Effects of different heat treatments during processing on nutrient digestibility of soybean meal in growing swine.
Four soybean meals (SBM) were prepared in a commercial solvent-extraction plant to give a much wider range in heat treatment than is usually found among commercially available SBM. The meals were designated in ascending order of heat treatment as Under, Normal, Over and Rumen Escape. The Normal meal was processed using standard operating conditions. The Under meal received less heat treatment by reducing the steam pressure and retention time in the desolventizer-toaster. Over and Rumen Escape meals received further heat treatment in an additional four-compartment toaster. The Over meal received less heat treatment than the Rumen Escape meal by reducing steam pressure and retention time in both toasters. Crude protein content was similar for the four meals, but lysine tended to decrease with increasing heat treatment. In general, urease activity, trypsin inhibitor, protein dispersibility index and nitrogen solubility index decreased with increasing heat treatment. The +a Hunterlab color values increased as heat treatment increased. Apparent ileal digestibility of N and amino acids were similar for all meals (P greater than .05); however lysine digestibility for the Rumen Escape meal was 3.3 percentage units lower than the average of the lesser-heated meals. Energy digestibilities and nitrogen balance data were also similar (P greater than .05) for the four meals, but the apparent biological value of the Rumen Escape meal was 4.5 percentage units lower than the average of the other meals. There were no differences in nutritional value among the Under, Normal and Over meals, which represent the range in heat treatment usually found among SBM. The Rumen Escape meal, which received more severe heat treatment, tended to have lower nutritional value than the lesser-heated meals.


Effect of antihypertensive treatment on the left ventricular isomyosin profile in one-clip, two kidney hypertensive rats.
In order to investigate the cardiac effects of antihypertensive therapies in one-clip two-kidney hypertension in rats, we compared the consequences on myosin isoenzyme profile and on left ventricular hypertrophy of two treatments: one was a new converting enzyme inhibitor (S9490), the second a more standard tripletherapy associating clonidine, dihydralazine and furosemide. The two treatments were initiated 4 weeks after clipping and administered during 5 weeks. During the treatment period average systolic blood pressure was 215 +/- 32 mmHg in the hypertensive untreated group (HC2, n = 12) and 144 +/- 13 mm Hg in the CEI group (HT1, n = 13), which is not significantly different from the value found in the sham-operated group (139 +/- 4 mm Hg, C2, n = 13). Blood pressure was lowered only to 173 +/- 18 mm Hg in the group treated with tripletherapy (HT2, n = 12). The left ventricular weight decreased significantly in the CEI-treated group toward values similar to those of the sham-operated animals (2.2 +/- 0.13 mg/g vs. 1.9 +/- 10 mg/g, respectively NS), whereas it did not change in the tripletherapy group when compared to the untreated hypertensive animals despite the fall in blood pressure. In the hypertensive untreated rats the percentage of V1 isoenzyme of cardiac myosin was lower than in the sham-operated group (42.8 +/- 9.0% vs. 57.5 +/- 7.6% P less than .001). In parallel the V3 form of cardiac myosin increased (24.1 +/- 7.4% vs. 15.7 +/- 4.3%, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)


Hitting the bullseye with a nonlethal payload: resistance in CD123-positive malignancies.
The interleukin 3 receptor (CD123) is a transmembrane protein that is absent or hardly expressed on normal hematopoietic stem cells, but highly expressed on the surface of cancer cells in several hematologic malignancies. In this issue of the JCI, Togami et al. investigated the mechanism of resistance to the recently approved anti-CD123 agent tagraxofusp, which consists of interleukin 3 fused to a truncated diphtheria toxin (DT) molecule. The authors demonstrated that loss of the intracellular target for DT, diphthamide, a conservative modification of histidine 715 in eukaryotic elongation factor 2, resulted in tagraxofusp resistance. Specifically, hypermethylation of the DPH1 gene, encoding a key enzyme in diphthamide synthesis, resulted in diphthamide loss. Notably, treatment with a DNA hypomethylating agent restored DPH1 expression and resensitized cells to tagraxofusp. The recognition of this resistance mechanism may have important clinical implications and lead to the development of more effective multiagent therapies.


Accelerated Trajectories of Walking Capacity Across the Adult Life Span in Persons With Multiple Sclerosis: An Underrecognized Challenge.
Background. In the general population, trajectories of walking capacity is accelerated and nonlinear with advanced age. Whether this is more pronounced in persons with multiple sclerosis (pwMS), along with the prevalence of dismobility (ie, slow gait speed), are currently unknown. Our objective was to investigate trajectories of walking capacity and prevalence of dismobility across the adult life span in pwMS versus healthy controls (HC). Methods. Data on maximal timed 25-foot walk test (T25FWT), 2-minute walk test (2MWT), and 6-minute walk test (6MWT) along with prevalence of dismobility were assembled from 2 RIMS multicenter studies (n = 502 pwMS; age range 21-77 years, 6 age groups: 20-29, 30-39, 40-49, 50-59, 60-69, and 70-79 years). HC data were extracted from studies containing normative reference values (n = 1070-3780 HC). Results. Age trajectories of walking capacity was nonlinear and accelerated in pwMS versus HC. While measures of walking capacity in pwMS were suppressed already early in life, the gap between pwMS and HC significantly widened across the 6 age groups (pwMS performed 64%, 70%, 57%, 59%, 51%, and 37% of HC, respectively). This coincided with high prevalences of dismobility in pwMS across the 6 age groups when using usual gait speed cut-point values <1.0 m/s (corresponding to 33%, 32%, 51%, 59%, 75%, and 100%) and <0.6 m/s (corresponding to 19%, 12%, 26%, 23%, 33%, and 43%), markedly exceeding that observed in HC. Conclusion. The present data on walking capacity provide evidence for an accelerated deterioration in pwMS with advanced age, coinciding with high prevalences of dismobility (ie, slow gait speed).


Three Holy Men Get Haircuts: The Semiotic Analysis of a Joke.
This article deals with a typology of 45 techniques of humor that I found when doing research on the mechanisms that generate humor in texts, lists the techniques and applies them to a Jewish joke. It references the work of Vladimir Propp on folktales as analogous in that both are concerned with mechanisms in text that generate meaning. It also deals with four theories about why people find texts humorous, defines the joke as a short narrative with a punch line that is meant to generate mirthful laughter and defines Jewish humor as being about Jewish people and culture as told by Jewish people. It offers a paradigmatic analysis of the joke, and offers some insights into why Jewish people developed their distinctive kind of humor. This article is an enhanced and expanded version of an article which was published in a Chinese semiotics journal (doi:10.1515/css-2015-0022).


A specialist-generalist classification of the arable flora and its response to changes in agricultural practices.
Theory in ecology points out the potential link between the degree of specialisation of organisms and their responses to disturbances and suggests that this could be a key element for understanding the assembly of communities. We evaluated this question for the arable weed flora as this group has scarcely been the focus of ecological studies so far and because weeds are restricted to habitats characterised by very high degrees of disturbance. As such, weeds offer a case study to ask how specialization relates to abundance and distribution of species in relation to the varying disturbance regimes occurring in arable crops. We used data derived from an extensive national monitoring network of approximately 700 arable fields scattered across France to quantify the degree of specialisation of 152 weed species using six different ecological methods. We then explored the impact of the level of disturbance occurring in arable fields by comparing the degree of specialisation of weed communities in contrasting field situations.The classification of species as specialist or generalist was consistent between different ecological indices. When applied on a large-scale data set across France, this classification highlighted that monoculture harbour significantly more specialists than crop rotations, suggesting that crop rotation increases abundance of generalist species rather than sets of species that are each specialised to the individual crop types grown in the rotation. Applied to a diachronic dataset, the classification also shows that the proportion of specialist weed species has significantly decreased in cultivated fields over the last 30 years which suggests a biotic homogenization of agricultural landscapes. This study shows that the concept of generalist/specialist species is particularly relevant to understand the effect of anthropogenic disturbances on the evolution of plant community composition and that ecological theories developed in stable environments are valid in highly disturbed environments such as agro-ecosystems. The approach developed here to classify arable weeds according to the breadth of their ecological niche is robust and applicable to a wide range of organisms. It is also sensitive to disturbance regime and we show here that recent changes in agricultural practices, i.e. increased levels of disturbance have favoured the most generalist species, hence leading to biotic homogenisation in arable landscapes.


Astaxanthin acts via LRP-1 to inhibit inflammation and reverse lipopolysaccharide-induced M1/M2 polarization of microglial cells.
Microglia become activated during neuroinflammation and produce neurotoxic and neurotrophic factors, depending on whether they acquire M1 proinflammatory or M2 anti-inflammatory phenotypes. Astaxanthin (ATX), a natural carotenoid, has anti-inflammatory and neuroprotective effects. We investigated whether ATX could reverse M1/M2 polarization and suppress neuroinflammation via low-density lipoprotein receptor-related protein-1 (LRP-1). We observed increased expression of M1 (TNF-α, IL-1β, and CD86) and decreased expression of M2 (Arg-1, IL-10, and CD206) markers in BV2 microglial cells stimulated with lipopolysaccharide (LPS). These alterations were reversed by pretreating the cells with ATX. Activation of the NF-κB and JNK pathways was observed upon LPS stimulation, which was reversed by ATX. ATX-induced M2 polarization was attenuated by inhibition of NF-κB and JNK. Pretreatment of LPS-stimulated BV2 cells with ATX resulted in increased LRP-1 expression. The addition of receptor-associated protein, an LRP-1 antagonist, ameliorated ATX-induced inactivation of NF-κB and JNK signaling, and M2 polarization. ATX promotes M2 polarization to suppress neuroinflammation via LRP-1 by inhibiting NF-κB and JNK signaling. This novel mechanism may suppress neuroinflammation in diseases such as Alzheimer's disease.


A Retrospective Study of Treatment Outcomes and Prognostic Factors of Intense Pulsed Light Therapy Combined With Meibomian Gland Expression in Patients With Meibomian Gland Dysfunction.
To evaluate clinical changes after intense pulsed light and meibomian gland expression (IPL/MGX) treatment in meibomian gland dysfunction (MGD) patients, and to identify ideal candidates, and the therapeutic window, for IPL/MGX. This retrospective study reviewed the medical records of 44 MGD patients (44 eyes). The IPL/MGX treatment was applied on the eyelids three times at intervals of 4 weeks. Age, sex, relevant ocular history, Standard Patient Evaluation of Eye Dryness (SPEED), Ocular Surface Disease Index (OSDI), tear break-up time (TBUT), corneal fluorescein staining score (CFSS), meiboscore, meibomian gland loss score (MGLS), meibomian glands yielding secretion score (MGYSS), meibomian glands yielding clear secretion (MGYCS), and meibomian glands yielding liquid secretion (MGYLS) were analyzed. Standard Patient Evaluation of Eye Dryness, OSDI, TBUT, CFSS, MGYSS, MGYLS, and MGYCS were significantly improved after three IPL/MGX treatments, but the meiboscore and MGLS remained unchanged. In patients who had better treatment outcomes (improvement in MGYSS >7), younger age (36.0, 22.5 vs. 53.0, 25.0 years; P=0.012), a longer TBUT (8.0, 4.5 vs. 6.0, 3.0 sec; P=0.010), better meiboscore (1.0, 0.5 vs. 2.0, 1.0; P=0.012), and less gland loss (19.8%, 20.3% vs. 41.1%, 30.2%; P=0.008) before IPL/MGX were noted. Sex, relevant ocular history, SPEED, OSDI, MGYSS, MGYLS, and MGYCS before IPL/MGX showed no significant differences between patients with an improvement in MGYSS >7 versus those with an improvement of ≤7. Meibomian glands yielding secretion score changes in patients who had a meiboscore of 0 to 1 and MGYSS of 0 before IPL/MGX (12.0, 10.0) were significantly higher than those who had a meiboscore of 2 to 3 and MGYSS of 0 (6.5, 9.3; P=0.031), or a meiboscore of 0 to 1 and MGYSS >0 (5.0, 11.5; P=0.041). Improved dry eye symptoms, TBUT, corneal staining, and meibomian gland secretion were observed in MGD patients after IPL/MGX. Patients in the early stages of MGD maybe benefited most from IPL/MGX treatment.


Effect of simulated visual impairment on nighttime driving performance.
This study investigated the effects of simulated visual impairment on nighttime driving performance and pedestrian recognition under real-road conditions. Closed road nighttime driving performance was measured for 20 young visually normal participants (M = 27.5 +/- 6.1 years) under three visual conditions: normal vision, simulated cataracts, and refractive blur that were incorporated in modified goggles. The visual acuity levels for the cataract and blur conditions were matched for each participant. Driving measures included sign recognition, avoidance of low contrast road hazards, time to complete the course, and lane keeping. Pedestrian recognition was measured for pedestrians wearing either black clothing or black clothing with retroreflective markings on the moveable joints to create the perception of biological motion ("biomotion"). Simulated visual impairment significantly reduced participants' ability to recognize road signs, avoid road hazards, and increased the time taken to complete the driving course (p < 0.05); the effect was greatest for the cataract condition, even though the cataract and blur conditions were matched for visual acuity. Although visual impairment also significantly reduced the ability to recognize the pedestrian wearing black clothing, the pedestrian wearing "biomotion" was seen 80% of the time. Driving performance under nighttime conditions was significantly degraded by modest visual impairment; these effects were greatest for the cataract condition. Pedestrian recognition was greatly enhanced by marking limb joints in the pattern of "biomotion," which was relatively robust to the effects of visual impairment.


Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: results of a randomised, double-blind, phase III transition study.
Efficacy, safety and immunogenicity results from the phase III study of SB2, a biosimilar of reference infliximab (INF), were previously reported through 54 weeks. This transition period compared results in patients with rheumatoid arthritis (RA) who switched from INF to SB2 with those in patients who maintained treatment with INF or SB2. Patients with moderate to severe RA despite methotrexate treatment were randomised (1:1) to receive SB2 or INF at weeks 0, 2 and 6 and every 8 weeks thereafter until week 46. At week 54, patients previously receiving INF were rerandomised (1:1) to switch to SB2 (INF/SB2 (n=94)) or to continue on INF (INF/INF (n=101)) up to week 70. Patients previously receiving SB2 continued on SB2 (SB2/SB2 (n=201)) up to week 70. Efficacy, safety and immunogenicity were assessed up to week 78. Efficacy was sustained and comparable across treatment groups. American College of Rheumatology (ACR) 20 responses between weeks 54 and 78 ranged from 63.5% to 72.3% with INF/SB2, 66.3%%-69.4% with INF/INF and 65.6%-68.3% with SB2/SB2. Treatment-emergent adverse events during this time occurred in 36.2%, 35.6% and 40.3%, respectively, and infusion-related reactions in 3.2%, 2.0% and 3.5%. Among patients who were negative for antidrug antibodies (ADA) up to week 54, newly developed ADAs were reported in 14.6%, 14.9% and 14.1% of the INF/SB2, INF/INF and SB2/SB2 groups, respectively. The efficacy, safety and immunogenicity profiles remained comparable among the INF/SB2, INF/INF and SB2/SB2 groups up to week 78, with no treatment-emergent issues or clinically relevant immunogenicity after switching from INF to SB2. NCT01936181; EudraCT number: 2012-005733-37.


Molecular characterization of noroviruses and HBGA from infected Quilombola children in Espirito Santo State, Brazil.
Noroviruses (NoV) are the main etiological agents of gastroenteritis outbreaks worldwide and susceptibility to NoV infection has been related to the histo-blood group antigen (HBGA). This study aimed to determine the prevalence of NoV strains and to evaluate the HBGA phenotype and genotype of children from semi-isolated Quilombola communities, descendents of black slaves in Brazil. A total of 397 children up to eleven years old, with and without diarrhea, from Quilombola Communities in the Espirito Santo State, Brazil, were investigated for the presence of NoV from August 2007 to September 2009. Feces were collected from all the children, and blood from the NoV positive children. NoV was screened by reverse transcription-PCR with primers for the RNA-dependent RNA polymerase region; genogroup was determined by PCR with primers for the C and D regions and genotyped by sequencing. HBGA phenotype was performed by gel-spinning and FUT2 and FUT3 were analyzed by PCR or sequencing analysis. NoV were detected in 9.2% (12/131) of diarrheic and 1.5% (4/266) of non-diarrheic children (p<0.05, Fisher's exact test). GI and GII genogroups were present in 12.5% and 87.5% of the samples, respectively. The following genotypes were characterized: GII.4 (25%), GII.12 (25%), GII.6 (12.5%) and GI.1 (6.3%), GI.3 (12.5%) and GI.4 (6.3%). Children infected with NoV showed the A (n = 6), O (n = 6), and B (n = 2) HBGA phenotypes, and 13 of them were classified as secretors (Se) and one as a non secretor (se). Mutations of Se (40), (171,216,357,428,739,960) were found for the FUT2 gene and mutations of Le (59, 202, 314) for the FUT3 gene. The only se child was infected by NoV GI, whereas the Se children were indiscriminately infected by GI or GII. This study showed rates of NoV infection in symptomatic and asymptomatic Quilombola children consistent with other studies. However, children under 12 months were seven times more affected than those between 1 and 5 years old. GII.12 was as frequent as GII.4 and GI.1 and GI.4 were described for the first time in Brazil. Owing to the small number of cases studied, no clear pattern of susceptibility and/or HBGA resistance could be inferred.


Interventions for treating genital Chlamydia trachomatis infection in pregnancy.
Genital Chlamydia trachomatis (C.trachomatis) infection may lead to pregnancy complications such as miscarriage, preterm labour, low birthweight, preterm rupture of membranes, increased perinatal mortality, postpartum endometritis, chlamydial conjunctivitis and C.trachomatis pneumonia.This review supersedes a previous review on this topic. To establish the most efficacious and best-tolerated therapy for treatment of genital chlamydial infection in preventing maternal infection and adverse neonatal outcomes. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (26 June 2017) and reference lists of retrieved studies. Randomised controlled trials (RCTs) as well as studies published in abstract form assessing interventions for treating genital C.trachomatis infection in pregnancy. Cluster-RCTs were also eligible for inclusion but none were identified. Quasi-randomised trials and trials using cross-over design are not eligible for inclusion in this review. Two review authors independently assessed studies for inclusion, assessed trial quality and extracted the data using the agreed form. Data were checked for accuracy. Evidence was assessed using the GRADE approach. We included 15 trials (involving 1754 women) although our meta-analyses were based on fewer numbers of studies/women. All of the included studies were undertaken in North America from 1982 to 2001. Two studies were low risk of bias in all domains, all other studies had varying risk of bias. Four other studies were excluded and one study is ongoing.Eight comparisons were included in this review; three compared antibiotic (erythromycin, clindamycin, amoxicillin) versus placebo; five compared an antibiotic versus another antibiotic (erythromycin, clindamycin, amoxicillin, azithromycin). No study reported different antibiotic regimens. Microbiological cure (primary outcome) Antibiotics versus placebo: Erythromycin (average risk ratio (RR) 2.64, 95% confidence interval (CI) 1.60 to 4.38; two trials, 495 women; I2 = 68%; moderate-certainty evidence), and clindamycin (RR 4.08, 95% CI 2.35 to 7.08; one trial, 85 women;low-certainty evidence) were associated with improved microbiological cure compared to a placebo control. In one very small trial comparing amoxicillin and placebo, the results were unclear, but the evidence was graded very low (RR 2.00, 95% CI 0.59 to 6.79; 15 women). One antibiotic versus another antibiotic: Amoxicillin made little or no difference in microbiological cure in comparison to erythromycin (RR 0.97, 95% CI 0.93 to 1.01; four trials, 466 women; high-certainty evidence), probably no difference compared to clindamycin (RR 0.96, 95% CI 0.89 to 1.04; one trial, 101 women; moderate-quality evidence), and evidence is very low certainty when compared to azithromycin so the effect is not certain (RR 0.89, 95% CI 0.71 to 1.12; two trials, 144 women; very low-certainty evidence). Azithromycin versus erythromycin (average RR 1.11, 95% CI 1.00 to 1.23; six trials, 374 women; I2 = 53%; moderate-certainty evidence) probably have similar efficacy though results appear to favour azithromycin. Clindamycin versus erythromycin (RR 1.06, 95% CI 0.97 to 1.15; two trials, 173 women; low-certainty evidence) may have similar numbers of women with a microbiological cure between groups.Evidence was downgraded for design limitations, inconsistency, and imprecision in effect estimates. Side effects of the treatment (maternal) (secondary outcome) Antibiotics versus placebo: side effects including nausea, vomiting, and abdominal pain, were reported in two studies (495 women) but there was no clear evidence whether erythromycin was associated with more side effects than placebo and a high level of heterogeneity (I2 = 78%) was observed (average RR 2.93, 95% CI 0.36 to 23.76). There was no clear difference in the number of women experiencing side effects when clindamycin was compared to placebo in one small study (5/41 versus 1/44) (RR 6.35, 95% CI 0.38 to 107.45, 62 women). The side effects reported were mostly gastrointestinal and also included resolving skin rashes. One antibiotic versus another antibiotic: There was no clear difference in incidence of side effects (including nausea, vomiting, diarrhoea and abdominal pain) when amoxicillin was compared to azithromycin based on data from one small study (36 women) (RR 0.56, 95% CI 0.24 to 1.31).However, amoxicillin was associated with fewer side effects compared to erythromycin with data from four trials (513 women) (RR 0.31, 95% CI 0.21 to 0.46; I2 = 27%). Side effects included nausea, vomiting, diarrhoea, abdominal cramping, rash, and allergic reaction.Both azithromycin (RR 0.24, 95% CI 0.17 to 0.34; six trials, 374 women) and clindamycin (RR 0.44, 95% CI 0.22 to 0.87; two trials, 183 women) were associated with a lower incidence of side effects compared to erythromycin. These side effects included nausea, vomiting, diarrhoea and abdominal cramping.One small study (101 women) reported there was no clear difference in the number of women with side effects when amoxicillin was compared with clindamycin (RR 0.57, 95% CI 0.14 to 2.26; 107 women). The side effects reported included rash and gastrointestinal complaints. Other secondary outcomes Single trials reported data on repeated infections, preterm birth, preterm rupture of membranes, perinatal mortality and low birthweight and found no clear differences between treatments.Many of this review's secondary outcomes were not reported in the included studies. Treatment with antibacterial agents achieves microbiological cure from C.trachomatis infection during pregnancy. There was no apparent difference between assessed agents (amoxicillin, erythromycin, clindamycin, azithromycin) in terms of efficacy (microbiological cure and repeat infection) and pregnancy complications (preterm birth, preterm rupture of membranes, low birthweight). Azithromycin and clindamycin appear to result in fewer side effects than erythromycin.All of the studies in this review were conducted in North America, which may limit the generalisability of the results. In addition, study populations may differ in low-resource settings and these results are therefore only applicable to well-resourced settings. Furthermore, the trials in this review mainly took place in the nineties and early 2000's and antibiotic resistance may have changed since then.Further well-designed studies, with appropriate sample sizes and set in a variety of settings, are required to further evaluate interventions for treating C.trachomatis infection in pregnancy and determine which agents achieve the best microbiological cure with the least side effects. Such studies could report on the outcomes listed in this review.


Birt Hogg-Dubé syndrome-associated FLCN mutations disrupt protein stability.
Germline mutations in the FLCN gene cause Birt-Hogg-Dubé syndrome, familial spontaneous pneumothorax, or apparently nonsyndromic inherited RCC. The vast majority of reported FLCN mutations are predicted to result in a truncated/absent gene product and so infrequent missense and inframe-deletion (IFD) FLCN mutations might indicate critical functional domains. To investigate this hypothesis we (1) undertook an in silico evolutionary analysis of the FLCN sequence and (2) investigated in vitro the functional effects of naturally occurring FLCN missense/IFD mutations. The folliculin protein sequence evolved more slowly and was under stronger purifying selection than the average gene, most notably at a region between codons 100 and 230. Pathogenic missense and IFD FLCN mutations that impaired folliculin tumor suppressor function significantly disrupted the stability of the FLCN gene product but two missense substitutions initially considered to be putative mutations did not impair protein stability, growth suppression activity, or intracellular localization of folliculin. These findings are consistent with the distribution of FLCN mutations throughout the coding sequence, and suggest that multiple protein domains contribute to folliculin stability and tumor suppressor activity. In vitro assessment of protein stability and tumor suppressor activity provides a practical strategy for assessing the pathogenicity of potential FLCN mutations.


Kernel-based feature selection techniques for transport proteins based on star graph topological indices.
The transport of the molecules inside cells is a very important topic, especially in Drug Metabolism. The experimental testing of the new proteins for the transporter molecular function is expensive and inefficient due to the large amount of new peptides. Therefore, there is a need for cheap and fast theoretical models to predict the transporter proteins. In the current work, the primary structure of a protein is represented as a molecular Star graph, characterized by a series of topological indices. The dataset was made up of 2,503 protein chains, out of which 413 have transporter molecular function and 2,090 have no transporter function. These indices were used as input to several classification techniques to find the best Quantitative Structure Activity Relationship (QSAR) model that can evaluate the transporter function of a new protein chain. Among several feature selection techniques, the Support Vector Machine Recursive Feature Elimination allows us to obtain a classification model based on 20 attributes with a true positive rate of 83% and a false positive rate of 16.7%.


Geographic variation in sex-chromosome differentiation in the common frog (Rana temporaria).
In sharp contrast with birds and mammals, sex-determination systems in ectothermic vertebrates are often highly dynamic and sometimes multifactorial. Both environmental and genetic effects have been documented in common frogs (Rana temporaria). One genetic linkage group, mapping to the largest pair of chromosomes and harbouring the candidate sex-determining gene Dmrt1, associates with sex in several populations throughout Europe, but association varies both within and among populations. Here, we show that sex association at this linkage group differs among populations along a 1500-km transect across Sweden. Genetic differentiation between sexes is strongest (FST = 0.152) in a northern-boreal population, where male-specific alleles and heterozygote excesses (FIS = -0.418 in males, +0.025 in females) testify to a male-heterogametic system and lack of X-Y recombination. In the southernmost population (nemoral climate), in contrast, sexes share the same alleles at the same frequencies (FST = 0.007 between sexes), suggesting unrestricted recombination. Other populations show intermediate levels of sex differentiation, with males falling in two categories: some cluster with females, while others display male-specific Y haplotypes. This polymorphism may result from differences between populations in the patterns of X-Y recombination, co-option of an alternative sex-chromosome pair, or a mixed sex-determination system where maleness is controlled either by genes or by environment depending on populations or families. We propose approaches to test among these alternative models, to disentangle the effects of climate and phylogeography on the latitudinal trend, and to sort out how this polymorphism relates to the 'sexual races' described in common frogs in the 1930s.


Lattice Boltzmann method for miscible gases: A forcing-term approach.
A lattice Boltzmann method for miscible gases is presented. In this model, the standard lattice Boltzmann method is employed for each species composing the mixture. Diffusion interaction among species is taken into account by means of a force derived from kinetic theory of gases. Transport coefficients expressions are recovered from the kinetic theory. Species with dissimilar molar masses are simulated by also introducing a force. Finally, mixing dynamics is recovered as shown in different applications: an equimolar counterdiffusion case, Loschmidt's tube experiment, and an opposed jets flow simulation. Since collision is not altered, the present method can easily be introduced in any other lattice Boltzmann algorithms.


The relationship of acculturation to cardiovascular disease risk factors among U.S. South Asians: Findings from the MASALA study.
We investigated the association between acculturation strategies and cardiometabolic risk among South Asian (SA) immigrants in the US. In this cross-sectional analysis of data from 849 SA participants in the Mediators of Atherosclerosis in SAs Living in America (MASALA), we performed multidimensional measures of acculturation to categorize the participants into three acculturation classes: separation (preference for SA culture), assimilation (preference for US culture), and integration (similar preference for both cultures). Differences in glycemic indices, blood pressure, lipid parameters and body composition by acculturation strategy were examined. Women in the integration class had the lowest prevalence of diabetes (16.4%), prediabetes (29.7%), fasting and 2-h glucose compared to women in the separation class with the highest prevalence of diabetes (29.3%), prediabetes (31.5%), fasting and 2-h glucose and 2-hr insulin (all p < 0.05). Women in the assimilation class had significantly lower triglycerides, BMI, and waist circumference and higher HDL compared to women in the separation class after adjusting for age, study site, and years in the US. After additionally accounting for socioeconomic/lifestyle factors, women in the assimilation class had significantly lower triglyceride and higher HDL levels compared to women in the separation class (p < 0.01). There was no significant association between acculturation strategies and cardiometabolic risk in SA men. SA women who employed an assimilation or integration strategy had a more favorable cardiometabolic profile compared to women using a separation strategy. Future research should investigate the behavioral and psychosocial pathways linking acculturation strategies with cardiometabolic health to inform preventive interventions among SAs living in America.


2-Year Outcomes After Complete or Staged Procedure for Tetralogy of Fallot in Neonates.
There is ongoing debate about the best strategy to treat patients with tetralogy of Fallot who are symptomatic in the neonatal period. The aim of this study was to compare the outcomes of complete versus staged surgery (i.e., initial palliative procedure for possible later complete repair). A retrospective cohort study was performed using the Pediatric Health Information System database, including patients who underwent complete or staged tetralogy of Fallot repair prior to 30 days of age. The primary outcome was death during 2-year follow-up after the initial procedure. Inverse probability-weighted Cox and logistic regression models were used to examine the association between surgical approach group and mortality while accounting for patient- and hospital-level factors. Causal mediation analyses examined the role of intermediate variables. A total of 2,363 patients were included (1,032 complete and 1,331 staged). There were 239 deaths. Complete neonatal repair was associated with a significantly higher risk for mortality during the 2-year follow-up period (hazard ratio: 1.51; 95% confidence interval: 1.05 to 2.06), between 7 and 30 days after the initial procedure (hazard ratio: 2.29; 95% confidence interval: 1.18 to 4.41), and during the initial hospital admission (odds ratio: 1.72; 95% confidence interval: 1.15 to 2.62). Post-operative cardiac complications were more common in the complete repair group and mediated the differences in 30-day and 2-year mortality. Complete surgical repair for neonates with tetralogy of Fallot is associated with a significantly higher risk for early and 2-year mortality compared with the staged approach, after accounting for patient and hospital characteristics. Post-operative cardiac complications mediated these findings.


[Evaluation of the direct analgesic effect of ministimulators].
Percutaneous electrostimulation is a new method of analgesia and it is hoped that good effects can be obtained in painful syndromes resistant to other therapeutic methods. Its basic advantage is the possibility of controlling the parameters during the stimulation by the patient who is wearing a miniaturized apparatus generating impulses of desired parameters. The authors tried out the effectiveness of ministimulators of Polish design for the treatment of neuralgic pains in inpatients and outpatients. The electrodes were placed at the sites of greatest pain and along peripheral nerves. The immediate analgesic effect of the stimulation, its degree and duration were evaluated. In 67% of patients an immediate improvement was obtained, and in 16% of them the pain disappeared completely. The authors stress that the effectiveness of this method equals that of various types of acupuncture and discuss a possible common mechanism of action of both methods.


Analysis of Serum microRNA Expression Profiles and Comparison with Small Intestinal microRNA Expression Profiles in Weaned Piglets.
Weaning stress induces tissue injuries and impairs health and growth in piglets, especially during the first week post-weaning. MicroRNAs (miRNAs) play vital roles in regulating stresses and diseases. Our previous study found multiple differentially expressed miRNAs in small intestine of piglets at four days post-weaning. To better understand the roles of miRNAs during weaning stress, we analyzed the serum miRNA expressional profile in weaned piglets (at four days post-weaning) and in suckling piglets (control) of the same age using miRNA microarray technology. We detected a total of 300 expressed miRNAs, 179 miRNAs of which were differentially expressed between the two groups. The miRNA microarray results were validated by RT-qPCR. The biological functions of these differentially expressed miRNAs were predicted by GO terms and KEGG pathway annotations. We identified 10 highly expressed miRNAs in weaned piglets including miR-31, miR-205, and miR-21 (upregulated) and miR-144, miR-30c-5p, miR-363, miR-194a, miR-186, miR-150, and miR-194b-5p (downregulated). Additionally, miR-194b-5p expression was significantly downregulated in serum and small intestine of weaned piglets. Our results suggest that weaning stress affects serum miRNA profiles in piglets. And serum miR-194b-5p levels can reflect its expressional changes in small intestine of piglets by weaning stress.


Surgical nuances for removal of olfactory groove meningiomas using the endoscopic endonasal transcribriform approach.
Olfactory groove meningiomas represent 10% of intracranial meningiomas and arise in the midline of the anterior cranial fossa along the dura of the cribriform plate and planum sphenoidale. Hyperostosis of the adjacent underlying bone is common, and further extension into ethmoid sinuses and nasal cavity can occur in 15%-25% of cases. Radical tumor resection including the involved dural attachment and underlying hyperostotic bone offers the best chance of a Simpson Grade I resection to minimize recurrence. Incomplete removal of involved hyperostotic bone can result in tumor recurrence at the cribriform plate with extension into the paranasal sinuses. Resection has traditionally been performed using a bifrontal or pterional approach, both of which require some degree of brain retraction or manipulation to expose the tumor. The endoscopic endonasal transcribriform approach offers the most direct and immediate exposure to the tumor without brain retraction and manipulation of neurovascular structures. An endonasal "keyhole craniectomy" is performed in the ventral skull base directly over the basal dural attachment, extending from the posterior wall of the frontal sinus to the planum sphenoidale and tuberculum sellae in the anteroposterior plane, and from one medial orbit to the other in the coronal plane. Excellent panoramic visualization of the keyhole skull base defect can be obtained with a 30° endoscope after performing a modified Lothrop procedure. Because the dural attachment is adjacent to the paranasal sinuses, early devascularization and total Simpson Grade I removal of the tumor including the dural attachment and underlying hyperostotic bone can be achieved in properly selected patients. This approach is also very suitable for meningiomas that have recurred or extended into the paranasal sinuses. Extracapsular, extraarachnoid dissection of the tumor from the frontal lobes and neurovascular structures can be performed using conventional bimanual microsurgical techniques. In this report, we review the surgical technique and describe our operative nuances for removal of olfactory groove meningiomas, including recurrent tumors with extension into the nasal cavity, using a purely endoscopic endonasal transcribriform approach. In addition, we discuss the advantages, limitations, patient selection, and complications of this approach. We specifically highlight our technique for multilayer reconstruction of large anterior skull base dural defects using fascia lata and acellular dermal allograft supplemented by bilateral vascularized pedicled nasoseptal flaps. Three new cases of endoscopically resected olfactory groove meningiomas are also presented.


[Atypical antipsychotics in elderly patients with dementia].
Antipsychotic medication is often prescribed to persons with dementia exhibiting behavioural and psychological symptoms (BPSD). Use of atypical antipsychotics in elderly persons with dementia is associated with an increased risk of serious cerebrovascular adverse events and increased mortality. Based on a review of available literature, we conclude that atypical antipsychotics have a modest effect on BPSD and potentially serious side effects and that conventional antipsychotics appear to have even less favourable effects and adverse event profiles. Antipsychotic medication in patients with dementia exhibiting BPSD should only be prescribed for short-term treatment of severe symptoms associated with considerable distress or serious risk. Non-pharmacological interventions should be the first-line treatment approach in most cases.


Management of major obstetric hemorrhage prior to peripartum hysterectomy and outcomes across nine European countries.
Peripartum hysterectomy is applied as a surgical intervention of last resort for major obstetric hemorrhage. It is performed in an emergency setting except for women with a strong suspicion of placenta accreta spectrum (PAS), where it may be anticipated before cesarean section. The aim of this study was to compare management strategies in the case of obstetric hemorrhage leading to hysterectomy, between nine European countries participating in the International Network of Obstetric Survey Systems (INOSS), and to describe pooled maternal and neonatal outcomes following peripartum hysterectomy. We merged data from nine nationwide or multi-regional obstetric surveillance studies performed in Belgium, Denmark, Finland, France, Italy, the Netherlands, Slovakia, Sweden and the UK collected between 2004 and 2016. Hysterectomies performed from 22 gestational weeks up to 48 h postpartum due to obstetric hemorrhage were included. Stratifying women with and without PAS, procedures performed in the management of obstetric hemorrhage prior to hysterectomy between countries were counted and compared. Prevalence of maternal mortality, complications after hysterectomy and neonatal adverse events (stillbirth or neonatal mortality) were calculated. A total of 1302 women with peripartum hysterectomy were included. In women without PAS who had major obstetric hemorrhage leading to hysterectomy, uterotonics administration was lowest in Slovakia (48/73, 66%) and highest in Denmark (25/27, 93%), intrauterine balloon use was lowest in Slovakia (1/72, 1%) and highest in Denmark (11/27, 41%), and interventional radiology varied between 0/27 in Denmark and Slovakia to 11/59 (79%) in Belgium. In women with PAS, uterotonics administration was lowest in Finland (5/16, 31%) and highest in the UK (84/103, 82%), intrauterine balloon use varied between 0/14 in Belgium and Slovakia to 29/103 (28%) in the UK. Interventional radiology was lowest in Denmark (0/16) and highest in Finland (9/15, 60%). Maternal mortality occurred in 14/1226 (1%), the most common complications were hematologic (95/1202, 8%) and respiratory (81/1101, 7%). Adverse neonatal events were observed in 79/1259 (6%) births. Management of obstetric hemorrhage in women who eventually underwent peripartum hysterectomy varied greatly between these nine European countries. This potentially life-saving procedure is associated with substantial adverse maternal and neonatal outcome.


Chronic angiotensin II infusion causes differential responses in regional sympathetic nerve activity in rats.
Angiotensin II (AngII)-induced hypertension in experimental animals has been proposed to be attributed in part to activation of the sympathetic nervous system. This sympathetic activation appears to be accentuated in animals consuming a high-salt diet (AngII-salt hypertension). However, accurate quantification of sympathetic activity is difficult, and controversy remains. It is particularly important to ask which are the critical vascular beds targeted by increased sympathetic nerve activity (SNA) in AngII-salt hypertension. To address this issue, mean arterial pressure and renal SNA or lumbar SNA were continuously recorded during a 5-day control period, 11 days of AngII (150 ng/kg per minute, SC), and a 5-day recovery period in conscious rats on a high-salt (2% NaCl) diet. Although mean arterial pressure reached a new steady-state level of 30 to 35 mm Hg above control levels by the end of the AngII period, renal SNA decreased by 40% during the first 7 days of AngII and then returned toward control levels by day 10 of AngII. In contrast, lumbar SNA remained at control levels throughout the AngII period. In another experiment we measured hindlimb norepinephrine spillover in conscious rats on normal (0.4%) or high- (2.0%) salt diets before and during 14 days of AngII administration. AngII had no significant affect on hindlimb norepinephrine spillover in either group. We conclude that chronic AngII modulates renal and lumbar SNAs differentially in rats consuming a high-salt diet and that AngII-salt hypertension in the rat is not caused by increased SNA to the renal or hindlimb vascular beds.


A model for voles interference in cultivated orchards.
We consider a dynamical system involving seven populations to model the presence of voles in a cultivated orchard. The plant population is stratified by age (three groups) and by health status (being damaged or not). The last equation models the voles with a modified logistic equation with Allee effect, where the modification takes into account the disturbance provided by the human activity on the orchard. Both an analytical investigation and numerical simulations on a case study are presented. The latter support the observed differences in the literature, in terms of number of voles, between cultivated and uncultivated fields.


Preparation and evaluation of molecularly imprinted solid-phase microextraction fibers for selective extraction of bisphenol A in complex samples.
Molecular imprinted polymer (MIP) as solid-phase microextraction (SPME) fibers coating has gained great attention in recent years. In this study, a simple preparation approach for bisphenol A (BPA) MIP coating with controlled thickness on fused-silica capillaries was developed. A capillary was inserted into a larger bore capillary to form a sleeve as mold. The prepolymer solution containing the template BPA was introduced into the interspace between the two capillaries for polymerization under photoirradiation. The larger bore capillary was removed away after the polymerization, and MIP coating with certain thickness on the surface of the inserted capillary was obtained. SPME conditions based on the MIP-coated fibers were optimized, and the extraction performance of the fibers with different thickness coating was compared. Finally, the MIP fibers were used for selective extraction of BPA spiked in tap water, human urine, and milk samples. The average recoveries of spiked BPA in the three samples were 92.5%, 81.6%, and 87.5%, respectively. The present analytical performance is not up to par for applicability to real environmental matrices. Further improvement will be necessary for analysis of real complex samples.


Science Translation During the COVID-19 Pandemic: An Academic-Public Health Partnership to Assess Capacity Limits in California.
On the basis of an extensive academic-public health partnership around COVID-19 response, we illustrate the challenge of science-policy translation by examining one of the most common nonpharmaceutical interventions: capacity limits. We study the implementation of a 20% capacity limit in retail facilities in the California Bay Area. Through a difference-in-differences analysis, we show that the intervention caused no material reduction in visits, using the same large-scale mobile device data on human movements (mobility data) originally used in the academic literature to support such limits. We show that the lack of effectiveness stems from a mismatch between the academic metric of capacity relative to peak visits and the policy metric of capacity relative to building code. The disconnect in metrics is amplified by mobility data losing predictive power after the early months of the pandemic, weakening the policy relevance of mobility-based interventions. Nonetheless, the data suggest that a better-grounded rationale for capacity limits is to reduce risk specifically during peak hours. To enhance the connection between science, policy, and public health in future times of crisis, we spell out 3 strategies: living models, coproduction, and shared metrics. (Am J Public Health. 2022;112(2):308-315. https://doi.org/10.2105/AJPH.2021.306576).


Increasing incidence of methicillin-resistant Staphylococcus aureus in hand infections: a 3-year county hospital experience.
Staphylococcus aureus is the most common cause of skin and soft-tissue infections. Methicillin-resistant S. aureus and community-acquired methicillin-resistant S. aureus have shown an increase in prevalence among soft-tissue infections over the past several years, with overall rates approaching 50 percent at the authors' institution in 2002. The object of this study was to determine the incidence of methicillin-resistant S. aureus with respect to hand infections, the antibiotic resistance pattern of methicillin-resistant S. aureus isolates, and implications for a change in antibiotic treatment algorithms for hand infections. A retrospective chart review of 761 patients with hand infections tracked by International Classification of Diseases, 9th Revision codes for finger or hand abscesses from 2001 to 2003 was performed at Parkland Memorial Hospital, Dallas, Texas. Culture results were obtained from 436 patients and analyzed for type of organism, and sensitivity profiles were obtained for all methicillin-resistant S. aureus isolates. The median age of 761 patients was 40 years (range, 16 to 77 years); 71 percent were male and 28 percent were female. Of the 436 cultures reviewed, 371 (85 percent) had organisms identified. Methicillin-resistant S. aureus was the dominant single organism in hand infections cultured in all 3 years. The overall methicillin-resistant S. aureus rate was 61 percent of all hand infections in 2003. The percentage of S. aureus isolates identified as methicillin-resistant S. aureus increased from 55 percent to 78 percent over 3 years, up from 34 percent in 2001. Fortunately, 86 percent of these methicillin-resistant S. aureus isolates demonstrated sensitivity to conventional antibiotics, but a trend of resistance is developing. The incidence of community-acquired methicillin-resistant S. aureus increased from 34 percent to 61 percent over a 3-year period at the authors' county institution. An increasing trend of resistance patterns among conventional antibiotics was also demonstrated. As a result of this study, the treatment algorithm at Parkland Memorial Hospital has been modified to include abscess drainage accompanied by an antibiotic regimen targeted specifically at methicillin-resistant S. aureus. These data also have implications for broader application regarding simple skin infections and current antibiotic treatment algorithms.


Low-loss single-mode guidance in large-core antiresonant hollow-core fibers.
We present an approach how to combine large-mode field diameters with effective single-mode guidance in a hollow-core antiresonant optical fiber. We demonstrate experimentally and in simulations that single-mode guidance is achieved in a simplified hollow-core fiber design with a core diameter of 30 μm by shifting the effective indices of the first cladding modes close to those of higher order core modes. Our fiber shows low loss propagation and effective single-mode operation from the near infrared to deep ultraviolet wavelengths down to 270 nm on a loss level of approximately 3 dB/m.


Family-based association analysis of S100A8 genetic polymorphisms with aggressive periodontitis.
It is known that S100A8, a member of the S100 calcium-binding protein family, is associated with inflammatory diseases, including periodontitis. Our previous population-based study found an association between two polymorphisms, rs3795391 (A > G) and rs3806232 (A > G), in the upstream region of the S100A8 gene and aggressive periodontitis (AgP) in Chinese people. Based on those results, this investigation set out to analyze and corroborate whether the association also exists within families. Two hundred and four subjects from 73 nuclear families were recruited. All probands and their relatives were diagnosed according to the 1999 classification of periodontal diseases. Anticoagulated peripheral blood samples were collected from all the subjects, and DNA was extracted. The two single nucleotide polymorphisms (SNPs; rs3795391 and rs3806232) were detected and analyzed by standard polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Analysis of genotype/allele was performed by Family-Based Association Test (FBAT) software ( http://www.biostat.harvard.edu/~fbat/default.html). There was a statistically significant association of the SNP rs3795391 with AgP in the additive genetic model (chi(2) = 3.9836, d.f. = 1, p = 0.0459). Allele A showed significantly preferential transmission to the AgP affected individuals (Z = 1.996, p = 0.0459). The other SNP, rs3806232, showed no significant results in all models. This family-based association study supports the previous findings that SNP rs3795391 (A > G) of the S100A8 gene might contribute to AgP susceptibility. This is, to our knowledge, the first investigation about AgP using FBAT in genetic analysis.


LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT(2A) receptor.
Compounds that activate the 5-HT(2A) receptor, such as lysergic acid diethylamide (LSD), act as hallucinogens in humans. One notable exception is the LSD congener lisuride, which does not have hallucinogenic effects in humans even though it is a potent 5-HT(2A) agonist. LSD and other hallucinogens have been shown to disrupt prepulse inhibition (PPI), an operational measure of sensorimotor gating, by activating 5-HT(2A) receptors in rats. We tested whether lisuride disrupts PPI in male Sprague-Dawley rats. Experiments were also conducted to identify the mechanism(s) responsible for the effect of lisuride on PPI and to compare the effects of lisuride to those of LSD. Confirming a previous report, LSD (0.05, 0.1, and 0.2 mg/kg, s.c.) reduced PPI, and the effect of LSD was blocked by pretreatment with the selective 5-HT(2A) antagonist MDL 11,939. Administration of lisuride (0.0375, 0.075, and 0.15 mg/kg, s.c.) also reduced PPI. However, the PPI disruption induced by lisuride (0.075 mg/kg) was not blocked by pretreatment with MDL 11,939 or the selective 5-HT(1A) antagonist WAY-100635 but was prevented by pretreatment with the selective dopamine D(2)/D(3) receptor antagonist raclopride (0.1 mg/kg, s.c). The effect of LSD on PPI is mediated by the 5-HT(2A) receptor, whereas activation of the 5-HT(2A) receptor does not appear to contribute to the effect of lisuride on PPI. These findings demonstrate that lisuride and LSD disrupt PPI via distinct receptor mechanisms and provide additional support for the classification of lisuride as a non-hallucinogenic 5-HT(2A) agonist.


Dose-dependent effects of human prolactin on the immature hypophysectomized rat testis.
We have studied dose-dependent effects of highly purified human PRL (39 IU/mg) on the testis of immature (22-day-old) hypophysectomized rats daily supplemented for 7 days with 2, 10, or 30 micrograms hormone. Dose-dependent stimulation was observed for all parameters: testis weight (1.6- and 2-fold above control for 10 and 30 micrograms PRL), basal and hCG-stimulated testosterone (14- and 21-fold), intratesticular testosterone (7- and 21-fold) and estradiol (1.2- and 1.5-fold), LH receptor concentration (1.8- and 2.5-fold), in vitro pregnenolone production by cholesterol side-chain cleavage enzyme (3-, 5- and 7-fold), and aromatase activity (2.1- and 2.4-fold). The number of Leydig cells exhibiting immunoreactivity toward anti-P450scc, anti-P450(17 alpha), and anti-3 beta-hydroxysteroid dehydrogenase antibodies also underwent a dose-dependent increase (under conditions revealing many immunopositive cells in hypox control animals). The respective increases were 8- to 14-fold for anti-P450scc and P450(17 alpha) and 1.5- to 2-fold for anti-3 beta-hydroxysteroid dehydrogenase. The number of germ cells and the percentage of tubular sections containing late pachytene spermatocytes as most advanced stages of spermatogenesis were subject to similar dose-dependent effects. These results suggest that during puberty PRL stimulates testicular function by promoting multiplication and differentiation of Leydig cells (acting at various steps of steroidogenesis and on tissue responsiveness to LH) and germ cells.


Anthropology in cognitive science.
This paper reviews the uneven history of the relationship between Anthropology and Cognitive Science over the past 30 years, from its promising beginnings, followed by a period of disaffection, on up to the current context, which may lay the groundwork for reconsidering what Anthropology and (the rest of) Cognitive Science have to offer each other. We think that this history has important lessons to teach and has implications for contemporary efforts to restore Anthropology to its proper place within Cognitive Science. The recent upsurge of interest in the ways that thought may shape and be shaped by action, gesture, cultural experience, and language sets the stage for, but so far has not fully accomplished, the inclusion of Anthropology as an equal partner.


Robotic Inguinal Hernia Repair After Prostatectomy: How to Navigate Safely.
In recent decades, minimally invasive approaches have found their place in treating a specific subset of patients with inguinal hernias, predominantly those with recurrent or bilateral disease. Classically, prior history of urologic pelvic operations, such as prostatectomy, has been listed as relative contraindication for minimally invasive inguinal hernia repair. As the adoption of the robotics platform continues to grow, we aim to outline a feasible robotic-assisted inguinal hernia repair technique in patients with previous prostatectomies. We report the outcomes of 15 patients who underwent repair at 2 institutions. This is a retrospective case series of 15 patients who underwent robotic transabdominal preperitoneal approach repair of their inguinal hernias after prostatectomy. Demographics, intraoperative variables, and outcomes of our cases are described. Fifteen patients were included in our cohort. All patients had a history of prostatectomy (7 open, 2 laparoscopic, and 6 robotic) due to prostate cancer. Median age was 70 years old (range: 60 to 89 y), with a median body mass index of 26.3 kg/m2 (range: 20.5 to 37.4 kg/m2). Hernia defects were bilateral in 6 patients and unilateral in the remaining 9 (right; 6, left; 3). The shortest interval between prostatectomy and subsequent hernia repair was 4 months (range: 4 to 216 mo). The median operative time was 139 min (range: 91 to 281 min). All defects were repaired using a polypropylene mesh except in 1 case, where a coated monofilament polyester mesh was used after having a large peritoneal defect to close, preventing future adhesions to the bowel. Mesh sizes used were large (16×11 cm), extra-large (17×12 cm) for anatomic mesh, and 20×15 cm for the monofilament polyester mesh. The mesh was fixed in 14 of 15 cases. Fixation was accomplished with absorbable suture (n=13), barbed suture (n=1), and fibrin sealant (n=1). Peritoneal closure was always performed using a continuous running v-loc suture. There were no documented major intraoperative complications, no 30-day readmission, or recurrences recorded within the follow-up period. Postoperatively, only 2 seromas and 1 hematoma were documented during the follow-up period. Robotic inguinal hernia repairs in patients with previous prostatectomy is safe and feasible in most patients. Larger patient series are needed to confirm these findings.


Determinants of maternal adaptation to mentally disabled children in El Minia, Egypt.
This study was carried out in a governmental school for mentally disabled children in El Minia. We assessed maternal adaptation and the relationship between maternal sociodemographic factors and adaptation as well as examining maternal distress. All 100 mothers with children aged 6-18 years attending the school were recruited in the study. Three tools were used: demographic data sheet, adaptation scale to assess the nature of mothers' interaction and patterns of psychosocial adaptation and depression scale to detect the presence of psychiatric disorders among the mothers. Only 35.0% of the mothers adapted positively to their child's condition; 62.9% of those had female children. Negatively adapted mothers were slightly older than positively adapted mothers and had more children. Maternal education and occupation were significantly associated with psychosocial adaptation. Knowledge of mothers about their child's condition significantly affected adaptation as well as the dependency of children in eating, drinking and sleeping. Two-thirds of mothers had high levels of psychopathology.


Lateral pelvic displacement during gait: abnormalities after stroke and changes during the first month of rehabilitation.
To measure the amplitude and symmetry of lateral pelvic displacement (LPD) in patients with acute hemiparetic stroke; to assess the relationship between LPD and walking speed; and to quantify changes in LPD during 1- and 4-week intervals in the early stages of gait rehabilitation. LPD amplitude and symmetry were measured in stroke patients on admission to acute rehabilitation, 1 week later, and at 4-week follow-up. Performance was compared with sex-, height-, and age-matched control subjects. Urban geriatric inpatient rehabilitation facility in Australia. Fifteen patients with a single-hemisphere stroke, confirmed by computed tomography, were compared with the data from 12 control subjects. Patients' FIM trade mark instrument scores ranged from 54 to 124. Gait rehabilitation involved twice-daily individual physical therapy sessions of 45 to 60 minutes, 5 days a week, incorporating whole and part practice, mental rehearsal, verbal feedback on performance, manual guidance, and strengthening techniques. Three-dimensional motion analysis of LPD amplitude and symmetry; and preferred walking speed over 10m. Compared with controls, stroke patients initially showed increased amplitude of LPD, with no difference in LPD symmetry. A statistically significant linear relationship existed between walking speed and amplitude of LPD (r=-.53; P=.04), yet not between walking speed and symmetry (r=-.41, P=.13). Amplitude and symmetry values remained consistent during the 4-week period of rehabilitation. These results provide baseline LPD values for patients with acute hemiparetic stroke and demonstrate the relationship between LPD and walking speed. Change in LPD during inpatient rehabilitation was not uniform or predictable, particularly during longer periods. This highlights the need for therapists to regularly reassess each patient during the early rehabilitation phase after stroke, especially given that individual differences can be marked.


Rectangular method: a modified technique for sampling the ischemic border zone in a rat model of transient middle cerebral artery occlusion.
To date, there have been three common methods for sampling the cerebral ischemic border zone in a rat model of transient middle cerebral artery occlusion (tMCAO): the "two o'clock method", the "diagonal method", and the "parallel line method". However, these methods have their own advantages and limitations. Here, we propose a modified technique (the "rectangular method") for sampling the ischemic border zone. A rat tMCAO model was prepared under the support of a compact small animal anesthesia machine. Cerebral blood flow was monitored by high-resolution laser Doppler to control the quality of modeling, and 2,3,5-triphenyl tetrazolium chloride (TTC) staining was used for cerebral infarction location assessment. Superoxide dismutase 2 (SOD2), cysteinyl aspartate specific proteinase (caspase)-3, caspase-9, and heat shock protein 70 (HSP70) were used to verify the reliability and reproducibility of the rectangular method. The expression of biomarkers (SOD2, caspase-3, caspase-9, and HSP70) in the traditional (two o'clock method after TTC staining) and modified (rectangular method) groups were increased. There were no significant differences between the groups. The rectangular method proposed herein is based on a modification of the diagonal method and parallel line method, which could provide a directly observable infarct borderline and a sufficient sampling area for subsequent experimental operations regardless of the cerebral infarct location. The assessed biomarkers (SOD2, caspase-3, caspase-9, and HSP70) demonstrated the reliability and reproducibility of the rectangular method, which may facilitate inter-laboratory comparisons.


Homo-oligomerization of the porcine reproductive and respiratory syndrome virus nucleocapsid protein and the role of disulfide linkages.
As a step toward understanding the assembly pathway of the porcine reproductive and respiratory syndrome virus (PRRSV), the oligomeric properties of the nucleocapsid (N) protein were investigated. In this study, we have demonstrated that under nonreducing conditions the N protein forms disulfide-linked homodimers. However, inclusion of an alkylating agent (N-ethylmaleimide [NEM]) prevented disulfide bond formation, suggesting that these intermolecular disulfide linkages were formed as a result of spurious oxidation during cell lysis. In contrast, N protein homodimers isolated from extracellular virions were shown to have formed NEM-resistant intermolecular disulfide linkages, the function of which is probably to impart stability to the virion. Pulse-chase analysis revealed that N protein homodimers become specifically disulfide linked within the virus-infected cell, albeit at the later stages of infection, conceivably when the virus particle buds into the oxidizing environment of the endoplasmic reticulum. Moreover, NEM-resistant disulfide linkages were shown to occur only during productive PRRSV infection, since expression of recombinant N protein did not result in the formation of NEM-resistant disulfide-linked homodimers. Mutational analysis indicated that of the three conserved cysteine residues in the N protein, only the cysteine at position 23 was involved in the formation of disulfide linkages. The N protein dimer was shown to be stable both in the presence and absence of intermolecular disulfide linkages, indicating that noncovalent interactions also play a role in dimerization. Non-disulfide-mediated N protein interactions were subsequently demonstrated both in vitro by the glutathione S-transferase (GST) pull-down assay and in vivo by the mammalian two-hybrid assay. Using a series of N protein deletion mutants fused to GST, amino acids 30 to 37 were shown to be essential for N-N interactions. Furthermore, since RNase A treatment markedly decreased N protein-binding affinity, it appears that at least in vitro, RNA may be involved in bridging N-N interactions. In cross-linking experiments, the N protein was shown to assemble into higher-order structures, including dimers, trimers, tetramers, and pentamers. Together, these findings demonstrate that the N protein possesses self-associative properties, and these likely provide the basis for PRRSV nucleocapsid assembly.


Impact of metformin use on the prognostic value of lactate in sepsis.
The objective of this study is to determine if metformin use affects the prevalence and prognostic value of hyperlactatemia to predict mortality in septic adult emergency department (ED) patients. This is a single-center retrospective cohort study. Emergency department providers identified study subjects; data were collected from the medical record. Adult ED patients with suspected infection and 2 or more systemic inflammatory response syndrome criteria were included. The outcome was 28-day mortality. The primary risk variable was serum lactate (<2.0, 2.0-3.9, ≥ 4.0 mmol/L) categorized by metformin use; covariates: demographics, Predisposition, Infection, Response, Organ Dysfunction score and metformin use contraindications. The study was conducted at an urban teaching hospital; February 1, 2007 to October 31, 2008. A total of 1947 ED patients were enrolled; 192 (10%) were taking metformin; 305 (16%) died within 28 days. Metformin users had higher median lactate levels than nonusers (2.2 mmol/L [interquartile range, 1.6-3.2] vs 1.9 mmol/L [interquartile range, 1.3-2.8]) and a higher, although nonsignificant, prevalence of hyperlactatemia (lactate ≥ 4.0 mmol/L) (17% vs 13%) (P = .17). In multivariate analysis (reference group nonmetformin users, lactate <2.0 mmol/L), hyperlactatemia was associated with an increased adjusted 28-day mortality risk among nonmetformin users (odds ratio [OR], 3.18; P < .01) but not among metformin users (OR, 0.54; P = .33). In addition, nonmetformin users had a higher adjusted mortality risk than metformin users (OR, 2.49; P < .01). These differences remained significant when only diabetic patients were analyzed. In this study of adult ED patients with suspected sepsis, metformin users had slightly higher median lactate levels and prevalence of hyperlactatemia. However, hyperlactatemia did not predict an increased mortality risk in patients taking metformin.


The Effects of Add-on Fronto-Temporal Transcranial Direct Current Stimulation (tDCS) on Auditory Verbal Hallucinations, Other Psychopathological Symptoms, and Insight in Schizophrenia: A Randomized, Double-Blind, Sham-Controlled Trial.
The efficacy of fronto-temporal transcranial direct current stimulation in treating auditory verbal hallucinations and other psychopathological symptoms of schizophrenia patients has been examined in a small number of clinical trials with limited sample sizes, but the results are mixed. Fronto-temporal transcranial direct current stimulation has also been demonstrated to enhance patients' insight into their mental illness in an open-label pilot study. The current investigation aimed to investigate the therapeutic effects of fronto-temporal transcranial direct current stimulation on the severity of auditory verbal hallucinations, other schizophrenia symptoms, and insight in a large double blind, randomized, sham-controlled trial. Sixty patients with medication-refractory auditory verbal hallucinations were randomized over 2 conditions: transcranial direct current stimulation with 2-mA, twice-daily sessions for 5 consecutive days, with anodal stimulation to the left prefrontal cortex and cathodal stimulation to the left temporo-parietal junction, and sham treatment. Fronto-temporal transcranial direct current stimulation failed to cause significant changes in the severity of auditory verbal hallucinations and other schizophrenia symptoms. The levels of insight into illness (effect size=0.511, P<.001) and positive symptoms (effect size=0.781, P<.001) were largely promoted by 5 days of transcranial direct current stimulation relative to sham treatment. The beneficial effects on the 2 insight dimensions remained 1 month after transcranial direct current stimulation. Fronto-temporal transcranial direct current stimulation is not more effective for auditory verbal hallucinations and other schizophrenia symptoms than sham treatment. But the results of transcranial direct current stimulation-associated improvement in awareness of illness and positive symptoms show promise and provide a new direction for future research into insight promotion interventions in schizophrenia.


Breast Milk and Saliva Lactoferrin Levels and Postnatal Cytomegalovirus Infection.
Very low birth weight preterm infants are at risk for life-threatening infections in the NICU. Breast milk protects against infections but carries the risk of infection by cytomegalovirus (CMV) shed in mother's milk. Lactoferrin is a breast milk and saliva protein with potent neutralizing activity against CMV. VLBW, maternal breast milk fed infants in the NICU and their lactating mothers were enrolled and followed for 3 months/discharge. Breast milk and infant saliva samples were collected biweekly. Maternal CMV status was determined on breast milk. CMV was measured using quantitative polymerase chain reaction and lactoferrin by enzyme-linked immunosorbent assay. In an in vitro neutralization assay, the IC90 of purified human lactoferrin against CMV was 2.08 ng/mL. Bovine lactoferrins were more potent, IC90s > 10-fold higher. Lactoferrin was detected in all breast milk (median: 3.3 × 106 ng/mL) and saliva (median: 84.4 ng/swab) samples. Median CMV load in breast milk was 893 copies/mL. There was no correlation between breast milk lactoferrin concentration and CMV load. Five infants acquired postnatal CMV. There was no difference in saliva or breast milk lactoferrin concentration for mother-infant pairs and postnatal CMV acquisition. Lactoferrin neutralizes CMV in vitro, but concentrations in breast milk and saliva are likely too low for effective neutralization in vivo.


Wiring specificity in the direction-selectivity circuit of the retina.
The proper connectivity between neurons is essential for the implementation of the algorithms used in neural computations, such as the detection of directed motion by the retina. The analysis of neuronal connectivity is possible with electron microscopy, but technological limitations have impeded the acquisition of high-resolution data on a large enough scale. Here we show, using serial block-face electron microscopy and two-photon calcium imaging, that the dendrites of mouse starburst amacrine cells make highly specific synapses with direction-selective ganglion cells depending on the ganglion cell's preferred direction. Our findings indicate that a structural (wiring) asymmetry contributes to the computation of direction selectivity. The nature of this asymmetry supports some models of direction selectivity and rules out others. It also puts constraints on the developmental mechanisms behind the formation of synaptic connections. Our study demonstrates how otherwise intractable neurobiological questions can be addressed by combining functional imaging with the analysis of neuronal connectivity using large-scale electron microscopy.


Toxic effects of Aroclor 1254 on rat liver and modifying roles of selenium.
Polychlorinated biphenyls (PCBs) were used in different industrial areas and banned due to their high toxicity. Aroclor 1254 (A1254), commercial PCB congener, accumulates in environment leading to high human exposure. A1254 may cause hepatotoxicity, metabolic and endocrine disorders. In our study, 3-week-old male rats were separated into 6 groups: C (0.15 mg/kg Se in diet); SeS (1 mg/kg Se in diet); SeD (0.05 mg/kg Se in diet); A1254 receiving groups (A; ASeS; ASeD) were given 10 mg/kg/day A1254 orally for last 15 days of feeding period with control, SeD or SeS diet, respectively, for 5 weeks. Histopathology, oxidant/antioxidant balance, apoptosis and cell cycle proteins (p53, p21) in liver were evaluated. Our results suggest that A1254 leads to changes in histology, oxidative stress and apoptosis. Selenium deficiency augments oxidative stress and apoptosis while selenium supplementation is partially protective. More mechanistic in vivo experiments are necessary for evaluation of hepatotoxicity of PCBs.


The linearity of the visual analogue scale in patients with severe acute pain.
The visual analogue scale (VAS) is a standard measurement tool in pain research and clinical practice, and has been shown to have linear scale properties for mild to moderate pain. Our aim was to evaluate the scaling properties of the VAS in subjects with severe acute pain. After Ethics Committee approval we studied 22 patients and asked them to rate the severity of their pain on a 100 mm VAS at the initial assessment (VAS1), and again after administration of analgesic medication. The subject was asked to nominate when they considered their pain intensity had halved, and at this time they were asked to rate this on a second VAS (VAS0.5). When the subject had received satisfactory relief of their pain, they were asked to describe how much their pain had been relieved and were then asked to rate their final pain state using a third VAS (VASfinal). The mean (SD) scores were VAS1 84 (14) (range 56-100), VAS0.5 42 (13) and VASfinal 21 (16). The mean (95% CI) for VASratio was 0.51 (0.45-0.57). The mean (SD) patients' estimate of pain relief was 77 (21)% from that of baseline, with a mean (SD) VASfinal 0.26 (0.20), 95% CI 0.17-0.38. The correlation of the patients' estimate of pain relief with the VASfinal was r=0.89, rho=0.87, both P<0.001. The VAS is a linear scale in subjects with severe acute pain. Changes in the VAS score represent a relative change in the magnitude of pain sensation.


An Optimized Federated Learning Approach with the Data-Sharing Function to the Analysis of Cardiothoracic Time-Series Signals.
Machine/deep learning has been widely used for big data analysis in the field of healthcare, but it is still a question to ensure both computation efficiency and data security/confidentiality for the protection of private information. Referring to the data-sharing function of the federated learning (FedL) model, we propose an optimized data-sharing FedL (DSFedL) framework via a data-sharing hub by evaluating an accuracy-privacy loss function. When applied to the derived non-identically and independently distributed (nonIID) datasets simulated from three open-source cardiothoracic databases (i.e., ICBHI, Coswara COVID-19, MIT-BIH Arrhythmia), our optimized DSFedL works efficiently and the results show an optimal outcome of both the accuracy/efficiency and data security/confidentiality management.Clinical Relevance-This provides a proof of concept for using DSFedL in clinical applications, particularly in those settings that require data confidentiality control.


Policy Progress in Reducing Sodium in the American Diet, 2010-2019.
Most Americans consume dietary sodium exceeding age-specific government-recommended targets of 1,500-2,300 mg/day per person. The majority (71%) of US dietary sodium comes from restaurant and packaged foods. Excess sodium intake contributes to hypertension and cardiovascular disease, which is the leading cause of death in the United States. This review summarizes evidence for policy progress to reduce sodium in the US food supply and the American diet. We provide a historical overview of US sodium-reduction policy (1969-2010), then examine progress toward implementing the 2010 National Academy of Medicine (NAM) sodium report's recommendations (2010-2019). Results suggest that the US Food and Drug Administration made no progress in setting mandatory sodium-reduction standards, industry made some progress in meeting voluntary targets, and other stakeholders made some progress on sodium-reduction actions. Insights from countries that have significantly reduced population sodium intake offer strategies to accelerate US progress toward implementing the NAM sodium-reduction recommendations in the future.


Insect herbivores should follow plants escaping their relatives.
Neighboring plants within a local community may be separated by many millions of years of evolutionary history, potentially reducing enemy pressure by insect herbivores. However, it is not known how the evolutionary isolation of a plant affects the fitness of an insect herbivore living on such a plant, especially the herbivore's enemy pressure. Here, we suggest that evolutionary isolation of host plants may operate similarly as spatial isolation and reduce the enemy pressure per insect herbivore. We investigated the effect of the phylogenetic isolation of host trees on the pressure exerted by specialist and generalist enemies (parasitoids and birds) on ectophagous Lepidoptera and galling Hymenoptera. We found that the phylogenetic isolation of host trees decreases pressure by specialist enemies on these insect herbivores. In Lepidoptera, decreasing enemy pressure resulted from the density dependence of enemy attack, a mechanism often observed in herbivores. In contrast, in galling Hymenoptera, enemy pressure declined with the phylogenetic isolation of host trees per se, as well as with the parallel decline in leaf damage by non-galling insects. Our results suggest that plants that leave their phylogenetic ancestral neighborhood can trigger, partly through simple density-dependency, an enemy release and fitness increase of the few insect herbivores that succeed in tracking these plants.


Construction of an anti-IL-1β scfv and TNFRI fusion protein and its therapeutic effect on RA mice model.
IL-1β and TNF-α play key roles in the inflammatory response. Their abnormal expression may cause the occurrence of various diseases, such as RA. Recently, medicines of target TNF-α and IL-1β have become popular in the clinical practice. Although these biological agents can get mostly good results, they are not effective in all patients. The reason for this result may be that these biological agents could not fully inhibit a variety of inflammatory cytokines in the inflammatory response. In the present study, a fusion protein gene which encoded human interleukin-1β scfv and soluble TNF receptor I (sTNFRI) was cloned. A number of in vitro assays demonstrated that anti-IL-1β scfv/TNFRI simultaneously bound to both targets. The bioactivity assay showed that the fusion protein could inhibit both the cytotoxicity of hTNF-α on L929 cells and hIL-1β-induced proliferation of L929 cells, indicating that the fusion protein has the ability to neutralize both hTNF-α and hIL-1β. In this study, we established the chicken type II collagen-induced rheumatoid arthritis model in Kunming mice, and evaluated the pharmacological effect of the fusion protein in vivo. Model mice were randomly divided into 8 groups (n=8): CIA model control group, DEX treatment group (1 mg/kg), intraperitoneal treatment group (highdose: 5 mg/kg; medium-dose: 2 mg/kg; low-dose: 0.8 mg/kg), subcutaneous treatment group (high-dose: 5 mg/kg; medium- dose: 2 mg/kg; low-dose: 0.8 mg/kg), and healthy mice as control. The control group received the same volume of saline. The mice were administrated once every 2 days. Arthritis index, anti-CII antibody titers, cytokine levels, histopathological changes were examined. The results showed that anti-IL-1β scfv/TNFRI fusion protein could reduce the degree of joint swelling, inflammatory cell infiltration, synovial cell proliferation and the level of CII antibody in the sera. The Real-time PCR analysis showed that anti-IL-1β scfv/TNFRI had the ability to reduce the expression of IL-1β, TNF-α, IL-17A, MMP-3, IL-6 and improve the expression of IL-10 in a dose-dependent manner, suggesting that the fusion protein is the mediator for IL-1β and TNF-α involved in the RA process. Compared with DEX positive medicine control, anti-IL-1β scfv/TNFRI appeared more beneficial in treatment of CIA mice. The therapeutic effect of the anti-IL-1β scfv/TNFRI at 5mg/kg was significantly better than that of DEX treatment. So the anti-IL-1β scfv/TNFRI can become a candidate for treatment of RA.


Combining Medicinal Plant In Vitro Culture with Machine Learning Technologies for Maximizing the Production of Phenolic Compounds.
We combined machine learning and plant in vitro culture methodologies as a novel approach for unraveling the phytochemical potential of unexploited medicinal plants. In order to induce phenolic compound biosynthesis, the in vitro culture of three different species of Bryophyllum under nutritional stress was established. To optimize phenolic extraction, four solvents with different MeOH proportions were used, and total phenolic content (TPC), flavonoid content (FC) and radical-scavenging activity (RSA) were determined. All results were subjected to data modeling with the application of artificial neural networks to provide insight into the significant factors that influence such multifactorial processes. Our findings suggest that aerial parts accumulate a higher proportion of phenolic compounds and flavonoids in comparison to roots. TPC was increased under ammonium concentrations below 15 mM, and their extraction was maximum when using solvents with intermediate methanol proportions (55-85%). The same behavior was reported for RSA, and, conversely, FC was independent of culture media composition, and their extraction was enhanced using solvents with high methanol proportions (>85%). These findings confer a wide perspective about the relationship between abiotic stress and secondary metabolism and could serve as the starting point for the optimization of bioactive compound production at a biotechnological scale.


Meta-analysis of hemorrhagic complications from ventriculostomy placement by neurosurgeons.
Ventriculostomy placement is an important diagnostic and therapeutic tool for neurosurgeons. Multiple authors have presented retrospective series of patients evaluating periprocedure hemorrhage. We performed a meta-analysis of existing studies to determine a more accurate rate of hemorrhage. A MEDLINE and PubMed search was performed to find all studies of 25 or more patients conducted since 1970 that found a hemorrhagic complication rate from placement of a ventriculostomy. Studies in which a non-neurosurgeon placed the ventriculostomy and studies involving premature infants were excluded. Sixteen studies were used to obtain data from 2428 ventriculostomy procedures. Hemorrhage was found after 203 procedures, and 52 of these hemorrhages were deemed significant by the authors. The cumulative rate of hemorrhage was 7.0% (95% confidence interval: 4.5%-9.4%), with P < .05. The cumulative rate of significant hemorrhage was 0.8% (95% confidence interval: 0.2%-1.4%) with P < .05. Based on our meta-analysis, the overall hemorrhagic complication rate from ventriculostomy placement by neurosurgeons is approximately 7%. The rate of significant hemorrhage from ventriculostomy placement is approximately 0.8%. Further prospective studies are warranted to better address this question.


Case reports of juvenile GM1 gangliosidosisis type II caused by mutation in GLB1 gene.
Type II or juvenile GM1-gangliosidosis is an autosomal recessive lysosomal storage disorder, which is clinically distinct from infantile form of the disease by the lack of characteristic cherry-red spot and hepatosplenomegaly. The disease is characterized by slowly progressive neurodegeneration and mild skeletal changes. Due to the later age of onset and uncharacteristic presentation, diagnosis is frequently puzzled with other ataxic and purely neurological disorders. Up to now, 3-4 types of GM1-gangliosidosis have been reported and among them type I is the most common phenotype with the age of onset around 6 months. Various forms of GM1-gangliosidosis are caused by GLB1 gene mutations but severity of the disease and age of onset are directly related to the position and the nature of deleterious mutations. However, due to its unique genetic cause and overlapping clinical features, some researchers believe that GM1 gangliosidosis represents an overlapped disease spectrum instead of four distinct types. Here, we report a less frequent type of autosomal recessive GM1 gangliosidosis with perplexing clinical presentation in three families in the southwest part of Iran, who are unrelated but all from "Lurs" ethnic background. To identify disease-causing mutations, Whole Exome Sequencing (WES) utilizing next generation sequencing was performed. Four patients from three families were investigated with the age of onset around 3 years old. Clinical presentations were ataxia, gate disturbances and dystonia leading to wheelchair-dependent disability, regression of intellectual abilities, and general developmental regression. They all were born in consanguineous families with no previous documented similar disease in their parents. A homozygote missense mutation in GLB1 gene (c. 601 G > A, p.R201C) was found in all patients. Using Sanger sequencing this identified mutation was confirmed in the proband, their parents, grandparents, and extended family members, confirming its autosomal recessive pattern of inheritance. Our study identified a rare pathogenic missense mutation in GLB1 gene in patients with complex neurodevelopmental findings, which can extend the list of differential diagnoses for childhood ataxia in Iranian patients.


Sorafenib, a dual Raf kinase/vascular endothelial growth factor receptor inhibitor has significant anti-myeloma activity and synergizes with common anti-myeloma drugs.
Multiple myeloma is characterized by increased bone marrow neovascularization driven in part by vascular endothelial growth factor (VEGF). In addition, the Ras/Raf/MEK/ERK pathway is critical for the proliferation of myeloma cells and is often upregulated. Sorafenib (Nexavar) is a novel multi-kinase inhibitor that acts predominantly through inhibition of Raf-kinase and VEGF receptor 2, offering the potential for targeting two important aspects of disease biology. In in vitro studies, sorafenib-induced cytotoxicity in MM cell lines as well as freshly isolated patient myeloma cells. It retained its activity against MM cells in co-culture with stromal cells or with interleukin-6, VEGF or IGF; conditions mimicking tumor microenvironment. Examination of cellular signaling pathways showed downregulation of Mcl1 as well as decreased phosphorylation of the STAT3 and MEK/ERK, as potential mechanisms of its anti-tumor effect. Sorafenib induces reciprocal upregulation of Akt phosphorylation; and simultaneous inhibition of downstream mTOR with rapamycin leads to synergistic effects. Sorafenib also synergizes with drugs such as proteasome inhibitors and steroids. In a human in vitro angiogenesis assay, sorafenib showed potent anti-angiogenic activity. Sorafenib, through multiple mechanisms exerts potent anti-myeloma activity and these results favor further clinical evaluation and development of novel sorafenib combinations.


The Effectiveness of Counseling with a Cognitive-Behavioral Approach on Infertile Women's Stress.
Aim: Infertility is defined as failure to achieve a clinical pregnancy after 12 months or more of regular unprotected sexual intercourse. It is a major crisis, triggering psychological stress for most people, and can cause many negative psychological reactions. This study aimed to explore the effects of group counseling sessions by a cognitive approach on infertile women's stress. Materials and methods: In this study, 50 infertile women who were referred to an infertility center were selected using convenient sampling. The selected participants were randomly assigned to two groups: experimental and control. First, the Newton Infertility Stress questionnaire was filled as a pre-test by both groups. The control group had no counseling, while the experimental group received 10 sessions of group counseling in the field of stress management and controlling irrational thoughts about infertility during a two-week period. After this time, both groups completed the same questionnaire again and the obtained data were analyzed. Results: In this study, a significant difference in the mean score of all five aspects of the infertility specific total stress questionnaire and that of total stress after counseling (P = 0.002) was found between the experimental and control groups. Conclusion: The study showed the effects of group counseling by a participatory approach on infertility specific stress.


Optimal Donor Selection for Hematopoietic Cell Transplantation Using Bayesian Machine Learning.
Donor selection practices for matched unrelated donor (MUD) hematopoietic cell transplantation (HCT) vary, and the impact of optimizing donor selection in a patient-specific way using modern machine learning (ML) models has not been studied. We trained a Bayesian ML model in 10,318 patients who underwent MUD HCT from 1999 to 2014 to provide patient- and donor-specific predictions of clinically severe (grade 3 or 4) acute graft-versus-host disease or death by day 180. The model was validated in 3,501 patients from 2015 to 2016 with archived records of potential donors at search. Donor selection optimizing predicted outcomes was implemented over either an unlimited donor pool or the donors in the search archives. Posterior mean differences in outcomes from optimal donor selection versus actual practice were summarized per patient and across the population with 95% intervals. Event rates were 33% (training) and 37% (validation). Among donor features, only age affected outcomes, with the effect consistent regardless of patient features. The median (interquartile range) difference in age between the youngest donor at search and the selected donor was 6 (1-10) years, whereas the number of donors per patient younger than the selected donor was 6 (1-36). Fourteen percent of the validation data set had an approximate 5% absolute reduction in event rates from selecting the youngest donor at search versus the actual donor used, leading to an absolute population reduction of 1% (95% interval, 0 to 3). We confirmed the singular importance of selecting the youngest available MUD, irrespective of patient features, identified potential for improved HCT outcomes by selecting a younger MUD, and demonstrated use of novel ML models transferable to optimize other complex treatment decisions in a patient-specific way.


An observer study methodology for evaluating detection of motion abnormalities in gated myocardial perfusion SPECT.
To address the task of detecting nonischemic motion abnormalities from animated displays of gated myocardial perfusion single photon emission computed tomography data, we performed an observer study to evaluate the difference in detection performance between gating to 8 and 16 frames. Images were created from the NCAT mathematical phantom with a realistic heart simulating hypokinetic motion in the left lateral wall. Realistic noise-free projection data were simulated for both normal and defective hearts to obtain 16 frames for the cardiac cycle. Poisson noise was then simulated for each frame to create 50 realizations of each heart, All datasets were processed in two ways: reconstructed as a 16-frame set, and collapsed to 8 frames and reconstructed. Ten observers viewed the cardiac images animated with a realistic real-time frame rate. Observers trained on 100 images and tested on 100 images, rating their confidence on the presence of a motion defect on a continuous scale. None of the observers showed a significant difference in performance between the two gating methods. The 95% confidence interval on the difference in areas under the ROC curve (Az8 - Az16) was -0.029-0.085. Our test did not find a significant difference in detection performance between 8-frame gating and 16-frame gating. We conclude that, for the task of detecting abnormal motion, increasing the number of gated frames from 8 to 16 offers no apparent advantage.


Prevalence of spontaneous bacterial peritonitis in liver cirrhosis with ascites.
Spontaneous bacterial peritonitis (SBP) is a common bacterial infection in patients with cirrhosis and ascites requiring prompt recognition and treatment. The aim of this study was to determine the prevalence, and characteristics of SBP among in-patients with cirrhosis and ascites seen at our facility. Thirty one patients with liver cirrhosis and ascites who were admitted into the Medical ward of the Ekiti State University Teaching Hospital (EKSUTH), Ado-Ekiti, Nigeria from August 2009 to July 2010 were retrospectively studied. All the patients had abdominal paracentesis done within 48 hours of admission under aseptic condition and the data obtained were analyzed. The mean age of the studied population was 62±9 years (age range 43-78 years). Of the 21 that developed SPB, culture positive SBP was present in 66.7% (14/21) while CNNA was found in 33.3% (7/21). The prevalence of MNB was 26% (8/31) in this study. Of those with SBP, 93% had monomicrobial infection with aerobic Gram negative bacilli being responsible in 66.7% of the cases with E. coli (70%) being the predominant organism followed by Klebsiella species. Gram positive organisms accounted for 33.3% with Streptococcal species (60%) being the predominant organism followed by Staphylococcus aureus (40%). Patients with SBP had significantly lower platelet count when compared with those without SBP, p < 0.05. Also, international normalization ratio (INR) was significantly higher in those patients with SBP compared with those without SBP, p < 0.05. The poor prognostic indicators found in this study were; low ascitic protein, hepatic encephalopathy, coagulopathy, renal dysfunction (creatinine >2 mg/dl) and leukocytosis (p < 0.05). It is therefore imperative to do diagnostic abdominal paracentesis for cell count and culture in any patient with onset of ascites or cirrhotic patients with ascites and suggestive symptoms compatible or suggestive of SBP.