Prevalence and Correlates of Active Transportation to School Among Colombian Children and Adolescents.
In Colombia, active transportation has been assessed in multiple local and regional studies, but national data on active transportation are scarce. This study aims to describe the prevalence and factors associated with active transportation to/from school among Colombian children and adolescents. The authors analyzed nationally representative data from the National Survey of Nutrition 2015, with a sample of 11,466 children and adolescents aged between 3 and 17 years. Descriptive statistics were calculated, and prevalence ratios were estimated using Poisson regression multivariable models with robust variance. Approximately 70% of Colombian children and adolescents reported engaging in active transportation to/from school over the last week. There were no differences by sex among preschoolers nor school-aged children. Fewer adolescent females than males used active transportation. Preschoolers and school-aged children living in Bogota were more likely to report active transport than children from other regions (prevalence ratios for other regions ranged from 0.59 to 0.86). School-aged children and adolescents with a lower wealth index were more likely to use active transportation than their counterparts (prevalence ratios = 1.32 and 1.22, respectively). The wealthiest children and adolescents, adolescents from rural areas, and female adolescents should be a focus for future interventions. Actions need to be implemented to improve the involvement in active transportation to/from school in Colombia.


Adverse effect of amphotericin B administration on renal hemodynamics in the rat. Neurohumoral mechanisms and influence of calcium channel blockade.
The effect of administration of amphotericin B (AMPHO) on renal hemodynamics was studied in the rat. Acute infusion (1.2 mg/kg) of AMPHO resulted in a significant fall in glomerular filtration rate (GFR) (0.82 vs. 1.33 ml/min, P less than .01) and renal plasma flow (3.38 vs. 6.24 ml/min; P less than .01) and a rise in renal vascular resistance (23.55 vs. 11.25 mm Hg.min/ml; P less than .05) compared with base-line values. Administration of AMPHO (5 mg/kg/day i.p.) for 21 days resulted in similar changes in GFR, renal plasma flow and renal vascular resistance. Pretreatment of rats with the angiotensin II receptor blocker, sar-gly angiotensin II, did not prevent the renal vasoconstriction or fall in GFR with AMPHO. Unilateral renal denervation did not prevent the decreased GFR or effective renal plasma flow after AMPHO when compared with the contralateral, innervated kidney. Pretreatment of rats with verapamil completely inhibited renal vasoconstriction during and after AMPHO. Verapamil markedly attenuated the fall in GFR observed during AMPHO (AMPHO + verapamil vs. AMPHO + vehicle; 0.73 vs. 0.26 ml/min; P less than .05); however, the GFR observed in the postinfusion period was significantly decreased (base line vs. final; 1.17 vs. 0.84 ml/min; P less than .01). The authors conclude that 1) the adverse renal hemodynamic effects of AMPHO are not directly mediated by the renin-angiotensin or renal sympathetic nervous systems and 2) pretreatment with verapamil completely prevents AMPHO-induced renal vasoconstriction.


Memory Binding Test and Its Associations With Hippocampal Volume Across the Cognitive Continuum Preceding Dementia.
Innovative memory paradigms have been introduced to capture subtle memory changes in early Alzheimer's disease (AD). We aimed to examine the associations between different indexes of the challenging Memory Binding Test (MBT) and hippocampal volume (HV) in a sample of individuals with subjective cognitive decline (SCD; n = 50), amnestic mild cognitive impairment (aMCI) due to AD (n = 31), and cognitively normal (CN) older adults (n = 29) recruited from the Czech Brain Aging Study, in contrast to traditional verbal memory tests. Both MBT free and cued recall scores in immediate and delayed recall conditions were associated with lower HV in both SCD and aMCI due to AD, whereas in traditional verbal memory tests only delayed recall scores were associated with lower HV. In SCD, the associations with lower HV in the immediate recall covered specific cued recall indexes only. In conclusion, the MBT is a promising test for detecting subtle hippocampal-associated memory decline during the predementia continuum.


Participation of chromatin-remodeling proteins in the repair of ultraviolet-B-damaged DNA.
The genome of plants is organized into chromatin, affecting the rates of transcription, DNA recombination, and repair. In this work, we have investigated the consequences of reduced expression of some chromatin-remodeling factors and histone acetylation in maize (Zea mays) and Arabidopsis (Arabidopsis thaliana) in their participation in DNA repair after ultraviolet (UV)-B irradiation. Plants deficient in NFC102/NFC4 or SDG102/SDG26 showed more damaged DNA than wild-type plants; however, the Arabidopsis chc1 mutant showed similar accumulation of cyclobutane pyrimidine dimers as wild-type plants, in contrast to the increased DNA damage measured in the maize chc101 RNA interference line. In Arabidopsis, plants deficient in chromatin remodeling are also affected in the accumulation of pigments by UV-B. Plants treated with an inhibitor of histone acetyltransferases, curcumin, previous to the UV-B treatment show deficiencies in DNA repair; in addition, the chromatin remodeling-deficient plants have altered levels of acetylated histones after the UV-B treatment, demonstrating that histone acetylation is important during DNA repair in these two plant species. Arabidopsis mutants ham1 and ham2 also showed increased DNA damage after UV-B, suggesting that the role of these proteins in DNA damage repair has been conserved through evolution. However, cyclobutane pyrimidine dimer accumulation was higher in ham1 than in ham2; suggesting that HAM1 has a major role in DNA repair after UV-B. In summary, in this work, we have demonstrated that chromatin remodeling, and histone acetylation in particular, is important during DNA repair by UV-B, demonstrating that both genetic and epigenetic effects control DNA repair in plants.


Genetic Variants of HIV Type 1 in Men Who Have Sex with Men in Russia.
The men who have sex with men (MSM) population infected with HIV is poorly studied in Russia because of stigma and discrimination. In the first years of the HIV epidemic, the only HIV genetic variant that circulated among MSM was subtype B, usually acquired abroad. Meanwhile, the massive epidemic of HIV in Russia was caused by a highly homogenic subtype A variant, AFSU (A6), and spread mainly among drug users. In this study, 155 HIV pol sequences from MSM collected during the 2006-2016 period were analyzed. Phylogenetic analysis found that 19.4% of the viral sequences from MSM clustered with HIV genetic variants A6 and BFSU, which were previously identified only among drug users and their heterosexual partners. These data show that the MSM population in Russia is gradually becoming less isolated from the general epidemic process. Urgent measures should be taken to prevent the spread of HIV among the MSM population.


Disseminated pulmonary blastomycosis in an immunosuppressed patient. Diagnosis by fiberoptic bronchoscopy.
A 73-year-old man with malignant lymphoma who was undergoing treatment with systemic chemotherapy presented with an acute, febrile illness associated with cough and sputum production. The patient developed bilateral, diffuse, pulmonary interstitial infiltrates with rapidly progressive respiratory insufficiency. The diagnosis was made by demonstrating Blastomyces dermatitidis in bronchial brush and transbronchial lung biopsy specimens obtained through fiberoptic bronchoscopy.


Prognostic impact of the extracapsular lymph node involvement on disease-free survival according to the 7th edition of American Joint Committee on Cancer Staging System.
The 7th edition of American Joint Committee on Cancer (AJCC) staging system of oesophageal cancer and gastro-oesophageal junction has re-staged positive nodes into N1-3 according to the number of invaded lymph nodes (LNs). However, this new classification does not consider the potential negative impact of the extracapsular breakthrough on survival. This study aims at assessing prognosis according to whether LN involvement is intracapsular (ICLNI) or extracapsular (ECLNI) on disease-free survival (DFS) among the three sub-groups of LN-positive patients. Four hundred and sixteen consecutive R0 patients who underwent transthoracic oesophagectomy for cancer between 1996 and 2011 were retrospectively re-classified using the latest AJCC TNM classification. Among them, 230 (55%) patients have received a neoadjuvant chemoradiotherapy. Prognostic impact of ICLNI and ECLNI on DFS was assessed according to their new LN status. Multivariate analysis was drawn to determine factors affecting DFS. Among the 416 patients, there were 138 (33%) patients with positive LN: 79 (57%) with ICLNI and 59 (43%) with ECLNI. The proportion of ECLNI was 21 of 73 (28%), 21 of 41 (51%) and 17 of 24 (70%) in N1, N2 and N3 patients, respectively. In N1 patients, median DFS was 48 months in ICLNI and 13 months in ECLNI (P = 0.068). In N2 patients, median DFS was 19 months in ICLNI and 9 months in ECLNI (P = 0.07). In N3 patients, median DFS was not reached in ICLNI and was 6 months in ECLNI (P = 0.002). On multivariate analysis, the ECLNI (P < 0.001, hazard ratio, HR: 2.51) and the post-T stage (P = 0.03, HR: 1.62) were the two independent factors affecting DFS. Based on our limited study population, the existence of an ECLNI seems to have an additive negative impact on DFS, regardless of the pN stage. This suggests that extracapsular breakthrough status should be added to the new TNM staging system. This information has to be validated by further investigations.


Molecular characterization of enterovirus 71 and coxsackievirus A16 using the 5' untranslated region and VP1 region.
Enterovirus 71 (EV71) and coxsackievirus A16 (CVA16) are members of the species Human enterovirus A, and are both major and independent aetiological agents of hand-foot-and-mouth disease. The human enterovirus (HEV) 5' untranslated region (UTR) is fundamentally important for efficient virus replication and for virulence, whilst the VP1 region correlates well with antigenic typing by neutralization, and can be used for virus identification and evolutionary studies. A comparison was undertaken of the 5'UTR and VP1 nucleotide sequences of five EV71 clinical isolates and 10 CVA16 clinical isolates from one laboratory with the 5'UTR and VP1 sequences of 104 EV71 strains and 45 CVA16 strains available in GenBank. The genetic relationships were analysed using standard phylogenetic methods. The EV71 phylogenetic analysis showed that the VP1 sequences were clustered into three genogroups, A, B and C, with genogroups B and C further divided into five subgenogroups, B1-B5 and C1-C5, respectively. All EV71 strains were clustered similarly in the 5'UTR and VP1 trees, except for one Taiwanese strain, which demonstrated different clustering in the two trees, suggesting a recombination event in the phylogeny. The CVA16 phylogenetic analysis showed that the VP1 sequences were clustered into two genogroups, A and B, with genogroup B further divided into B1 (B1a and B1b), B2 and a possible B3; and that a similar pattern and grouping of all strains were displayed in the 5'UTR tree. This study demonstrated that comparing the two regions provides evidence of epidemiological linkage of HEV-A strains, and that mutation in the two regions plays a vital role in the evolution of these viruses. The combination of molecular typing and phylogenetic sequence analysis will be beneficial in both individual patient diagnosis and public health measures.


The association of maternal lymphocytotoxic antibodies with obstetric complications.
The immunologic relation between mother and fetus has become of interest to those concerned with reproductive physiology. One method to assay this type of relation is to determine the immunologic response to HLA antigens expressed by the fetus which are of paternal origin. Although 20 to 50% of multiparous women develop lymphocytotoxic antibodies during pregnancy, the effect of these antibodies on gestation or the fetus has not been established. In a prospective study, 23 patients at the time of spontaneous abortion had negative cytotoxic antibodies. Of 129 obstetric patients followed with antibody screening over a 6 to 7 month period until delivery, 28 developed positive lymphocytotoxic antibodies (22%). These 28 patients with cytotoxic antibodies delivered male infants by a ratio of 4 to 3, and 11 patients (39.3%) had complications during the gestation. The responsiveness to the paternal histocompatibility antigens is valuable information for furthering the understanding of the fetal-maternal relation.


Cost-effectiveness of colorectal cancer screening in high-risk Spanish patients: use of a validated model to inform public policy.
The European Community has made a commitment to colorectal cancer (CRC) screening, but regional considerations may affect the design of national screening programs. We developed a decision analytic model tailored to a pilot screening program for high-risk persons in Spain with the aim of informing public policy decisions. We constructed a decision analytic Markov model based on our validated model of CRC screening that reflected CRC epidemiology and costs in persons with first-degree relatives with CRC in Aragón, Spain, and superimposed colonoscopy every 5 or 10 years from ages 40 to 80 years. The pilot program's preliminary clinical results and our modeling results were presented to regional health authorities. In the model, without screening, 88 CRC cases occurred per 1,000 persons from age 40 to 85 years. In the base case, screening reduced this by 72% to 77% and gained 0.12 discounted life years per person. Screening every 10 years was cost saving, and screening every 5 years versus every 10 years cost 7,250 euros per life year gained. Based on these savings, 36 to 39 euros per person per year could go toward operating costs while maintaining a neutral budget. If screening costs doubled, screening remained highly cost-effective but no longer cost saving. These results contributed to the health authorities' decision to expand the pilot program to the entire region in 2009. Colonoscopic screening of first-degree relatives of persons with CRC may be cost saving in public systems like that of Spain. Decision analytic modeling tailored to regional considerations can inform public policy decisions. Tailored decision analytic modeling can inform regional policy decisions on cancer screening.


Impact of age and sex on primary preventive treatment for cardiovascular disease in the West Midlands, UK: cross sectional study.
To establish the impact of age and sex on primary preventive treatment for cardiovascular disease in a typical primary care population. Cross sectional study of anonymised patient records. All 41,250 records of patients aged ≥ 40 registered at 19 general practices in the West Midlands, United Kingdom, were extracted and analysed. Patients' demographics, risk factors for cardiovascular disease (blood pressure, total cholesterol concentration), and prescriptions for primary preventive drugs were extracted from patients' records. Patients were subdivided into five year age bands up to 85 (patients aged ≥ 85 were analysed as one group) and prescribing trends across the population were assessed by estimating the proportion of patients prescribed with antihypertensive drug or statin drug, or both, in each group. Of the 41,250 records screened in this study, 36,679 (89%) patients did not have a history of cardiovascular disease and therefore could be considered for primary preventive treatment. The proportion receiving antihypertensive drugs increased with age (from 5% (378/6978) aged 40-44 to 57% (621/1092) aged ≥ 85) as did the proportion taking statins up to the age of 74 (from 3% (201/6978) aged 40-44 to 29% (675/2367) aged 70-74). In those aged 75 and above, the odds of a receiving prescription for a statin (relative to the 40-44 age group) decreased with every five year increment in age (odds ratio 12.9 (95% confidence interval 10.8 to 15.3) at age 75-79 to 5.7 (4.6 to 7.2) at age ≥ 85; P<0.001). There were no consistent differences in prescribing trends by sex. Previously described undertreatment of women in secondary prevention of cardiovascular disease was not observed for primary prevention. Low use of statins in older people highlights the need for a stronger evidence base and clearer guidelines for people aged over 75.


The use of toads (Bufo regularis) in a new biological assay for screening chemicals or drugs which induce leukaemia in man.
Injection of Egyptian toads Bufo regularis, with adriamycin subcutaneously in the dorsal lymph sac at a dose level of 0.1 mg/toad, once every 3 weeks for 3 months induced pronounced alterations in the blood cells. These alterations were more or less similar to the criteria reported in human leukaemia. These changes were all comparable to those observed after the treatment of the experimental animals with the chemical carcinogen 7,12-dimethylbenz(a)anthracene. It is speculated that toads (Bufo regularis) can be used as biological test animals for screening chemicals or drugs which induce leukaemia in man.


Role of liquid compressional viscosity in the dynamics of a sonoluminescing bubble.
The well-known Rayleigh-Plesset ( RP ) equation is the basis of almost all hydrodynamical descriptions of single-bubble sonoluminescence ( SBSL ). A major deficiency of the RP equation is that it accounts for viscosity of an incompressible liquid and compressibility, separately. By removing this approximation, a new modification of the RP equation is presented considering effect of compressional viscosity of the liquid. This modification leads to addition of a new viscous term to the traditional bubble boundary equation. Influence of this new term in the dynamics of a sonoluminescing bubble has numerically been studied considering effects of heat transfer at the bubble wall, nonequilibrium evaporation and condensation of water vapor, chemical reactions, and diffusion of the reactions products in the liquid. The results show that the new term has a significant damping role in the bubble motion at the end of collapse and during the rebounds, so that its consideration dramatically reduces amplitude of the afterbounces. Dependence of this new damping mechanism on the driving pressure amplitude and on the ambient radius has been investigated. The results indicate that the more intense the collapse, the more important the damping of the liquid compressional viscosity.


Defining anatomical landmarks for robotic facelift thyroidectomy.
Robotic facelift thyroidectomy (RFT) is a straightforward remote access thyroidectomy technique. While the anatomy encountered during RFT is well known to surgeons, the vector of approach during this technique may be less familiar. In order to facilitate safe and efficient performance of RFT, the relationships of key anatomical landmarks associated with this technique were determined. Eight anatomical dissections were performed in cadavers and included performance of RFT and definition of discrete anatomical relationships. Morphologic assessments of the great auricular nerve (GAN), omohyoid (OH) muscle, inferior constrictor (IC) muscle, and recurrent laryngeal nerve (RLN) were conducted. The mean distance from the incision apex to the anterior and posterior aspects of the GAN were 3.8 ± 1.2 and 7.7 ± 0.8 cm. From the apex of the incision to the OH muscle was 11.1 ± 1.7 cm on average. The OH muscle was located 1.3 ± 0.5 cm inferior to an axial line drawn through the inferior aspect of the thyroid notch. The anterior branch of the RLN was identified coursing deep to the inferior margin of the IC muscle a mean of 1.2 ± 0.2 cm lateral to the origin of this muscle on the cricoid cartilage. Characterization of the key anatomical landmarks of the lateral neck and thyroid compartment associated with RFT, including the GAN, OH muscle, and RLN, allows for rapid recognition of these critical structures during this operation. Surgeons learning this approach should be familiar with these relationships.


Stepwise reintroduction of carbohydrate during refeeding after prolonged fasting.
In an attempt to minimize fluid retention and obtain a gradual return to the pre-fast metabolic state, 14 nondiabetic obese subjects, who had fasted totally for 32 +/- 3 days, were fed a hypocaloric diet that incorporated stepwise increments in carbohydrate beginning at 20 g/day. During the refeeding period of 14 days, the total caloric intake for the first 9 days was 800 kcal/day and 1000 kcal/day thereafter. No untoward clinical events occurred. A weight regain of 2.2 +/- 0.4 kg during the first 7 days was accounted for by fluid retention. The return to pre-fast postabsorptive plasma glucose levels (82 +/- 3 to 93 +/- 3 mg dl-1) and a rise in immunoreactive insulin (0.5 +/- 0.1 to 0.8 +/- 0.1 ng ml-1) occurred by day 7. Blood 3-hydroxybutyrate and acetoacetate concentrations (4.1 and 0.6 mM, respectively) declined more slowly to reach pre-fast values by day 14; urinary excretion of 3-hydroxybutyrate dropped from 64 mmol/day to pre-fast levels by day 10. Urinary nitrogen excretion increased from 2.6 to a plateau of 5.5-6.0 g/day from day 3 onward; nitrogen balance was at least +3 g/day throughout refeeding. This approach to refeeding is associated with acceptable clinical response and may be appropriate after other states of marked caloric deprivation.


Switch in 3' splice site recognition between exon definition and splicing catalysis is important for sex-lethal autoregulation.
Maintenance of female sexual identity in Drosophila melanogaster involves an autoregulatory loop in which the protein Sex-lethal (SXL) promotes skipping of exon 3 from its own pre-mRNA. We have used transient transfection of Drosophila Schneider cells to analyze the role of exon 3 splice sites in regulation. Our results indicate that exon 3 repression requires competition between the 5' splice sites of exons 2 and 3 but is independent of their relative strength. Two 3' splice site AG's precede exon 3. We report here that, while the distal site plays a critical role in defining the exon, the proximal site is preferentially used for the actual splicing reaction, arguing for a switch in 3' splice site recognition between exon definition and splicing catalysis. Remarkably, the presence of the two 3' splice sites is important for the efficient regulation by SXL, suggesting that SXL interferes with molecular events occurring between initial splice site communication across the exon and the splice site pairing that leads to intron removal.


Neglected anterior shoulder dislocation: open remplissage of the Hill-Sachs lesion with the infraspinatus tendon.
Neglected anterior shoulder dislocation is a rare condition; reduction usually requires an open procedure. There is usually a concurrent Hill-Sachs lesion, with the humeral head impaled over the anterior rim of the glenoid. Large, engaging Hill-Sachs lesions can contribute to continued shoulder instability, and therefore require a specific action. Reconstruction of the humeral head with an osteochondral allograft has been advocated, but allografts are not easily available in some countries, such as Egypt. For this reason, I switched to the open infraspinatus remplissage technique. I report the results with this technique, in four young adult patients who presented with a locked anterior shoulder dislocation, which had been left unreduced for 10 to 20 weeks. The infraspinatus tendon was pulled into the humeral defect with a four limbs suture anchor; as a result, the lesion became extra-articular. A Putti-Platt procedure was added to obtain anterior stability, except in one patient with a concurrent glenoid defect which required a Latarjet procedure. The mean follow-up period was 32 months, without recurrence or other complications. The mean postoperative Constant score was 74, and the range of motion was satisfactory, with a functional range of external rotation.


Impact of rpoS deletion on Escherichia coli biofilms.
Slow growth has been hypothesized to be an essential aspect of bacterial physiology within biofilms. In order to test this hypothesis, we employed two strains of Escherichia coli, ZK126 (DeltalacZ rpoS(+)) and its isogenic DeltarpoS derivative, ZK1000. These strains were grown at two rates (0.033 and 0.0083 h(-1)) in a glucose-limited chemostat which was coupled either to a modified Robbins device containing plugs of silicone rubber urinary catheter material or to a glass flow cell. The presence or absence of rpoS did not significantly affect planktonic growth of E. coli. In contrast, biofilm cell density in the rpoS mutant strain (ZK1000), as measured by determining the number of CFU per square centimeter, was reduced by 50% (P < 0.05). Deletion of rpoS caused differences in biofilm cell arrangement, as seen by scanning confocal laser microscopy. In reporter gene experiments, similar levels of rpoS expression were seen in chemostat-grown planktonic and biofilm populations at a growth rate of 0.033 h(-1). Overall, these studies suggest that rpoS is important for biofilm physiology.


Myocardial Fatty Foci in Adult Patients with Tuberous Sclerosis Complex: Association with Gene Mutation and Multiorgan Involvement.
To estimate the association between myocardial fatty foci (MFF) on chest computed tomographic (CT) images and type of gene mutation or multiorgan involvement in patients with tuberous sclerosis complex (TSC). This retrospective case-control study was approved by the ethics committee, which waived the need for patient consent. Forty-eight patients with definite TSC (41 women; mean age, 35 years ± 11 [standard deviation]) and 96 age- and sex-matched patients without TSC who had undergone chest CT were evaluated. Two blinded readers independently scored MFF as low-attenuation areas within the myocardium. Patient history, gene mutation, and multiorgan involvement were obtained from clinical records. Cohen κ, Mann-Whitney U, χ(2) or Fisher exact, Kruskal-Wallis, and Spearman statistics were calculated. One or more MFF was detected in 50% (24 of 48) of patients with TSC; however, no MFF was detected in control patients (P < .001). MFFs were oval (62%, 15 of 24) or linear (38%, nine of 24) and involved the left ventricle in 13 patients and both ventricles in 24 patients (mostly the apical or midleft ventricle); median size was 127 mm(2). After four patients with TSC and unknown mutational status (two with MFF) were excluded, MFF was detected in 53% (10 of 19) of patients with TSC1 mutation, 65% (11 of 17) of patients with TSC2 mutation, and 12% (one of eight) of patients with TSC but without an identified mutation (P = .044). MFF presence was associated with brain (P = .011) and multiorgan (P = .008) involvement. The number of MFF per patient correlated with the degree of multiorgan involvement (P = .014). With MFF considered predictive of TSC, 50% (24of 48) sensitivity, 100% (96 of 96) specificity, 100% (24 of 24) positive predictive value, and 80% (96 of 120) negative predictive value were obtained. MFF was highly specific for TSC. MFF presence was associated with TSC gene mutations and with brain or multiorgan involvement; their number per patient was correlated with the degree of multiorgan involvement.


[Changes in suprachiasmatic and paraventricular hypothalamic nuclei in essential hypertension].
Suprachiasmatic and paraventricular hypothalamic nuclei (SCN and PVN, respectively) were studied in humans with essential hypertension (EH) and in healthy individuals who had normal blood pressure and died by accident (control group). Immunohistochemistry, hybridization in situ using computer image analysis have shown that EH patients have decreased number of vasopressin (VP) positive cells in SCN, high number of corticotropin-releasing hormone (CRH) producing neurones in PVN and increased amount of mRNA for CRH in them. A negative linear correlation was found between the number of CRH-producing cells in PVN, amount of mRNA for CRH in them and the number of VP-synthesizing cells in SCN. The presence of GABA in VP-producing cells in SCN together with the data obtained suggest the presence of certain "disinhibition" of CRH-producing cells in PVN in EH which could cause enhanced synthesis of ACTH in anterior hypophysis and increased secretion of corticosteroids by the adrenal gland.


Acute heat stress reduces biomarkers of endothelial activation but not macro- or microvascular dysfunction in cervical spinal cord injury.
Cardiovascular diseases (CVD) are highly prevalent in spinal cord injury (SCI), and peripheral vascular dysfunction might be a contributing factor. Recent evidence demonstrates that exposure to heat stress can improve vascular function and reduce the risk of CVD in uninjured populations. We therefore aimed to examine the extent of vascular dysfunction in SCI and the acute effects of passive heating. Fifteen participants with cervical SCI and 15 uninjured control (CON) participants underwent ultrasound assessments of vascular function and venous blood sampling for biomarkers of endothelial activation (i.e., CD62e+) and apoptosis (i.e., CD31+/42b-) before and after a 60-min exposure to lower limb hot water immersion (40°C). In SCI, macrovascular endothelial function was reduced in the brachial artery [SCI: 4.8 (3.2)% vs. CON: 7.6 (3.4)%, P = 0.04] but not the femoral artery [SCI: 3.7 (2.6)% vs. CON: 4.0 (2.1)%, P = 0.70]. Microvascular function, via reactive hyperemia, was ~40% lower in SCI versus CON in both the femoral and brachial arteries ( P < 0.01). Circulating concentrations of CD62e+ were elevated in SCI versus CON [SCI: 152 (106) microparticles/µl vs. CON: 58 (24) microparticles/µl, P < 0.05]. In response to heating, macrovascular and microvascular function remained unchanged, whereas increases (+83%) and decreases (-93%) in antegrade and retrograde shear rates, respectively, were associated with heat-induced reductions of CD62e+ concentrations in SCI to levels similar to CON ( P = 0.05). These data highlight the potential of acute heating to provide a safe and practical strategy to improve vascular function in SCI. The chronic effects of controlled heating warrant long-term testing. NEW & NOTEWORTHY Individuals with cervical level spinal cord injury exhibit selectively lower flow-mediated dilation in the brachial but not femoral artery, whereas peak reactive hyperemia was lower in both arteries compared with uninjured controls. After 60 min of lower limb hot water immersion, femoral artery blood flow and shear patterns were acutely improved in both groups. Elevated biomarkers of endothelial activation in the spinal cord injury group decreased with heating, but these biomarkers remained unchanged in controls.


In situ visualization of DSBs to assess the extranuclear/extracellular effects induced by low-dose alpha-particle irradiation.
Extranuclear/extracellular effects may have a significant effect on low-dose radiation risk assessment as well as on the shape of the dose-response relationship. Numerous studies using different end points such as sister chromatid exchanges, micronuclei and mutation have shown that this phenomenon exists in many cell types. However, these end points mostly reflect the late events after radiation damage, and little is known about the early response in this phenomenon. DNA double-strand breaks (DSBs) induced by ionizing radiation or carcinogenic chemicals can be visualized in situ using gamma-H2AX immunofluorescence staining, and there is evidence that the number of gamma-H2AX foci can be closely correlated with DSBs induced. Here we used gamma-H2AX as a biomarker to assess the extranuclear/extracellular effects induced by low-dose alpha particles in situ. The results show that a greater fraction of positive cells with DSBs (48.6%) was observed than the number of cells whose nuclei were actually traversed by the 1-cGy dose of alpha particles (9.2%). The fraction of DSB-positive cells was greatly reduced after treatment with either lindane or DMSO. These results suggest that in situ visualization of DSBs can be used to assess radiation-induced extranuclear/extracellular effects soon after irradiation. Moreover, the in situ DSB assay may provide a means to evaluate the spatial effect on unirradiated cells that are located in the neighboring region of cells irradiated by alpha particles.


Biosorption Performance of Encapsulated Candida krusei for the removal of Copper(II).
The use of microorganisms in biosorption is one of the most promising ways to remove trace amounts of heavy metal ions. Nevertheless, the enhancement of the successful removal of heavy metal ions by using different combinations of biosorbents is not generally guaranteed which leaves room to explore the application of the technique. In this study, the performance of free and immobilized forms of a yeast strain, Candida krusei (C. krusei), and calcium alginate (CaAlg) are evaluated for their ability to remove copper(II). Infrared spectroscopy, studies on the effects of pH and temperature, and kinetics and isotherm modelling are carried out to evaluate the biosorption. The infrared spectroscopy shows that the primary biosorption sites on the biosorbents are carboxylate groups. In addition, a higher pH and higher temperatures promote biosorption while a decline in biosorption ability is observed for C. krusei at 50 °C. The kinetics study shows that C. krusei, CaAlg and immobilized C. krusei (MCaAlg) conform with good correlation to pseudo-second order kinetics. MCaAlg and CaAlg fit well to the Langmuir isotherm while C. krusei fits well to the Temkin isotherm. From the experimental data, encapsulating C. krusei showed improved biosoprtion and address clogging in practical applications.


Unraveling Signatures of Local Adaptation among Indigenous Groups from Mexico.
Few studies have addressed how selective pressures have shaped the genetic structure of the current Native American populations, and they have mostly limited their inferences to admixed Latin American populations. Here, we searched for local adaptation signals, based on integrated haplotype scores and population branch statistics, in 325 Mexican Indigenous individuals with at least 99% Native American ancestry from five previously defined geographical regions. Although each region exhibited its own local adaptation profile, only PPARG and AJAP1, both negative regulators of the Wnt/β catenin signaling pathway, showed significant adaptation signals in all the tested regions. Several signals were found, mainly in the genes related to the metabolic processes and immune response. A pathway enrichment analysis revealed the overrepresentation of selected genes related to several biological phenotypes/conditions, such as the immune response and metabolic pathways, in agreement with previous studies, suggesting that immunological and metabolic pressures are major drivers of human adaptation. Genes related to the gut microbiome measurements were overrepresented in all the regions, highlighting the importance of studying how humans have coevolved with the microbial communities that colonize them. Our results provide a further explanation of the human evolutionary history in response to environmental pressures in this region.


Human cytomegalovirus-stimulated peripheral blood mononuclear cells induce HIV-1 replication via a tumor necrosis factor-alpha-mediated mechanism.
Human cytomegalovirus (HCMV) is a potential cofactor in HIV-1 infection. To investigate the mechanism whereby HCMV promotes HIV-1 replication, a PBMC coculture assay which measures HIV-1 p24 antigen release was used as an index of viral replication. HCMV-stimulated PBMC were capable of inducing HIV-1 replication in cocultures with acutely infected PBMC; however, this occurred only when the PBMC were from HCMV-seropositive donors (598 +/- 207 versus 27 +/- 10 pg/ml p24 antigen with PBMC from HCMV-seronegative donors on day 6 of coculture). Upon stimulation with HCMV, PBMC obtained exclusively from HCMV-seropositive donors released tumor necrosis factor (TNF)-alpha (270 +/- 79 pg/ml at 18 h of culture). Monoclonal antibodies to TNF-alpha blocked the activity of HCMV-stimulated PBMC in cocultures both with acutely HIV-1-infected PBMC and with the chronically infected promonocytic line U1. Also, treatment of HCMV-stimulated PBMC with pentoxifylline, an inhibitor of TNF-alpha mRNA, markedly reduced HIV-1 replication in cocultures both with acutely and chronically infected cells. These results indicate that TNF-alpha is a key mediator of HIV-1 replication induced by HCMV-stimulated PBMC and support the concept that this cytokine plays an important role in the pathogenesis of HIV-1 infection.


Management of isolated systolic hypertension.
Isolated systolic hypertension (ISH) [systolic blood pressure (SBP) > or = l60mm Hg with diastolic blood pressure (DBP) <90mm Hg] is the commonest form of hypertension in the elderly, and accounts for about 60% of all hypertensive conditions in the population aged over 65 years. It is associated with a significantly increased risk of cardiovascular and cerebrovascular morbidity and mortality. The landmark Systolic Hypertension in the Elderly Program (SHEP) study, published in 1991, has shown that lowering the SBP in elderly patients with ISH results in a significant reduction in cardiovascular events. These results have had a major impact on clinical practice in hypertension. On theoretical grounds, considering the pathophysiological mechanisms of ISH in the elderly, any drug which lowers total peripheral resistance and/or arterial stiffness should reduce SBP effectively in these patients. This effect has been observed in outcome studies and short term clinical trials using a variety of drugs from the 4 major antihypertensive classes: diuretics, beta(1)-blockers, calcium channel antagonists and ACE inhibitors. Other drugs, including alpha antagonists, may also be effective. In general, there is compelling evidence to support active treatment of any individual with an SBP > or = 160mm Hg. As in essential hypertension, the maximum benefit is gained by aggressive treatment of those individuals at highest risk because of coexisting cardiovascular risk factors. In these people, an SBP of 140 to 159mm Hg should be considered to be an indication for active management. Initial management should be by manipulation of lifestyle factors such as bodyweight, salt and alcohol intake and aerobic exercise. Drug therapy, generally well tolerated in low doses, should be considered if SBP remains > or = 160mm Hg, or > or = 140mm Hg in the presence of multiple risk factors. The choice of initial drug therapy should be influenced by the particular clinical situation. If there are no coexisting contraindications or co-indications for particular drugs, it is reasonable to begin treatment with a low dose of a thiazide-like diuretic, as used in the SHEP study. However, in short term treatment trials calcium channel antagonists and ACE inhibitors have been shown to lower SBP effectively and can be used in the appropriate clinical context. Beta-blockers appear to be less effective as monotherapy in ISH. Combination therapy is frequently required and can be effective and well tolerated if carefully chosen.


Young Adult Brain Capital: A New Opportunity for Dementia Prevention.
The potential for future prevention of Alzheimer's disease and related dementias (ADRD) through healthy lifestyle change is spurring a positive brain health movement. However, most ADRD research continues to focus on mid- and later life. We lack evidence regarding risk exposure and protective factors in young adulthood, i.e., 18-39 years. Brain capital is an emerging framework that represents the combination of education, knowledge, skills, and optimal brain health that people accumulate over their lives. Building on this framework, we present a new model that focuses on optimizing brain health in young adulthood; namely, young adult brain capital. Increasing focus on younger populations is critical for developing citizens who are emotionally intelligent, resilient and can anticipate and cope with rapid changes in the world. By understanding the values that are key drivers and motivators for young adults, we can empower the next generation to become active agents in optimizing their brain health and reducing their risk for future ADRD.


Helicobacter pylori infection and growth delay in older children.
It is thought that Helicobacter pylori infection may influence growth rate in children. The aim of this study was to evaluate the prevalence of H pylori infection in healthy Italian children, and to look for differences in height between infected and non-infected subjects. Two hundred and sixteen children, aged 3 to 14 years, were tested for H pylori infection by 13C-urea breath test. Centile values for height were calculated. Composite indices for socioeconomic class and household crowding were also determined. Forty nine of 216 children (22.7%) were H pylori positive. The prevalence of infection increased with age. Eight of 49 H pylori positive children (16.3%) were below the 25th centile for height, compared with 13 of 167 H pylori negative children (7.8%). This difference became significant in children aged 8.5 to 14 years; in this group (n = 127), eight of 31 infected children (25.8%) were below the 25th centile for height, compared with eight of 96 non-infected children (8.3%). A significant correlation was found between socioeconomic conditions, household crowding, and H pylori status. By using stepwise logistic regression, only the centile value for height was significantly related to H pylori status in older children. Thus H pylori infection was associated with growth delay in older children, poor socioeconomic conditions, and household overcrowding. This finding is consistent with the hypothesis that H pylori infection is one of the environmental factors capable of affecting growth.


Minor amputation and palliative wound care as a strategy to avoid major amputation in patients with foot infections and severe peripheral arterial disease.
Foot infections occurring in patients with severe peripheral arterial disease (PAD) who are not considered candidates for revascularization and limb salvage efforts are generally treated with major amputations. Herein we describe our early experiences in managing foot infections with minor amputations and palliative wound care as a strategy to avoid the functional disability often associated with major amputations. Patients with severe PAD that underwent minor amputations and subsequent palliative wound care for moderate/severe infections were paired with age-matched controls with PAD that underwent primary major amputations for foot infections. Eleven patients who underwent minor amputations and palliative wound care of 13 limbs were compared to an age-matched cohort of 12 patients undergoing 13 major amputations.The median age was 80 years in both groups. Survival at 1 and 2 years did not differ significantly between groups. All patients who were ambulatory and/or independently living remained so following palliative management; in contrast, major amputation changed ambulatory status in 75% of patients and independent living status in 50%. Palliative management did not result in ascending/systemic sepsis or progressive necrosis. The need for reoperations was uncommon in both groups. In summary, minor amputations and operative drainage with subsequent palliative wound care appears to be a safe management option in patients with severe PAD and moderate or severe foot infections that are not candidates for revascularization. Palliative management may result in less functional impairment than major amputation.


Separation and some properties of the major proteins of the human erythrocyte membrane.
A fractionation procedure is described which allows the isolation of three major human erythrocyte membrane proteins. Their isolation involves three sequential extraction procedures followed by gel filtration in 1% sodium dodecyl sulphate and preparative gel electrophoresis. All three proteins can be isolated from a single preparation. One of the proteins is the erythrocyte sialoglycoprotein, for which no C- or N-terminal residues were found. The other two proteins, which have not previously been isolated, have subunit molecular weights of 74000 and 93000 and contain 9 and 7% carbohydrate respectively. These glycoproteins have blocked N-terminal residues and show similarities in their chemical properties. Preparations derived from blood-group O erythrocytes contain no N-acetylgalactosamine, but similar preparations from blood-group A erythrocytes do contain this sugar. These three proteins cannot easily be solubilized by gentle aqueous procedures and represent about half of the erythrocyte ;ghost' protein. They carry a large proportion of the cell-surface carbohydrate.


Spatial modeling of HIV and HSV-2 among women in Kenya with spatially varying coefficients.
Disease mapping has become popular in the field of statistics as a method to explain the spatial distribution of disease outcomes and as a tool to help design targeted intervention strategies. Most of these models however have been implemented with assumptions that may be limiting or altogether lead to less meaningful results and hence interpretations. Some of these assumptions include the linearity, stationarity and normality assumptions. Studies have shown that the linearity assumption is not necessarily true for all covariates. Age for example has been found to have a non-linear relationship with HIV and HSV-2 prevalence. Other studies have made stationarity assumption in that one stimulus e.g. education, provokes the same response in all the regions under study and this is also quite restrictive. Responses to stimuli may vary from region to region due to aspects like culture, preferences and attitudes. We perform a spatial modeling of HIV and HSV-2 among women in Kenya, while relaxing these assumptions i.e. the linearity assumption by allowing the covariate age to have a non-linear effect on HIV and HSV-2 prevalence using the random walk model of order 2 and the stationarity assumption by allowing the rest of the covariates to vary spatially using the conditional autoregressive model. The women data used in this study were derived from the 2007 Kenya AIDS indicator survey where women aged 15-49 years were surveyed. A full Bayesian approach was used and the models were implemented in R-INLA software. Age was found to have a non-linear relationship with both HIV and HSV-2 prevalence, and the spatially varying coefficient model provided a significantly better fit for HSV-2. Age-at first sex also had a greater effect on HSV-2 prevalence in the Coastal and some parts of North Eastern regions suggesting either early marriages or child prostitution. The effect of education on HIV prevalence among women was more in the North Eastern, Coastal, Southern and parts of Central region. The models introduced in this study enable relaxation of two limiting assumptions in disease mapping. The effects of the covariates on HIV and HSV-2 were found to vary spatially. The effect of education on HSV-2 status for example was lower in North Eastern and parts of the Rift region than most of the other parts of the country. Age was found to have a non-linear effect on HIV and HSV-2 prevalence, a linearity assumption would have led to wrong results and hence interpretations. The findings are relevant in that they can be used in informing tailor made strategies for tackling HIV and HSV-2 in different counties. The methodology used here may also be replicated in other studies with similar data.


A large outbreak of shigellosis commencing in an internally displaced population, Papua New Guinea, 2013.
The objective of this study was to investigate a large outbreak of shigellosis in Papua New Guinea that began in a camp for internally displaced persons before spreading throughout the general community. Outbreak mitigation strategies were implemented in the affected area to curtail the spread of the disease. Data were collected from the surveillance system and analysed by time, place and person. Rectal swab samples were tested by standard culture methods and real-time polymerase chain reaction to determine the etiology of the outbreak. Laboratory analysis at two independent institutions established that the outbreak was caused by Shigella sp., with one strain further characterized as Shigella flexneri serotype 2. Approximately 1200 suspected cases of shigellosis were reported in a two-month period from two townships in Morobe Province, Papua New Guinea. The outbreak resulted in at least five deaths, all in young children. This outbreak of shigellosis highlights the threat of enteric diseases to vulnerable populations such as internally displaced persons in Papua New Guinea, as has been observed in other global settings.


Stimulation of fluid intake by nutrients: oil is less effective than carbohydrate.
It has been thought that the ability of nutrients to reinforce ingestion is related to their ability to provide metabolizable energy. This implies that the reinforcing effect of carbohydrate should be similar to that of fat. To test this concept, rats were trained in an apparatus that infused water or nutritive solutions/suspensions into their stomachs every time they drank a sapid solution. Each training trial lasted for 1 day. Successive training trials were interspersed by 1-day periods in which the rats were infused with plain water and offered plain water or a tastant different from the training taste (i.e., taste paired with vehicle infusion). Three different sapid solutions were used: a sweet solution (saccharin), a nonsweet solution (NaCl), and a mixture of sweet and nonsweet. Starch or maltodextrin infusions strongly and consistently stimulated intake of these solutions. Oil infusions also significantly stimulated intake, but feebly and less consistently. Indeed, in the one experiment in which the only sapid fluid offered was saccharin, oil infusions had no significant effect. Two different oil suspensions (one fine and one coarse) were equally ineffective in stimulating saccharin intake. To determine whether some unsuspected flaw in the infusion experiments somehow produced invalid results, an additional experiment was conducted in which rats ingested starch or oil suspensions by mouth. Consistent with the infusion experiments, starch stimulated ingestion to a much greater degree than did oil. It is concluded that intragastric infusion of triglyceride oil is a less potent reinforcer of ingestion than is equicaloric infusion of carbohydrate.


Effects of 50 Hz electric currents on mood and verbal reasoning skills.
Seventy-six male volunteers were studied in a crossover trial to assess the impact on the central system of electric currents such as might be induced by exposure to an intense power frequency electric field. Currents totalling 500 microamperes (50 Hz) were passed through electrodes attached to the head, upper arms, and feet, simulating exposure of and average man to a vertical electric field of about 36 kV/m. Exposure was continuous for a single day (5.5 hours) and the experiment was based on a double blind, counterbalanced, within subject design. A series of psychological tests examining self reports of both stress and arousal (mood checklist) and performance tests of memory, attention, and verbal skills were administered. Although the double blind conditions were compromised to some extent by reported sensations at electrode sites, the duration of these sensations was small in relation to the overall exposure or sham exposure time and did not interact with the effects apparently associated with exposure that were found. No significant difference between the exposed and sham-exposed groups was found on the first day, but on the second day the sham exposed group felt more aroused at the end of the day and their response times had improved more on the complex problems of a syntactic reasoning test. No exposure effects were apparent in self reports of stress or in performance in a semantic reasoning test, although both showed some influence of sensations. Interpretation of the exposure effects is complicated by their apparent restriction of the second test day, which may indicate some type of state dependent transfer phenomenon.


Computer-aided prediction and cytotoxicity evaluation of dithiocarbamates of 9,10-anthracenedione as new anticancer agents.
Anticancer activity as an associated action for a series of dithiocarbamates of 9,10-anthracenedione was predicted using the PASS computer program and analysed with PharmaExpert software. The predicted cytotoxic activity of the dithiocarbamate derivatives of 9,10-anthracenedione was evaluated in vitro on cancer cells of the human lung (A549), prostate (PC3), colon (HT29) and human breast (MCF7) using the sulforhodamine B (SRB) cell viability assay. Among these compounds, 9,10-dioxo-9,10-dihydroanthracen-1-yl pyrrolidin-1-carbodithioate and 9,10-dioxo-9,10-dihydroanthracen-2-yl pyrrolidin-1-carbodithioate were identified as the most potent anticancer agents with cytotoxic activity against the MCF-7 human breast cell line with GI50 values of 1.40 μM and 1.52 μM, whereas the GI50 value for the reference anticancer drug mitoxantrone was 3.93 μM. Thus, anticancer activity predicted by PASS with a probability Pa > 30% was confirmed by the experiment. Relatively small Pa values estimated by PASS indicated the novelty of the considered derivatives comparing to the compounds from the PASS training set.


LONG-TERM OUTCOMES OF LIGATION OF INTERSPHINCTERIC FISTULA TRACT FOR COMPLEX FISTULA-IN-ANO: MODIFIED OPERATIVE PROCEDURE EXPERIENCE.
It is important but difficult to treat complex fistula-in-ano due to the high recurrent rate and following incontinence. Ligation of the intersphincteric fistula tract (LIFT), a novel surgical procedure with the advantage of avoiding anal incontinence, has a variable success rate of 57-94.4 %. To evaluate the long-term outcomes of modified LIFT operative procedure - ligation of intersphincteric fistula tract - to treat complex fistula-in-ano. Retrospective analysis of 62 cases of complex fistula-in-ano. The group was treated with the modified approach of LIFT (curved incision was made in the anal canal skin; purse-string suture was performed around the fistula; the residual fistulas were removed in a tunnel-based way) and had a follow-up time of more than one year. Patient´s preoperative general condition, postoperative efficacy and their anal function were compared. The median age of the participants was 34, and 43 (69.4%) cases were male. Forty-one (66.1%) cases were of high transsphincteric fistula, four (6.5%) cases of high intrasphincter fistula, and 17 (27.4%) cases of anterior anal fistula in female. The median follow-up duration was 24.5 (range, 12-51) months. The success rate in the end of follow-up was 83.9% (52/62). The anorectal pressure and Cleveland Clinic Florida Fecal Incontinence (CCF-FI) evaluated three months before and after the operation did not find apparent changes. Compared with LIFT, the modified LIFT remarkably reduces postoperative failure and the recurrence rate of complex fistula with acceptable long-term outcomes.


Polycyclic aromatic hydrocarbon (PAH) dispersion and deposition to vegetation and soil following a large scale chemical fire.
Polycyclic aromatic hydrocarbons (PAHs) were determined in soil and vegetation following a large scale chemical fire involving 10,000 ton of polypropylene. In comparison with sites outside the plume from the fire, PAH concentrations were elevated in grass shoots (by up to 70-fold) and in soil (by up to 370-fold). The pattern of PAH dispersion under the plume was dependent on the physical-chemical properties of individual PAHs. The lighter, least hydrophobic PAHs were dispersed into the environment at greater distances than heavier, more hydrophobic PAHs. At the most distant sampling point (4.5 km) under the plume, the low molecular weight PAHs were still considerably elevated in vegetation samples compared to control sites. Dispersion appeared to be regulated by the compounds partitioning between the vapour and particulate phase, with dry particulate deposition occurring closer to the fire source than gaseous deposition. For all PAHs, the fire resulted in greater contamination of soils compared to grasses, with the relative ratio of plant/soil contamination decreasing as hydrophobicity increased.


Is Utilitarianism Risky? How the Same Antecedents and Mechanism Produce Both Utilitarian and Risky Choices.
Philosophers and psychologists have long been interested in identifying factors that influence moral judgment. In the current analysis, we compare the literatures on moral psychology and decision making under uncertainty to propose that utilitarian choices are driven by the same forces that lead to risky choices. Spanning from neurocognitive to hormonal to interpersonal levels of analysis, we identify six antecedents that increase both utilitarian and risky choices (ventromedial prefrontal cortex brain lesions, psychopathology, testosterone, incidental positive affect, power, and social connection) and one antecedent that reduces these choices (serotonin activity). We identify the regulation of negative affect as a common mechanism through which the effects of each antecedent on utilitarian and risky choices are explained. By demonstrating that the same forces and the same underlying mechanism that produce risky choices also promote utilitarian choices, we offer a deeper understanding of how basic psychological systems underlie moral judgment.


Neural networks-based regularization for large-scale medical image reconstruction.
In this paper we present a generalized Deep Learning-based approach for solving ill-posed large-scale inverse problems occuring in medical image reconstruction. Recently, Deep Learning methods using iterative neural networks (NNs) and cascaded NNs have been reported to achieve state-of-the-art results with respect to various quantitative quality measures as PSNR, NRMSE and SSIM across different imaging modalities. However, the fact that these approaches employ the application of the forward and adjoint operators repeatedly in the network architecture requires the network to process the whole images or volumes at once, which for some applications is computationally infeasible. In this work, we follow a different reconstruction strategy by strictly separating the application of the NN, the regularization of the solution and the consistency with the measured data. The regularization is given in the form of an image prior obtained by the output of a previously trained NN which is used in a Tikhonov regularization framework. By doing so, more complex and sophisticated network architectures can be used for the removal of the artefacts or noise than it is usually the case in iterative NNs. Due to the large scale of the considered problems and the resulting computational complexity of the employed networks, the priors are obtained by processing the images or volumes as patches or slices. We evaluated the method for the cases of 3D cone-beam low dose CT and undersampled 2D radial cine MRI and compared it to a total variation-minimization-based reconstruction algorithm as well as to a method with regularization based on learned overcomplete dictionaries. The proposed method outperformed all the reported methods with respect to all chosen quantitative measures and further accelerates the regularization step in the reconstruction by several orders of magnitude.


Characterisation of Physiological Tremor using Multivariate Empirical Mode Decomposition and Hilbert Transform.
Fatigue-induced physiological tremor (FIPT) is undesirable when performing micromanipulation tasks that require high precision. It is important to characterise this form of tremor to aid in identifying and suppressing it from the intended micromanipulation task. Researchers have used surface electromyography (sEMG) and mechanomyography (MMG) separately or in combination to study tremor, which is further processed using Fourier transform-based techniques. The major drawback of using these techniques is that it assumes the signals are linear and stationary. On the contrary, Empirical Mode Decomposition (EMD) can provide localised information on energy of the non-linear and non-stationary signals at a particular time and frequency and hence is considered superior to the Fourier transform-based techniques when analysing signals like physiological tremor. This paper characterises physiological tremor by extracting the frequency band of interest using multivariate empirical mode decomposition (MEMD). The extracted frequency band is assessed using Hilbert spectral analysis for energy estimation. Energy Ratio (ER) is the parameter proposed in this study to indicate fatigue-induced physiological tremor. The linear regression of the ratio across task epoch (TE) showed an increasing trend with R2≈0.7 for sEMG signals and R2≈0.9 for accelerometer signals to indicate levels of fatigue increase.Clinical Relevance - This study presents an effective & versatile indicator of FIPT. The characterisation method discussed in this paper will form an integral part of creating control strategies that can eliminate undesired consequences of fatigue-induced tremor in prolonged surgical manipulation. In addition, in surgical training modules, it aids the learning rate of novice surgeons.


Astrocytic Gq-GPCR-linked IP3R-dependent Ca2+ signaling does not mediate neurovascular coupling in mouse visual cortex in vivo.
Local blood flow is modulated in response to changing patterns of neuronal activity (Roy and Sherrington, 1890), a process termed neurovascular coupling. It has been proposed that the central cellular pathway driving this process is astrocytic Gq-GPCR-linked IP3R-dependent Ca(2+) signaling, though in vivo tests of this hypothesis are largely lacking. We examined the impact of astrocytic Gq-GPCR and IP3R-dependent Ca(2+) signaling on cortical blood flow in awake, lightly sedated, responsive mice using multiphoton laser-scanning microscopy and novel genetic tools that enable the selective manipulation of astrocytic signaling pathways in vivo. Selective stimulation of astrocytic Gq-GPCR cascades and downstream Ca(2+) signaling with the hM3Dq DREADD (designer receptors exclusively activated by designer drugs) designer receptor system was insufficient to modulate basal cortical blood flow. We found no evidence of observable astrocyte endfeet Ca(2+) elevations following physiological visual stimulation despite robust dilations of adjacent arterioles using cyto-GCaMP3 and Lck-GCaMP6s, the most sensitive Ca(2+) indicator available. Astrocytic Ca(2+) elevations could be evoked when inducing the startle response with unexpected air puffs. However, startle-induced astrocytic Ca(2+) signals did not precede corresponding startle-induced hemodynamic changes. Further, neurovascular coupling was intact in lightly sedated, responsive mice genetically lacking astrocytic IP3R-dependent Ca(2+) signaling (IP3R2 KO). These data demonstrate that astrocytic Gq-GPCR-linked IP3R-dependent Ca(2+) signaling does not mediate neurovascular coupling in visual cortex of awake, lightly sedated, responsive mice.


Ancient DNA analysis of food remains in human dental calculus from the Edo period, Japan.
Although there are many methods for reconstructing diets of the past, detailed taxon identification is still challenging, and most plants hardly remain at a site. In this study, we applied DNA metabarcoding to dental calculus of premodern Japan for the taxonomic identification of food items. DNA was extracted from 13 human dental calculi from the Unko-in site (18th-19th century) of the Edo period, Japan. Polymerase chain reaction (PCR) and sequencing were performed using a primer set specific to the genus Oryza because rice (Oryza sativa) was a staple food and this was the only member of this genus present in Japan at that time. DNA metabarcoding targeting plants, animals (meat and fish), and fungi were also carried out to investigate dietary diversity. We detected amplified products of the genus Oryza from more than half of the samples using PCR and Sanger sequencing. DNA metabarcoding enabled us to identify taxa of plants and fungi, although taxa of animals were not detected, except human. Most of the plant taxonomic groups (family/genus level) are present in Japan and include candidate species consumed as food at that time, as confirmed by historical literature. The other groups featured in the lifestyle of Edo people, such as for medicinal purposes and tobacco. The results indicate that plant DNA analysis from calculus provides information about food diversity and lifestyle habits from the past and can complement other analytical methods such as microparticle analysis and stable isotope analysis.


Acoustic Energy Harvesting and Sensing via Electrospun PVDF Nanofiber Membrane.
This paper introduces a new usage of piezoelectric poly (vinylidene fluoride) (PVDF) electrospun nanofiber (NF) membrane as a sensing unit for acoustic signals. In this work, an NF mat has been used as a transducer to convert acoustic signals into electric voltage outcomes. The detected voltage has been analyzed as a function of both frequency and amplitude of the excitation acoustic signal. Additionally, the detected AC signal can be retraced as a function of both frequency and amplitude with some wave distortion at relatively higher amplitudes and within a certain acoustic spectrum region. Meanwhile, the NFs have been characterized through piezoelectric responses, beta sheet calculations and surface morphology. This work is promising as a low-cost and innovative solution to harvest acoustic signals coming from wide resources of sound and noise.


Red hot chili pepper. A new Calluella stoliczka, 1872 (Lissamphibia: Anura: Microhylidae) from Sarawak, East Malaysia (Borneo).
A new brightly-coloured (olive and red) species of microhylid frog of the genus Calluella Stoliczka 1872 is described from the upper elevations of Gunung Penrissen and the Matang Range, Sarawak, East Malaysia (Borneo). Calluella capsa, new species, is diagnosable in showing the following combination of characters: SVL up to 36.0 mm; dorsum weakly granular; a faint dermal fold across forehead; toe tips obtuse; webbing on toes basal; lateral fringes on toes present; outer metatarsal tubercle present; and dorsum greyish-olive, with red spots; half of venter bright red, the rest with large white and dark areas. The new species is the eighth species of Calluella to be described, and the fourth known from Borneo. A preliminary phylogeny of Calluella and its relatives is presented, and the new taxon compared with congeners from Malaysia and other parts of south-east Asia.


Adiponectin in umbilical cord blood is inversely related to low-density lipoprotein cholesterol but not ethnicity.
Adiponectin is a recognized protective risk marker for cardiovascular disease in adults and is associated with an optimal lipid profile. The role of adiponectin at birth is not well understood, and its relationship with the neonatal lipid profile is unknown. Because ethnic disparities in cardiovascular risk have been attributed to low adiponectin and its associated low high-density lipoprotein cholesterol (HDL-C), investigation at birth may help determine the etiology of these risk patterns. Our objective was to investigate the relationship between neonatal adiponectin and lipid profile at birth in two ethnic groups in cord blood. Seventy-four healthy mothers and their newborns of South Asian and White European origin were studied in this cross-sectional study at St. Mary's Hospital, Manchester, United Kingdom. Serum adiponectin, total cholesterol, HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels were measured in umbilical venous blood at birth and in maternal blood collected at 28 wk gestation. Cord adiponectin was significantly inversely associated with cord LDL-C (r = -0.32; P = 0.005) but not HDL-C. In a multiple regression analysis, cord LDL-C remained the most significant association of cord adiponectin (beta = -0.13; P < 0.001). We did not find any significant ethnic differences in cord adiponectin or lipids with the exception of triglycerides, which were significantly lower in South Asian newborns (P < 0.05). This is the first report of an inverse relationship between cord adiponectin and LDL-C at birth. In contrast to adult studies, we found no significant association between adiponectin and HDL-C in cord blood. Our results and the strong independent association between adiponectin and HDL-C observed in adult studies suggest a role for adiponectin in lipid metabolism. Ethnic differences in adiponectin may arise after birth.


Use of monoclonal antibodies for quantitative analysis of antigens in normal and neoplastic tissues.
We describe two methods of analyzing tissues for cell-surface antigens identified by monoclonal antibodies. The first method is a binding assay, in which a membrane fraction prepared by differential centrifugation of a tissue homogenate is incubated with 125I-labeled antibody. The specificity of the observed binding is established by competition with unlabeled antibody. The second method, double-determinant immunoassay, involves two monoclonal antibodies that recognize two distinct epitopes of the antigen molecule. An immunoabsorbent prepared from one of the antibodies is incubated with a detergent lysate of the tissue. The immunoabsorbent is then washed and incubated with the 125I-labeled second antibody. In both assays the amount of radiolabeled antibody bound is proportional to the amount of antigen in the test sample, and the limit of detection is approximately 10 pg of antibody, corresponding to less than 1 fmol of antigen.


[Collembola--possible intermediate hosts of Avitellina arctica (Cestoda, Anoplocephalata)].
A brief description of larvae of cestodes of A. arctica at their different developmental stages in experimentally infected collembola Onychiurus (Protaphorura) taimyrica and O. (P.) furcifer is given. Developed cysticercoids were observed 70 days after the infection. Collembola under natural conditions are supposed to be intermediate hosts of cestodes of A. arctica, parasites of reindeer.


"He who pays the piper calls the tune": Researcher experiences of funder suppression of health behaviour intervention trial findings.
Governments commonly fund research with specific applications in mind. Such mechanisms may facilitate 'research translation' but funders may employ strategies that can also undermine the integrity of both science and government. We estimated the prevalence and investigated correlates of funder efforts to suppress health behaviour intervention trial findings. Our sampling frame was lead or corresponding authors of papers (published 2007-2017) included in a Cochrane review, reporting findings from trials of interventions to improve nutrition, physical activity, sexual health, smoking, and substance use. Suppression events were based on a previous survey of public health academics. Participants answered questions concerning seven suppression events in their efforts to report the trial, e.g., [I was…] "asked to suppress certain findings as they were viewed as being unfavourable." We also examined the association between information on study funder, geographical location, targeted health behaviour, country democracy rating and age of publication with reported suppression. We received responses from 104 authors (50%) of 208 eligible trials, from North America (34%), Europe (33%), Oceania (17%), and other countries (16%). Eighteen percent reported at least one of the seven suppression events relating to the trial in question. The most commonly reported suppression event was funder(s) expressing reluctance to publish because they considered the results 'unfavourable' (9% reported). We found no strong associations with the subject of research, funding source, democracy, region, or year of publication. One in five researchers in this global sample reported being pressured to delay, alter, or not publish the findings of health behaviour intervention trials. Regulation of funder and university practices, establishing study registries, and compulsory disclosure of funding conditions in scientific journals, are needed to protect the integrity of public-good research.


Image Analysis for MRI Based Brain Tumor Detection and Feature Extraction Using Biologically Inspired BWT and SVM.
The segmentation, detection, and extraction of infected tumor area from magnetic resonance (MR) images are a primary concern but a tedious and time taking task performed by radiologists or clinical experts, and their accuracy depends on their experience only. So, the use of computer aided technology becomes very necessary to overcome these limitations. In this study, to improve the performance and reduce the complexity involves in the medical image segmentation process, we have investigated Berkeley wavelet transformation (BWT) based brain tumor segmentation. Furthermore, to improve the accuracy and quality rate of the support vector machine (SVM) based classifier, relevant features are extracted from each segmented tissue. The experimental results of proposed technique have been evaluated and validated for performance and quality analysis on magnetic resonance brain images, based on accuracy, sensitivity, specificity, and dice similarity index coefficient. The experimental results achieved 96.51% accuracy, 94.2% specificity, and 97.72% sensitivity, demonstrating the effectiveness of the proposed technique for identifying normal and abnormal tissues from brain MR images. The experimental results also obtained an average of 0.82 dice similarity index coefficient, which indicates better overlap between the automated (machines) extracted tumor region with manually extracted tumor region by radiologists. The simulation results prove the significance in terms of quality parameters and accuracy in comparison to state-of-the-art techniques.


Transductional instability of Tn5-induced mutations: generalized and specialized transduction of Tn5 by bacteriophage P1.
Generalized transduction is commonly used to move transposon-induced mutations among bacterial strains by selecting for inheritance of a transposon-encoded resistance determinant. Although complete cotransduction of the resistance determinant and the chromosomal mutation might be expected, it is often found that when Tn5(Kan) insertion mutations are transduced by bacteriophage P1 most of the nonmutant kanamycin-resistant transductants area due to specialized transduction of Tn5. Such P1::Tn5 specialized transducing phage are not found when a mutant Tn5 element lacking a functional transposase is employed.


Insights into Endothelin-3 and Multiple Sclerosis.
Endothelins are powerful vasoconstrictor peptides that play numerous other roles. Endothelin-1 (ET1) is the principal isoform produced by the endothelium in the human cardiovascular system. Endothelin-3 (ET3) and its rPptor affinity have been demonstrated to support neuronal repair mechanisms throughout life. In multiple sclerosis (MS), the role of vasoactive peptides are not well defined. Here we focus on ET3, specifically the plasma levels between MS patients and healthy subjects. Furthermore, we evaluated the changes in ET1 and ET3 plasma levels during different disease phases, the correlation between ET3 and cerebral circulation time, and the relationship between ET1 and ET3. In MS patients, the ET3 plasma levels were altered in a time-dependent manner. These results could support a putative role of ET3 in neuroprotection and/or neuroimmune modulation over time.


Boron stimulates yeast (Saccharomyces cerevisiae) growth.
Boron is required for the growth of vascular plants and embryonic development in fish. The molecular basis of boron's essentiality, however, remains unknown for both. The objective of this study was to determine whether yeast (Saccharomyces cerevisiae) could be used as a model for the evaluation of intracellular boron trafficking. Three experiments were conducted to assess the effect of boron supplementation on yeast growth. Cultures were grown in low boron media containing 0.04 micromol B/L. After 24 h, a new flask was inoculated with this culture; it was allowed to reach early log phase growth (9 h) and was then divided between two flasks. One flask was supplemented with ultrapure boric acid to achieve a concentration of 185 micromol B/L (+B); the other was supplemented with an equivalent volume of ultrapure water (NB). Boron significantly stimulated cell growth rate into the stationary phase of growth. Yeast cell boron concentrations decreased in both treatments over the course of the experiment, but analysis by inductively coupled plasma-mass spectrometry (ICPMS) did not detect differences in cellular concentration between the boron supplemented (B) and nonsupplemented (NB) groups. Ethanol concentrations did not differ between the two treatments, demonstrating that boron-stimulated growth was not a secondary effect of alcohol dehydrogenase inhibition. The demonstration of boron-dependent growth stimulation in yeast suggests that Saccharomyces cerevisiae can be used as a model system for the study of intracellular boron trafficking.


Directing the flow of medium in controlled cocultures of HeLa cells and human umbilical vein endothelial cells with a microfluidic device.
A microfluidic device was integrated with a controlled coculture system of HeLa cells and human umbilical vein endothelial cells (HUVECs). This integrated assembly allowed control of the direction of flow of medium (along with signaling factors secreted from cells) across the cultured cells. We grew HeLa cells and HUVECs to confluency on separate substrates and then joined the two substrates. A microfluidic device was then assembled onto the substrates and a cell coculture was initiated with controlled perfusion of the medium. When the medium flow was directed from the HeLa side to the HUVEC side, the HUVECs retreated and the HeLa cells migrated into the newly vacated areas. By contrast, when the medium flow was in the opposite direction, there was essentially no net movement of either cell type. Our results suggest that the migration of HeLa cells and HUVECs in coculture was likely mediated by soluble factors produced by HeLa cells.


MRI native T1 and T2 mapping of myocardial segments in hypertrophic cardiomyopathy: tissue remodeling manifested prior to structure changes.
The aim of this study was to examine the local myocardial segments in hypertrophic cardiomyopathy (HCM) by MRI T1 and T2 mapping, and to investigate how tissue remodeling correlates with structural and functional remodeling in HCM. 47 patients with HCM and 19 healthy volunteers were enrolled in this study. All subjects underwent cardiac MRI at 3.0 T. Native T1 and T2 values, end-diastolic wall thickness (EDTH), and percentage of systolic wall thickening (PSWT) were assessed in the left ventricular segments according to the American Heart Association model. Myocardial segments were categorized as normal, non-hypertrophic, mild-hypertrophic, moderate-hypertrophic, and severe-hypertrophic based on EDTH. The difference among all five groups, and the correlation between native T1 and T2 values, EDTH, and PSWT were evaluated. Native T1 and T2 values were significantly elevated in both non-hypertrophic and hypertrophic segments of HCM patients compared to controls (both p < 0.001). PSWT was preserved in non-hypertrophic segments (p = 0.838), while significantly impaired (p < 0.001) in hypertrophic segments. Native T1 value of severe hypertrophic segments in HCM was significantly higher than segments of mild and moderate hypertrophy (p < 0.05). In HCM patients, the non-hypertrophic myocardial segments already demonstrated significantly elevated T1 and T2 values, despite normal wall thickness and preserved contraction function. The finding suggests that tissue remodeling may precede morphological and functional remodeling in HCM. MRI native T1 and T2 mapping can provide additional value for HCM diagnosis at an early stage. Myocardial tissue remodeling, as detected by MRI native T1 and T2 mapping, occurs earlier than morphological and functional changes in HCM patients.


Lateral inferior prefrontal cortex and anterior cingulate cortex are engaged at different stages in the solution of insight problems.
Two studies used puzzles that required participants to find a word that satisfied a set of constraints. The first study used a remote-association task, where participants had to find a word that would form compound words with 3 other words. The second study required participants to complete a word fragment with an associate of another word. Both studies produced distinct patterns of activity in the lateral inferior prefrontal cortex (LIPFC) and the anterior cingulate cortex (ACC). Activation in the LIPFC rose only as long as the participants were trying to retrieve the solution and dropped off as soon as the solution was obtained. However, activation in the ACC increased upon the retrieval of a solution, reflecting the need to process that solution. The data of the second experiment are fit by an information-processing model that interprets the activity in the LIPFC as reflecting retrieval operations and the activity in the ACC as reflecting subgoal setting.


Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.
Vascular insults can initiate a cascade of molecular events leading to neurodegeneration, cognitive impairment, and dementia. Here, we review the cellular and molecular mechanisms in cerebral blood vessels and the pathophysiological events leading to cerebral blood flow dysregulation and disruption of the neurovascular unit and the blood-brain barrier, which all may contribute to the onset and progression of dementia and Alzheimer's disease (AD). Particularly, we examine the link between neurovascular dysfunction and neurodegeneration including the effects of AD genetic risk factors on cerebrovascular functions and clearance of Alzheimer's amyloid-β peptide toxin, and the impact of vascular risk factors, environment, and lifestyle on cerebral blood vessels, which in turn may affect synaptic, neuronal, and cognitive functions. Finally, we examine potential experimental treatments for dementia and AD based on the neurovascular model, and discuss some critical questions to be addressed by future studies. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock.


Efaproxiral: GSJ 61, JP 4, KDD 86, RS 4, RSR 13.
Efaproxiral [RSR 13, GSJ 61, JP 4, KDD 86, RS 4] is a synthetic, small-molecule, radiation-sensitising agent being developed by Allos Therapeutics primarily for the treatment of cancer. It works by binding and allosterically stabilising deoxyhaemoglobin in hypoxic regions of tumour tissue. This increases oxygen uptake of the tumour tissue and restores its sensitivity to radiation therapy, making therapy potentially more successful. This first-of-its-class compound is particularly applicable for the treatment of certain tumour types that lack oxygen, such as brain metastases. In contrast to conventional chemotherapeutic agents or radiation sensitisers, there is no requirement for efaproxiral to be administered directly into tumours or to cross the blood-brain barrier for it to display efficacy. Efaproxiral is under review for approval in the US and EU as an adjunct to whole-brain radiation therapy (WBRT) for the treatment of brain metastases originating from breast cancer. It is also under clinical evaluation for a variety of other cancers, including glioblastoma, non-small cell lung cancer (NSCLC) and cervical cancer. Allos is seeking partnership opportunities for efaproxiral's development and marketing. The company has indicated that the development of efaproxiral would be in cooperation with a corporate partner, according to its 2003 Annual Report. In 1994, Allos Therapeutics acquired exclusive worldwide rights to intellectual property relating to efaproxiral from the Center for Innovative Technology (CIT). Allos has entered into arrangements with two contract manufacturers for the supply of efaproxiral, and a third manufacturer for the supply of the formulated drug product. Hovione FarmaCiencia is the primary supplier of efaproxiral, and is contracted to manufacture sufficient quantities on a commercial scale. In addition, a second manufacturer, Raylo Chemicals, is also producing quantities of efaproxiral. In December 2003, Allos entered into a long-term development and supply agreement with Baxter Healthcare who will formulate the efaproxiral into an injection. Allos is also seeking to establish an alternate supplier of efaproxiral injection. Allos submitted a rolling NDA to the US FDA consisting of three data components. Submission began in the third quarter of 2003 and was completed by the fourth quarter of 2003. The first part of the application containing non-clinical information was submitted on 5 August 2003. The second part of the NDA containing information about efaproxiral's chemistry, manufacture and controls (CMC) was submitted in October 2003. Allos submitted its final component of the rolling NDA in December 2003. In February 2004, Allos announced that the FDA had accepted the company's NDA under priority review status. The FDA granted efaproxiral orphan drug status in August 2004 as an adjunct to WBRT for the treatment of brain metastases among breast cancer patients. Efaproxiral also received fast-track status in November 2000 for the same indication in the US. In February 2004, Allos initiated a phase III trial, called ENRICH (Enhancing Whole Brain Radiation Therapy In Patients with Breast Cancer and Hypoxic Brain Metastases) to investigate efaproxiral as an adjunct to WBRT for the treatment of brain metastases. Median survival time is the primary endpoint of the study. The National Breast Cancer Coalition (NBCC) is collaborating with the company to support trial enrolment and to gain additional insight about ways to improve radiation treatment in this patient population. The ENRICH trial protocol was approved by the FDA under a Special Protocol Assessment process; as part of the protocol, two interim analyses for safety and efficacy will be performed.This multicentre, randomised, open-label study has a target enrolment of approximately 360 patients at >100 medical centres across the US, Canada, Europe and South America. Allos announced in September 2004 that recruitment of clinical sites for the trial is ongoing across the US and Canada. Completion of trial enrolment in North America is anticipated in December 2005. Subsequently, Allos announced in January 2005 that recruitment into the ENRICH trial has commenced and is ongoing in Europe; enrolment at European sites is expected to conclude by the third quarter of 2006. Allos Therapeutics announced in June 2004 that it had filed an MAA with the EMEA for marketing of exaproxiral as an adjunct to WBRT for treatment of patients with brain metastases originating from breast cancer. The application is based on positive data from a pivotal phase III (REACH, RT-009) trial in this indication. The completed REACH trial investigated efaproxiral among patients with brain metastases undergoing WBRT. The trial was conducted at multiple sites in 11 countries, including the US, Canada, Europe and Australia. In August 2002 Allos completed the enrolment of 538 patients in the study. Initially only 408 patients were to be enrolled, but the company increased the size of the trial to conduct an appropriately powered subgroup analysis in patients with brain metastases from breast and NSCLC. The study was designed to demonstrate a 35% increase in median survival in the subgroup of patients compared with standard WBRT alone. The primary endpoint was survival. Allos began screening US patients for a phase III trial in NSCLC in early 2003. However, in May 2003, the company announced that as part of its revised operating plan it had suspended the screening of patients for this trial. The trial, which was known as ELITE (Enhanced Lung cancer treatment with Induction chemotherapy and Thoracic radiation and Efaproxiral), was comparing induction chemotherapy followed by thoracic radiation therapy with supplemental oxygen, with or without efaproxiral. The trial was enrolling patients with locally advanced, unresectable NSCLC. ELITE was planned to enrol up to 600 patients across North America and Western and Eastern Europe. Phase II trials in patients with inoperable NSCLC have been conducted in the US and Canada. Patient enrolment in one of these studies was completed in August 2000, with a total of 52 patients enrolled. This was an open-label, multicentre study of induction therapy with paclitaxel plus carboplatin followed by chest irradiation and efaproxiral in patients with locally advanced NSCLC. Positive results from this study were reported at the annual meeting of the European Society for Therapeutics Radiology and Oncology in September 2002. Efaproxiral has completed phase I trials as a treatment of surgical hypoxia in elective surgery patients receiving general anaesthesia. However, no recent development has been reported for these indications. In 1994, Allos signed an agreement with CIT for the exclusive worldwide rights to 17 US patents, a European patent covering the UK, France, Italy and Germany plus two pending patents in these territories, two issued patents in Japan, and a pending patent in Canada. These patents cover methods of allosterically modifying haemoglobin with efaproxiral and other compounds, the binding site of efaproxiral and therapy in certain indications including cancer, ischaemia and hypoxia. In addition to the licensed patents from CIT, Allos exclusively owns two patent families with pending applications directed to a formulation of efaproxiral and to methods of its use in BLOD MRI (blood oxygenation level-dependent magnetic resonance imaging) applications. These patents are pending in the US, Canada and Europe, and include an international patent application. In a May 2002 interview with the Wall Street Transcript, the CEO of Allos estimated the overall market for radiation therapy to be approximately 750 000 patients/year. Of this, brain metastases, NSCLC and glioblastoma therapy accounts for about 170 000, 140 000 and 6000 patients, respectively. Allos intend to use a speciality sales force to market efaproxiral directly to radiation therapists in North America. To penetrate the non-oncology market in the US, the company will seek partnership with one or more pharmaceutical companies with direct sales forces and with established distribution systems. Allos is also hoping to secure an oncology marketing partner for non-North American territories. At the time, the company had been issued 21 patents in the US, Canada, Europe and Japan.


Emergency department visit classification using the NYU algorithm.
Reliable measures of emergency department (ED) use are important for studying ED utilization and access to care. We assessed the association of emergent classification of an ED visit based on the New York University ED Algorithm (EDA) with hospital mortality and hospital admission. Using diagnosis codes, we applied the EDA to classify ED visits into emergent, intermediate, and nonemergent categories and studied associations of emergent status with hospital mortality and hospital admissions. We used a nationally representative sample of patients with visits to hospital-based EDs from repeated cross sections of the National Hospital Ambulatory Medical Care Survey from 2006 to 2009. We performed survey-weighted logistic regression analyses, adjusting for year and patient demographic and socioeconomic characteristics, to estimate the association of emergent ED visits with the probability of hospital mortality or hospital admission. The EDA measure of emergent visits was significantly and positively associated with mortality (odds ratio [OR]: 3.79, 95% confidence interval [CI]: 2.50-5.75) and hospital admission (OR: 5.28, 95% CI, 4.93-5.66). This analysis assessed the NYU algorithm in measuring emergent and nonemergent ED use in the general population. Emergent classification based on the algorithm was strongly and significantly positively associated with hospitalization and death in a nationally representative population. The algorithm can be useful in studying ED utilization and evaluating policies that aim to change it.


Analysis of ingredient functionality and formulation optimization of an instant peanut beverage mix.
Powder for an instant shake-style beverage was created using partially defatted peanut flour (12% fat), granulated sugar, and nonfat dry milk (NFDM). The 3 main components, along with constant amounts of stabilizing gums and anti-caking silica, were mixed together and finely milled in a Super Wing Mill to further reduce the particle sizes. Drinks from each formula variation were prepared and analyzed for viscosity (digital viscometer), color (colorimeter), and separation rate. Each beverage was also analyzed by consumers to determine acceptability of flavor, mouth-feel, and color. Physical test results show that viscosity increased with increasing proportion of peanut flour in the formula, and viscosity decreased with increasing levels of sugar and NFDM. For each formula, the samples at refrigerated temperature (4 degrees C) were less viscous than those at ambient temperatures (23 to 25 degrees C). Color values show that the beverage powder color was mostly influenced by peanut flour percentage, becoming darker with increasing levels of peanut flour. Prepared beverage color was influenced by both NFDM and peanut flour percentage; lightness increased with increasing NFDM percentage and decreased with increasing peanut flour percentage. Separation rates were most affected by the proportion of NFDM in the formula; higher levels decreased the rate of separation. Refrigeration slowed the rate of separation in all samples. Response surface analysis of consumer test data showed that the most acceptable formulation for the peanut beverage included approximately equal amounts of peanut flour, sugar, and NFDM.


Online behavioural activation during the COVID-19 pandemic decreases depression and negative affective bias.
The COVID-19 pandemic highlighted the need for mental health interventions that can be easily disseminated during a crisis. Behavioural activation (BA) is a cost-effective treatment that can be administered by non-specialists; however, it is unclear whether it is still effective during a time of lockdown and social distancing, when opportunities for positive activity are significantly constrained. Between May and October 2020, we randomised 68 UK participants with mild to moderate low mood to either a 4-week online programme of non-specialist administered BA or to a passive control group. Before and after the intervention, we collected self-report data on mood and COVID-related disruption, as well as measuring emotional cognition as an objective marker of risk for depression. In comparison to the control group, the BA group showed a significant decrease in depression, anxiety and anhedonia after the intervention, as well as an increase in self-reported activation and social support. Benefits persisted at 1-month follow-up. BA also decreased negative affective bias on several measures of the Facial Emotion Recognition Task and early change in bias was associated with later therapeutic gain. Participants rated the intervention as highly acceptable. This study highlights the benefits of online BA that can be administered by non-specialists after brief training. These findings can help inform the policy response towards the rising incidence of mental health problems during a crisis situation such as a pandemic. They also highlight the use of objective cognitive markers of risk across different treatment modalities.


TMC4 is a novel chloride channel involved in high-concentration salt taste sensation.
"Salty taste" sensation is evoked when sodium and chloride ions are present together in the oral cavity. The presence of an epithelial cation channel that receives Na+ has previously been reported. However, no molecular entity involving Cl- receptors has been elucidated. We report the strong expression of transmembrane channel-like 4 (TMC4) in the circumvallate and foliate papillae projected to the glossopharyngeal nerve, mediating a high-concentration of NaCl. Electrophysiological analysis using HEK293T cells revealed that TMC4 was a voltage-dependent Cl- channel and the consequent currents were completely inhibited by NPPB, an anion channel blocker. TMC4 allowed permeation of organic anions including gluconate, but their current amplitudes at positive potentials were less than that of Cl-. Tmc4-deficient mice showed significantly weaker glossopharyngeal nerve response to high-concentration of NaCl than the wild-type littermates. These results indicated that TMC4 is a novel chloride channel that responds to high-concentration of NaCl.