While two-thirds reported that they are recommending influenza vaccination to their pregnant patients, many were adopting principles of patient-informed choice in their approach and encouraged women to decide for themselves whether they would receive the vaccine. General practitioners have varied knowledge, attitudes, and beliefs about influenza vaccination during pregnancy, which influence their practices. Addressing these could have a significant impact on improving vaccine uptake during pregnancy.


Minocycline attenuates the development of diabetic neuropathic pain: possible anti-inflammatory and anti-oxidant mechanisms.
Painful neuropathy, a common complication of diabetes mellitus is characterized by allodynia and hyperalgesia. Recent studies emphasized on the role of non-neuronal cells, particularly microglia in the development of neuronal hypersensitivity. The purpose of the present study is to evaluate the effect of minocyline, a selective inhibitor of microglial activation to define the role of neuroimmune activation in experimental diabetic neuropathy. Cold allodynia and thermal and chemical hyperalgesia were assessed and the markers of inflammation and oxidative and nitrosative stress were estimated in streptozotocin-induced diabetic rats. Chronic administration of minocycline (40 and 80 mg/kg, i.p.) for 2 weeks started 2 weeks after diabetes induction attenuated the development of diabetic neuropathy as compared to diabetic control animals. In addition, minocyline treatment reduced the levels of interleukin-1β and tumor necrosis factor-α, lipid peroxidation, nitrite and also improved antioxidant defense in spinal cords of diabetic rats as compared to diabetic control animals. In contrast, minocycline (80 mg/kg, per se) had no effect on any of these behavioral and biochemical parameters assessed in age-matched control animals. The results of the present study strongly suggest that activated microglia are involved in the development of experimental diabetic neuropathy and minocycline exerted its effect probably by inhibition of neuroimmune activation of microglia. In addition, the beneficial effects of minocycline are partly mediated by its anti-inflammatory effect by reducing the levels of proinflammatory cytokines and in part by modulating oxidative and nitrosative stress in the spinal cord that might be involved in attenuating the development of behavioral hypersensitivity in diabetic rats.