Effects of the Mi-1 and the N root-knot nematode-resistance gene on infection and reproduction of Meloidogyne enterolobii on tomato and pepper cultivars.
Meloidogyne enterolobii is widely considered to be an aggressive root-knot nematode species that is able to reproduce on root-knot nematode-resistant tomato and pepper cultivars. In greenhouse experiments, M. enterolobii isolates 1 and 2 from Switzerland were able to reproduce on tomato cultivars carrying the Mi-1 resistance gene as well as an N-carrying pepper cultivar. Reproduction factors (Rf) ranged between 12 and 109 depending on the plant cultivar, with M. enterolobii isolate 2 being more virulent when compared to isolate 1. In contrast, M. arenaria completely failed to reproduce on these resistant tomato and pepper cultivars. Although some variability in virulence and effectiveness of root-knot nematode-resistance genes was detected, none of the plant cultivars showed Rf values less than 1 or less than 10% of the reproduction observed on the susceptible cv. 'Moneymaker' (Rf = 23-44) used to characterize resistance. The ability of M. enterolobii to overcome the resistance of tomato and pepper carrying the Mi-1 and the N gene makes it difficult to manage this root-knot nematode species, particularly in organic farming systems where chemical control is not an option.


Clinical characteristics, 4-year course, and DSM-IV classification of patients with nonaffective acute remitting psychosis.
The authors examined the clinical characteristics and 48-month illness course of cases of nonaffective acute remitting psychosis and described the classification of these cases in the DSM-IV system. The data were derived from the Suffolk County (N.Y.) Mental Health Project, a study of first-admission patients with psychotic disorders admitted to psychiatric facilities between September 1989 and December 1995. The authors compared the demographic and clinical characteristics, 48-month course, and longitudinal research diagnoses of 16 patients with nonaffective acute remitting psychosis, defined by onset in 2 weeks or less and duration of less than 6 months, to those of 26 patients with other nonaffective remitting psychoses. Nonaffective acute remitting psychosis had a distinctly benign course-46% of the patients remained in full remission throughout the 48-month follow-up, compared with 14% of patients with other remitting psychoses. Nonaffective acute remitting psychosis was also associated with fewer negative symptoms than other remitting psychoses. By 24-month follow-up, only 6% of the patients with nonaffective acute remitting psychosis, compared with 77% of the patients with other remitting psychoses, received a research diagnosis of schizophrenia or schizoaffective disorder, whereas 44% of patients with nonaffective acute remitting psychosis, compared with 12% of patients with other remitting psychoses, were given the residual diagnosis of psychotic disorder not otherwise specified. Nonaffective acute remitting psychosis is a highly distinctive yet not adequately classified condition. Better delineation of nonaffective acute remitting psychosis in current diagnostic systems could lead to better understanding of this condition and improve the applicability of diagnostic systems in developing countries, where these conditions are more common than in industrialized countries.


Sessile serrated adenomas: high-risk lesions?
Sessile serrated adenomas (SSAs) were unrecognized in pathology and gastroenterology practice until about 2005; we have diagnosed them since 2001, allowing up to 10 years of follow-up. We evaluated follow-up of patients with sessile serrated adenoma diagnosed between 2002 and 2004 in our teaching institution and compared it to follow-up of randomly selected tubular adenomas. Materials from patients diagnosed with sessile serrated adenoma from January 2002 to December 2004 were reviewed. A control group of patients with sporadic tubular adenomas was selected. Ninety-nine sessile serrated adenomas from 93 patients were diagnosed between January 2002 and December 2004. Forty three patients (46.2%) had follow-up colonoscopy. One or more lesions were found in 42 (97.6%) of 43 patients. Mucinous adenocarcinoma was diagnosed in 1 (2.3%) of 43 patients, and 1 (2.3%) of 43 patients had high-grade dysplasia in an sessile serrated adenoma. Sessile serrated adenomas were found in 22 (51.2%) of 43 patients, 16 (37.2%) of 43 patients had tubular adenomas, and hyperplastic polyps were diagnosed in 18 (41.9%) of 43. Ninety-two patients with tubular adenomas between January 2002 and December 2004 formed the control group. Sixty-six patients (71.7%) received follow-up colonoscopy. Most (53/66, 80.3%) patients had tubular adenomas on follow-up, 12 (18.2%) of 66 patients had hyperplastic polyps, and 2 (3.0%) of 66 patients had a sessile serrated adenoma. The follow-up of sessile serrated adenomas from the study period (2002 to 2004) was more rigorous than proposed for sporadic tubular adenomas (patients with sporadic tubular adenomas were also followed up more aggressively than suggested by guidelines). Those with follow-up were managed as per advanced adenomas; their clinical outcomes supported this. These results suggest that guidelines for following up patients with sessile serrated adenomas as per advanced adenomas are warranted.


Emerging Applications of Therapeutic Ultrasound in Neuro-oncology: Moving Beyond Tumor Ablation.
: Transcranial focused ultrasound (FUS) can noninvasively transmit acoustic energy with a high degree of accuracy and safety to targets and regions within the brain. Technological advances, including phased-array transducers and real-time temperature monitoring with magnetic resonance thermometry, have created new opportunities for FUS research and clinical translation. Neuro-oncology, in particular, has become a major area of interest because FUS offers a multifaceted approach to the treatment of brain tumors. FUS has the potential to generate cytotoxicity within tumor tissue, both directly via thermal ablation and indirectly through radiosensitization and sonodynamic therapy; to enhance the delivery of therapeutic agents to brain tumors by transiently opening the blood-brain barrier or improving distribution through the brain extracellular space; and to modulate the tumor microenvironment to generate an immune response. In this review, we describe each of these applications for FUS, the proposed mechanisms of action, and the preclinical and clinical studies that have set the foundation for using FUS in neuro-oncology. BBB, blood-brain barrierCED, convection-enhanced delivery5-Ala, 5-aminolevulinic acidFUS, focused ultrasoundGBM, glioblastoma multiformeHSP, heat shock proteinMRgFUS, magnetic resonance-guided focused ultrasoundpFUS, pulsed focused ultrasound.


The protective effects of long-term oral administration of marine collagen hydrolysate from chum salmon on collagen matrix homeostasis in the chronological aged skin of Sprague-Dawley male rats.
To investigate the long-term effects of marine collagen hydrolysate (MCH) from Chum Salmon skin on the aberrant collagen matrix homeostasis in chronological aged skin, Sprague-Dawley male rats of 4-wk-old were orally administrated with MCH at the diet concentrations of 2.25% and 4.5% for 24 mo. Histological and biochemical analysis revealed that MCH had the potential to inhibit the collagen loss and collagen fragmentation in chronological aged skin. Based on immunohistochemistry and western blot analysis, collagen type I and III protein expression levels in MCH-treated groups significantly increased as compared with the aged control group. Furthermore, quantitative real-time polymerase chain reaction and western blot analysis showed MCH was able to increase the expressions of procollagen type I and III mRNA (COL1A2 and COL3A1) through activating Smad signaling pathway with up-regulated TGF-βRII (TβRII) expression level. Meanwhile, MCH was shown to inhibit the age-related increased collagen degradation through attenuating MMP-1 expression and increasing tissue inhibitor of metalloproteinases-1 expression in a dose-dependent manner. Moreover, MCH could alleviate the oxidative stress in chronological aged skin, which was revealed from the data of superoxide dismutase activity and the thiobarbituric acid reactive substances level in skin homogenates. Therefore, MCH was demonstrated to have the protective effects on chronological skin aging due to the influence on collagen matrix homeostasis. And the antioxidative property of MCH might play an important role in the process.


Sustained perfusion of revascularized bioengineered livers heterotopically transplanted into immunosuppressed pigs.
Implanted bioengineered livers have not exceeded three days of continuous perfusion. Here we show that decellularized whole porcine livers revascularized with human umbilical vein endothelial cells and implanted heterotopically into immunosuppressed pigs whose spleens had been removed can sustain perfusion for up to 15 days. We identified peak glucose consumption rate as a main predictor of the patency of the revascularized bioengineered livers (rBELs). Heterotopic implantation of rBELs into pigs in the absence of anticoagulation therapy led to sustained perfusion for three days, followed by a pronounced immune responses directed against the human endothelial cells. A 10 day steroid-based immunosuppression protocol and a splenectomy at the time of rBEL implantation reduced the immune responses and resulted in continuous perfusion of the rBELs for over two weeks. We also show that the human endothelial cells in the perfused rBELs colonize the liver sinusoids and express sinusoidal endothelial markers similar to those in normal liver tissue. Revascularized liver scaffolds that can maintain blood perfusion at physiological pressures might eventually help to overcome the chronic shortage of transplantable human livers.


Neighborhood socioeconomic status effects on adolescent alcohol outcomes using growth models: exploring the role of parental alcoholism.
There is conflicting evidence regarding the impact of neighborhood socioeconomic status (SES) on adolescent alcohol use. The current study tested whether the prospective effects of neighborhood SES on adolescent alcohol outcomes varied across parental alcoholism subgroups. Data from a group of adolescents (N=361) from an ongoing longitudinal study of children of alcoholics (COAs) and matched controls were collected at three initial annual assessments. Latent growth models were estimated with a range of related time-invariant and time-varying predictors. Among non-COAs, higher neighborhood SES predicted increased rates in alcohol use and consequences, whereas among COAs, lower neighborhood SES was predictive of increased rates in alcohol use and marginally predicted rates of consequences. There were also time-specific effects of family mobility on alcohol outcomes. The current study provides evidence for differential effects of neighborhood SES on adolescent alcohol use and consequences for non-COAs and COAs. The group differences found in this study may help explain the equivocal findings from previous neighborhood studies, which may use samples with an unmeasured mix of high- and low-risk adolescents. Future research should identify pathways to alcohol use and problems for high- and low-risk adolescents living in neighborhoods that span the range of the socioeconomic spectrum.


Evaluation of DNA methylation of inflammatory genes following treatment of chronic periodontitis: A pilot case-control study.
To evaluate the influence of periodontal therapy on DNA methylation in patients with chronic periodontitis as compared to healthy individuals. Twenty patients were enrolled into two groups: (i) 10 diagnosed as clinically healthy; and (ii) 10 diagnosed with chronic periodontitis. Clinical measures were recorded and gingival biopsies were harvested at baseline (both patient groups) and at 2 and 8 weeks post-baseline for diseased individuals. Molecular DNA methylation analysis was performed by pyrosequencing for the putative inflammation-associated genes LINE-1, COX-2, IFN-γ and TNF-α. Random-intercept linear regression models were applied to evaluate methylation levels across groups at baseline and the methylation changes over time in the diseased and normal tissues. Periodontal therapy did not influence gene expression methylation of TNF-α, IFN-γ and LINE-1 levels at normal and periodontitis sites over time. However, it significantly reduced COX-2 methylation levels comparable to healthy individuals at both 2 and 8 weeks post-treatment (p < .05). Periodontal therapy resets the DNA methylation status of inflammatory gene for COX-2 in patients with periodontal disease. DNA methylation levels of TNF-α, IFN-γ and LINE-1 were sustained in periodontitis sites despite therapy. Future studies should consider an expanded panel of inflammatory genes over time. (ClinicalTrials.gov NCT02835898).


Prolonged treatment with low-dose intravenous pulse cyclophosphamide may reduce rate of relapse in ANCA-associated vasculitis.
Cyclophosphamide has transformed the outcome of ANCA-associated vasculitis, but it is highly toxic. Recent studies have suggested that pulsed intravenous cyclophosphamide (pCyc) is an effective alternative with less complications, but may lead to an increased rate of relapse. However, these studies used relatively short courses of treatment with cyclophosphamide. In this study we used a prolonged course of low-dose intravenous cyclophosphamide for 18-24 months for ANCA-associated vasculitis, evaluated the effectiveness of pCyc and analysed the outcome of a prolonged treatment on the rate of relapse. A retrospective analysis of all the patients treated with pCyc from 1995 to 2002 was performed. Thirty-seven patients were followed for an average of 38 months. Thirty-four of 37 patients (91.9%) achieved complete remission at 3 months. Eight (21%) episodes of relapse occurred in 7 patients. The cyclophosphamide was well tolerated with a low rate of infections (18.9%) and 1 death (2.7%) due to sepsis whilst on cyclophosphamide. In this study, pCyc was effective in achieving rapid remission and had a low complication rate. If prolonged, this treatment may reduce the rate of relapse.


[Delayed traumatic diaphragmatic hernia with strangulated stomach; report of a case].
A 30-year-old male who had suffered from the left hemopneumothorax due to the traffic accident 13 years before was admitted to our hospital suffering from abdominal pain. Computed tomography revealed the stomach was incarcerated through the left central tendon of the left diaphragm. He was diagnosed as delayed traumatic diaphragmatic hernia and emergency operation was performed via thoracic approach. Stomach and omentum, densely adhered to the lung and the chest wall, were strangulated in the left pleural cavity and hardly reducible. Stomach and omentum were reduced through the enlarged hernia and necrotized stomach was totally resected under the subsequent laparotomy. Hernia was closed directly via thoracic approach. A prompt diagnosis is necessary for a case highly suspicious of delayed traumatic diaphragmatic hernias presenting with strangulation.


Massive genomic variation and strong selection in Arabidopsis thaliana lines from Sweden.
Despite advances in sequencing, the goal of obtaining a comprehensive view of genetic variation in populations is still far from reached. We sequenced 180 lines of A. thaliana from Sweden to obtain as complete a picture as possible of variation in a single region. Whereas simple polymorphisms in the unique portion of the genome are readily identified, other polymorphisms are not. The massive variation in genome size identified by flow cytometry seems largely to be due to 45S rDNA copy number variation, with lines from northern Sweden having particularly large numbers of copies. Strong selection is evident in the form of long-range linkage disequilibrium (LD), as well as in LD between nearby compensatory mutations. Many footprints of selective sweeps were found in lines from northern Sweden, and a massive global sweep was shown to have involved a 700-kb transposition.


Instability of default mode network connectivity in major depression: a two-sample confirmation study.
Major depression is associated with altered static functional connectivity in various brain networks, particularly the default mode network (DMN). Dynamic functional connectivity is a novel tool with little application in affective disorders to date, and holds the potential to unravel fluctuations in connectivity strength over time in major depression. We assessed stability of connectivity in major depression between the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC), key nodes in the DMN that are implicated in ruminative cognitions. Functional connectivity stability between the mPFC and PCC over the course of a resting-state functional magnetic resonance imaging (fMRI) scan was compared between medication-free patients with major depression and healthy controls matched for age, sex and handedness. We tested replicability of the results in an independent sample using multi-echo resting-state fMRI. The primary sample included 20 patients and 19 controls, while the validation sample included 19 patients and 19 controls. Greater connectivity variability was detected in major depression between mPFC and PCC. This was demonstrated in both samples indicating that the results were reliable and were not influenced by the fMRI acquisition approach used. Our results demonstrate that alterations within the DMN in major depression go beyond changes in connectivity strength and extend to reduced connectivity stability within key DMN regions. Findings were robustly replicated across two independent samples. Further research is necessary to better understand the nature of these fluctuations in connectivity and their relationship to the aetiology of major depression.


A consideration of age-dependent differences in susceptibility to organophosphorus and pyrethroid insecticides.
Evidence that neonates are more sensitive than adults to organophosphorus (OP) and pyrethroid insecticides is largely based on studies that compare toxicity at acute lethal doses. Under such circumstances, the greater susceptibility of the neonate appears to be due to limited metabolic capacity rather than an inherent difference in the sensitivity of target sites. For purposes of risk assessment with food-use pesticides, the more relevant issue is whether the neonate is more sensitive than the adult to lower levels of exposure, approximating levels used to establish acceptable residue limits (tolerances) on various food products. If infants and children are not more sensitive to environmentally-relevant levels of exposure, then the existing tolerances for dietary exposure will provide adequate protection. If, on the other hand, they may be more sensitive, then additional studies with young animals or an additional uncertainty factor may be needed for added protection. This paper examines two sets of studies that address this issue. The first involves multi-generation reproduction studies with rats that were treated with OP insecticides (coumaphos, fenamiphos, tribufos, trichlorfon, or oxydemeton-methyl) through the diet and examined for effects, including cholinesterase (ChE) inhibition. The second involves rats that were treated by gavage with an acute dose of a pyrethroid (cismethrin, permethrin, deltamethrin or cypermethrin) to establish relative sensitivity to either a lethal dose or to a low, behaviorally-active dose. The results with the OP insecticides support ChE inhibition as the most sensitive measure of exposure and the critical effect (i.e., the lowest NOEL) for each study was based on ChE inhibition in the adult. The magnitude of ChE inhibition in pups (measured on postnatal day (PND) 4 and 21) was consistently less than for adults at a given dietary level. For the representative Type I pyrethroids, there was no evidence that pups are more sensitive than adults at any dose level. For both Type II pyrethroids, young rats were considerably more sensitive than adults to a lethal dose but not to lower doses. Levels of deltamethrin in whole-brain tissue support kinetics as the basis for the greater sensitivity of young rats to a lethal dose, with the immature systems involved with detoxification being overwhelmed at such high dose levels. These findings indicate that young animals are not more sensitive than adults to lower doses of OP or pyrethroid insecticides. This outcome supports the conclusion that infants and children are protected by existing tolerances, without the need for an additional uncertainty factor.


The reduction of DSS-induced colitis severity in mice exposed to cigarette smoke is linked to immune modulation and microbial shifts.
Exposure to cigarette smoke (CS) causes detrimental health effects, increasing the risk of cardiovascular, pulmonary diseases and carcinogenesis in exposed individuals. The impact of CS on Inflammatory Bowel Disease (IBD) has been established by a number of epidemiological and clinical studies. In fact, CS is associated with a higher risk of developing Crohn's disease (CD) while inversely correlates with the development, disease risks, and relapse rate of ulcerative colitis (UC). To investigate the effect of CS exposure on experimental colitis, we performed a comprehensive and integrated comparative analysis of colon transcriptome and microbiome in mice exposed to dextran sodium sulfate (DSS) and CS. Colon transcriptome analysis revealed that CS downregulated specific pathways in a concentration-dependent manner, affecting both the inflammatory state and composition of the gut microbiome. Metagenomics analysis demonstrated that CS can modulate DSS-induced dysbiosis of specific bacterial genera, contributing to resolve the inflammation or accelerate recovery. The risks of smoking far outweigh any possible benefit, thus smoking cessation must always be encouraged because of its significant health benefits. However, the inverse association between active smoking and the development of UC cannot be ignored and the present study lays the foundation for investigating potential molecular mechanisms responsible for the attenuation of colitis by certain compounds of tobacco when decoupled from combustion.


Characteristics of problem gamblers 56 years of age or older: a statewide study of casino self-excluders.
Gambling among older adults appears to be increasing, though little is known about the characteristics of older adult problem gamblers. The purpose of this study was to compare older adults to younger and middle-aged adults in a cohort of problem gamblers participating in a state-administered casino self-exclusion program. Self-reported problem gamblers (N = 1,601) who voluntary banned themselves from Missouri casinos from 2001 to 2003 were categorized by age as younger adults (ages 21 to 35; n = 490), middle-aged adults (ages 36 to 55; n = 950), and older adults (ages 56 to 79; n = 161), and were compared with respect to demographic variables, gambling participation, and reasons for self-exclusion. Older adult self-excluders typically began gambling in midlife, experienced gambling problems around age 60, reported preferences for nonstrategic forms of gambling, and identified fear of suicide as the primary reason for self-excluding. Implications for intervention, prevention and treatment are discussed.


Autogenous regulation of the positive regulatory qa-1F gene in Neurospora crassa.
In Neurospora crassa, the qa-1F regulatory gene positively controls transcription of all genes in the quinic acid (qa) gene cluster. qa-1F is transcribed at a low, uninduced level but is subject to strong (50-fold), autogenous regulation as well as to control by the negative regulatory gene, qa-1S, and the inducer quinic acid. Cloned qa-1F DNA sequences hybridize to two related mRNAs of 2.9 and 3.0 kilobases. When wild-type (qa-1F+) cultures are transferred to inducing conditions, qa-1F mRNA increases for 4 h, remains somewhat level, and decreases after 8 to 10 h. That this control is autogenous, i.e., that the qa-1F gene controls the synthesis of its own mRNA, is indicated by the presence of approximately the same low level of qa-1F mRNA in poly(A)+ RNA from noninducible qa-1F- mutant cultures under inducing conditions as that observed in uninduced wild-type cultures. The qa-1S gene also regulates the transcription of qa-1F, since a qa-1S- mutant, whether in noninducing or inducing conditions, contains a level of qa-1F mRNA that corresponds to the low level observed in uninduced wild-type cultures. These results corroborate the hypothesis (M. E. Case and N. H. Giles, Proc. Natl. Acad. Sci. USA 72:553-557, 1975; V. B. Patel, M. Schweizer, C. C. Dykstra, S. R. Kushner, and N. H. Giles, Proc. Natl. Acad. Sci. USA 78:5783-5787, 1981; L. Huiet, Proc. Natl. Acad. Sci. USA 81:1174-1178, 1984) that the qa-1F gene encodes an activator protein and acts positively in controlling transcription of itself and the other qa genes.


Adult combination antiretroviral therapy in sub-Saharan Africa: lessons from Botswana and future challenges.
Numerous national public initiatives offering first-line combination antiretroviral therapy (cART) for HIV infection have commenced in sub-Saharan Africa since 2002. Presently, 2.1 million of an estimated seven million Africans in need of cART are receiving treatment. Analyses from the region report favorable clinical/treatment outcomes and impressive declines in AIDS-related mortality among HIV-1-infected adults and children receiving cART. While immunologic recovery, virologic suppression and cART adherence rates are on par with resource-rich settings, loss to follow-up and high mortality rates, especially within the first 6 months of treatment, remain a significant problem. Over the next decade, cART coverage rates are expected to improve across the region, with attendant increases in healthcare utilization for HIV- and non-HIV-related complications and the need for expanded laboratory and clinical services. Planned and in-progress trials will evaluate the use of cART to prevent primary HIV-1 infection with so-called 'test and treat' expansions of coverage and treatment. Education and training programs as well as patient-retention strategies will need to be strengthened as national cART programs are expanded and more people require lifelong monitoring and care.


The influence of psychological factors on postpartum weight retention 12 months post-birth.
Background During the first postpartum year 20% of women retain excessive weight from pregnancy (postpartum weight retention; PPWR), which predicts long-term overweight/obesity. Objective The aim of this study was to explore the associations between psychological factors (depression, anxiety and stress symptoms and body attitudes) in late gestation and at 12-months postpartum with PPWR one-year post-birth. Methods Pregnant women (N = 176) completed questionnaires in early-mid pregnancy (Time 1; mean (SD) = 16.97 (1.35) weeks), late pregnancy (Time 2; mean (SD) = 33.33 (2.05) weeks), and one year postpartum (Time 3; mean (SD) = 53.12 (3.34) weeks). Women provided demographic characteristics, height and pre-pregnancy weight at Time 1. At Times 2 and 3, weight, depressive, anxiety and stress symptoms and body attitudes (salience of weight and shape, attractiveness, feeling fat, and strength and fitness) were assessed in addition to physiological, socio-contextual and lifestyle factors. Gestational weight gain and PPWR were calculated. Hierarchical linear regression models were conducted to explore variance in 12-month PPWR. Results Overall, models explained 26-39% variance in PPWR. Gestational weight gain in late pregnancy and low attractiveness at 12 months postpartum were the only variables associated significantly with 12-month PPWR. Conclusion While psychological factors did not appear to be important direct contributors to PPWR at 12 months, the overall contribution of all variables suggests that such factors may be implicated in a small and incremental way. Exploration of the interactions between variables will help unpack potential mechanisms of the development of PPWR at 12 months post-birth.


A Deep Learning Algorithm for Objective Assessment of Hypernasality in Children With Cleft Palate.
Evaluation of hypernasality requires extensive perceptual training by clinicians and extending this training on a large scale internationally is untenable; this compounds the health disparities that already exist among children with cleft. In this work, we present the objective hypernasality measure (OHM), a speech-based algorithm that automatically measures hypernasality in speech, and validate it relative to a group of trained clinicians. We trained a deep neural network (DNN) on approximately 100 hours of a publicly-available healthy speech corpus to detect the presence of nasal acoustic cues generated through the production of nasal consonants and nasalized phonemes in speech. Importantly, this model does not require any clinical data for training. The posterior probabilities of the deep learning model were aggregated at the sentence and speaker-levels to compute the OHM. The results showed that the OHM was significantly correlated with perceptual hypernasality ratings from the Americleft database (r = 0.797, p < 0.001) and the New Mexico Cleft Palate Center (NMCPC) database (r = 0.713, p < 0.001). In addition, we evaluated the relationship between the OHM and articulation errors; the sensitivity of the OHM in detecting the presence of very mild hypernasality; and established the internal reliability of the metric. Further, the performance of the OHM was compared with a DNN regression algorithm directly trained on the hypernasal speech samples. The results indicate that the OHM is able to measure the severity of hypernasality on par with Americleft-trained clinicians on thisdataset.


Necrotizing Enterocolitis (NEC): A Devastating Disease of Prematurity.
Necrotizing Enterocolitis (NEC) is a common and devastating gastrointestinal emergency that primarily affects premature infants. The incidence of necrotizing enterocolitis is 6-10% among infants with birth weight less than 1500 grams. The mortality due to NEC has not improved significantly despite advances in neonatal care and better understanding of clinical and basic sciences. The pathogenesis of NEC is not well understood and several factors such as prematurity, abnormal colonization with pathogenic bacteria, feeding practices, blood transfusion and altered intestinal barrier function may be involved. The clinical presentation of NEC could be sudden and the treatment plan could vary with the stage and type of presentation. Further research is needed to better understand the pathophysiology of NEC and, biomarkers for prediction, prevention and treatment need to be developed. Further clinical trials are needed to determine prevention and treatment modalities for this devastating disease.


Female Genital Mutilation/Cutting Resulting in Genital Tract Obstruction and Sexual Dysfunction: A Case Report and Literature Review.
Female Genital Mutilation/Cutting (FGM/C) is the practice of cutting parts of the female external genitalia in fulfillment of sociocultural obligations and in some cases for nonmedical reasons. It is classified into 4 main types depending on the extent of cutting. Some forms of FGM/C are common in at least 29 countries globally, mainly in Africa. The overall prevalence of FGM/C in Ghana is approximately 4%. The motivation for this practice varies from community to community but includes the fulfillment of cultural values, uplifting the girl child, and, according to some reports, reducing sexual desire and promiscuity. The objective of this article is to illustrate how FGM/C resulted in sexual dysfunction in a young woman married for 2 years. We present a 19-year-old female who was subjected to female genital cutting in her formative years who presented with apareunia for 2 years in her marriage. We illustrated how FGM/C led to a genital tract obstruction with resultant sexual dysfunction. Examination revealed a Type 3 FGM/C (infibulation) with almost complete occlusion of the genital tract. She underwent a successful defibulation and resumed sexual activity with her husband within 6 weeks of the procedure.


Characterization of biological types of cattle (Cycle VII): Carcass, yield, and longissimus palatability traits.
The objective of this experiment was to provide a current evaluation of the seven most prominent beef breeds in the United States and to determine the relative changes that have occurred in these breeds since they were evaluated with samples of sires born 25 to 30 yr earlier. Carcass (n = 649), yield (n = 569), and longissimus thoracis palatability (n = 569) traits from F(1) steers obtained from mating Hereford, Angus, and MARC III cows to Hereford (H), Angus (A), Red Angus (RA), Charolais (C), Limousin (L), Simmental (S), or Gelbvieh (G) sires were compared. Data were adjusted to constant age (445 d), carcass weight (363 kg), fat thickness (1.1 cm), fat trim percent (25%), and marbling (Small(35)) endpoints. For Warner-Bratzler shear force and trained sensory panel traits, data were obtained on LM from steaks stored at 2 degrees C for 14 d postmortem. The following comparisons were from the age-constant endpoint. Carcasses from L-, G-, and H-sired steers (361, 363, and 364 kg, respectively) were lighter (P < 0.05) than carcasses from steers from all other sire breeds. Adjusted fat thickness for carcasses from A-, RA-, and H-sired steers (1.5, 1.4, and 1.3 cm, respectively) was higher (P < 0.05) than for carcasses from steers from all other sire breeds (0.9 cm). Longissimus muscle areas were largest (P < 0.05) for carcasses from L-, C-, S-, and G-sired steers (89.9, 88.7, 87.6, and 86.5 cm(2), respectively) and smallest for carcasses from H- and RA-sired steers (79.5 and 78.4 cm(2)). A greater (P < 0.05) percentage of carcasses from RA- and A-sired steers graded USDA Choice (90 and 88%, respectively) than from carcasses from other sire breeds (57 to 66%). Carcass yield of boneless, totally trimmed retail product was least (P < 0.05) for RA- and A-sired steers (59.1 and 59.2%, respectively) and greatest (P < 0.05) for G, L-, C-, and S-sired steers (63.0 to 63.8%). Longissimus muscle from carcasses of A-sired steers (4.0 kg) had lower (P < 0.05) Warner-Bratzler shear force values than LM from carcasses of G- and C-sired steers (4.5 to 4.3 kg, respectively). Trained sensory panel tenderness and beef flavor intensity ratings for LM did not differ (P < 0.05) among the sire breeds. Continental European breeds (C, L, S, and G) were still leaner, more heavily muscled, and had higher-yielding carcasses than did British breeds (H, A, and RA), with less marbling than A or RA, although British breeds have caught up in growth rate.


Modeling COVID-19 vaccine booster-elicited antibody response and impact of infection history.
The 3-dose COVID-19 vaccine (booster vaccination) has been offered worldwide. As booster vaccinations continue, it is important to understand the antibody dynamics elicited by booster vaccination in order to evaluate and develop vaccination needs and strategies. Here, we investigated longitudinal data by monitoring IgG antibodies against the receptor binding domain (RBD) in health care workers. We extended our previously developed mathematical model to booster vaccines and successfully fitted antibody titers over time in the absence and presence of past SARS-CoV-2 infection. Quantitative analysis using our mathematical model indicated that anti-RBD IgG titers increase to a comparable extent after booster vaccination, regardless of the presence or absence of infection, but infection history extends the duration of antibody response by 1.28 times. Such a mathematical modeling approach can be used to inform future vaccination strategies on the basis of an individual's immune history. Our simple quantitative approach can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.


Palmitate induces apoptosis in Schwann cells via both ceramide-dependent and independent pathways.
Peripheral neuropathy has been reported to prevail in obese or pre-diabetic individuals, yet its etiology remains unknown. Palmitate, a saturated fatty acid increased in obesity and diabetes, is known to induce apoptosis in multiple types of cells and this effect may be mediated by ceramide, a member of the sphingolipid family. To clarify whether de novo ceramide synthesis from palmitate contributes to apoptosis of Schwann cells, we cultured immortalized mouse Schwann cells (IMS) and rat primary Schwann cells with palmitate, a ceramide analogue C2-ceramide as well as inhibitors of the de novo ceramide synthesis (myriocin and fumonisin B1). Apoptosis of IMS detected by nuclear staining and cell membrane inversion was significantly increased by incubation with palmitate for 48 h in a dose-dependent fashion. This enhanced apoptosis was partially but significantly suppressed by myriocin and fumonisin B1. Western blot analysis and immunostaining revealed that palmitate clearly activated caspase-3 in IMS. Unexpectedly, the ceramide synthesis inhibitors failed to suppress the palmitate-induced caspase-3 activation in spite of complete restoration in ceramide accumulation. The results seemed relevant to the observations that C2-ceramide did not activate caspase-3 while provoking apoptosis with a clear dose-dependency. In agreement, the pro-apoptotic action of C2-ceramide was not attenuated by caspase inhibitors that partially suppressed palmitate-induced apoptosis. These results in IMS were well reproducible in rat primary Schwann cells, indicating that the observed phenomena are not specific to the cell line. Collectively, we have reached a conclusion that palmitate induces apoptosis in Schwann cells via both a ceramide-mediated, caspase-3-independent pathway and ceramide-independent, caspase-3-dependent pathways. Given the fact that palmitate and ceramide are increased in obese or pre-diabetic subjects, these lipids may be implicated in the pathogenesis of peripheral neuropathy observed in these disorders.


"Paper trail" for patient flow.
Two systems which can help the doctor and staff stay on track with patients are Treatment Progress Record and the Pending Treatment File. The Treatment Progress Record will allow the doctor and staff to see at a glance the date treatment was recommended, the date treatment was accepted and finally, the date treatment was completed. The Pending Treatment File serves as a "holding place" for those patients who have not yet scheduled their next appointment. Both systems were designed to help improve patient flow.


Spontaneous Muscle Hematoma in Japanese Patients with Severe COVID-19 Treated with Unfractionated Heparin: Two Case Reports.
In hospitalized coronavirus disease 2019 (COVID-19) patients, anticoagulation therapy is administered to prevent thrombosis. However, anticoagulation sometimes causes bleeding complications. We herein report two Japanese cases of severe COVID-19 in which spontaneous muscle hematomas (SMH) developed under therapeutic anticoagulation with unfractionated heparin. Although the activated partial prothrombin time was within the optimal range, contrast-enhanced computed tomography (CECT) revealed SMH in the bilateral iliopsoas muscles in both cases, which required emergent transcatheter embolization. Close monitoring of the coagulation system and the early diagnosis of bleeding complications through CECT are needed in severe COVID-19 patients treated with anticoagulants.


Bcl-2 family members in childhood acute lymphoblastic leukemia: relationships with features at presentation, in vitro and in vivo drug response and long-term clinical outcome.
We have found that, in addition to Bcl-2 and Bax, the expression levels of apoptosis inducers (Bad, Bak) and inhibitors (Bcl-xL, Mcl-1) were highly variable in blasts from 78 children with newly diagnosed acute lymphoblastic leukemia (ALL). The patients were enrolled in the national study ALL-7 of the Dutch Childhood Leukemia Study Group. In contrast to Bcl-2 that inversely correlated with %S-phase cells and WBC, and was lower in T than in B-lineage ALL, the Bcl-2 family members were not found to be associated with features at presentation. These expression levels were also compared with drug resistance in in vitro MTT (methyl-thiazol-tetrazolium) assays for prednisolone, vincristine and asparaginase in 46 children. Protein expression levels of the Bcl-2 family were not found to correlate with in vitroresistance to the individual drugs or the combined drug resistance profile. In addition, neither peripheral blast reduction after 1 week of prednisone monotherapy nor long-term disease-free interval or survival showed a correlation with protein expression. Our results indicate that the anti-proliferative function of Bcl-2 dominates its anti-apoptotic function in ALL, but neither Bcl-2 nor the Bcl-2 family members gained prognostic information in the risk-adapted protocol ALL-7.


The class II phosphoinositide 3-kinase PI3K-C2alpha is concentrated in the trans-Golgi network and present in clathrin-coated vesicles.
In recent years, a large family of phosphoinositide 3-kinase (PI3K) isozymes has been characterized and cloned. Several of these PI3K enzymes have overlapping tissue distributions and it remains unclear if and how their 3-phosphoinositide products elicit differential, intracellular effects. One possibility is that the PI3K enzymes display a restricted distribution within the cell to produce their 3-phospholipid products in specific, subcellular compartments. In the present study we characterize the subcellular distribution of the novel class II PI3K isozyme PI3K-C2alpha in several mammalian cell types. Differential centrifugation of COS-1 and U937 cells together with Western blot analysis demonstrated that PI3K-C2alpha is constitutively associated with phospholipid membranes. Centrifugation of rat brain homogenates and Western blotting revealed that in contrast to the class IA PI3K enzymes, PI3K-C2alpha could be co-purified with a population of clathrin-coated vesicles (CCVs). Furthermore, a PI3K activity refractory to wortmannin treatment was detected in CCV preparations consistent with the presence of the PI3K-C2alpha isozyme. These biochemical observations were supported by immunofluorescence analysis that revealed PI3K-C2alpha to have a punctate distribution and an enrichment of immunoreactivity within a perinuclear site consistent with its presence in the endoplasmic reticulum or Golgi apparatus. Dual label immunofluorescence demonstrated that in this region, the distribution of PI3K-C2alpha closely paralleled that of gamma-adaptin, a component of the AP-1 adaptor that is present in the trans-Golgi and the trans-Golgi network (TGN) resident protein TGN-46. Neither the phospholipid association nor the subcellular localization of PI3K-C2alpha was dependent upon either its COOH-terminal PX or C2 domains. Mutants lacking these domains demonstrated a similar distribution to the wild type enzyme when expressed as recombinant proteins. Treatment of cells with brefeldin A disrupted the perinuclear staining pattern of both PI3K-C2alpha and the AP-1 complex demonstrating that the localization of both molecules at the TGN is dependent upon ADP-ribosylation factor GTPase activity.


Disparities in the Implementation of School-Based Mental Health Supports Among K-12 Public Schools.
The authors sought to explore the availability of mental health supports within public schools during the COVID-19 pandemic by using survey data from a nationally representative sample of U.S. K-12 public schools collected in October-November 2021. The prevalence of 11 school-based mental health supports was examined within the sample (N=437 schools). Chi-square tests and adjusted logistic regression models were used to identify associations between school-level characteristics and mental health supports. School characteristics included level (elementary, middle, or high school), locale (city, town, suburb, or rural area), poverty level, having a full-time school nurse, and having a school-based health center. Universal mental health programs were more prevalent than more individualized and group-based supports (e.g., therapy groups); however, prevalence of certain mental health supports was low among schools (e.g., only 53% implemented schoolwide trauma-informed practices). Schools having middle to high levels of poverty or located in rural areas or towns and elementary schools and schools without a health infrastructure were less likely to implement mental health supports, even after analyses were adjusted for school-level characteristics. For example, compared with low-poverty schools, mid-poverty schools had lower odds of implementing prosocial skills training for students (adjusted OR [AOR]=0.49, 95% CI=0.27-0.88) and providing confidential mental health screening (AOR=0.42, 95% CI=0.22-0.79). Implementation levels of school-based mental health supports leave substantial room for improvement, and numerous disparities existed by school characteristics. Higher-poverty areas, schools in rural areas or towns, and elementary schools and schools without a health infrastructure may require assistance in ensuring equitable access to mental health supports.


Distinct responses to hypoxia in subpopulations of distal pulmonary artery cells contribute to pulmonary vascular remodeling in emphysema.
We have shown previously that hypoxia inhibits the growth of distal human pulmonary artery smooth muscle cells (PASMC) isolated under standard normoxic conditions (PASMC(norm)). By contrast, a subpopulation of PASMC, isolated through survival selection under hypoxia was found to proliferate in response to hypoxia (PASMC(hyp)). We sought to investigate the role of hypoxia-inducible factor (HIF) in these differential responses and to assess the relationship between HIF, proliferation, apoptosis, and pulmonary vascular remodeling in emphysema. PASMC were derived from lobar resections for lung cancer. Hypoxia induced apoptosis in PASMC(norm) (as assessed by TUNEL) and mRNA expression of Bax and Bcl-2, and induced proliferation in PASMC(hyp) (as assessed by (3)H-thymidine incorporation). Both observations were mimicked by dimethyloxallyl glycine, a prolyl-hydroxylase inhibitor used to stabilize HIF under normoxia. Pulmonary vascular remodeling was graded in lung samples taken from patients undergoing lung volume reduction surgery for severe heterogenous emphysema. Carbonic anhydrase IX expression in the medial compartment was used as a surrogate of medial hypoxia and HIF stabilization and increased with increasing vascular remodeling. In addition, a mixture of proliferation, assessed by proliferating-cell nuclear antigen, and apoptosis, assessed by active caspase 3 staining, were both higher in more severely remodeled vessels. Hypoxia drives apoptosis and proliferation via HIF in distinct subpopulations of distal PASMC. These differential responses may be important in the pulmonary vascular remodeling seen in emphysema and further support the key role of HIF in hypoxic pulmonary hypertension.


Measuring online and offline social rejection sensitivity in the digital age.
Social rejection sensitivity has been proposed as a central risk factor for depression. Yet, its assessment has typically been limited to offline contexts. Many of today's social interactions, however, take place online. Here, we developed a measure to assess social rejection sensitivity in both online and offline environments. Across four separate samples including a total of 2381 individuals (12-89 years), the Online and Offline Social Sensitivity Scale was shown to offer a reliable measure of social rejection sensitivity. The study provides evidence that rejection sensitivity across online and offline social environments shows a moderate to strong association with depressive symptoms and maladaptive ruminative brooding. We also found age-related differences in social rejection sensitivity in online and offline contexts with rejection sensitivity decreasing from early adolescence to older age. The scale has the potential to advance future research on the role of social rejection sensitivity in mental health in a digital age. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


[Features of the sleep/wakefulness cycle in long-term isolation].
The sleep/wakefulness cycle was the subject of polysomonographic and actographic studies in two experiments with isolation and confinement of six volunteer operators for 135 and 90 days. The dynamics of sleep structure was the target parameter before, during, and after the experiments. The sleep structure dynamics and changes in the motor activity differed in their directionality. At all the stages of experiments the operators' sleep structure had some unique peculiarities. Discussion is centered around the cases of shortened duration of delta-sleep and altered latent periods of specific stages. During the off-nominal situation (ONS) with 45 hour sleep deprivation polysomnographs recorded episodes of latent sleep which became more multiple during the second ONS and were combined with signs of "slow" sleep, and increases in the index of motor activity during night sleep post ONS. Hence, adaptation to changed physical and social environments is manifested by a specific functional restructurization of the sleep/wakefulness cycle.


Leukonychia punctata and pitted nails in alopecia areata.
A 36-year-old man with long-standing alopecia areata was noted to have both leukonychia punctata and pitted nails. Histopathologic evaluation of the leukonychia punctata revealed multiple discrete parakeratotic foci throughout the entire thickness of the nail plate, suggesting both proximal and distal matrix involvement. The finding of shallow pits lined with residual adherent parakeratotic cells suggests that the pathogenesis of nail pits in alopecia areata is similar to that of psoriasis; a result of shedding of parakeratotic cell aggregates from the nail plate.


Patient Navigator and Community Health Worker Attitudes Toward End-of-Life Care.
Background: There are racial/ethnic disparities in hospice use and end-of-life (EOL) care outcomes in the United States. Although the use of community health workers (CHWs) and patient navigators (PNs) has been suggested as a means of reducing them, CHW/PNs' attitudes toward a palliative care philosophy remain unknown. The purpose of this study was to examine how personal attributes affect a CHW/PN's attitude toward EOL care. Methods: CHWs/PNs were recruited from two state-wide organizations and invited to complete an online survey. We collected information on demographics, attitudes toward the palliative care philosophy, and comfort with caring for patients at the EOL. Results: Of the 70 CHWs/PNs who responded to the survey, 82.5% identified as female, 56.4% identified as black, and 56.2% had a four-year college degree or higher. The mean score on a validated scale to assess attitudes toward EOL care was 33.5 (SD = 4.9; possible range, 8-40). Eighty percent strongly agreed or agreed with being open to discussing death with a dying patient. Higher self-efficacy scores were associated with more favorable attitudes toward hospice (r = 0.306, p = 0.016). Conclusions: CHWs/PNs have an overall favorable attitude toward the palliative care philosophy and may be inclined to providing EOL care.


Changes in efferent pulmonary sympathetic nerve activity during systemic hypoxia in anesthetized cats.
Changes in efferent sympathetic nerve activity to the pulmonary vessels during systemic hypoxia have yet to be elucidated. The purpose of this study was to determine the pulmonary sympathetic nerve activity (PSNA) changes in response to acute systemic hypoxia before and after sinoaortic denervation plus vagotomy in anesthetized cats. The denervation was performed to estimate the central nervous system-mediated peripheral chemoreceptor- and baroreceptor-independent PSNA change. PSNA was recorded from the central end of the cut nerve bundle, which was isolated from the lobar artery supplying the diaphragmatic lobe. Renal sympathetic nerve activity (RSNA) and systemic and pulmonary arterial pressures were also measured simultaneously. The animals were submitted to approximately 3-min periods of graded hypoxia (16, 12, 8, 5, and 3% O2 inhalations). PSNA did not change from normoxia down to an arterial O2 partial pressure (PaO2) of approximately 45 Torr (with 12-21% O2 inhalations). Below this level, PSNA began to increase, and markedly so (approximately 2.5-fold) at a PaO2 of approximately 15 Torr (with 3% O2). The hypoxic PSNA increase was significantly larger than that for RSNA, with a PaO2 of less than approximately 30 Torr (with 3-8% O2). Particularly at a PaO2 of approximately 15 Torr, the magnitude of the PSNA increase was two times greater than that for RSNA. After denervation, the hypoxic PSNA increase was significantly attenuated at a PaO2 of approximately 25 to approximately 45 Torr (with 5-12% O2), but the attenuation was very small; therefore most of the PSNA increase persisted. The hypoxic RSNA increase, in contrast, was mostly abolished after denervation. The data indicate that the neural reflex effect of systemic hypoxia on PSNA is significantly greater than that on RSNA and suggest that the hypoxic PSNA increase is mostly mediated by central mechanisms, whereas that for RSNA is chiefly caused by peripheral chemoreceptors.


Antinociceptive synergy between the cannabinoid receptor agonist WIN 55,212-2 and bupivacaine in the rat formalin test.
The analgesic interaction between cannabinoids and local anesthetics has not been investigated. We sought to determine the nature of the interaction between the intrathecal cannabinoid receptor agonist (WIN 55,212-2) and bupivacaine using the formalin test. Lumbar intrathecal catheters were implanted in male Sprague-Dawley rats. After intrathecal administration of WIN 55,212-2, bupivacaine, or their combination, 50 microL of 5% formalin was injected subcutaneously into the hindpaw. Dose-response curves were established and the respective ED50 (50% effective dose) values were determined for each agent alone. Fixed-ratio combinations of WIN 55,212-2 and bupivacaine were tested for combined antinociceptive effects in the formalin test and an isobolographic analysis was performed to characterize the pharmacologic interaction of both drugs. Intrathecally administered WIN 55,212-2, bupivacaine, or their combination produced a dose-dependent decrease in the number of flinches during Phase 1 and 2 of the formalin test. Isobolographic analysis revealed a synergistic interaction between intrathecal WIN 55,212-2 and bupivacaine in both phases of the formalin test. In combination, the ED50 value was significantly smaller than the theoretical additive value (P < 0.05). These results demonstrate that intrathecally coadministered WIN 55,212-2 and bupivacaine provide synergistic antinociceptive interaction in both phases of the formalin test.


Effects of black soybean [Glycine max (L.) Merr.] seed coats and its anthocyanidins on colonic inflammation and cell proliferation in vitro and in vivo.
Anti-inflammatory and antiproliferative activities of anthocyanidins and anthocyanin-rich black soybean seed coats were studied in HT-29 human colon adenocarcinoma cells and carcinogen-treated F344 rats, respectively. Cyanidin and delphinidin significantly inhibited cell growth at concentrations of >or=1 microM. Anthocyanidins suppressed cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) mRNAs in TPA-stimulated HT-29 cells. Both yellow and black soybean seed coat supplementation (10%, w/w) did not significantly reduce the number of aberrant crypt foci (ACF), although a modest decrease in the number of ACF was observed in animals fed soybean seed coats. The colonic COX-2 mRNA level was suppressed in rats fed both soybean seed coat diet. The plasma prostaglandin E 2 (PGE 2) level was reduced only in rats fed black soybean seed coats. No difference was observed in either colonic iNOS mRNA or plasma nitric oxide level. These results indicate that anthocyanidins are possible anti-inflammatory agents; however, further studies are required to determine required intake levels in vivo to exert antitumor effect.


Screening mammography among Chinese Canadian women.
Though breast cancer is the most common malignancy among Chinese women, screening mammography is underutilized. This study examined barriers and facilitators of screening mammography among Chinese Canadian women. Using community-based sampling, Chinese women in British Columbia were interviewed in 1999 about multiple preventive health behaviours. We included 213 women in the mammography analysis; main outcome measures were ever having a mammogram and routine mammography. Seventy-five percent of women 50 to 79 years old reported ever having had a mammogram, and 53% had two or more mammograms within the last five years. Receiving a recommendation for a mammogram from medical personnel or from a family member, and believing that cancer cannot be prevented by faith were independently associated with both screening outcomes. A multifaceted approach to screening mammography promotion in Chinese Canadian women is suggested. Interventions that include education of and by medical providers and family members should be considered.


Ex Vivo and In Vivo CD46 Receptor Utilization by Species D Human Adenovirus Serotype 26 (HAdV26).
Human adenovirus serotype 26 (Ad26) is used as a gene-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and HIV-1. However, its primary receptor portfolio remains controversial, potentially including sialic acid, coxsackie and adenovirus receptor (CAR), integrins, and CD46. We and others have shown that Ad26 can use CD46, but these observations were questioned on the basis of the inability to cocrystallize Ad26 fiber with CD46. Recent work demonstrated that Ad26 binds CD46 with its hexon protein rather than its fiber. We examined the functional consequences of Ad26 for infection in vitro and in vivo. Ectopic expression of human CD46 on Chinese hamster ovary cells increased Ad26 infection significantly. Deletion of the complement control protein domain CCP1 or CCP2 or the serine-threonine-proline (STP) region of CD46 reduced infection. Comparing wild-type and sialic acid-deficient CHO cells, we show that the usage of CD46 is independent of its sialylation status. Ad26 transduction was increased in CD46 transgenic mice after intramuscular (i.m.) injection but not after intranasal (i.n.) administration. Ad26 transduction was 10-fold lower than Ad5 transduction after intratumoral (i.t.) injection of CD46-expressing tumors. Ad26 transduction of liver was 1,000-fold lower than that ofAd5 after intravenous (i.v.) injection. These data demonstrate the use of CD46 by Ad26 in certain situations but also show that the receptor has little consequence by other routes of administration. Finally, i.v. injection of high doses of Ad26 into CD46 mice induced release of liver enzymes into the bloodstream and reduced white blood cell counts but did not induce thrombocytopenia. This suggests that Ad26 virions do not induce direct clotting side effects seen during coronavirus disease 2019 (COVID-19) vaccination with this serotype of adenovirus. IMPORTANCE The human species D Ad26 is being investigated as a low-seroprevalence vector for oncolytic virotherapy and gene-based vaccination against HIV-1 and SARS-CoV-2. However, there is debate in the literature about its tropism and receptor utilization, which directly influence its efficiency for certain applications. This work was aimed at determining which receptor(s) this virus uses for infection and its role in virus biology, vaccine efficacy, and, importantly, vaccine safety.


Liposome-encapsulated doxorubicin citrate (Myocet) for treatment of recurrent epithelial ovarian cancer: a retrospective analysis.
The aim of this study was to assess the clinical activity and toxicity of liposome-encapsulated doxorubicin citrate (Myocet) in a retrospective multicenter cohort of epithelial ovarian, primary peritoneal, and tubal cancer patients. Records of patients with recurrent epithelial ovarian, primary peritoneal, and tubal cancer treated with liposome-encapsulated doxorubicin citrate (60 mg/m on day 1 of a 21-day cycle) after failure of more than one previous regimen were reviewed. Fifty-three patients were evaluated for efficacy and toxicity. The median age of the patients was 59 (range 39-73). The median follow-up was 6 months (range 1-17). One patient (1.9%) showed a complete response and 13 patients (24.5%) showed a partial response, yielding an overall response rate of 26.4% (14/53 patients). Clinical benefit was achieved in 36 patients (67.9%). The median progression-free survival (PFS) for the entire study population was 4.0 months (range 1.0-14.8). The median PFS for platinum-sensitive and platinum-resistant patients was 4.0 months (ranges 1.0-14.8 and 1.0-9.4, respectively; P=0.652). The median overall survival from the start of liposome-encapsulated doxorubicin citrate was 10.0 months. Multivariate survival analysis showed no association between the liposome-encapsulated doxorubicin citrate line of treatment or platinum sensitivity to PFS in age and BRCA status-adjusted models. Only 11.3% of patients experienced grade 3-4 hematologic toxicities, 80% grade-2 alopecia, and 50% grade-1-2 fatigue. No other grade-4 toxicities, no significant cardiac events, or hand and foot syndromes were reported. Liposome-encapsulated doxorubicin citrate was well tolerated, with a good response and high clinical benefit rate. Further evaluation in a larger prospective cohort is warranted.


Cochlear Dysfunction is not Common in Human Meningioma of the Internal Auditory Canal.
Cochlear dysfunction is not common in human meningioma of the internal auditory canal. Meningiomas arising from the cerebellopontine angle and internal auditory canal typically cause hearing loss. Cochlear dysfunction is known to contribute to sensorineural hearing loss induced by vestibular schwannoma, the most common tumor of the internal auditory canal. Detailed cochlear histopathology in meningioma has not been reported. Retrospective analysis of cochlear histopathology in five unoperated and five operated meningiomas of the internal auditory canal identified after screening human temporal bone collections from three academic medical centers. While some dysfunction of all analyzed cochlear cell types was identified, a predominant or exclusive loss of hair cells was not observed in any meningioma. Only 14.3% of temporal bones showed significantly more hair cell damage on the side of the tumor when compared with the contralateral ear; cochlear neuronal damage was more prevalent in meningiomas. The incidence of hydrops, perilymphatic precipitate, or endolymphatic precipitate was low. Substantial cochlear damage in human meningioma of the internal auditory canal is not common. This may explain the anecdotal hearing improvement observed after surgical resection of meningioma. Our findings underline the importance of developing therapeutic strategies to prevent cochlear neuronal degeneration due to tumors of the internal auditory canal.


Highly luminescent olefin-linked covalent organic frameworks.
A new olefin-linked covalent organic framework (COF) was developed using 1,3,5-triformylbenzene (TFB) and tetraethyl p-xylylenediphosphonate (TEXDP) as building blocks through a Horner-Wadsworth-Emmons reaction. By combination of the aromatic columnar ordering and high conjugation, the resulting TFB-TEXDP-COF exhibits a fluorescence quantum yield of up to 41%, which constitutes the new record value among COFs.


Transient periodic lateralised epileptiform discharges (PLEDs) following internal carotid artery stenting.
Background. Periodic lateralised epileptiform discharges (PLEDs) are EEG patterns consisting of periodic or pseudoperiodic unilateral, focal or hemispheric epileptiform discharges at a rate of 1-2 Hz. PLEDs may be triggered by acute brain injuries or systemic metabolic changes such as fever, hyperglycaemia or electrolyte imbalance and may result in disturbance of consciousness and/or neurological deficits. Case report. A 58-year-old female with a history of focal epilepsy and deep brain haematoma presented with acute change in awareness, associated with EEG evidence of PLEDs, three days after a left internal carotid artery stenting procedure. Clinical examination, laboratory testing and MRI were unchanged with respect to pre-stenting investigations. Conclusion. In this patient, PLEDs may have been triggered by local haemodynamic changes due to reperfusion after stenting in a previously damaged brain area.


Vitrectomy without face-down posturing for idiopathic macular holes.
To report the results of vitrectomy with internal limiting membrane peeling and C3F8 tamponade for macular hole without postoperative face-down posturing in 208 eyes. The study included 208 eyes on an uncontrolled retrospective review, undergoing pars plana vitrectomy with trypan blue-assisted internal limiting membrane peeling and C3F8 tamponade, without subsequent face-down posturing. All patients were followed-up at 1 day, 1 week, 3 months, and 12 months postoperatively. Biomicroscopy and optical coherence tomography were used to assess macular hole closure at 1 day, 1 week, 3 months, and 12 months postoperatively. Pre- and postoperative visual acuity by Snellen chart was compared. In 208 eyes with idiopathic macular hole, preoperative mean visual acuity was 20/200 and final visual acuity was 20/40 (P = 0.00017). Anatomic macular hole closure rate was 81.3%. In agreement with published studies, combined phacovitrectomy without face-down posturing after macular hole surgery seems effective and safe, showing anatomical improvement and favorable best-corrected visual acuity. Isolating the macula from vitreous fluid with a large long-lasting gas-fill may render postoperative posturing unnecessary. Eliminating face-down posturing may increase patient acceptance and compliance.


Evidence of Cosmic Impact at Abu Hureyra, Syria at the Younger Dryas Onset (~12.8 ka): High-temperature melting at >2200 °C.
At Abu Hureyra (AH), Syria, the 12,800-year-old Younger Dryas boundary layer (YDB) contains peak abundances in meltglass, nanodiamonds, microspherules, and charcoal. AH meltglass comprises 1.6 wt.% of bulk sediment, and crossed polarizers indicate that the meltglass is isotropic. High YDB concentrations of iridium, platinum, nickel, and cobalt suggest mixing of melted local sediment with small quantities of meteoritic material. Approximately 40% of AH glass display carbon-infused, siliceous plant imprints that laboratory experiments show formed at a minimum of 1200°-1300 °C; however, reflectance-inferred temperatures for the encapsulated carbon were lower by up to 1000 °C. Alternately, melted grains of quartz, chromferide, and magnetite in AH glass suggest exposure to minimum temperatures of 1720 °C ranging to >2200 °C. This argues against formation of AH meltglass in thatched hut fires at 1100°-1200 °C, and low values of remanent magnetism indicate the meltglass was not created by lightning. Low meltglass water content (0.02-0.05% H2O) is consistent with a formation process similar to that of tektites and inconsistent with volcanism and anthropogenesis. The wide range of evidence supports the hypothesis that a cosmic event occurred at Abu Hureyra ~12,800 years ago, coeval with impacts that deposited high-temperature meltglass, melted microspherules, and/or platinum at other YDB sites on four continents.


Morphological, Release and Antibacterial Performances of Amoxicillin-Loaded Cellulose Aerogels.
Cellulose has been widely used in the biomedical field. In this study, novel cellulose aerogels were firstly prepared in a NaOH-based solvent system by a facile casting method. Then amoxicillin was successfully loaded into cellulose aerogels with different loadings. The morphology and structure of the cellulose aerogels were characterized using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). The drug release and antibacterial activities were also evaluated. The drug release results showed that cellulose aerogels have controlled amoxicillin release performance. In vitro antibacterial assay demonstrated that the cellulose aerogels exhibited excellent antibacterial activity with the amoxicillin dose-dependent activity. Therefore, the developed cellulose aerogels display controlled release behavior and efficient antibacterial performance, thus confirming their potential for biomedical applications.


PET imaging of αvβ3 expression in cancer patients.
Imaging of αvβ3 expression in malignant diseases has been extensively studied in the last years, mainly because the level of integrin αvβ3 expression might be a surrogate parameter of angiogenic activity. Most studies have been performed using preclinical tumor models but recently first results if imaging αvβ3 expression in patients have been published. The first approach used was the radiotracer approach with tracers for positron emission tomography (PET) like [(18)F]Galacto-RGD or tracers for single photon emission computed tomography (SPECT) like [(99m)Tc]NC100692. In this article we will focus on the experimental design and methodology of PET imaging of αvβ3 expression with the tracer [(18)F]Galacto-RGD. Common difficulties and pitfalls in image acquisition and interpretation will be discussed. Finally, the performance of PET will be compared to other methods of imaging of αvβ3 expression, like magnetic resonance imaging, ultrasound, or optical imaging.


Measuring Prosodic Entrainment in Conversation: A Review and Comparison of Different Methods.
This study aims to further our understanding of prosodic entrainment and its different subtypes by analyzing a single corpus of conversations with 12 different methods and comparing the subsequent results. Entrainment on three fundamental frequency features was analyzed in a subset of recordings from the LUCID corpus (Baker & Hazan, 2011) using the following methods: global proximity, global convergence, local proximity, local convergence, local synchrony (Levitan & Hirschberg, 2011), prediction using linear mixed-effects models (Schweitzer & Lewandowski, 2013), geometric approach (Lehnert-LeHouillier, Terrazas, & Sandoval, 2020), time-aligned moving average (Kousidis et al., 2008), HYBRID method (De Looze et al., 2014), cross-recurrence quantification analysis (e.g., Fusaroli & Tylén, 2016), and windowed, lagged cross-correlation (Boker et al., 2002). We employed entrainment measures on a local timescale (i.e., on adjacent utterances), a global timescale (i.e., over larger time frames), and a time series-based timescale that is larger than adjacent utterances but smaller than entire conversations. We observed variance in results of different methods. Results suggest that each method may measure a slightly different type of entrainment. The complex implications this has for existing and future research are discussed.


Infusion rates and levels of premedication in tumescent liposuction.
Tumescent liposuction has proven to be an extremely safe and effective method of liposuction. However, the infusion of tumescent anesthesia can take 1 hour or more to complete. To document the types, dosages, and routes of administration of premedication utilized by four experienced tumescent liposuction surgeons. To determine if infusion rates for tumescent anesthesia are affected by types of premedication. Four experienced liposuction surgeons were asked to review their most recent 100 tumescent liposuction patients with respect to types and dosages of premedication and routes of administration. Data were also provided on corresponding infusion pump settings and infusion rates. Volumes of tumescent anesthesia and corresponding volumes of fat aspirated were also collected on the same 400 patients. Infusion of tumescent anesthesia could be performed more rapidly in patients who were given greater amounts of premedication. Volumes of tumescent anesthesia infused were generally two or more times the volume of fat aspirated. Patients could be infused with less premedication if slow infiltration was employed. Infusion rates for tumescent anesthesia can be increased of greater amounts of premedication are given. However, this must be balanced against the safety of the premedication.


Enhanced ER Ca2+ store filling by overexpression of SERCA2b promotes IP3-evoked puffs.
Liberation of Ca(2+) from the endoplasmic reticulum (ER) through inositol trisphosphate receptors (IP(3)R) is modulated by the ER Ca(2+) content, and overexpression of SERCA2b to accelerate Ca(2+) sequestration into the ER has been shown to potentiate the frequency and amplitude of IP(3)-evoked Ca(2+) waves in Xenopus oocytes. Here, we examined the effects of SERCA overexpression on the elementary IP(3)-evoked puffs to elucidate whether ER [Ca(2+)] may modulate IP(3)R function via luminal regulatory sites in addition to simply determining the size of the available store and electrochemical driving force for Ca(2+) release. SERCA2b and Ca(2+) permeable nicotinic plasmalemmal channels were expressed in oocytes, and hyperpolarizing pulses were delivered to induce Ca(2+) influx and thereby load ER stores. Puffs evoked by photoreleased IP(3) were significantly potentiated in terms of numbers of responding sites, frequency and amplitude following transient Ca(2+) influx in SERCA-overexpressing cells, whereas little change was evident with SERCA overexpression alone or following Ca(2+) influx in control cells not overexpressing SERCA. Intriguingly, we observed the appearance of a new population of puffs that arose after long latencies and had prolonged durations supporting the notion of luminal regulation of IP(3)R gating kinetics.


Mutation of the regulatory phosphorylation site of tobacco nitrate reductase results in constitutive activation of the enzyme in vivo and nitrite accumulation.
In wild-type Nicotiana plumbaginifolia and other higher plants, nitrate reductase (NR) is rapidly inactivated/activated in response to dark/light transitions. Inactivation of NR is believed to be caused by phosphorylation at a special conserved regulatory Ser residue, Ser 521, and interactions with divalent cations and inhibitory 14-3-3 proteins. A transgenic N. plumbaginifolia line (S(521)) was constructed where the Ser 521 had been changed by site-directed mutagenesis into Asp. This mutation resulted in complete abolishment of inactivation in response to light/dark transitions or other treatments known to inactivate NR. During prolonged darkness, NR in wild-type plants is in the inactivated form, whereas NR in the S(521) line is always in the active form. Differences in degradation rate between NR from S(521) and lines with non-mutated NR were not found. Kinetic constants like Km values for NADH and NO3(-) were not changed, but a slightly different pH profile was observed for mutated NR as opposed to non-mutated NR. Under optimal growth conditions, the phenotype of the S(521) plants was not different from the wild type (WT). However, when plants were irrigated with high nitrate concentration, 150 mM, the transgenic plants accumulated nitrite in darkness, and young leaves showed chlorosis.


Experimental metastasis correlates with cyclic AMP accumulation in B16 melanoma clones.
Metastasis is a complex process whereby tumour cells from a primary neoplastic growth disseminate throughout the body and establish secondary tumour foci in distant organs. Biochemical traits associated with, or essential for, the expression of the metastatic phenotype have not yet been identified. In the course of examining stimulation of the B16 murine melanoma adenylate cyclase by melanocyte-stimulating hormone (MSH) and by the diterpene forskolin, we noted that tumour cell clones isolated from common parent cell populations differed widely in their responses to these agonists. We report here that the accumulation of cyclic AMP induced by MSH or forskolin shows a strong positive correlation with the ability of B16 melanoma clones to form pulmonary tumour colonies when injected intravenously (i.v.) into syngeneic mice ('experimental metastasis'). In parallel in vitro analyses of cyclic AMP metabolism and in vivo assays of experimental metastasis using replicate cell preparations, highly metastatic tumour cell clones consistently show greater than a 30-fold increase in cellular cyclic AMP when exposed to MSH or forskolin. By contrast, clones with limited metastatic abilities respond to the same agonists with only a two- to threefold increase in cellular cyclic AMP. These data suggest that cyclic AMP metabolism is linked with biochemical pathways that are responsible for the formation of experimental metastasis by the B16 melanoma.


Effects of tobacco exposure on lung health and pulmonary biomarkers in young, healthy smokers aged 12-25 years: a systematic review.
Chronic obstructive pulmonary disease (COPD) is associated with high personal and societal burden and mortality. COPD is usually diagnosed during middle or late adult life, but the starting point for a 'COPD career' may be found earlier in life, during adolescence: first, because of smoking initiation and subsequent accumulation of risk, and second, because of the adverse effects of cigarette smoking on lung-function development. The objective of this paper is to systematically review the literature on the effects of active smoking on lung health in 12-25-year-old healthy boys and girls, measured with simple and noninvasive methods: lung function by spirometry, exhaled gases (including nitric oxide, carbon monoxide and hydrocarbons) and exhaled breath condensate. The identification of biomarkers may be useful for early detection of tobacco-related respiratory disease in this population, for targeted smoking prevention or smoking-cessation programs and, in the long term, for a reduction of personal and societal impact of COPD and other smoking-related diseases.


[Effect of metformin addition to an acute lymphoblastic leukemia chemotherapy treatment].
Recently it has been reported a benefit effect with the use of metformin in patients with malignant disease. Our objective was to evaluate the effect of adding metformin to chemotherapy regimen over the percentage of early relapse in acute lymphoblastic leukemia. A prospective, longitudinal and experimental study was performed in patients with de novo acute lymphoblastic leukemia enrolled in the Hospital General de México. They were divided in two groups: first group received chemotherapy + metformin (850 mg three times a day); second group only received standard chemotherapy. The sample was randomized 3:1 in favor of the second group. 93 patients were included (73 treated with chemotherapy + metformin and 20 received standard chemotherapy), with 303 ± 53 days of follow-up. Complete remission was higher in the group without metformin (81.3 % [n = 61] versus 70 % [n = 14]), which also presented more patients with relapse (47.9 % versus 25 %). Overall survival at one year was of 68 % and free survival disease was 64 %, without significant differences between groups. Absence of metformin was the only variable of adverse prognostic considered significant (p = 0.55). Cox regression showed that adding metfomin reduced 56 % the risk of relapse. The adding metformin to the treatment of leukemias showed that was useful in our research. However, randomized and double-blind studies must be designed in order to express final recommendations about its use.


Inhibition of the NOD-Like Receptor Protein 3 Inflammasome Is Protective in Juvenile Influenza A Virus Infection.
Influenza A virus (IAV) is a significant cause of life-threatening lower respiratory tract infections in children. Antiviral therapy is the mainstay of treatment, but its effectiveness in this age group has been questioned. In addition, damage inflicted on the lungs by the immune response to the virus may be as important to the development of severe lung injury during IAV infection as the cytotoxic effects of the virus itself. A crucial step in the immune response to IAV is activation of the NOD-like receptor protein 3 (NLRP3) inflammasome and the subsequent secretion of the inflammatory cytokines, interleukin-1β (IL-1β), and interleukin-18 (IL-18). The IAV matrix 2 proton channel (M2) has been shown to be an important activator of the NLRP3 inflammasome during IAV infection. We sought to interrupt this ion channel-mediated activation of the NLRP3 inflammasome through inhibition of NLRP3 or the cytokine downstream from its activation, IL-1β. Using our juvenile mouse model of IAV infection, we show that inhibition of the NLRP3 inflammasome with the small molecule inhibitor, MCC950, beginning 3 days after infection with IAV, improves survival in juvenile mice. Treatment with MCC950 reduces NLRP3 levels in lung homogenates, decreases IL-18 secretion into the alveolar space, and inhibits NLRP3 inflammasome activation in alveolar macrophages. Importantly, inhibition of the NLRP3 inflammasome with MCC950 does not impair viral clearance. In contrast, inhibition of IL-1β signaling with the IL-1 receptor antagonist, anakinra, is insufficient to protect juvenile mice from IAV. Our findings suggest that targeting the NLRP3 inflammasome in juvenile IAV infection may improve disease outcomes in this age group.


Psychological testing in the workplace.
Describing psychological testing as a controlled observation of human mental functioning through behavior, this chapter examines the variety, settings, and advantages and limitations of psychological tests commonly used in the work setting. Types of tests considered include achievement tests, aptitude tests, and personality and psychological functioning assessments.


Opening the black box of selection.
Medical school selection is currently in the paradoxical situation in which selection tools may predict study outcomes, but which constructs are actually doing the predicting is unknown (the 'black box of selection'). Therefore, our research focused on those constructs, answering the question: do the internal structures of the tests in an outcome-based selection procedure reflect the content that was intended to be measured? Downing's validity framework was applied to organize evidence for construct validity, focusing on evidence related to content and internal structure. The applied selection procedure was a multi-tool, CanMEDS-based procedure comprised of a video-based situational judgement test (focused on (inter)personal competencies), and a written aptitude test (reflecting a broader array of CanMEDS competencies). First, we examined content-related evidence pertaining to the creation and application of the competency-based selection blueprint and found that the set-up of the selection procedure was a robust, transparent and replicable process. Second, the internal structure of the selection tests was investigated by connecting applicants' performance on the selection tests to the predetermined blueprint using cognitive diagnostic modeling. The data indicate 89% overlap between the expected and measured constructs. Our results support the notion that the focus placed on creating the right content and following a competency-blueprint was effective in terms of internal structure: most items measured what they were intended to measure. This way of linking a predetermined blueprint to the applicants' results sheds light into the 'black box of selection' and can be used to support the construct validity of selection procedures.


The critical role of hemodynamics in the development of cerebral vascular disease.
Atherosclerosis and intracranial saccular aneurysms predictably localize in areas with complex arterial geometries such as bifurcations and curvatures. These sites are characterized by unique hemodynamic conditions that possibly influence the risk for these disorders. One hemodynamic parameter in particular has emerged as a key regulator of vascular biology--wall shear stress (WSS). Variations in geometry can change the distribution and magnitude of WSS, thus influencing the risk for vascular disorders. Computer simulations conducted using patient-specific data have suggested that departures from normal levels of WSS lead to aneurysm formation and progression. In addition, multiple studies indicate that disturbed flow and low WSS predispose patients to extracranial atherosclerosis, and particularly to carotid artery disease. Conversely, in the case of intracranial atherosclerosis, more studies are needed to provide a firm link between hemodynamics and atherogenesis. The recognition of WSS as an important factor in cerebral vascular disease may help to identify individuals at risk and guide treatment options.


Fitness of cell-mediated immunity independent of repertoire diversity.
Fitness of cell-mediated immunity is thought to depend on TCR diversity; however, this concept has not been tested formally. We tested the concept using JH(-/-) mice that lack B cells and have TCR Vbeta diversity <1% that of wild-type mice and quasimonoclonal (QM) mice with oligoclonal B cells and TCR Vbeta diversity 7% that of wild-type mice. Despite having a TCR repertoire contracted >99% and defective lymphoid organogenesis, JH(-/-) mice rejected H-Y-incompatible skin grafts as rapidly as wild-type mice. JH(-/-) mice exhibited T cell priming by peptide and delayed-type hypersensitivity, although these responses were less than normal owing either to TCR repertoire contraction or defective lymphoid organogenesis. QM mice with TCR diversity contracted >90%, and normal lymphoid organs rejected H-Y incompatible skin grafts as rapidly as wild type mice and exhibited normal T cell priming and normal delayed-type hypersensitivity reactions. QM mice also resisted Pneumocystis murina like wild-type mice. Thus, cell-mediated immunity can function normally despite contractions of TCR diversity >90% and possibly >99%.


Vasculitis in cytomegalovirus infection.
A 7-year-old girl had fever, arthralgia, and a mild cutaneous vaculitis with papules, nodules, and livedo. A biopsy specimen of a papule showed lymphocytic small-vessel vasculitis, with some atypical lymphocytic nuclei. Splenomegaly developed, and results of subsequent studies supported a diagnosis of cytomegalovirus (CMV) infection, with atypical peripheral blood lymphocytes and a characteristic pattern of complement-fixing antibodies to CMV antigen. The CMV mononucleosis syndrome is rarely reported in children, and the cutaneous manifestations are usually rubelliform. Distinctive cutaneous pathologic characteristics have been described previously only in neonates ("blueberry muffin" syndrome) and in immunosuppressed patients (viral inclusion bodies in endothelial cells).


Intermittent preventive therapy for malaria: progress and future directions.
This review summarizes recent evidence regarding the efficacy of intermittent preventive treatment with focus on infancy (IPTi) and the rationale behind such a control strategy. Pooled safety and efficacy analyses of all six trials of IPTi with sulfadoxine-pyrimethamine conducted between 1999 and 2007 have demonstrated a 30% protective efficacy against clinical malaria, a 24% protective efficacy against all-cause hospital admissions, a 37% protective efficacy against malaria-related hospital admissions, and a 15% protective efficacy against anemia, all in the first year of life. Rebound in malaria following discontinuation of the intervention has not been noted in pooled analyses of the IPTi trials. Given the efficacy, excellent safety and tolerability of the intervention and the fact that it is inexpensive and easily deliverable if linked to the Expanded Programme on Immunization, IPTi-sulfadoxine-pyrimethamine appears to add a valuable tool to the malaria-control armamentarium in endemic areas of Africa. Routine monitoring of sulfadoxine-pyrimethamine efficacy will be required to guide future IPTi programme implementation. Variations of IPTi that target older children may be required for areas of Africa with highly seasonal malaria transmission.


Components of change in the evolution of learning and unlearned preference.
Several phenomena in animal learning seem to call for evolutionary explanations, such as patterns of what animals learn and do not learn. While several models consider how evolution should influence learning, we have very little data testing these models. Theorists agree that environmental change is a central factor in the evolution of learning. We describe a mathematical model and an experiment, testing two components of change: reliability of experience and predictability of the best action. Using replicate populations of Drosophila we varied statistical patterns of change across 30 generations. Our results provide the first experimental demonstration that some types of environmental change favour learning while others select against it, giving the first experimental support for a more nuanced interpretation of the selective factors influencing the evolution of learning.


Phase separation of mixed polymer brushes on surfaces with nonuniform curvature.
Using numerical simulations and a simple scaling theory, we study the microphase separation of a mixture of polymer brushes with different chain lengths tethered to surfaces with nonuniform curvature. We measure the free energy difference of the phase separated configurations as a function of spheroid eccentricity and ordering of the microdomains formed on them. We find that there is a preference for the longer chains to locate in high curvature regions, and identify and quantify the driving forces associated with this phenomenon. We also find that nonuniform curvature typically limits the number of striped domains that would normally form on a spherical surface under identical physical conditions. Finally, we generalize the scaling theory developed for brushes on spherical surfaces to include prolate and oblate spheroids, and show explicitly that while immiscibility between the chains is required for phase separation to occur on spheroids, it is unnecessary for certain surfaces with regions of positive and negative curvature. We present a phase diagram showing the conditions under which curvature-driven phase separation of miscible, but lengthwise asymmetric chains is expected to occur.


Analysis of human mitochondrial transcripts using electron microscopic in situ hybridization.
Human mitochondrial transcripts have been examined at the ultrastructural level. After contact with ultrathin sections of a human lymphoid cell line (CEM) embedded in Lowicryl K4M, biotinylated mitochondrial probes yield specific hybrids identified by a colloidal gold immunocytochemistry marker that visualizes rRNA and mRNA coding for respiratory chain polypeptides CO II, CO III and ATPase-6. The mitochondrial transcripts are preferentially located close to the inner membrane, particularly the cristae, suggesting that intra-organelle protein synthesis is intimately associated with the mitochondrial membrane system. Quantitative analysis indicates that the mitochondria concentrate the labeling with intensities that vary with the type of RNA and that the nucleus induces a light hybridization signal with each mitochondrial probe. The visualization of human mitochondrial DNA expression in correlation with the fine anatomy of the mitochondria constitutes a new approach for fundamental research on the organelle and for analyzing its behaviour in human mitochondrial diseases.


Nitric oxide synthase does not participate in negative inotropic effect of acetylcholine in frog heart.
In the heart, the parasympathetic neurotransmitter acetylcholine (ACh) reduces the force of contraction. Although the effect of ACh can be partly explained by an inhibition of adenylyl cyclase, some of the effects of ACh may also be mediated via stimulation of nitric oxide synthase (NOS) and production of guanosine 3', 5'-cycle monophosphate (cGMP). NOS inhibitors can prevent the negative chronotropic effect of ACh on spontaneously beating cardiomyocytes and suppress the inhibition of the L-type calcium current (ICa) by ACh in sinoatrial myocytes. This pathway may be relevant not only to the chronotropic effect of ACh but also to its inotropic effect, because ACh, NO, and cGMP regulate the force of contraction and ICa in the cardiac ventricle. Here we report the effects of L-arginine (L-Arg), the substrate of NOS, and NG-monomethyl-L-arginine (L-NMMA) and NG-nitro-L-arginine (L-NNA), two NOS inhibitors, on muscarinic effects in the cardiac ventricle. We found that L-Arg, L-NMMA, and L-NNA have no effect on the muscarinic inhibition of ICa in isolated frog myocytes. In addition, these compounds have no significant effects on basal ICa or beta-adrenergic stimulation of ICa. L-Arg and its analogues did not change the negative inotropic effect of ACh in frog ventricular fibers. Basal active tension and the positive inotropic effect of isoproterenol, a beta-adrenergic agonist, also were unaffected. We conclude that NOS in not involved in muscarinic inhibition of ICa in isolated from ventricular myocytes or the negative inotropic effect of ACh in the frog ventricle.


Clinical implications of the infratentorial rosette-forming glioneuronal tumor: case report.
This article describes our experience with two patients who presented with unusual tumors in the cerebellar vermis and cerebral aqueduct. Although sparing the fourth ventricle proper, both tumors had histological features consistent with the rare diagnosis of a rosette-forming glioneuronal tumor of the fourth ventricle, of which only 19 cases have been reported previously. A review of the clinical features and courses of all 21 cases is presented and management recommendations are given. Patient 1 was a 42-year-old man who presented with a headache of 1 day's duration and no neurological signs, in whom magnetic resonance imaging disclosed a nonenhancing mass lesion occupying the proximal cerebral aqueduct. Patient 2 was a 38-year-old woman with a long history of intermittent giddiness, no neurological signs, and a magnetic resonance imaging scan that demonstrated a nonenhancing and subtle abnormality in the cerebellar vermis. Biopsy was performed on both lesions, the first endoscopically and the second via craniotomy. The only postoperative complication was short-lived double vision and poor upgaze in Patient 1. These cases demonstrate that the rosette-forming glioneuronal tumor may be more accurately categorized as an infratentorial tumor rather than a tumor of the fourth ventricle. Because the literature indicates that this is a tumor with little potential for malignant behavior and considerable morbidity can accompany attempts at resection, a conservative management approach would seem well advised. If this tumor is to be managed conservatively, because of the paucity of extended follow-up data, long-term radiological and clinical surveillance is strongly recommended.


Breath tests for determining alcohol in the blood.
The "drunk driver" represents one social problem that medicine and the exact sciences have been asked to help solve. Once the decision to employ the criminal justice system for that purpose was made, they were asked to provide both a more precise measure of intoxication, in order that criminal sanctions might be brought into play, and means of determining that measure in individual defendants. The use of breath tests in the courtroom to determine alcohol in the blood, along with evidence of related scientific issues, thus serves well to illustrate the mechanisms by which these scientific contributions may enter into the social scheme.


Applied neuroanatomy elective to reinforce and promote engagement with neurosensory pathways using interactive and artistic activities.
One in six Americans is currently affected by neurologic disease. As the United States population ages, the number of neurologic complaints is expected to increase. Thus, there is a pressing need for more neurologists as well as more neurology training in other specialties. Often interest in neurology begins during medical school, so improving education in medical neural courses is a critical step toward producing more neurologists and better neurology training in other specialists. To this end, a novel applied neuroanatomy elective was designed at the University of Texas Health Science Center at San Antonio (UTHSCSA) to complement the traditional first-year medical neuroscience course and promote engagement and deep learning of the material with a focus on neurosensory pathways. The elective covered four neurosensory modalities (proprioception/balance, vision, auditory, and taste/olfaction) over four sessions, each with a short classroom component and a much longer activity component. At each session, students reviewed the neurosensory pathways through structured presentations and then applied them to preplanned interactive activities, many of which allowed students to utilize their artistic talents. Students were required to complete subjective pre-course and post-course surveys and reflections. The survey results and positive student comments suggest that the elective was a valuable tool when used in parallel with the traditional medical neuroscience course in promoting engagement and reinforcement of the neurosensory material.


Numerical simulations of scattering in a two-photon optical data storage system.
Scattering effects in a two-photon optical data storage system are numerically studied. Surface scattering analysis with a scalar, beam propagation model is performed. We analyze the problem by modeling scattering from randomly varying surfaces and also by Fourier surface decomposition. Scattering induced by propagation through multiple pages of randomly recorded data marks is also studied with a hybrid finite-difference-time-domain/angular-spectrum model. Both surface and bulk scattering are shown to influence the spatial properties of the optical beam. Results and some possible implications are presented.