Prospective study of healthcare utilisation and respiratory morbidity due to RSV infection in prematurely born infants.
A study was undertaken to determine the impact of respiratory syncytial virus (RSV) infection, both in hospital and the community, on healthcare utilisation and respiratory morbidity in prematurely born infants and to identify risk factors for symptomatic RSV infection. A hospital and community follow up study was undertaken of 126 infants born before 32 weeks of gestational age. Healthcare utilisation (hospital admissions and general practitioner attendances) in the first year, respiratory morbidity at follow up (wheeze and cough documented by parent completed diary cards), and RSV positive lower respiratory tract infections (LRTIs) were documented. Nasopharyngeal aspirates were obtained for immunofluorescence and culture for RSV whenever the infants had an LRTI, either in the community or in hospital. Forty two infants had an RSV positive LRTI (RSV group), 50 had an RSV negative LRTI (RSV negative LRTI group), and 32 infants had no LRTI (no LRTI group). Compared with the RSV negative LRTI and the no LRTI groups, the RSV group required more admissions (p=0.392, p<0.001) and days in hospital (p=0.049, p=0.006) and had more cough (p=0.05, p=0.038) and wheeze (p=0.003, p=0.003) at follow up. Significant risk factors for symptomatic RSV LRTI were number of siblings (p=0.035) and maternal smoking in pregnancy (p=0.005), for cough were number of siblings (p=0.002) and RSV LRTI (p=0.02), and for wheeze was RSV LRTI (p=0.019). RSV infection, even if hospital admission is not required, is associated with increased subsequent respiratory morbidity in prematurely born infants.


Drug residues in syringes and other injecting paraphernalia in Hungary.
The appearance and spread of new psychoactive substances (NPS) is a phenomenon seen throughout Europe since 2008. Synthetic cathinones, a group of NPS, have been self-reported as the drug injected by the vast majority of people who inject drugs (PWID) in Hungary. This study aims at updating our knowledge of what exactly are the compounds injected by PWID. This multi-site study analysed residues from used injecting drug paraphernalia collected from PWID via low-threshold services and from public places in Budapest, Debrecen, Miskolc, Szeged, Békéscsaba and Pécs between March 2015 and February 2016. The paper describes the results of the chemical analysis of 2985 analytical samples created out of the 22 005 objects collected in this period. Active agents and their occurrences (compound cases) were identified using GC-MS. The study detected 161 different compounds, mostly synthetic cathinones (29%), non-psychoactive compounds (14%), amines (12%), non-psychoactive medications (12%) and other substances (32%). Of the 12 762 compound cases, 50% were cathinones, 18% substitution medications, 9% non-controlled psychoactive substances and 24% other substances. Among compound cases, the most frequent cathinones were pentedrone (21%) and α-PHP (12%). Among substitution medications, most were methadone (93%), and non-controlled psychoactive substances were caffeine (74%) and nicotine (21%). Overall, the most prevalent substances were methadone (16%), pentedrone (10%) and caffeine (7%) with considerable variation detected among participating cities. Our results are consistent with previous self-reported data showing a high prevalence of synthetic cathinone injection among PWID in Hungary. We also detected a large-scale misuse of methadone by PWID.


Increased numbers of opioid expressing inflammatory cells do not affect intra-articular morphine analgesia.
Both locally expressed beta-endorphin (END) and low doses of morphine relieve pain within inflamed knee joints. Here we examined whether enhanced inflammation and END expression within the synovial tissue of patients undergoing arthroscopic knee surgery might shift the analgesic dose-response curve of intra-articular (i.a.) morphine. Following IRB approval and informed consent, patients were randomly assigned to the following i.a. treatments at the end of surgery: group I (n=39), isotonic saline; group II (n=40), 1 mg morphine hydrochloride; group III (n=48), 2 mg morphine hydrochloride; group IV (n=39), 4 mg morphine hydrochloride. Postoperative pain intensity was assessed by the visual analogue scale (VAS), by the time to first analgesic request and by the supplemental piritramide consumption. Synovial specimens from each patient were stained for the presence of inflammatory cells and END and were discriminated into groups with low versus high numbers of these cells. Differences between groups were statistically analyzed by chi(2), anova and mancova where appropiate. Patient characteristics and VAS scores did not differ between groups. Total postoperative piritramide consumption decreased and the time to first analgesic request increased significantly with increasing doses of i.a. morphine (P<0.05, anova and linear regression). These dose-response relationships were not different between patients with low versus high numbers of inflammatory and END-containing synovial cells (P>0.05, mancova). The dose-response relationship of i.a. morphine analgesia is not shifted by enhanced inflammation and END expression within synovial tissue. Thus, the presence of END within inflamed synovial tissue does not seem to interfere with i.a. morphine analgesia.


Management of occupational back injuries: differences among African Americans and Caucasians.
This study examined differences in the case management of occupational low back injuries in a large, racially diverse population of Workers' Compensation claimants in Missouri. Participants were African Americans (N=580) and non-Hispanic whites (N=892) who had filed occupational injury claims that were settled over an 18-month period. Telephone interview data were gathered regarding diagnoses, legal representation, demographics, and socioeconomic status. The Missouri Division of Workers' Compensation also provided information on medical and temporary disability expenditures, claim duration, final disability ratings, and settlement awards. Simultaneous-entry, hierarchical multiple and logistic regression analyses showed significant and substantial effects for injury-related variables, socioeconomic status, and race across all Workers' Compensation variables. Differences remained for both injury and African Americans and lower socioeconomic status workers after controlling for injury, and for African Americans after controlling for both injury and socioeconomic status. Because Workers' Compensation mandates equal access to treatment and disability reimbursement for all injured workers, the differences observed in this study may reflect sociocultural biases in disability management among healthcare providers.


Digestion of native proteins for proteomics using a thermocycler.
Efficient protein digestion is a critical step for successful mass spectrometry analysis. Here we describe simultaneous tryptic digestion and gradual unfolding of native proteins by application of a temperature gradient using a single cycle of 5 min or less in a PCR thermocycler. Chemicals typically used for chromatographic techniques did not affect the digestion efficiency. Tryptic digestion was performed in a small volume (3 microL) with 1.5 microg of trypsin without denaturing agents. This rapid procedure yielded more peptides than conventional methods utilizing chemical denaturation for 18 proteins out of 20. Samples were directly spotted on the MALDI-TOF target plate, without additional purification, thus reducing losses on reversed-phase resins.


[A preliminary study of the influence of different consonants on the vowel in normal people].
To study the influence of different consonants on the vowel in normal people for guiding research and treatment of cleft palate misarticulations. 35 normal students including 15 males and 20 females were selected for this study. The average age was 20.43 year. The six test syllables were divided into three groups: /si/-/ji/, /bo/-/po/ and /jü/-/qü/. The measured indexes of vowel, which were input into CSL4400, were duration (Dur), pitch, the first three formants (F1, F2, F3) and energy (E). The acoustic features of the vowel of each group were compared by SPSS software with Paired t test. Dur of the vowel was 0.39+/-0.08 in /si/ and 0.31+/-0.07 in /ji/, F2 of the vowel was 2093.55+/-350.62 in /si/ and 2454.33+/-422.00 in /ji/, there was significant difference in Dur and F2 between the vowels of /si/-/ji/ (P<0.01); Dur of the vowel was 0.35+/-0.09 in /bo/ and 0.53+/-0.07 in /po/, E of the vowel was 64.11+/-4.58 in /bo/ and 69.94+/-3.59 in /po/, there was significant difference in Dur and E between the vowels of /bo/-/po/ (P<0.01); Dur of the vowel was 0.29+/-0.07 in /jü/ and 0.35+/-0.09 in /qü/, F3 of the vowel was 3180.30+/-301.72 in /jü/ and 2901.06+/-259.75 in /qü/, E of the vowel was 68.99+/-4.59 in /jü/ and 71.70+/-5.21 in /qü/, there was significant difference in Dur, E and F3 between the vowels of /jü/-/qü/ (P<0.05). It is suggested that the aspiration of the consonant, the part and the extent of the block of the consonant could affect the next vowel, but couldn't change its quality.


Psychotropic drug use in a representative community sample: the Upper Bavarian study.
A sample of 1979 community residents aged 15 years and above was assessed in a major survey of health status and consumption of psychotropic medication. Interviews were conducted in the subjects' home by a psychiatrically trained physician, who actually inspected the subjects' medical supplies. Of all subjects 6.9% (4.3% of the males and 9.0% of the females) had used a drug containing a benzodiazepine at least once in the 4 weeks preceding the interview. In the same period 3.6% had taken a medication containing a barbiturate, 2.2% a medicine containing an opioid (mainly codeine), 1.8% had taken a neuroleptic drug, 1.5% an antidepressant, 0.8% a carbamine-acid derivative and 0.1% lithium. High use of psychotropic medication was associated with higher age, female sex, higher psychiatric morbidity, higher somatic morbidity, reduced work capacity and higher neuroticism but not with social class and not with the personality factor extra- or introversion.


Medication utilization problems among the elderly.
The improper use of medication can frequently threaten the health and well-being of elderly persons. This article alerts social work practitioners to the possible dangers of drug utilization among the elderly and explains the factors commonly associated with the inappropriate use of drugs.


CXCR4 and a cell-extrinsic mechanism control immature B lymphocyte egress from bone marrow.
Leukocyte residence in lymphoid organs is controlled by a balance between retention and egress-promoting chemoattractants sensed by pertussis toxin (PTX)-sensitive Gαi protein-coupled receptors (GPCRs). Here, we use two-photon intravital microscopy to show that immature B cell retention within bone marrow (BM) was strictly dependent on amoeboid motility mediated by CXCR4 and CXCL12 and by α4β1 integrin-mediated adhesion to VCAM-1. However, B lineage cell egress from BM is independent of PTX-sensitive GPCR signaling. B lineage cells expressing PTX rapidly exited BM even though their motility within BM parenchyma was significantly reduced. Our experiments reveal that when immature B cells are near BM sinusoids their motility is reduced, their morphology is predominantly rounded, and cells reverse transmigrate across sinusoidal endothelium in a largely nonamoeboid manner. Immature B cell egress from BM was dependent on a twofold CXCR4 down-regulation that was antagonized by antigen-induced BCR signaling. This passive mode of cell egress from BM also contributes significantly to the export of other hematopoietic cells, including granulocytes, monocytes, and NK cells, and is reminiscent of erythrocyte egress.


Psychometrics of the Drinker Inventory of Consequences (DrInC).
The Drinker Inventory of Consequences (DrInC) was developed for Project MATCH to assess the consequences of drinking in five domains. The present study, using baseline data from the 1382 participants involved in the COMBINE Study, analyzed the psychometrics of the 50-item DrInC and its shorter form, the 15-item SIP. Findings indicate the DrInC is reliable, valid, and clinically useful and that DrInC subscales are internally consistent and non-redundant. In an examination of the shorter version of the DrInC, findings suggest that the SIP is suitable when assessing the overall level of drinking-related consequences.


Neurodevelopmental implications of "deformational" plagiocephaly.
Over the past decade there has been a dramatic increase in referrals to specialty clinics, craniofacial centers, plastic surgeons, and neurosurgeons for assessment and treatment of deformational plagiocephaly (DP). Though considered a medically benign condition, preliminary reports suggest that DP may be associated with developmental problems. However, mechanisms to account for this association have not been hypothesized or empirically tested. Although treatment justifications often center on prevention of atypical appearance, little is known about the cosmetic outcomes of treated and untreated children. In this review we hypothesize different etiological pathways linking DP with neurodevelopment (e.g., environmental positioning limitations with and without underlying CNS pathology). We outline directions for research on incidence and prevalence, developmental outcomes, sex differences, determinants of treatment participation, and craniofacial appearance. Despite the paucity of existing research, preliminary findings suggest that children with this condition should be screened and monitored for developmental delays or deficits, as we await more conclusive information from future studies.


Outcomes for children with deaf-blindness with cochlear implants: a multisite observational study.
Children with dual sensory impairments are receiving cochlear implants; however, little is known regarding their language outcomes. Children between the ages of 6 months and 8 years with dual sensory impairment and cochlear implant(s) were recruited from across the United States to participate in an evaluation of language skills using the Reynell-Zinkin Developmental Scales, a tool validated on children with vision impairment and adapted for children with hearing loss. Basic demographic information was also collected from care givers. Ninety-one children completed assessments after implantation. For receptive language abilities, 32% of children obtained a level of sound detection, 15% obtained the ability to understand simple words, 21% could identify words, 5% could follow simple directions, and 22% could follow directions related to the functional use of objects. Four children had no response to sound after cochlear implantation. For expressive language abilities, 49% only had sound production skills, 9% could jargon, 18% could communicate with some words, 12% could communicate with simple sentences, and 12% could communicate with complex sentences. Children with lower developmental ages (or quotients) tended to obtain lower level expressive language skills such as sound production and jargoning. Developmental abilities, rather than age at implant, were the most robust predictor associated with outcomes. This information can guide cochlear implant centers when discussing outcomes with families in the cochlear implant candidacy process. There is great heterogeneity in outcomes and caution should be used in discussing possible language outcomes for children with dual sensory impairments.


[Adjuvant therapy in lymph node positive prostate carcinoma?].
Few patients with prostate cancer metastatic to the lymphnodes can be cured by radiotherapy, radical prostatectomy or androgen deprivation. Inevitably serum PSA levels will rise after a few years whereas the clinical recurrence appears after 5 to 10 years. Prospective trials regarding adjuvant treatment of lymphnode positive prostate cancer do not exist. Retrospective studies involving adjuvant endocrine treatment reveal a prolonged disease free survival time. Scientific proof of the best treatment for prostate cancer with lymphnode metastasis does not exist. The decision how to treat is based on our personal experience and philosophy as well as on our knowledge and interpretation of the available literature. The art of medicine is the feeling for the best treatment of each individual patient.


The effect of rat bone marrow derived mesenchymal stem cells transplantation for restoration of olfactory disorder.
The purpose of the study was to investigate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) transplantation on olfactory epithelium (OE) of morphologic and functional restoration following neural Sensorineural Disorder in rats. Except the Normal group, twenty-one rats underwent Triton X-100 (TX-100) irrigation to induce degeneration of OE, and then BMSCs and PBS were treated from the both medial canthus to the rear part of the both nasal cavity into the experimental group and then were observed for restoration according to time point. At two and four weeks after transplantation with BMSCs, restoration of OE was observed with olfactory marker protein (OMP) and behavioral test. And we observed the expression of OMP, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). After TX-100 irrigation, the OE almost disappeared in 3 days. At four weeks after transplantation with BMSCs, the thickness and cellular composition of OE was considerably restored to normal group and expression of OMP was markedly increased when compared with PBS group and reduced the searching time in the behavioral test. Furthermore at two weeks after treatment with BMSCs, expression of NGF and BDNF was greatly increased when compared with PBS group. However at four weeks after treatment with BMSCs, expression of NGF and BDNF was slightly decreased. Our results suggest the BMSCs transplantation affect restoration of OE and olfaction, most likely via regulation of the neurotrophic factor expression, especially the expression of NGF and BDNF and has a possibility of a new therapeutic strategy for the treatment of olfactory disorder caused by the degeneration of OE.


Intraventricular haemorrhage and periventricular leukomalacia in Nigerian infants of very low birth weight.
Transfontanelle ultrasound scans were performed on 93 very low birth weight neonates admitted at the University of Ilorin Teaching Hospital (UITH), Ilorin, Nigeria, between January 1992 and April 1994, to ascertain the pattern and determinants of intraventricular haemorrhage and periventricular leukomalacia. Forty-seven percent of the infants had normal ultrasound; 22% had mild intraventricular haemorrhage (IVH), 7.5% had moderate to severe IVH and 23% had periventricular leukomalacia (PVL) and a 3.5 fold increase in IVH. Infants with apgar scores < or = 3 at 5 minutes had a 6-fold increase in IVH and 2-fold increase in PVL. There was no association with birth weight, gestational age, respiratory distress and place of delivery. Our study suggests that antepartum events proximate to delivery and the immediate post partum events play significant roles in the development of IVH and PVL in this population. Improvement in antenatal, labour and delivery, and immediate newborn care; including provision of basic resuscitation equipment and skills to midwives in the rural maternity centers will reduce the incidence and severity of IVH and PVL.


Single-cell landscape and spatial transcriptomic analysis reveals macrophage infiltration and glycolytic metabolism in kidney renal clear cell carcinoma.
The present study investigates the clinical relevance of glycolytic factors, specifically PGAM1, in the tumor microenvironment of kidney renal clear cell carcinoma (KIRC). Despite the established role of glycolytic metabolism in cancer pathophysiology, the prognostic implications and key targets in KIRC remain elusive. We analyzed GEO and TCGA datasets to identify DEGs in KIRC and studied their relationship with immune gene expression, survival, tumor stage, gene mutations, and infiltrating immune cells. We explored Pgam1 gene expression in different kidney regions using spatial transcriptomics after mouse kidney injury analysis. Single-cell RNA-sequencing was used to assess the association of PGAM1 with immune cells. Findings were validated with tumor specimens from 60 KIRC patients, correlating PGAM1 expression with clinicopathological features and prognosis using bioinformatics and immunohistochemistry. We demonstrated the expression of central gene regulators in renal cancer in relation to genetic variants, deletions, and tumor microenvironment. Mutations in these hub genes were positively associated with distinct immune cells in six different immune datasets and played a crucial role in immune cell infiltration in KIRC. Single-cell RNA-sequencing revealed that elevated PGAM1 was associated with immune cell infiltration, specifically macrophages. Furthermore, pharmacogenomic analysis of renal cancer cell lines indicated that inactivation of PGAM1 was associated with increased sensitivity to specific small-molecule drugs. Altered PGAM1 in KIRC is associated with disease progression and immune microenvironment. It has diagnostic and prognostic implications, indicating its potential in precision medicine and drug screening.


[Correlation Between Serological Indices and Liver Histological Pathology in Patients with HBV Infection].
To analyze the correlation between serological indices and liver histological pathology in the patients with hepatitis B virus ( HBV) infection. This study enrolled 301 patients with HBV infection. All of them received liver biopsy, serum biochemical examination, including alanineamino transferase (ALT), aspart ateaminotransferase (AST), albumin (ALB), globulin (GLB ), HBV DNA test and HBV genotype detection. ALT, AST and AST/ALT in G2/G(3+4) group were significantly higher than those in group G0/G1 (P < 0.05), and all showed positive correlation with liver inflammation (r = 0.487, 0.648, 0.509, P < 0.05). GLB in S2/S(3+4) group was significantly higher than that in group S0/S1 (P < 0.05), which had positive correlation with liver fibrosis (r = 0.674, P < 0.05). ALB/GLB (A/G) in S2/S(3+4) group was significantly lower than that in group S0/S1 (P < 0.05), it had negative correlation with liver fibrosis(r = -0.500, P < 0.05). The inflammation and fibrosis level in patients with C genotype was higher than that of B genotype (χ2 = 11.460, 12.729, P < 0.05). ALT, AST and AST/ALT show better diagnostic value in liver inflammation. GLB and A/G show better diagnostic value in liver fibrosis. The progress of this disease is relatively faster in the patients with C genotype HBV infection.


[Bullous amyloidosis].
The occurrence of skin damage during systemic amyloidosis is common, but the appearance of bullous lesions is rare. Only twenty-seven cases have been reported in the literature. We report our observation of bullous amyloidosis during progression of renal amyloidosis. A 61 year-old man, presented with white, soft, palpebral edemas of the lower limbs, without scutulum involvement, associated with a large cubital nerve that had appeared in March 1997. Biological explorations revealed a nephrotic syndrome. Pathologic study of the renal biopsy concluded in amyloidosis. Treatment with colchinine stabilized the renal damage. One year later, a non-pruriginous, papular and bullous eruption occurred, localized essentially in the axillary and inguinal-crural folds of the forearms and legs. In the presence of an amyloidal deposit and intra-epidermal detachment, the cutaneous biopsy was evocative of bullous amyloidosis. The search for concomitant myeloma was negative. Treatment with colchinine was effective. The bullous lesions disappeared after 2 months, and 21 months later, renal damage was still stable. These particularities in evolution are exceptional and have never been described. A hypothetical modification in the physico-chemical properties of the amyloidal protein might explain the bullous eruption and stabilization of renal damage.


Key to the species of Eotrechinae (Hemiptera: Heteroptera: Gerridae) of Thailand and review of the fauna of the Phetchabun Mountain Range.
Water striders of the subfamily Eotrechinae from the Phetchabun Mountain Range can be found at the margins of rock pools and puddles, and in hygropetric habitats including waterfalls. Twenty-two species in three genera are known from Thailand. In the Phetchabun Mountain Range, 12 species representing all three genera were recorded from over a decade of collections (2002-2012). This paper provides taxonomic, biological, and ecological information for taxa of the Phetchabun Mountain Range in Thailand and a taxonomic key to all known species from Thailand.


Thermal influence on the embryonic development and hatching rate of the flameback pygmy angelfish Centropyge aurantonotus eggs.
The flameback pygmy angelfish Centropyge aurantonotus, highly appreciated and valued by the aquarium market, is heavily harvested and traded. Temperature is one of the abiotic factors that has the most influence on fish development, especially in the early stages of life. For captive production, it is essential to know the appropriate environmental parameters for each species. In this sense, this study aimed to evaluate the influence of temperature on the embryonic development and hatching rates of C. aurantonotus incubated at six different temperatures (20, 22, 24, 26, 28, 30°C). Embryonic development events were very similar in terms of morphological and chronological characteristics compared with other species of the genus Centropyge. Incubation time was inversely proportional to temperature. The treatment at 22°C required twice the time of that required by 30°C treatment for hatching to occur. The best incubation temperature range was 24-28°C. Values below 22°C and at 30°C showed lower hatching rates compared with other treatments. Based on these results, the recommended temperature at which to incubate C. aurantonotus eggs is between 24-28°C.


Relation of admission glucose levels, short- and long-term (20-year) mortality after acute myocardial infarction.
We examined temporal trends in mortality after myocardial infarction from 1985 to 2008 depending on admission glucose levels. We included 11,324 consecutive patients admitted to our intensive coronary care unit for myocardial infarction from 1985 to 2008. Patients were categorized into normal, mild, and severe hyperglycemia groups (admission glucose levels <140, 140 to 200, and ≥200 mg/dl, respectively). Temporal trends were determined using 3 groups: 1985 to 1990, 1990 to 2000, and 2000 to 2008. The prevalence of hyperglycemia increased from 26% in the 1980s to 49% in the 2000s. The prevalence of hyperglycemia primarily increased in patients without diabetes. Kaplan-Meier mortality was 4%, 8%, and 17% at 30 days and 64%, 71%, and 82% at 20 years in patients with normal, mild, and severe hyperglycemia, respectively. Compared with normal admission glucose level, adjusted 30-day mortality was 3.6-fold greater (95% confidence interval 2.9 to 4.3) in patients with severe hyperglycemia. This association was not dependent on diabetic status (p for interaction = 0.43) but was dependent on the decade of hospitalization with a stronger association from 2000 to 2008 (adjusted odds ratio 7.7, 95% confidence interval 5.4 to 11, p for interaction <0.001). Compared with diabetes, hyperglycemia was a better discriminator for 30-day mortality. Mortality at 30 days decreased from 1985 to 2008, however, it decreased less in patients with hyperglycemia compared with those with normoglycemia. In conclusion, elevated admission glucose levels are common in patients with myocardial infarction and are strongly associated with increased mortality. Mortality decreased less from 1985 to 2008 in patients with hyperglycemia compared with those with normoglycemia. Efforts that establish optimal treatment for these patients remain warranted.


Classification of congenital abnormalities of the sacrum. Patterns of associated dysfunctions.
Fifty-eight patients with a congenital abnormality of the sacrum were studied; a modified classification is suggested. Type 1a is characterized by an abrupt termination of the sacrum with an otherwise normal spinal column. Type 1b shows a similar sacral deficit, but with abnormalities evident higher in the spine. In Type 2 the terminal spine is malformed, and in Type 3 there is posterior sacral dysraphism. A high incidence of concomitant congenital abnormalities was found in Types 1 b and 2. Bladder dysfunction in the absence of typical clinical signs was often found in Types 1a and 1b.


A comparative evaluation of self-report and biological measures of cigarette use in nondaily smokers.
A large subset of individuals who smoke cigarettes do not smoke regularly, but the assessments used to collect data on cigarette consumption in nondaily smokers have not been rigorously evaluated. The current study examined several self-report and biomarker approaches to the assessment of cigarette use in a sample of nondaily smokers (n = 176). Participants were randomly assigned to a daily monitoring condition (n = 89), requiring a daily report of the number of cigarettes smoked in the previous 24 hours, or a no monitoring condition (n = 87). Number of cigarettes smoked over the first 28 days of the study was assessed using 2 quantity frequency measures, a graduated frequency measure, and a timeline follow back (TLFB) interview at the Session 5 study visit. Hair nicotine (NIC), hair cotinine (COT), and expired-air carbon monoxide (CO) were collected from each participant. Total cigarettes reported via daily report were strongly correlated with all Session 5 measures of total cigarettes, but were most strongly associated with TLFB total cigarettes. Collapsed CO across 5 sessions was the biomarker most strongly correlated with daily report total cigarettes. The results support the use of daily report and TLFB methods of assessing cigarette use in nondaily smokers. Results also support the use of CO as appropriate biological markers of exposure in nondaily smokers, and point to some limitations in the use of hair biomarkers in this population. (PsycINFO Database Record


Anal incontinence: relationship to pregnancy, vaginal delivery, and cesarean section.
To review the current literature concerning anal incontinence (AI), pregnancy, and route of delivery. AI is the involuntary loss of flatus, liquid, or solid stool that is a social or hygienic problem. AI has been reported in 5% to 26% of women during the first year following vaginal delivery. AI is strongly associated with occult and overt sphincter lacerations and operative vaginal delivery. The role of pregnancy itself and the impact of cesarean delivery on AI are unclear. Elective cesarean section has not been shown to decrease the risk of AI. The majority of current studies lack the power, matched controls, and long-term follow up to make recommendations concerning the mode of delivery and prevention of AI. The natural history of AI and development of symptoms as women age also remains unclear.


Immunotherapy for advanced gastric cancer.
Gastric cancer (GC) is believed to be the fifth most common cancer and the third most common cause of death worldwide. Treatment techniques include radiation, chemotherapy, gastrectomy, and targeted treatments are often employed. Some hopeful results from the development of GC immunotherapy have already changed treatment approaches. Along with previous combination medicines, new immunotherapies have been developed that target distinct molecules. Despite ongoing studies into the current therapeutic options and significant improvements in this field, the prognosis for the ailment is poor. Since there are few treatment options and a delay in detection, the illness actually advances, spreads, and metastasizes. The bulk of immunotherapies in use today rely on cytotoxic immune cells, monoclonal antibodies, and gene-transferred vaccines. Immune checkpoint inhibitors have become more popular. In this review, we sought to examine the viewpoint and development of several immunotherapy treatment modalities for advanced GC, as well as the clinical results thus far reported. Additionally, we outlined tumor immune escape and tumor immunosurveillance.


Pulp size in molars: underestimation on radiographs.
The aim was to determine whether radiographs provide a clinically useful indication of pulp size in diseased/restored human first molar teeth, and to investigate accessibility of pulp tissue for diagnostic testing using laser Doppler flowmetry (LDF). Extracted teeth of known age were collected. Restorative materials were removed and teeth with evidence of pulp exposures excluded. Fifty-six teeth were radiographed from buccal and mesial aspects, and then their crowns were sectioned axiobuccolingually and photographed. Images were digitally scanned and measurements made of the total pulp area (above a line across the most superior part of the pulpal floor) and the pulp area in the clinical crown (superior to a line between the amelocemental junctions). The pulp width at the cervix and the highest point of the pulp were also recorded. Data were analysed using Pearson correlations. Pulp areas within the clinical crowns were significantly larger than indicated by radiographs, by 23% in the case of the clinically attainable buccal view (P < 0.05). Pulps may be more accessible to flowmeter testing than they appear. Absence of pulp tissues in the crown was recorded in equal numbers of teeth on radiographs and sections, but with agreement for only one tooth. Sixteen per cent of the teeth had no pulp area in the clinical crown when sectioned, but might still be suitable for testing using LDF.


Characterization of Mu-Like Yersinia Phages Exhibiting Temperature Dependent Infection.
Yersinia pestis is the etiological agent of plague. Marmota himalayana of the Qinghai-Tibetan plateau is the primary host of flea-borne Y. pestis. This study is the report of isolation of Mu-like bacteriophages of Y. pestis from M. himalayana. The isolation and characterization of four Mu-like phages of Y. pestis were reported, which were named as vB_YpM_3, vB_YpM_5, vB_YpM_6, and vB_YpM_23 according to their morphology. Comparative genome analysis revealed that vB_YpM_3, vB_YpM_5, vB_YpM_6, and vB_YpM_23 are phylogenetically closest to Escherichia coli phages Mu, D108 and Shigella flexneri phage SfMu. The role of LPS core structure of Y. pestis in the phages' receptor was pinpointed. All the phages exhibit "temperature dependent infection," which is independent of the growth temperature of the host bacteria and dependent of the temperature of phage infection. The phages lyse the host bacteria at 37°C, but enter the lysogenic cycle and become prophages in the chromosome of the host bacteria at 26°C. IMPORTANCE Mu-like bacteriophages of Y. pestis were isolated from M. himalayana of the Qinghai-Tibetan plateau in China. These bacteriophages have a unique temperature dependent life cycle, follow a lytic cycle at the temperature of warm-blooded mammals (37°С), and enter the lysogenic cycle at the temperature of its flea-vector (26°С). A switch from the lysogenic to the lytic cycle occurred when lysogenic bacteria were incubated from lower temperature to higher temperature (initially incubating at 26°C and shifting to 37°C). It is speculated that the temperature dependent lifestyle of bacteriophages may affect the population dynamics and pathogenicity of Y. pestis.


Strains of JC virus in Amerind-speakers of North America (Salish) and South America (Guaraní), Na-Dene-speakers of New Mexico (Navajo), and modern Japanese suggest links through an ancestral Asian population.
Previously we showed that strains of human polyoma virus JC among the Navajo in New Mexico, speakers of an Athapaskan language in the Na-Dene language phylum, and among the Salish people in Montana, speakers of a language of the Salishan group in the Amerind family, were mainly of a northeast Asian genotype found in Japan (type 2A). We now report partial VP1-gene, regulatory region, and complete genome sequences of JC virus (JCV) from the Guaraní Indians of Argentina. The Tupí-Guaraní language represents the Equatorial branch of the Amerind language family proposed by Greenberg ([1987] Language in the Americas, Stanford: Stanford University Press). The partial VP1 gene sequences of the Guaraní revealed several variants of strains found in northeast Asia (Japan), as did the Salish. In contrast, the strains in the Navajo largely conformed to the prototype type 2A sequence (MY). Phylogenetic reconstruction with both the neighbor-joining and maximum parsimony methods utilized three complete Guaraní JCV genome sequences, three genomes from the Salish people, and 27 other complete JCV genomes, including three from the Navajo and three from Japan. Both trees showed that all type 2A JCV strains from the North and South Americans are closely related phylogenetically to strains in present-day Japan. However, variant sites in the coding regions, the T-antigen intron, and the regulatory region link the type 2A strains in Amerind groups (Guaraní and Salish), but differentiate them from those in a Na-Dene-speaking (Navajo) population. The data suggest separation from a population ancestral to modern Japanese, followed by a second division within the ancestral group that led to Amerind- and Na-Dene-speaking groups. The data cannot, however, localize the latter split to the Asian mainland (two migrations) or to North America (one migration).


Mutagenesis and expression of the scaffolding Aalpha and Abeta subunits of PP2A: assays for measuring defects in binding of cancer-related Aalpha and Abeta mutants to the regulatory B and catalytic C subunits.
Protein phosphatase 2A (PP2A) holoenzymes are composed of three subunits: one scaffolding A subunit, one regulatory B subunit, and one catalytic C subunit. The A subunit exists as two isoforms: Aalpha and Abeta. The C subunit also exists as two isoforms (Calpha and Cbeta) and B subunits fall into three families (B, B', and B") comprising over 15 members. The Aalpha and Abeta subunits consist of 15 nonidentical repeats, which are composed of two amphipathic alpha helices that are connected by a loop (intrarepeat loop). These loops are instrumental in binding regulatory B and catalytic C subunits. The genes encoding the Aalpha and Abeta subunits are relatively frequent targets for mutation in human cancer. The mutations often affect the intrarepeat loops and cause defects in the binding of specific B subunits or of B and C subunits. Here, we describe in vitro and in vivo binding assays for measuring these defects. Knowing which B subunits are affected in binding to the mutant A subunits sheds light on which holoenzymes might be involved in growth control and cancer.


[Dehydration and rehydration of the human body. Physiopathologic and clinical considerations].
Dehydration is a frequent and important problem either occupational or athletic. Equally important is the research for a correct rehydration. The most capable beverages for the rehydration are composed by water, carbohydrates (glucose and its polymers), and electrolytes, because the absorptions of water, glucose and sodium are correlated. Moreover these solutions if properly dosed and balanced do not slacken the gastric emptying and the fluid absorption, they replace part of the exhausted carbohydrates and guarantee a good plasma electrolyte balance. To these benefits can be added the organic "stress" reduction and the physical endurance enhancement.


Metallohydrogel with Tunable Fluorescence, High Stretchability, Shape-Memory, and Self-Healing Properties.
Aiming at the problem that the reported smart optical metallohydrogels were limited with poor mechanical properties, we reported here a novel smart optical metallohydrogel (Al-hydrogel) with excellent elongation, shape-memory ability, self-healing property, and controllable fluorescence intensity. The Al-hydrogel was obtained by the HHPMA-Al3+ and carboxylate-Al3+ coordination after one-pot micellar copolymerization of acrylic acid (AAc), acrylamide (AAm), and hydrophobic arylhydrazone-based ligand (HHPMA). This hydrogel was able to extend up to 5000% of its original length without fracture. Its emission intensity was tunable by OH-/H+ or Zn2+/AAc and increased by 500% with 0.1 M OH- or Zn2+. Its tunable fluorescence enabled us to repeatedly pattern it. A reversible system consisting of Fe3+/H+, was implemented to control the shape of the Al-hydrogel, endowing the Al-hydrogel with shape-memory ability. This highly stretchable and multifunctional Al-hydrogel has potential applications in information transmission, wearable devices, and flexible sensors.


A realistic model under which the genetic code is optimal.
The genetic code has a high level of error robustness. Using values of hydrophobicity scales as a proxy for amino acid character, and the mean square measure as a function quantifying error robustness, a value can be obtained for a genetic code which reflects the error robustness of that code. By comparing this value with a distribution of values belonging to codes generated by random permutations of amino acid assignments, the level of error robustness of a genetic code can be quantified. We present a calculation in which the standard genetic code is shown to be optimal. We obtain this result by (1) using recently updated values of polar requirement as input; (2) fixing seven assignments (Ile, Trp, His, Phe, Tyr, Arg, and Leu) based on aptamer considerations; and (3) using known biosynthetic relations of the 20 amino acids. This last point is reflected in an approach of subdivision (restricting the random reallocation of assignments to amino acid subgroups, the set of 20 being divided in four such subgroups). The three approaches to explain robustness of the code (specific selection for robustness, amino acid-RNA interactions leading to assignments, or a slow growth process of assignment patterns) are reexamined in light of our findings. We offer a comprehensive hypothesis, stressing the importance of biosynthetic relations, with the code evolving from an early stage with just glycine and alanine, via intermediate stages, towards 64 codons carrying todays meaning.


Blood pressure response to cold pressor test in siblings of hypertensives.
One hundred and five female and thirty-four male student volunteers were divided into three groups. Each group was again divided into siblings of hypertensives (SH) and siblings of normotensives (C). SH group had higher basal seated and supine Systolic and Diastolic Blood Pressures (SBPs and DBPs, respectively). During cold pressor test (CPT), the SH group showed higher rise of SBPs and DBPs. All the volunteers were again regrouped as hyperreactors (HR) (the criteria of a rise of more than 22 mmHg systolic and 18 mmHg diastolic blood pressure during (CPT) and normoreactors (NR). HR showed higher resting seated SBPs and DBPs, and higher rise of SBPs & DBPs during CPT as compared to control groups. The rise in SBPs and DBPs in hyperreactors was significantly higher than SH groups only in 16-19 years female group. The rise of SBPs and DBPs during CPT were also higher in HR as compared to NR of all age groups. The rise of SBPs and DBPs during CPT was significantly higher in controls than in NR in the two female groups. The study suggests that identification of hyperreactors in population gives a better indication of potential hypertensives of future than the children of hypertensives.


Intestinal preconditioning prevents inflammatory response by modulating heme oxygenase-1 expression in endotoxic shock model.
Gut mucosal injury observed during ischemia-reperfusion is believed to trigger a systemic inflammatory response leading to multiple organ failure. It should be interesting to demonstrate this relationship between gut and multiple organ failure in a sepsis model. Intestinal preconditioning (PC) can be used as a tool to assess the effect of intestinal ischemia in inflammatory response after LPS challenge. The aim of this study was to investigate the protective effect of PC against LPS-induced systemic inflammatory and intestinal heme oxygenase-1 (HO-1) expression. ES was performed with LPS (10 mg/kg iv) with or without PC, which was done before LPS. Rats were first subjected to sham surgery or PC with four cycles of 1 min ischemia and 4 min of reperfusion 24 h before LPS challenge or saline administration. PC significantly reduced fluid requirements, lung edema, intestinal lactate production, and intestinal injury. Inflammatory mRNA expressions for intestine and lung ICAM and TNF were significantly reduced after PC, and these effects were significantly abolished by zinc-protoporphyrin (a specific HO-1 activity inhibitor) and mimicked by bilirubin administration. Intestinal PC selectively increased HO-1 mRNA expression in intestine, but we have observed no expression in lungs. These findings demonstrate that intestinal injury is a important event for inflammatory response and multiple organ injury after LPS challenge. Intestinal HO-1 expression attenuates LPS-induced multiple organ failure by modulating intestine injury and its consequences on inflammatory response. Identification of the exact mechanisms responsible for intestine HO-1 induction may lead to the development of new pharmacological interventions.


Magnesium ascorbyl phosphate and coenzyme Q10 protect keratinocytes against UVA irradiation by suppressing glutathione depletion.
The aim of this study was to investigate whether magnesium ascorbyl phosphate (MAP) and coenzyme Q10 (CoQ10) can protect keratinocytes against ultraviolet (UV)A irradiation by increasing the levels of glutathione (GSH). The cell survival fraction was 89.9% when the keratinocytes were irradiated with UVA at a dose of 4 J/cm2. The cell survival fractions were 48.4, 9.1 and 4.8%, at doses of 8, 16 and 32 J/cm2, respectively. MAP was added to the cells prior to UVA irradiation at a dose of 8 J/cm2 and then the cell viability was assayed. The cell survival fractions were 51.6, 55.5, 64.8 and 76.7%, when MAP was added at concentrations of 125, 250, 500 µM and 1 mM, respectively. The results showed that MAP is capable of protecting keratinocytes against UVA irradiation. The cell survival fractions were 77.2, 89.4 and 90.1%, when CoQ10 was added at concentrations of 2.5, 5 and 10 µM, respectively. The results revealed that CoQ10 is capable of protecting keratinocytes against UVA irradiation. At the same time, the levels of GSH within cells were detected. The level of GSH within cells was 0.3 mmol/g protein when the keratinocytes were irradiated with UVA at a dose of 8 J/cm2. We measured the levels of GSH within the cells after MAP or CoQ10 was added prior to UVA irradiation at a dose of 8 J/cm2. The levels of GSH within the cells were 0.344, 0.388, 0.456 and 0.5 mmol/g protein, when MAP was added at concentrations of 125, 250, 500 µM and 1 mM, respectively. The levels of GSH within the cells were 0.328, 0.35 and 0.394 mmol/g protein, when CoQ10 was added at concentrations of 2.5, 5 and 10 µM, respectively. These results imply that MAP and CoQ10 can protect the keratinocytes against UVA irradiation, possibly via increasing the levels of GSH.


A spectrum of renal tubular ectasia and hepatic fibrosis.
Renal tubular cystic disease and hepatic fibrosis exhibit a specific genetic pattern and pathological findings. The renal collecting tubules are dilated and the liver shows fibrosis with proliferation and dilatation of the bile ducts. The findings fall into a spectrum with marked renal disease and mild liver involvement at one end and mild renal involvement with severe liver disease at the other. Between these extremes lies an intermediate form which is genetically and pathologically similar, but exhibits a wide range of clinical and radiological findings due to the variability of renal and liver involvement.


Infant suffocation in place of sleep: New Zealand national data 2002-2009.
Accidental suffocation during sleep, leading to death, has been described as due to overlay or wedging of infants, particularly in a bed-sharing situation. Bed sharing is a risk factor for sudden infant death syndrome but the mechanism of death is not clearly defined. Accidental suffocation may be one such mechanism. To describe accidental suffocation deaths during sleep in New Zealand between 2002 and 2009. The New Zealand mortality database, which holds data collected by the Child Youth Mortality Review Committee and the Perinatal and Maternal Mortality Review Committee, was searched for potential deaths by accidental suffocation in infants less than 1 year of age. Deaths underwent a detailed analysis by demographic data and qualitative report. There were 48 deaths due to accidental suffocation between 2002 and 2009 in New Zealand, equating to a rate of 0.10 deaths per 1000 live births. The most common age at death was 1 month or under (n=11, 23%). Deaths were due to overlay (n=30, 63%) or wedging (n=18, 37%) and two-thirds (n=34, 71%) were in a bed-sharing situation. A quarter of deaths (n=12, 25%) occurred in makeshift bedding arrangements, some of which were away from home. Accidental suffocation in bed was responsible for 48 preventable deaths. Prevention of these accidental deaths needs to focus on supporting changes in family behaviour with safety messages that are consistent, persistent and disseminated widely.


A clinical guide to rare male sexual disorders.
Conditions referred to as 'male sexual dysfunctions' usually include erectile dysfunction, ejaculatory disorders and male hypogonadism. However, some less common male sexual disorders exist, which are under-recognized and under-treated, leading to considerable morbidity, with adverse effects on individuals' sexual health and relationships. Such conditions include post-finasteride syndrome, restless genital syndrome, post-orgasmic illness syndrome, post-selective serotonin reuptake inhibitor (SSRI) sexual dysfunction, hard-flaccid syndrome, sleep-related painful erections and post-retinoid sexual dysfunction. Information about these disorders usually originates from case-control trials or small case series; thus, the published literature is scarce. As the aetiology of these diseases has not been fully elucidated, the optimal investigational work-up and therapy are not well defined, and the available options cannot, therefore, adequately address patients' sexual problems and implement appropriate treatment. Thus, larger-scale studies - including prospective trials and comprehensive case registries - are crucial to better understand the aetiology, prevalence and clinical characteristics of these conditions. Furthermore, collaborative efforts among researchers, health-care professionals and patient advocacy groups will be essential in order to develop evidence-based guidelines and novel therapeutic approaches that can effectively address these disorders. By advancing our understanding and refining treatment strategies, we can strive towards improving the quality of life and fostering healthier sexual relationships for individuals suffering from these rare sexual disorders.


Isolation and genome characterization of Lloviu virus from Italian Schreibers's bats.
Lloviu cuevavirus (LLOV) was the first identified member of Filoviridae family outside the Ebola and Marburgvirus genera. A massive die-off of Schreibers's bats (Miniopterus schreibersii) in the Iberian Peninsula in 2002 led to its initial discovery. Recent studies with recombinant and wild-type LLOV isolates confirmed the zoonotic nature of the virus in vitro. We examined bat samples from Italy for the presence of LLOV in an area outside of the currently known distribution range of the virus. We detected one positive sample from 2020, sequenced the complete coding region of the viral genome and established an infectious isolate of the virus. In addition, we performed the first comprehensive evolutionary analysis of the virus, using the Spanish, Hungarian and the Italian sequences. The most important achievement of this study is the establishment of an additional infectious LLOV isolate from a bat sample using the SuBK12-08 cells, demonstrating that this cell line is highly susceptible to LLOV infection and confirming the previous observation that these bats are effective hosts of the virus in nature. This result further strengthens the role of bats as the natural hosts for zoonotic filoviruses.


A microfluidic system in combination with optical tweezers for analyzing rapid and reversible cytological alterations in single cells upon environmental changes.
We report on the development of an experimental platform where epi-fluorescence microscopy and optical tweezers are combined with a microfluidic system to enable the analysis of rapid cytological responses in single cells. The microfluidic system allows two different media to be merged in a Y-shaped channel. Microscale channel dimensions ensure purely laminar flow and, as a result, an environmental gradient can be created between the two media. Optical tweezers are used to move a single trapped cell repeatedly between the different environments. The cell is monitored continuously by fluorescence microscopy during the experiment. In a first experiment on yeast (Saccharomyces cerevisiae) we observed changes in cell volume as the cell was moved between environments with different osmolarity. This demonstrated that the platform allowed analysis of cytological alterations on a time scale shorter than 0.2 s. In a second experiment we observed the spatial migration of the Yap1p transcription factor fused to GFP as a cell was moved from an environment of low to high oxidative capacity. The system is universal allowing the response to numerous environmental changes to be studied on the sub second time scale in a variety of model cells. We intend to use the platform to study how the age of cells, their progression through the cell cycle, or their genetic landscape, alter their capacity (kinetics and amplitude) to respond to environmental changes.


Free radicals and sprint exercise in humans.
Sprint exercise ability has been critical for survival. The remarkably high-power output levels attained during sprint exercise are achieved through strong activation of anaerobic, and to a lesser extent, aerobic energy supplying metabolic reactions, which generate reactive oxygen and nitrogen species (RONS). Sprint exercise may cause oxidative stress leading to muscle damage, particularly when performed in severe acute hypoxia. However, with training oxidative stress is reduced. Paradoxically, total plasma antioxidant capacity increases during the subsequent 2 h after a short sprint due to the increase in plasma urate concentration. The RONS produced during and immediately after sprint exercise play a capital role in signaling the adaptive response to sprint. Antioxidant supplementation blunts the normal AMPKα and CaMKII phosphorylation in response to sprint exercise. However, under conditions of increased glycolytic energy turnover and muscle acidification, as during sprint exercise in severe acute hypoxia, AMPKα phosphorylation is also blunted. This indicates that an optimal level of RONS-mediated stimulation is required for the normal signaling response to sprint exercise. Although RONS are implicated in fatigue, most studies convey that antioxidants do not enhance sprint performance in humans. Although currently controversial, it has been reported that antioxidant ingestion during training may jeopardize some of the beneficial adaptations to sprint training.


PDZ domain-dependent regulation of NHE3 protein by both internal Class II and C-terminal Class I PDZ-binding motifs.
NHE3 directly binds Na+/H+ exchanger regulatory factor (NHERF) family scaffolding proteins that are required for many aspects of NHE3 regulation. The NHERFs bind both to an internal region (amino acids 586-660) of the NHE3 C terminus and to the NHE3 C-terminal four amino acids. The internal NHERF-binding region contains both putative Class I (-592SAV-) and Class II (-595CLDM-) PDZ-binding motifs (PBMs). Point mutagenesis showed that only the Class II motif contributes to NHERF binding. In this study, the roles in regulation of NHE3 activity of these two PBMs were investigated, revealing the following findings. 1) Interaction occurred between these binding sites because mutation of either removed nearly all NHERF binding. 2) Mutations in either significantly reduced basal NHE3 activity. Total and percent plasma membrane (PM) NHE3 protein expression was reduced in the C-terminal but not in the internal PBD mutation. 3) cGMP- and Ca2+-mediated inhibition of NHE3 was impaired in both the internal and the C-terminal PBM mutations. 4) There was a significant reduction in half-life of the PM pool of NHE3 in only the internal PBM mutation but no change in total NHE3 half-life in either. 5) There were some differences in NHE3-associating proteins in the two PBM mutations. In conclusion, NHE3 binds to NHERF proteins via both an internal Class II PBM and C-terminal Class I PBM, which interact. The former determines NHE3 stability in the PM, and the latter determines total expression and percent PM expression.


[Safety and efficacy of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) in Chinese patients with advanced colorectal cancer].
Objective: To establish the maximum tolerated dose (MTD) of 5-fluorouracil, leucovorin, oxaliplatin and irinotecan (FOLFOXIRI), and to evaluate the safety and efficacy in Chinese patients with advanced colorectal cancer. Methods: Patients were treated with a regimen consisting of infusional 5-fluorouracil (2 400 mg/m(2) on day 1), leucovorin (200 mg/m(2) on day 1), oxaliplatin (85 mg/m(2) on day 1), and irinotecan (at doses from 150 to 180 mg/m(2) on day 8) according to the dose-escalation schema. Treatment was repeated every 14 days. The UDP-glucuronosyl transferase (UGT) 1A1 genotypes were analyzed in the patients with dose-limiting toxicity (DLT). Results: A total of 12 patients with advanced colorectal cancer were included. The MTD of FOLFOXIRI in these patients was oxaliplatin 85 mg/m(2) day 1, leucovorin 200 mg/m(2) day 1, 5-fluorouracil 2 400 mg/m(2) day 1, and irinotecan 150 mg/m(2) day 8 every 2 weeks. The most common toxicities were nausea, diarrhea, leukopenia, neutropenia and fatigue. The DLTs were febrile neutropenia and diarrhea. The objective response rate was 66.7%. Conclusions: Our results indicate that FOLFOXIRI regimen is considered safe and effective in Chinese patients with advanced colorectal cancer, and the MTD of FOLFOXIRI regimen for Chinese patients with advanced colorectal cancer is recommended.


Specific and common epitopes in mating pheromones of Euplotes raikovi revealed by monoclonal antibodies.
Polypeptide mating pheromones Er-1 and Er-2, purified from the supernatant of Euplotes raikovi cultures of mating type I and mating type II, respectively, were used to immunize mice and obtain monoclonal antibodies. Five hybridoma clones producing antibodies specific to the mating pheromones were selected. They were analyzed for immunospecificity by immunoperoxidase assay, immunoblotting, and for their efficacy in inhibition of mating pheromone activity. Monoclonal antibodies from two hybridoma clones recognized only the mating pheromone used as antigen: those from the other three clones reacted, to comparable extents, with both mating pheromones. On the basis of these results it was assumed that two immunogenic sites exist in Er-1 and Er-2, one specific and the other common to both mating pheromones.


Risk of Emergency Operations, Adverse Maternal and Neonatal Outcomes according to the Planned Gestational Age for Cesarean Delivery.
The objective of this study was to assess the risk of emergency cesarean deliveries (CDs) and adverse neonatal/maternal outcomes according to the planned gestational age at delivery (GAD) for elective CD. The study population consisted of term singleton pregnant women who were booked for elective CD and were subsequently delivered at term by CD, after excluding cases with a trial of labor. The relationship between the planned GAD, risk of emergency CD prior to planned date, and adverse neonatal/maternal outcomes were determined. The frequency of emergency CD, adverse neonatal and maternal outcomes were 9.5%, 4.5%, and 5.9%, respectively. The risk of emergency CD prior to the planned delivery date increased significantly according to the planned GAD (5.8% at 37 weeks, 8.2% at 38 weeks, 13.6% at 39 weeks, and 26.7% at 40 weeks or more of planned GAD, P = 0.005). Emergency CD was associated with an increased risk of adverse maternal outcomes, whereas the risk of adverse neonatal outcomes did not differ. In the total study population including both cases with elective and emergency CD, the risk of adverse maternal outcomes did not increase according to the planned GAD, and the risk of adverse neonatal outcomes decreased significantly according to the planned GAD. The risk of emergency CD increased as the planned GAD increased, but the risk of adverse maternal outcomes did not increase and the risk of adverse neonatal outcomes decreased significantly according to the planned GAD in the total study population including elective/emergency CD.


Tissue dielectric constant (TDC) measurements as a means of characterizing localized tissue water in arms of women with and without breast cancer treatment related lymphedema.
Quantitative measurements to detect lymphedema early in persons at-risk for breast cancer (BC) treatment-related lymphedema (BCRL) can aid clinical evaluations. Since BCRL may be initially manifest in skin and subcutis, the earliest changes might best be detected via local tissue water (LTW) measurements that are specifically sensitive to such changes. Tissue dielectric constant (TDC) measurements, which are sensitive to skin-to-fat tissue water, may be useful for this purpose. TDC differences between lymphedematous and non-lymphedematous tissue has not been fully characterized. Thus we measured TDC values (2.5 mm depth) in forearms of three groups of women (N = 80/group): 1) healthy with no BC (NOBC), 2) with BC but prior to surgery, and 3) with unilateral lymphedema (LE). TDC values for all arms except LE affected arms were not significantly different ranging between 24.8 ± 3.3 to 26.8 ± 4.9 and were significantly less (p < 0.001) as compared to 42.9 ± 8.2 for LE affected arms. Arm TDC ratios, dominant/non-dominant for NOBC, were 1.001 ± 0.050 and at-risk/ contralateral for BC were 0.998 ± 0.082 with both significantly less (p < 0.001) than LE group affected/control arm ratios (1.663 ± 0.321). These results show that BC per se does not significantly change arm LTW and that the presence of BCRL does not significantly change LTW of non-affected arms. Further, based on 3 standard deviations of measured arm ratios, our data demonstrates that an at-risk arm/contralateral arm TDC ratio of 1.2 and above could be a possible threshold to detect pre-clinical lymphedema. Further prospective measurement trial are needed to confirm this value.


Recent Findings in the Regulation of Programmed Death Ligand 1 Expression.
With the recent approvals for the application of monoclonal antibodies that target the well-characterized immune checkpoints, immune therapy shows great potential against both solid and hematologic tumors. The use of these therapeutic monoclonal antibodies elicits inspiring clinical results with durable objective responses and improvements in overall survival. Agents targeting programmed cell death protein 1 (PD-1; also known as PDCD1) and its ligand (PD-L1) achieve a great success in immune checkpoints therapy. However, the majority of patients fail to respond to PD-1/PD-L1 axis inhibitors. Expression of PD-L1 on the membrane of tumor and immune cells has been shown to be associated with enhanced objective response rates to PD-1/PD-L1 inhibition. Thus, an improved understanding of how PD-L1 expression is regulated will enable us to better define its role as a predictive marker. In this review, we summarize recent findings in the regulation of PD-L1 expression.


The general pediatrician as care coordinator for children with chronic illness.
As the number of children with chronic illness increases due to advances in medical technology, general pediatricians are faced with the challenge of providing continuing care for such patients. These children and their families are most in need of a care coordinator to guide them through the complexities of obtaining optimal care in all aspects: medical, emotional, social, and developmental. The primary pediatrician is logically positioned to assumed the role of care coordinator. This undertaking requires a knowledge of the needs of such children and their families, an ability to interact with other professionals as member of a team, a sensitivity to the overall functional status of the child and family, and a commitment of a large amount of time and effort. Although these skills are rarely taught during residency training, they can be acquired through continuing education, thereby allowing the pediatrician to experience the satisfaction that derives from helping someone truly in need.


Neural interfaces at the nanoscale.
Bioelectrical neural interfaces provide a means of recording the activity from the nervous system and delivering therapeutic stimulation to restore neurological function lost during disease or injury. Although neural interfaces have reached clinical utility, reducing the size of the bioelectrical interface to minimize damage to neural tissue and maximize selectivity has proven problematic. Nanotechnology may offer a means of interfacing with the nervous system with unprecedented specificity. Emergent applications of nanotechnology to neuroscience include molecular imaging, drug delivery across the BBB, scaffolds for neural regeneration and bioelectrical interfaces. In particular, carbon nanotubes offer the promises of material stability and low electrical impedance at physical dimensions that could have a significant impact on the future on neural interfaces. The purpose of this review is to present recent advances in carbon nanotube-based bioelectrical interfaces for the nervous system and discuss research challenges and opportunities.


Depression and Anxiety Prevention Based on Cognitive Behavioral Therapy for At-Risk Adolescents: A Meta-Analytic Review.
Depression and anxiety disorders are among the most common mental disorders during adolescence. During this life phase, the incidence of these clinical disorders rises dramatically, and even more adolescents suffer from symptoms of depression or anxiety that are just below the clinical threshold. Both clinical and subclinical levels of depression or anxiety symptoms are related to decreased functioning in various areas, such as social and academic functioning. Prevention of depression and anxiety in adolescents is therefore imperative. We conducted a meta-analytic review of the effects of school-based and community-based prevention programs that are based on cognitive behavioral therapy with the primary goal preventing depression, anxiety, or both in high risk adolescents. Articles were obtained by searching databases and hand searching reference lists of relevant articles and reviews. The selection process yielded 32 articles in the meta-analyses. One article reported on two studies and three articles reported on both depression and anxiety. This resulted in a total of 36 studies, 23 on depression and 13 on anxiety. For depression prevention aimed at high risk adolescents, meta-analysis showed a small effect of prevention programs directly after the intervention, but no effect at 3-6 months and at 12 months follow-up. For anxiety prevention aimed at high risk adolescents, no short-term effect was found, nor at 12 months follow-up. Three to six months after the preventive intervention, symptoms of anxiety were significantly decreased. Although effects on depression and anxiety symptoms were small and temporary, current findings cautiously suggest that depression and anxiety prevention programs based on CBT might have small effects on mental health of adolescents. However, it also indicates that there is still much to be gained for prevention programs. Current findings and possibilities for future research are discussed in order to further improve the effectiveness of targeted prevention on internalizing disorders.


Nebivolol increases arterial distensibility in vivo.
Arterial stiffness is a key determinant of cardiovascular risk in hypertensive patients. beta-Blockers appear to be less effective than other drugs in improving outcome in hypertensive patients, and a potential explanation may be that beta-blockers are less effective in reducing arterial stiffness. The aim of this study was to assess the direct effect of beta-blockade on pulse wave velocity (PWV), a robust measure of arterial distensibility, using a local, ovine, hind-limb model. In addition, we hypothesized that the vasodilating beta-blocker nebivolol, but not atenolol, would increase arterial distensibility in vivo. All studies were conducted in anesthetized sheep. PWV was recorded in vivo using a dual pressure-sensing catheter placed in the common iliac artery. Intraarterial infusion of nebivolol reduced PWV by 6+/-3% at the higher dose (P<0.001), but did not alter mean arterial pressure (change of -1+/-3 mm Hg, P=0.1). In contrast, atenolol had no effect on PWV (P=0.11) despite a small drop in mean pressure (change of -5+/-3 mm Hg, P<0.01). Infusion of glyceryl trinitrate led to a dose-dependent fall in PWV, and 2 nmol/min produced a similar reduction in PWV to the higher dose of nebivolol (500 nmol/min). The effect of nebivolol on PWV was significantly attenuated during coinfusion of N(G)-monomethyl-L-arginine (P=0.003) and also during coinfusion of butoxamine (P=0.02). These results demonstrate that nebivolol, but not atenolol, increases arterial distensibility. This effect of nebivolol is mediated through the release of NO via a beta2 adrenoceptor-dependent mechanism. Thus, nebivolol may be of benefit in conditions of increased large artery stiffness, such as isolated systolic hypertension.


Contributions of spectral frequency analyses to the study of P50 ERP amplitude and suppression in bipolar disorder with or without a history of psychosis.
The present study investigated event-related brain potential (ERP) indices of auditory processing and sensory gating in bipolar disorder and subgroups of bipolar patients with or without a history of psychosis using the P50 dual-click procedure. Auditory-evoked activity in two discrete frequency bands also was explored to distinguish between sensory registration and selective attention deficits. Thirty-one individuals with bipolar disorder and 28 non-psychiatric controls were compared on ERP indices of auditory processing using a dual-click procedure. In addition to conventional P50 ERP peak-picking techniques, quantitative frequency analyses were applied to the ERP data to isolate stages of information processing associated with sensory registration (20-50 Hz; gamma band) and selective attention (0-20 Hz; low-frequency band). Compared to the non-psychiatric control group, patients with bipolar disorder exhibited reduced S1 response magnitudes for the conventional P50 peak-picking and low-frequency response analyses. A bipolar subgroup effect suggested that the attenuated S1 magnitudes from the P50 peak-picking and low-frequency analyses were largely attributable to patients without a history of psychosis. The analysis of distinct frequency bands of the auditory-evoked response elicited during the dual-click procedure allowed further specification of the nature of auditory sensory processing and gating deficits in bipolar disorder with or without a history of psychosis. The observed S1 effects in the low-frequency band suggest selective attention deficits in bipolar patients, especially those patients without a history of psychosis, which may reflect a diminished capacity to selectively attend to salient stimuli as opposed to impairments of inhibitory sensory processes.


Multipurpose conical orbital implant in evisceration.
To evaluate the safety and efficacy of the porous polyethylene multipurpose conical orbital implant for use in evisceration. A retrospective review of 31 eyes that underwent evisceration and received the multipurpose conical orbital implant. The orbits were evaluated at 1 week, 1 month, and 6 months after final prosthetic fitting for implant exposure, superior sulcus deformity, and prosthetic motility. There were no cases of extrusion, migration, or infection. All patients had a good cosmetic result after final prosthetic fitting. Prosthetic motility was good in all patients. Exposure developed in one eye (3%) and a superior sulcus deformity developed in one eye (3%). Placement of an multipurpose conical orbital implant in conjunction with evisceration is a safe and effective treatment for blind painful eye that achieves good motility and a good cosmetic result.


Overview of guidelines for establishing a face transplant program: a work in progress.
Since 2005, nine face transplants have been performed in four countries: France, the United States (US), China and Spain. These encouraging short-term outcomes, with the longest survivor approaching 5 years, have led to an increased interest in establishing face transplant programs worldwide. Therefore, the purpose of this article is to facilitate the dissemination of relevant details as per our experience in an effort to assist those medical centers interested in establishing a face transplant program. In this article, we address the logistical challenges involved with face transplantation; including essential program requirements, protocol details, face transplant team assembly, project funding, the organ procurement organization and the coroner. It must be emphasized that face transplantation is still experimental and its therapeutic value remains to be validated. All surgical teams pursuing this endeavor must dedicate an attention to detail and should accept a responsibility to publish their outcomes in a transparent manner in order to contribute to the international field. However, due to its inherent complexity, facial transplantation should only be performed by university-affiliated medical institutions capable of orchestrating a specialized multidisciplinary team with a long-term commitment to its success.


Whallwachsia illuminata n. gen., n. sp. (Trematoda: Digenea: Plagiorchiformes: Prosthogonimidae) in the steely-vented hummingbird Amazilia saucerrottei (Aves: Apodiformes: Trochilidae) and the yellow-olive flycatcher Tolmomyias sulphurescens (Aves: Passeriformes: Tyraninidae) from the Area de Conservación Guanacaste, Guanacaste, Costa Rica.
A new species of digenean found in the intestines of the steely-vented hummingbird Amazilia saucerrottei and the yellow-olive flycatcher Tolmomyias sulphurescens from the Area de Conservación Guanacaste, Guanacaste, Costa Rica, resembles members of the Prosthogonimidae in having a highly lobate ovary; an elongate cirrus sac containing the cirrus, pars prostatica, and internal seminal vesicle; no external seminal vesicle; 2 fields of extracecal vitelline follicles restricted to the area between the intestinal bifurcation and testes; and uterine loops occupying all available space in the hind body. The new species differs from all other members of the family in having genital pores opening laterally to the cecum, immediately anterior to the acetabular level, and markedly oblique rather than symmetrical testes. Consequently, we propose the new genus Whallwachsia for the species. Preliminary phylogenetic assessment suggests that the species is the sister group of all other prosthogonimids.


Survival analysis of infected mice reveals pathogenic variations in the genome of avian H1N1 viruses.
Most influenza pandemics have been caused by H1N1 viruses of purely or partially avian origin. Here, using Cox proportional hazard model, we attempt to identify the genetic variations in the whole genome of wild-type North American avian H1N1 influenza A viruses that are associated with their virulence in mice by residue variations, host origins of virus (Anseriformes-ducks or Charadriiformes-shorebirds), and host-residue interactions. In addition, through structural modeling, we predicted that several polymorphic sites associated with pathogenicity were located in structurally important sites, especially in the polymerase complex and NS genes. Our study introduces a new approach to identify pathogenic variations in wild-type viruses circulating in the natural reservoirs and ultimately to understand their infectious risks to humans as part of risk assessment efforts towards the emergence of future pandemic strains.


A computational model of urinary bladder smooth muscle syncytium : validation and investigation of electrical properties.
Certain smooth muscles, such as the detrusor of the urinary bladder, exhibit a variety of spikes that differ markedly in their amplitudes and time courses. The origin of this diversity is poorly understood but is often attributed to the syncytial nature of smooth muscle and its distributed innervation. In order to help clarify such issues, we present here a three-dimensional electrical model of syncytial smooth muscle developed using the compartmental modeling technique, with special reference to the bladder detrusor. Values of model parameters were sourced or derived from experimental data. The model was validated against various modes of stimulation employed experimentally and the results were found to accord with both theoretical predictions and experimental observations. Model outputs also satisfied criteria characteristic of electrical syncytia such as correlation between the spatial spread and temporal decay of electrotonic potentials as well as positively skewed amplitude frequency histogram for sub-threshold potentials, and lead to interesting conclusions. Based on analysis of syncytia of different sizes, it was found that a size of 21-cube may be considered the critical minimum size for an electrically infinite syncytium. Set against experimental results, we conjecture the existence of electrically sub-infinite bundles in the detrusor. Moreover, the absence of coincident activity between closely spaced cells potentially implies, counterintuitively, highly efficient electrical coupling between such cells. The model thus provides a heuristic platform for the interpretation of electrical activity in syncytial tissues.


Kinetics of two wave mixing gain for moving grating technique in photorefractive BaTiO3 crystal.
We present analytic expressions for time-dependent space charge field and two wave mixing gain under the external applied field accompanying the grating translation. The variations of complex space charge field are analyzed in a complex plane, and the explicit expressions for the resonance and optimum frequencies (or moving grating velocities), which maximize the magnitude and imaginary part of space charge field, respectively, are also obtained. In addition, two wave mixing experiment was conducted with a grating translation technique without the external applied field in a BaTiO(3) crystal and the transient behaviors of measured gain look like damped harmonic oscillations, showing excellent agreement with the theory for the entire time range.


Safe Robot Trajectory Control Using Probabilistic Movement Primitives and Control Barrier Functions.
In this paper, we present a novel means of control design for probabilistic movement primitives (ProMPs). Our proposed approach makes use of control barrier functions and control Lyapunov functions defined by a ProMP distribution. Thus, a robot may move along a trajectory within the distribution while guaranteeing that the system state never leaves more than a desired distance from the distribution mean. The control employs feedback linearization to handle nonlinearities in the system dynamics and real-time quadratic programming to ensure a solution exists that satisfies all safety constraints while minimizing control effort. Furthermore, we highlight how the proposed method may allow a designer to emphasize certain safety objectives that are more important than the others. A series of simulations and experiments demonstrate the efficacy of our approach and show it can run in real time.


Glycemic index, glycemic load, and carbohydrate intake in relation to risk of distal colorectal adenoma in women.
Case-control studies and a cohort study have shown inconsistent associations between a high glycemic index or a high glycemic load and risk of colorectal cancer. These dietary variables have not been examined in relation to risk of colorectal adenoma. We thus examined the associations between dietary glycemic index, glycemic load, and carbohydrate intake with risk of adenoma of the distal colon or rectum among 34,428 US women who were initially free of cancer or polyps, who completed a semi-quantitative food-frequency questionnaire in 1980, and who underwent endoscopy from 1980 through 1998. 1,715 adenoma cases (704 large adenomas, 894 small adenomas, 1,277 distal colon adenomas, and 504 rectal adenomas) were documented during 18 years of follow-up. Dietary glycemic index, glycemic load, and carbohydrate intake were not related to risk of total colorectal adenoma after adjustment for age and established risk factors [relative risk (RR) for extreme quintiles of glycemic index = 1.11, 95% confidence interval (CI) 0.94-1.32, P for trend = 0.66; RR for glycemic load = 0.92, 95% CI 0.76-1.11, P for trend = 0.63; RR for carbohydrate intake = 0.90, 95% CI 0.73-1.11, P for trend = 0.64]. In addition, no significant associations were found for large or small adenoma, distal colon or rectal adenoma, or across strata of body mass index. Our findings do not support the hypothesis that a high glycemic index diet, a high glycemic load diet, or high carbohydrate intake overall are associated with risk of colorectal adenoma.


Bacterial infections other than spontaneous bacterial peritonitis in cirrhosis.
Cirrhotic patients are immunocompromised with a high risk of infection. Proinflammatory cytokines and hemodynamic circulation derangement further facilitate the development of serious consequences of infections. Other than spontaneous bacterial peritonitis, bacteremia and bacterial infections of other organ systems are frequently observed. Gram-negative enteric bacteria are the most common causative organism. Other bacterial infections, such as enterococci, Vibrio spp., Aeromonas spp., Clostridium spp., Listeria monocytogenes, Plesiomonas shigelloides and Mycobacterium tuberculosis are more prevalent and more virulent. Generally, intravenous third generation cephalosporins are recommended as empirical antibiotic therapy. Increased incidences of gram-positive and drug-resistant organisms have been reported, particularly in hospital-acquired infections and in patients receiving quinolones prophylaxis. This review focuses upon epidemiology, microbiology, clinical features and treatment of infections in cirrhosis other than spontaneous bacterial peritonitis, including pathogen-specific and liver disease-specific issues.


Interactions between cochlear implant electrode insertion depth and frequency-place mapping.
While new electrode designs allow deeper insertion and wider coverage in the cochlea, there is still considerable variation in the insertion depth of the electrode array among cochlear implant users. The present study measures speech recognition as a function of insertion depth, varying from a deep insertion of 10 electrodes at 28.8 mm to a shallow insertion of a single electrode at 7.2 mm, in four Med-El Combi 40+ users. Short insertion depths were simulated by inactivating apical electrodes. Speech recognition increased with deeper insertion, reaching an asymptotic level at 21.6 or 26.4 mm depending on the frequency-place map used. Başkent and Shannon [J. Acoust. Soc. Am. 116, 3130-3140 (2004)] showed that speech recognition by implant users was best when the acoustic input frequency was matched onto the cochlear location that normally processes that frequency range, minimizing the spectral distortions in the map. However, if an electrode array is not fully inserted into the cochlea, a matched map will result in the loss of considerable low-frequency information. The results show a strong interaction between the optimal frequency-place mapping and electrode insertion depth. Consistent with previous studies, frequency-place matching produced better speech recognition than compressing the full speech range onto the electrode array for full insertion ranges (20 to 25 mm from the round window). For shallower insertions (16.8 and 19.2 mm) a mild amount of frequency-place compression was better than truncating the frequency range to match the basal cochlear location. These results show that patients with shallow electrode insertions might benefit from a map that assigns a narrower frequency range than patients with full insertions.


The enzymatic hydrolysis of a synthetic biomembrane: a new substrate for cholesterol and carboxyl esterases.
With the introduction of artificial implant devices, a new host of biomembrane-like structures have been introduced into the bio-media made up of the synthetic matrix, adsorbed proteins and lipids. Lysosomal hydrolases, e.g. cholesterol esterase (CE), are implicated during the tissue response near the tissue-implant interface. The enzymatic attack on a radiolabelled 'hybrid biomembrane', a polyester-urethane (PUU-CAP), was investigated using two esterases. Membrane stability was monitored by release of radiolabelled molecules. Although some radioactivity was released by buffer controls, upon the addition of CE, a burst of radiolabel release occurred which was due to an enzymatic reaction that could be saturated and inhibited by the specific esterase inhibitor, phenylmethylsulfonylfluoride. Carboxyl esterase (CXE) incubation with PUU-CAP caused less radiolabel release than CE which was similar to the latter's activity when common nitrophenyl ester substrates were used. When a factorial analysis was performed, it was found that side chain length for the common substrates was twice more important for CE, than CXE activity. This would suggest that CE activity is greater for substrates which have spacer segments between potential ester-carbonyl cleavage sites and the rigid ring structure.


Modeling and Electrochemical Characterization of Electrodes Based on Epoxy Composite with Functionalized Nanocarbon Fillers at High Concentration.
This paper deals with the electrochemical characterization and the equivalent circuit modeling of screen-printed electrodes, modified by an epoxy composite and loaded with carbon nanotubes (CNTs), pristine and functionalized NH2, and graphene nanoplates (GNPs). The fabrication method is optimized in order to obtain a good dispersion even at high concentration, up to 10%, to increase the range of investigation. Due to the rising presence of filler on the surface, the cyclic voltammetric analysis shows an increasing of (i) electrochemical response and (ii) filler concentration as observed by the scanning electron microscopy (SEM). Epoxy/CNTs-NH2 and epoxy/GNPs, at 10% of concentration, show the best electrochemical behavior. Furthermore, epoxy/CNTs-NH2 show a lower percolation threshold than epoxy/CNT, probably due to the direct bond created by amino groups. Furthermore, the electrochemical impedance spectroscopy (EIS) is used to obtain an electrical equivalent circuit (EEC). The EEC model is a remarkable evolution of previous circuits present in the literature, by inserting an accurate description of the capacitive/inductive/resistive characteristics, thus leading to an enhanced knowledge of phenomena that occur during electrochemical processes.


Dialogue and labeling. Are these helpful in finding volunteers?
Among social influence techniques, a special place is occupied by dialogue involvement - it is not only a means of improving chances for compliance, but it can also perform a synergistic function, reinforcing the workings of other influence techniques. In two field experiments, we explored what effectiveness the technique of dialogue involvement can have in acquiring volunteers (Study 1) and how it functions in combination with the labeling technique (Study 2). The achieved results demonstrate that dialogue involvement not only increases the chance of obtaining agreement to be a volunteer in a day room facility for children or in a pediatric ward of a local hospital, but it also increases the average number of hours that volunteers declare they will work. Dialogue involvement also demonstrates effectiveness in combination with the technique of labeling.


IACUC training: from new-member orientation to continuing education.
IACUC training is essential to ensure that the self-regulatory process is effective. Unfortunately, there are few official guidelines on methods to accomplish this goal. The author suggests multiple approaches for training new committee members and for the continuing education of the Committee as a whole.


West Nile virus methyltransferase domain interacts with protein kinase G.
The flaviviral nonstructural protein 5 (NS5) is a phosphoprotein, though the precise identities and roles of many specific phosphorylations remain unknown. Protein kinase G (PKG), a cGMP-dependent protein kinase, has previously been shown to phosphorylate dengue virus NS5. We used mass spectrometry to specifically identify NS5 phosphosites. Co-immunoprecipitation assays were used to study protein-protein interactions. Effects on viral replication were measured via replicon system and plaque assay titering. We identified multiple sites in West Nile virus (WNV) NS5 that are phosphorylated during a WNV infection, and showed that the N-terminal methyltransferase domain of WNV NS5 can be specifically phosphorylated by PKG in vitro. Expressing PKG in cell culture led to an enhancement of WNV viral production. We hypothesized this effect on replication could be caused by factors beyond the specific phosphorylations of NS5. Here we show for the first time that PKG is also able to stably interact with a viral substrate, WNV NS5, in cell culture and in vitro. While the mosquito-borne WNV NS5 interacted with PKG, tick-borne Langat virus NS5 did not. The methyltransferase domain of NS5 is able to mediate the interaction between NS5 and PKG, and mutating positive residues in the αE region of the methyltransferase interrupts the interaction. These same mutations completely inhibited WNV replication. PKG is not required for WNV replication, but does make a stable interaction with NS5. While the consequence of the NS5:PKG interaction when it occurs is unclear, mutational data demonstrates that this interaction occurs in a region of NS5 that is otherwise necessary for replication. Overall, the results identify an interaction between virus and a cellular kinase and suggest a role for a host kinase in enhancing flaviviral replication.


Appearance of RNA with a specific size class of poly(A) in oocytes and eggs in HCG-stimulated Xenopus laevis females.
Using a 3H-poly(U) binding technique, poly(A) content has been measured in Xenopus laevis eggs consisting of two groups: one was obtained from females 12 to 16 hr after a single injection of human chorionic gonadotropin (HCG) (designated "unstimulated" eggs), and the other was obtained one week later from the same females by the second injection of the hormone ("stimulated" eggs). The stimulated egg contained about a 1.2-fold larger amount of poly(A) than the unstimulated one. Gel electrophoresis has revealed that this slight but reproducible increase in the poly(A) content was due to the production of a specific size class of poly(A) (i.e., about 80 nucleotides long). This poly(A) was also detectable in the oocytes obtained one week after a single injection but not in those from uninjected females. Poly(A)+RNA was analyzed by sucrose density gradient centrifugation, and it has been shown that most of the 80 nucleotide-long poly(A) sequences in the stimulated eggs were associated with RNA whose size distribution was less heterogeneous than, and hence distinguishable from, that of the bulk poly(A)+RNA. The possibility is discussed that HCG hormone may stimulate the synthesis of a specific class of poly(A)+RNA in smaller oocytes, which may not normally take place to a significant extent during maturation.


Chronic wheel running reduces maladaptive patterns of methamphetamine intake: regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase.
We investigated whether prior exposure to chronic wheel running (WR) alters maladaptive patterns of excessive and escalating methamphetamine intake under extended access conditions, and intravenous methamphetamine self-administration-induced neurotoxicity. Adult rats were given access to WR or no wheel (sedentary) in their home cage for 6 weeks. A set of WR rats were injected with 5-bromo-2'-deoxyuridine (BrdU) to determine WR-induced changes in proliferation (2-h old) and survival (28-day old) of hippocampal progenitors. Another set of WR rats were withdrawn (WRw) or continued (WRc) to have access to running wheels in their home cages during self-administration days. Following self-administration [6 h/day], rats were tested on the progressive ratio (PR) schedule. Following PR, BrdU was injected to determine levels of proliferating progenitors (2-h old). WRc rats self-administered significantly less methamphetamine than sedentary rats during acquisition and escalation sessions, and demonstrated reduced motivation for methamphetamine seeking. Methamphetamine reduced daily running activity of WRc rats compared with that of pre-methamphetamine days. WRw rats self-administered significantly more methamphetamine than sedentary rats during acquisition, an effect that was not observed during escalation and PR sessions. WR-induced beneficial effects on methamphetamine self-administration were not attributable to neuroplasticity effects in the hippocampus and medial prefrontal cortex, but were attributable to WR-induced inhibition of methamphetamine-induced increases in the number of neuronal nitric oxide synthase expressing neurons and apoptosis in the nucleus accumbens shell. Our results demonstrate that WR prevents methamphetamine-induced damage to forebrain neurons to provide a beneficial effect on drug-taking behavior. Importantly, WR-induced neuroprotective effects are transient and continued WR activity is necessary to prevent compulsive methamphetamine intake.


Neighborhood Disadvantage Measures and COVID-19 Cases in Boston, 2020.
Understanding the pattern of population risk for coronavirus disease 2019 (COVID-19) is critically important for health systems and policy makers. The objective of this study was to describe the association between neighborhood factors and number of COVID-19 cases. We hypothesized an association between disadvantaged neighborhoods and clusters of COVID-19 cases. We analyzed data on patients presenting to a large health care system in Boston during February 5-May 4, 2020. We used a bivariate local join-count procedure to determine colocation between census tracts with high rates of neighborhood demographic characteristics (eg, Hispanic race/ethnicity) and measures of disadvantage (eg, health insurance status) and COVID-19 cases. We used negative binomial models to assess independent associations between neighborhood factors and the incidence of COVID-19. A total of 9898 COVID-19 patients were in the cohort. The overall crude incidence in the study area was 32 cases per 10 000 population, and the adjusted incidence per census tract ranged from 2 to 405 per 10 000 population. We found significant colocation of several neighborhood factors and the top quintile of cases: percentage of population that was Hispanic, non-Hispanic Black, without health insurance, receiving Supplemental Nutrition Assistance Program benefits, and living in poverty. Factors associated with increased incidence of COVID-19 included percentage of population that is Hispanic (incidence rate ratio [IRR] = 1.25; 95% CI, 1.23-1.28) and percentage of households living in poverty (IRR = 1.25; 95% CI, 1.19-1.32). We found a significant association between neighborhoods with high rates of disadvantage and COVID-19. Policy makers need to consider these health inequities when responding to the pandemic and planning for subsequent health needs.


Exceptional CO2 working capacity in a heterodiamine-grafted metal-organic framework.
An amine-functionalized metal-organic framework (MOF), dmen-Mg2(dobpdc) (dmen = N,N-dimethylethylenediamine), which contains a heterodiamine with both primary and tertiary amines, was prepared via a post-synthetic method. This material exhibits a significant selectivity factor for CO2 over N2 that is commensurate with top-performing MOFs. It is remarkable that the solid is fully regenerated under vacuum or flowing Ar at low desorption temperatures, and following this can take up CO2 at more than 13 wt%. An exceptionally high working capacity is achieved at low regeneration temperatures and after exposure to humid conditions, which are important parameters for a real post-combustion CO2 capture process.


Combining machine learning systems and multiple docking simulation packages to improve docking prediction reliability for network pharmacology.
Increased availability of bioinformatics resources is creating opportunities for the application of network pharmacology to predict drug effects and toxicity resulting from multi-target interactions. Here we present a high-precision computational prediction approach that combines two elaborately built machine learning systems and multiple molecular docking tools to assess binding potentials of a test compound against proteins involved in a complex molecular network. One of the two machine learning systems is a re-scoring function to evaluate binding modes generated by docking tools. The second is a binding mode selection function to identify the most predictive binding mode. Results from a series of benchmark validations and a case study show that this approach surpasses the prediction reliability of other techniques and that it also identifies either primary or off-targets of kinase inhibitors. Integrating this approach with molecular network maps makes it possible to address drug safety issues by comprehensively investigating network-dependent effects of a drug or drug candidate.