Comparison of tests and procedures to build clinically relevant genotypic scores: application to the Jaguar study.
To compare non-parametric tests and procedures of selection in building clinically validated genotypic scores. In the Jaguar study, 111 patients on a stable antiretroviral regimen experiencing virological failure were randomized in the didanosine (ddI) arm to receive ddI for 4 weeks in addition to their current combination therapy. The virological response was HIV-1 RNA reduction from baseline to week 4. The univariate impact of each mutation associated with resistance to ddI on virological response was quantified by comparing reduction in plasma HIV-1 RNA in patients with or without the specific mutation, using a Wilcoxon-Mann-Whitney test. The next step was to select the combination of mutations most strongly associated with the virological response. Two procedures and two tests were compared using either the set of resistance mutations or the set of resistance mutations and mutations providing a better virological response. The Kruskal-Wallis and the Jonckheere test for ordered alternatives were compared in order to build a genotypic score using the two distinct procedures. Eight mutations were associated with a reduced virological response to ddI: M41L, D67N, T69D, L74V, V1181, L210W, T215Y/F and K219Q/E and two mutations with a better virological response: K70R and M184V/I. The Jonckheere-Terpstra test for trend provided the combination of mutations (M41L+T69D-K70R+L74V-M184V /I+T215Y/F+ K219A/E) that were the most predictive for the week 4 virological response, that is, leading to the lowest P value. The 'removing' procedure, starting from a set of mutations retained and removing mutations one by one to find the best combination, provides lower P values than the 'adding' procedure starting with a single mutation and adding mutations one by one. Whatever the set of mutations and the procedure used, the Jonckheere-Terpstra test selects combinations of mutations leading to lower P values than the Kruskal-Wallis test. The Jonckheere-Terpstra test for trend is recommended for building a genotypic score when compared with the Kruskal-Wallis. The choice of the selection procedure is discussed here and may be dependent on the objective of the score.


Pragmatic language and school related linguistic abilities in siblings of children with autism.
Siblings of probands with autism spectrum disorders are at higher risk for developing the broad autism phenotype (BAP). We compared the linguistic abilities (i.e., pragmatic language, school achievements, and underling reading processes) of 35 school-age siblings of children with autism (SIBS-A) to those of 42 siblings of children with typical development. Results indicated lower pragmatic abilities in a subgroup of SIBS-A identified with BAP related difficulties (SIBS-A-BAP) whereas school achievements and reading processes were intact. Furthermore, among SIBS-A-BAP, significant negative correlations emerged between the severity scores on the Autism Diagnostic Observation Schedule and full and verbal IQ scores. These results are discussed in the context of the developmental trajectories of SIBS-A and in relation to the BAP.


Comparative acceptance of pertussis and influenza immunization among health-care personnel.
Pertussis and influenza immunization in health-care professionals (HCP) has been shown to lead to significant reduction of nosocomial infections. Parallel campaigns of pertussis and seasonal influenza immunization gave us a unique opportunity to compare attitudes towards influenza and pertussis immunization among HCP and to determine acceptance rates for both or either one of the two immunizations or refusal of both. A questionnaire was sent to HCP to anonymously obtain demographic data, profession, numbers of previous influenza immunizations, acceptance of influenza immunization in the current 2012/13 season, pertussis immunization currently or within the last 10 years, and reasons for acceptance or decline of pertussis and influenza vaccination. Of 638 HCP with patient contact, 314 (49%) responded and 303 (47%) were included in the analysis. Immunization acceptance rates were 33% for influenza, 57% for pertussis; 24% accepted both immunizations and 34% none of both. Acceptance of influenza immunization was significantly higher in those with one or more previous influenza vaccinations (p<0.005). Among 130 HCP who declined pertussis immunization, missed opportunity (28%) was the dominant reason. Of 204 HCP who declined influenza immunization, the most frequently stated reason was "lack of influenza immunization is not considered an issue" (36%). Misconceptions about the efficacy and necessity of pertussis and especially influenza immunization continue to prevail among HCP. Active promotion, personal encouragement, providing more immunization opportunities and other incentives are measures that should be considered to increase the rate of immunization among HCP.


Positive Massage: An Intervention for Couples' Wellbeing in a Touch-Deprived Era.
COVID-19 has brought not only fear and anxiety, but also legitimate restrictions of communication and consequential touch-deprivation in our daily lives. Couples' relational wellbeing continues to be impacted by these COVID-19 related stressors. Protecting both personal and relational wellbeing is therefore particularly important at this time. Using a preventative intervention approach, the current paper argues the theoretical benefit of the Positive Massage programme and reports a qualitative analysis of stressed but healthy couples' experience of engaging in the programme. Thirty-four participants completed 3 weekly classes and home-based practice of massage exchange. Data from an open text online questionnaire completed every week of the programme and again 3 weeks afterwards were analysed using thematic analysis. The identified themes included "holistic stress relief", "relationship-promotion", and "selves-care skill". Couples perceived Positive Massage as an effective mutual support skill to relax and help one another by de-stressing, both emotionally and physically through verbal and nonverbal communication, creating gratitude, deeper connection and self-efficacy via quality time together and pleasurable touch. Theoretically and experientially, Positive Massage can be an effective preventative selves-care skill. Promoting the concept of selves-care and its practical application through Positive Massage would be beneficial for couples' personal and relational wellbeing in a touch-deprived era.


Recovery from depression.
Full recovery from depression, as contrasted with symptom improvement, is a relatively new concept and therapeutic goal. It is an important goal, because the failure to achieve this goal leaves many patients with less productive and fulfilling lives, it leaves some children with lasting deficits, and it deprives families and societies of loved ones' and employees' care and investment. As a new therapeutic concept, recovery from depression is not as easy to define as it might seem; many or most patients were not euthymic before an episode of depression or have had some level of depression throughout their lives. There is no measurable definition of euthymia. In addition to definitional difficulties, we need to study and address other barriers to the achievement of recovery from depression. All the barriers to the diagnosis and treatment of depression are barriers against recovery: negative social and professional attitudes, comorbidity, lack of access to demonstrably efficacious professional and social services, and inability to match patients with the antidepressants most likely to help them. Efforts to address many of these knowledge and attitude gaps are already underway. Long-term studies are needed, both observational and experimental. Most published studies encompass only weeks or at best months of follow-up, but recovery must be sustained to be meaningful. As noted previously, there has been little or no attention to the developmental impact of depression. The restoration of premorbid function is not sufficient when depression has hindered a patient's ability to form satisfying relationships and choose and perform satisfying work. We need to learn how to remediate patients whose history of depression has stifled their talents and aspirations. Studying these issues will not be easy, but millions of individuals with depression, and their physicians, will profit by it; it will be well worth the effort.


Automatisation of chronic toxicities.
Automatisation of collection and processing of chronic toxicity tests are presented in a 'pharmaceutical research center environment'. The data are either analog signals or numerical values transmitted to the computer, from terminals posted in various laboratories. The minicomputer works under time-sharing system which allows many users to access to the programs in the same time. This system controls about 3000 results a day and prints complete reports in less than two days. Rewriting is then avoided thanks to this system, and in such a way, the reports are more reliable.


Oxygen in the Tumor Microenvironment: Mathematical and Numerical Modeling.
There are many reasons to try to achieve a good grasp of the distribution of oxygen in the tumor microenvironment. The lack of oxygen - hypoxia - is a main actor in the evolution of tumors and in their growth and appears to be just as important in tumor invasion and metastasis. Mathematical models of the distribution of oxygen in tumors which are based on reaction-diffusion equations provide partial but qualitatively significant descriptions of the measured oxygen concentrations in the tumor microenvironment, especially when they incorporate important elements of the blood vessel network such as the blood vessel size and spatial distribution and the pulsation of local pressure due to blood circulation. Here, we review our mathematical and numerical approaches to the distribution of oxygen that yield insights both on the role of the distribution of blood vessel density and size and on the fluctuations of blood pressure.


Meat and fish consumption, APC gene mutations and hMLH1 expression in colon and rectal cancer: a prospective cohort study (The Netherlands).
The aim of this study was to investigate the associations between meat and fish consumption and APC mutation status and hMLH1 expression in colon and rectal cancer. The associations were investigated in the Netherlands Cohort Study, and included 434 colon and 154 rectal cancer patients on whom case-cohort analyses (subcohort n = 2948) were performed. Total meat consumption was not associated with the endpoints studied. Meat product (i.e. processed meat) consumption showed a positive association with colon tumours harbouring a truncating APC mutation, whereas beef consumption was associated with an increased risk of colon tumours without a truncating APC mutation (incidence rate ratio (RR) highest versus lowest quartile of intake 1.61, 95% confidence interval (CI) 0.96-2.71, p-trend = 0.04 and 1.58, 95% CI 1.10-2.25, p-trend = 0.01, respectively). Consumption of other meat (horsemeat, lamb, mutton, frankfurters and deep-fried meat rolls) was associated with an increased risk of rectal cancer without a truncating APC mutation (RR intake versus no intake 1.79, 95% CI 1.10-2.90). No associations were observed for meat consumption and tumours lacking hMLH1 expression. Our data indicate that several types of meat may contribute differently to the aetiology of colon and rectal cancer, depending on APC mutation status but not hMLH1 expression of the tumour.


[Extremely advanced basal cell carcinoma in periocular region: a case report].
A case of extreme basal cell carcinoma affecting eyelids region in a 66-year old man is presented. Long time duration, large destruction of the face tissues and histopathological type of metatypic basal cell carcinoma (bcc) eliminated any way of therapy (surgery, radiotherapy, chemotherapy). We present this case because bcc as localy invasive tumor with low growth, diagnosed and treated at early stage can lead to complete recovery.


Treatment of very small vessels with 2.25-mm diameter sirolimus-eluting stents (from the RESEARCH registry).
A total of 91 patients with 112 lesions received 2.25-mm sirolimus-eluting stents (SESs), and these lesions were compared with those treated with SESs of > or =2.5-mm diameter in the same procedure (n = 109). The reference diameters were 1.88 +/- 0.34 and 2.52 +/- 0.57 mm, respectively (p <0.01). At follow-up, the late lumen loss was 0.07 +/- 0.48 mm for the 2.25-mm SES versus 0.03 +/- 0.38 mm for the larger SES (p = 0.5), and the binary restenosis rate was 10.7% versus 3.9%, respectively (p = 0.1). The 12-month target lesion revascularization rate was 5.5%. In conclusion, 2.25-mm SESs were associated with low rates of clinical and angiographic late complications.


Adjacent segment pathology: natural history or effect of anterior cervical discectomy and fusion? A 10-year follow-up radiological multicenter study using an evaluation scale of the ageing spine.
Aim of this study is to compare late degenerative MRI changes in a subset of patients operated on with ACDF to a second subset of patients presenting indication to ACDF but never operated on. Patients from both subgroups received surgical indication according to the same criteria. Both subgroups underwent a cervical spine MRI in 2004-2005 and 10 years later in 2015. These MRI scans were retrospectively evaluated with a cervical spine ageing scale. Comparing the two subset of patients both suffering from clinically relevant single-level disease returns no statistically significant difference in the degenerative condition of posterior ligaments, presence of degenerative spondylolisthesis, foraminal stenosis, diameter of the spinal canal, Modic alteration, and intervertebral discs degeneration at 10-year follow-up. The adjacent segment degeneration represents, in the present cohort, a result of the natural history of cervical spondylosis rather than a consequence of fusion.


Peptidoglycan recognition proteins-maintaining immune homeostasis and normal development.
Peptidoglycan recognition proteins (PGRPs) are innate immune molecules with a diverse array of functions. In this issue of Cell Host & Microbe, Maillet and colleagues demonstrate that a Drosophila PGRP, PGRP-LF, functions as a negative regulator of the Drosophila immune deficiency (IMD) pathway, an innate immune signaling mechanism responsive to Gram-negative bacteria. PGRP-LF deficiency results in unregulated immune signaling, causing excessive antimicrobial peptide synthesis and, surprisingly, developmental defects.


Metagenomic analysis revealed sources, transmission, and health risk of antibiotic resistance genes in confluence of Fenhe, Weihe, and Yellow Rivers.
Rivers are important vectors and reservoirs of antibiotics resistance genes (ARGs). Information regarding transmission and health risk of ARGs in river confluence is still lacking. In this study, metagenomics was used to distinguish contributions of human activities on ARGs and human pathogenic bacteria (HPB) in confluence of Fenhe, Weihe, and Yellow Rivers. Bacitracin resistance gene and bacA were the highest in all rivers, with 1.86 × 10-2-7.26 × 10-2 and 1.79 × 10-2-9.12 × 10-2 copies/16S rRNA copies, respectively. River confluence significantly increased the abundance of ARGs, especially at the confluence of three rivers with the highest 1.53 × 10-1 copies/16S rRNA copies. Antibiotic efflux and antibiotic target alteration were the dominant resistant mechanisms in three rivers. ARGs profiles were influenced by multiple factors, with the contributions of various factors ranked as microbial communities > physicochemical factors > human activities > mobile genetic elements (MGEs). Notably, human activities and animal feces were important potential contributors of ARGs in the Weihe River and Yellow River. Transposons, as the main MGEs in three rivers, played important roles in ARGs transfer. The confluence of three rivers had the highest abundance of MGEs with the greatest transfer potentials, and therefore exhibiting the largest exposure risk of ARGs with 232.4 copies/cap·d. Furthermore, correlations of ARGs, MGEs, and HPB in different rivers were constructed via co-occurrence modes to systematically illustrate the health risks of ARGs. This study firstly unveiled the transmission and health risk of ARGs in river confluence, providing supports for ARGs control in watershed.


[Detection of extended spectrum β-lactamase OXA-141 in Pseudomonas aeruginosa strains isolated from patients with cystic fibrosis].
The aims of this research were to study the presence of extended spectrum β-lactamases (ESBL) to investigate the location of the genes encoding these enzymes, and determine the clonal relationship of strains of ceftazidime-resistant Pseudomonas aeruginosa isolated from Mexican patients with cystic fibrosis. We determined the resistance profile to 11 antibiotics (CLSI) and phenotypic ESBL detection following a disk diffusion method adapted for P. aeruginosa. Characterization of ESBL genes and integrons was performed by polymerase chain reaction (PCR) and DNA sequencing, while analysis of the clonal relationship was performed by pulsed field gel electrophoresis (PFGE). Of the 148 strains studied, 22 were resistant to ceftazidime, and analysis by PCR and sequencing revealed the presence of the gene bla(OXA-141) in 7 strains, 6 of which were resistant and one, susceptible to ceftazidime. In addition, bla(GES) was detected in 11 strains. intI2 and intI3 genes were not detected by PCR, but in the 6 ceftazidime-resistant strains, the bla(OXA-141) gene was determined in a class 1 integron. Analysis of the clonal relationship of isolates showed that the majority of patients were infected during the study period with P. aeruginosa strains that exhibit different patterns, especially in individuals without a familial relationship. This report demonstrates the existence of the bla(OXA-141) gene associated with a class 1 integron in several strains of P. aeruginosa, as well as bla(GES) genes, and their location and variants are being studied by our research group. This, combined with the diversity of strains able to infect several susceptible individuals, suggests the risk of spread of P. aeruginosa-strain ESBL producers among Mexican populations with cystic fibrosis.


Association Between Perfusate Oxygenation and Acute Lung Injury in Tetralogy of Fallot Surgery.
Little is known regarding precise estimates of the association between perfusate oxygenation (PpO2) and acute lung injury (ALI) following tetralogy of Fallot repair. The objective is to investigate PpO2 and the risk of ALI following tetralogy of Fallot repair in pediatric patients. We conducted a nested case-control study within a prospective Chinese TedaICH cohort including 134 ALI patients aged 1 month to 18 years undergoing complete repair of tetralogy of Fallot, and each was matched to two controls. We selected the highest PpO2 during aortic crossclamp as the exposure. Conditional logistic regression was used to quantify the association between PpO2 and overall ALI risk by covariates of interest. We identified and integrated the risk covariates to build ALI nomograms and internally validated the nomograms using bootstrapping. After adjusting for covariates, continuously and categorically higher PpO2 values were associated with ALI risk (all P < 0.05), especially for those with a z-score of pulmonary annulus < -4.0 (P = 0.002), McGoon ratio < 1.5 (P = 0.029), and major aortopulmonary collateral arteries (P = 0.005), despite no statistical heterogeneity (all P interaction >0.05). Younger age, lower oxyhemoglobin saturation, untreated minor aortopulmonary collateral arteries, transannular patch, larger transpulmonary gradient, major transfusion, and longer cardiopulmonary bypass time were independent risk factors for ALI (all P < 0.05). Combining the PpO2 nomogram provided further risk discriminative information on ALI diagnosis compared with the covariate-based nomogram alone in the training cohort (AUC 0.865, 95% CI [0.828-0.903] vs. 0.869 [0.832-0.906], respectively) with no statistical significance (P = 0.445). The findings suggested an association between high PpO2 and ALI risk, and more importance should be attached to independent risk factors for ALI.


Relation between Ku80 and microRNA-99a expression and late rectal bleeding after radiotherapy for prostate cancer.
Late rectal bleeding is one of the severe adverse events after radiotherapy for prostate cancer. New biomarkers are needed to allow a personalized treatment. Four patients each with grade 0-1 or grade 2-3 rectal bleeding were randomly selected for miRNA array to examine miRNA expression in peripheral blood lymphocytes (PBLs). Based on results of miRNA array, 1 of 348 miRNAs was selected for microRNA assays. Then, expression of DNA-dependent protein kinase mRNA and miR-99a was analyzed in the PBLs of 97 patients. PBLs were exposed to 4Gy of X-ray ex-vivo. In the discovery cohort, grade 2-3 rectal bleeding was significantly higher in the Ku80 <1.09 expression group compared with ⩾1.09 group (P=0.011). In radiation-induced expression of miR-99a, grade 2-3 rectal bleeding was significantly higher in the miR-99a IR(+)/IR(-) >0.93 group compared with ⩽0.93 group (P=0.013). Most patients with grade 2-3 rectal bleeding were in the group with low Ku80 and high miR-99a expression. In the validation cohort, similar results were obtained. A combination of low Ku80 expression and highly-induced miR-99a expression could be a promising marker for predicting rectal bleeding after radiotherapy.


Analgesia by enkephalins injected into the nucleus reticularis gigantocellularis of rat medulla oblongata.
Methionine-enkephalin (0.2--20 microgram/rat) and leucine-enkephalin (1--20 microgram/rat) produced a dose-related and naloxone-antagonizable analgesia in the tail-pinch test, when microinjected into the nucleus reticularis gigantocellularis (NRGC) and nucleus reticularis paragigantocellularis (NRPG) of the medulla oblongata of the rat. The median analgesic doses were 1.4 and 4.8 microgram/rat for methionine- leucine-enkephalin, respectively. The possibility that the endogenous enkephalins play a part as pain control substances or modulators in the NRGC and NRPG was discussed.


Bright Fluorescence and Host-Guest Sensing with a Nanoscale M₄L₆ Tetrahedron Accessed by Self-Assembly of Zinc-Imine Chelate Vertices and Perylene Bisimide Edges.
A highly luminescent Zn4L6 tetrahedron is reported with 3.8 nm perylene bisimide edges and hexadentate Zn(II)-imine chelate vertices. Replacing Fe(II) and monoamines commonly utilized in subcomponent self-assembly with Zn(II) and tris(2-aminoethyl)amine provides access to a metallosupramolecular host with the rare combination of structural integrity at concentrations <10(-7) mol L(-1) and an exceptionally high fluorescence quantum yield of Φ(em) =0.67. Encapsulation of multiple perylene or coronene guest molecules is accompanied by strong luminescence quenching. We anticipate this self-assembly strategy may be generalized to improve access to brightly fluorescent coordination cages tailored for host-guest light-harvesting, photocatalysis, and sensing.


EcPV-2 is transcriptionally active in equine SCC but only rarely detectable in swabs and semen from healthy horses.
Squamous cell carcinomas (SCC) are malignant tumours arising from keratinocytes. In horses, there is increasing evidence for Equus caballus papillomavirus type 2 (EcPV-2) being causally involved in SCC development. However, only little is known regarding intralesional transcription of the virus, and sparse information on the incidence of EcPV-2 infection in healthy equids is available so far. Using RT-PCR, total mRNA from 8 EcPV-2 DNA-positive and 1 EcPV-2 negative SCC/SCC precursor lesions was screened for the presence of EcPV-2 E6 and E1 transcripts. Using PCR, we tested 193 sample specimens (30 ocular swabs, 94 genital swabs, 54 semen and 15 milk samples) from a total of 161 apparently healthy horses for the presence of EcPV-2 genes E7 and E6 or E2. Positive results were confirmed by repeating the PCR reactions, and by amplicon sequencing. E6 mRNA was detectable in 8/8 EcPV-2 DNA-positive lesions, whereas only 3/8 scored positive for E1 mRNA. EcPV-2 PCR scored positive for DNA from 1/30 ocular swabs, 4/94 genital swabs, 0/54 semen and 0/15 milk samples, thus resulting in an overall detection rate of 5/193, i.e. 2.6%. The demonstrated presence of viral mRNA in all EcPV-2 DNA-positive lesions is suggestive for an active pathogenic role of the virus in SCC development. This finding and the low incidence of EcPV-2 DNA in healthy equids further strengthen the concept of an aetiologic association of EcPV-2 with equine SCC disease.


Clinical study of papular urticaria.
To determine the clinical features and demographic profile of the patients having papular urticaria. A case-series. Dermatology Department of Combined Military Hospital, Abbottabad from January to December 2006. Individuals of all age groups and either gender either suspected of or having definite history of insect bite were included in the study. A specially-designed proforma was filled for each patient separately. The proforma included demographic features, information regarding clothing and sleeping habits, personal or family history of atopy and clinical patterns of the lesions. Computer programme SPSS 10 was used to manage and analyze the data. Out of 280 patients, 201 (71.8%) were children upto 12 years of age, 178 (63.6%) were males, 91 (32.5%) had atopy, 194 (69.3%) were non-locals, 212 (75.7%) came from urban/peri-urban areas and 173 (61.8%) presented during May-August. Lesions were present over exposed parts of the body in 36 (12.9%), arranged in groups in 152 (54.3%) and were papular urticaria in 185 (66.1%) patients. Children, adult males, non-locals and those belonging to urban/peri-urban areas are more vulnerable to papular urticaria in a particular region. Papular and urticarial lesions arranged in groups over both exposed as well as covered body parts of a single patient is the most common clinical pattern.


Decreased sympathetic innervation of spleen in aged Fischer 344 rats.
Splenic noradrenergic innervation in young adult and aged Fischer 344 rats was examined using fluorescence histochemistry for catecholamines and high performance liquid chromatography with electrochemical detection (LCEC) for the quantitation of norepinephrine (NE). In young adult rats, abundant noradrenergic plexuses followed the vasculature and trabeculae into splenic white pulp. In aged rats, noradrenergic innervation was reduced in density and in overall intensity of fluorescence, and splenic NE levels were significantly lower. The relationship between diminished noradrenergic innervation and diminished immune responsiveness in aging mammals, while not clear on a causal level, is presented as a hypothesis for further testing.


Endotoxin induces a delayed loss of TH-IR neurons in substantia nigra and motor behavioral deficits.
We have previously reported that a single injection of endotoxin, lipopolysaccharide (LPS, 5mg/kg, i.p.), causes a delayed and progressive loss of TH-IR neurons in the substantia nigra (SN) in C57BL/six male mice. In this study, we determined sex differences and behavioral deficits accompanying the loss of TH-IR neurons in response to peripheral LPS injection. A single injection of LPS (5mg/kg, i.p.) failed to produce any loss of TH-IR neurons in the SN of female mice over a 12-month period. To determine if multiple-injections were required, female mice received five injections of LPS (5mg/kg, i.p.) at either weekly or monthly intervals. Behavioral motor ability and TH-IR neuronal loss were determined after the first injection of LPS. We found significant differences in both behavioral activities and neuronal loss between these two injection paradigms. Between 7 and 20 months after the first injection of LPS, progressive behavioral changes, measured by rotor-rod and open-field activities, and neuronal loss in SN were observed in monthly injected, but not in weekly injected mice. In addition, reduced rotor-rod ability in monthly injected mice were restored following treatment of l-dopa/carbidopa (30 mg/3mg/kg), i.p.). Approximately 40 and 50% loss of TH-IR neurons at 9 and 20 months, respectively, was observed after exposure to LPS, suggesting that the behavioral deficit is related to loss of dopamine function in the nigra-striatal pathway. More intense immuno-staining of alpha-synuclein and inflammatory markers were detected in brain sections exposed to LPS. In conclusion, these results show that multi-LPS monthly injections can induce a delayed and progressive loss of TH-IR neurons and motor deficits which resemble the progressive nature of Parkinson's disease. Further, the present study reveals a clear sex difference: female mice are more resistant to LPS than male mice. Repeated monthly LPS injections are required to cause both motor behavioral deficits and DA neuronal loss in female mice.


New and sensitive assay for determining Pseudomonas aeruginosa metallo-beta-lactamase resistance to imipenem.
We present an imipenem lysate metallo-beta-lactamase (MBL) functional assay. This assay eliminates false-positive results due to the bactericidal effects of EDTA, can be performed with inexpensive reagents available in most laboratories, and is as accurate as the MBL Etest. It is appropriate for both high-accuracy screens and laboratories in developing countries with limited resources.


Outpatient surgical management of non-melanoma skin cancers of the head and neck in a regional centre: an analysis of costs and outcomes.
Non-melanoma skin cancer is the most commonly diagnosed malignancy in Australia. Lesions of the head and neck are often outside the scope of primary care providers. The challenges of cancer care in regional Australia necessitate careful resource planning. This study presents an outpatient model that minimizes health service cost with local general practitioner follow-up. A retrospective review of 105 patients with 122 skin lesions in a dedicated Facial Lesion Assessment Management and Excision clinic was performed from July 2018 to 2019. Clinical outcomes, patient travel and cost analysis/comparison were recorded. There were 85 malignant cases with 59 basal cell carcinomas and 25 squamous cell carcinomas. For basal cell carcinoma, clear margins (≥3 mm), close margins (<3 mm) and positive margins were achieved in 24 (48%), 23 (46%) and three (6%) cases, respectively. For squamous cell carcinoma, clear margins (≥5 mm), close margins (<5 mm) and positive margins were achieved in seven (38.8%), 11 (61.1%) and none (0%) of the cases, respectively. Complications included one haematoma and two wound infections. For 37% of patients living >100 km from the department, 72.3% had local general practitioner follow-up. Inpatient cost was $2870, $5697 and $9300 for primary closure, local flap and full-thickness skin graft, respectively, and outpatient cost was $746 for a single facial lesion. This study presents a cost-effective model for the management of non-melanoma skin cancers with improved departmental efficiency and streamlined patient care in an outpatient skin cancer management model in a regional centre.


Mechanisms governing the impact of nitrogen stress on the formation of secondary metabolites in Artemisia argyi leaves.
Nitrogen is a key factor in various physiological and metabolic processes in plants. Providing an adequate supply of nitrogen is essential for improving the total yield and quality of the medicinal plant Artemisia argyi (A. argyi), but the underlying mechanisms of how this nutrient alters the crop remains unclear. In this study, we conducted a series of pot experiments to investigate the agronomic traits and active components in the leaves of A. argyi plants under low and high nitrogen stress. Additionally, we used transcriptome analysis and RT-qPCR to explore the molecular pathways associated with nitrogen stress. Our results demonstrate a dramatic increase in the accumulation of phenolic acids and flavonoids in the low nitrogen (LN) stress group compared to the control (CK), with increases of 40.00% and 79.49%, respectively. Interestingly, plants in the high nitrogen (HN) stress group exhibited enhanced plant growth with larger leaves, thicker stems, and a 3% increase in volatile oil content compared to the CK. Moreover, A. argyi in the HN group displayed a 66% increase in volatile oil concentration compared to the LN group. Our combined transcriptome and q-PCR results indicate that LN stress promotes the expression of genes involved in flavonoid synthesis, while HN stress promotes the expression of genes related to terpene skeleton production and photosynthesis. Taken together, these findings suggest that different gene expression levels under LN and HN stress contribute to the photosynthesis capacity and the accumulation of active ingredients in A. argyi leaves. Our results elucidate the physiological and molecular mechanisms of nitrogen stress on A. argyi secondary metabolites and guide fertilization strategies for plant cultivation.


Risks of repeat sternotomy in pediatric cardiac operations.
Repeat sternotomy has been associated with increased perioperative risks. We reviewed 165 patients undergoing 192 repeat sternotomies between January 1985 and January 1997 (group 1) and a control group of 184 patients (group 2). The operations in group 1 were valve procedures in 94 patients, Fontan procedure in 46, ventricular septal defect closure in 10, pulmonary arterioplasty in 17, and others in 25; in group 2 ventricular or atrial septal defect closure in 120 patients, tetralogy of Fallot repair in 26, valve procedures in 16, bidirectional Glenn anastomosis in 7, repair of transposition of the great arteries in 7, pulmonary arterioplasty in 4, and others in 4. The hospital mortality was 2.6% in group 1 and 3.8% in group 2. Cardiac laceration occurred in 10 of 192 patients (5.2%), requiring emergent femorofemoral bypass in 6 patients. Two patients sustained an air embolism that was successfully treated with a hyperbaric chamber. Median total blood loss and requirements were not significantly different between the two groups. The length of stay in the intensive care unit and in the hospital were 4 days (range, 1 to 80 days) and 11 days (range, 1 to 135 days) in group 1, and 2 days (range, 1 to 87 days) and 7 days (range, 1 to 131 days) in group 2 (p < 0.02 and p < 0.002, respectively). The rate of complications was not significantly different in group 1 versus group 2. Overall survival was 97% (group 1) and 95% (group 2) at 120 months' follow-up (not significant). With careful surgical technique and judicious use of femorofemoral bypass, the risk of repeat sternotomy is minimized.


Left Main Coronary Artery Atresia in Young Man Examined With 99mTc-Tetrofosmin SPECT: A Rare and Challenging Anomaly.
A young man underwent Tc-tetrofosmin cardiac SPECT/CT for the evaluation of the 8-month history of exertional dyspnea without chest pain. Tc-tetrofosmin SPECT demonstrated absence of perfusion defects and a mildly decreased uptake in post-stress images, consistent with artifact, in the inferior myocardium. Cardiac catheterization showed a large right and a small left coronary artery opacified retrogradely by right collateral vessels without connections between the left main and the left coronary artery. In patients with anomalous coronary arteries, Tc SPECT can shows absence of perfusion defects, in the presence of a collateral circulation.


Tight vs liberal control of mild postpartum hypertension: a randomized controlled trial.
High-quality evidence to inform the management of postpartum hypertension, including the optimal blood pressure threshold to initiate therapy, is lacking. Randomized trials have been conducted in pregnancy, but there are no published trials to guide management in the postpartum period. This study aimed to test the hypothesis that initiating antihypertensive therapy in the postpartum period at a threshold of 140/90 mm Hg would result in less maternal morbidity than initiating therapy at a threshold of 150/95 mm Hg. We performed a pragmatic multicenter randomized controlled trial of patients aged 18 to 55 years with postpartum hypertension. Patients with chronic hypertension, gestational hypertension, and preeclampsia without severe features were randomized to 1 of 2 blood pressure thresholds to initiate treatment: persistent blood pressure of ≥150/95 mm Hg (institutional standard or "liberal control" group) or ≥140/90 mm Hg (intervention or "tight control" group). Our primary outcome was composite maternal morbidity defined as: severe hypertension (blood pressure ≥160/110 mm Hg) or preeclampsia with severe features, the need for a second antihypertensive agent, postpartum hospitalization >4 days, and maternal adverse outcome secondary to hypertension as evidenced by pulmonary edema, acute kidney injury (creatinine level ≥1.1 mg/dL), cardiac dysfunction (eg, elevated brain natriuretic peptide level) or cardiomyopathy, posterior reversible encephalopathy syndrome, cerebrovascular accident, or admission to an intensive care unit. Secondary outcomes included hospital readmission for hypertension, persistence of hypertension beyond 14 days, medication side effects, and time to blood pressure control. We calculated that 256 women would provide 90% power to detect a relative 50% reduction in the primary outcome from 36% in the standard blood pressure threshold group to 18%, with a 2-sided alpha set at 0.05 for significance. Data were analyzed using R statistical software. A total of 256 patients were randomized, including 128 to the "tight control" group (140/90 mm Hg) and 128 to the "liberal control" group (150/95 mm Hg). Patients in the "tight control" group had a higher body mass index at delivery (37.1±9.4 vs 34.9±8.1; P=.04); other demographic and obstetrical characteristics were similar between groups. The rate of the primary outcome was similar between groups (8.6% vs 11.7%; P=.41; relative risk, 0.73; 95% confidence interval, 0.35-1.53). The rates of all secondary outcomes and the individual components of the primary and secondary outcome measures were also similar between groups. In the postpartum period, initiation of antihypertensive therapy at a lower blood pressure threshold of 140/90 mm Hg did not decrease maternal morbidity or improve outcomes compared with a threshold of 150/95 mm Hg.


The Moderating Role of Sexual Orientation in the Association Between Religiosity and Sexual Behaviors Among College Students.
Past research has shown that religiosity can impact sexual behaviors of college-aged youth in both positive and negative directions. As many world religions promote doctrines that include negative views toward sexual minorities, the current study aimed to examine the potentially differential ways religiosity is related to sexual behaviors across various sexual orientations. College/university students across Oregon (N = 1553) completed an online cross-sectional survey in which they provided information about their sexual orientation, levels of religiosity, religious affiliation, and endorsed recent sexual behavior outcomes. Using logistic models in PROCESS, sexual orientation was examined as a moderator of the relations between religiosity (assessed via the Centrality of Religiosity Scale; Huber & Huber) and religious affiliation and the occurrence (yes vs. no) of three sexual behaviors in the past 6 months: birth control use during sex, sexual activity under the influence of substances, and testing positive for an STI. Covariates were age and natal sex. Religiosity was related to reduced birth control use in heterosexual and gay/lesbian individuals. Religiosity was not associated with sexual behaviors in bi/pansexual college students. Findings show that religiosity was a salient construct for understanding sexual behaviors in heterosexual and gay/lesbian college students, but not in bi/pansexual college students. Given that religiosity has differential effects for various sexual behaviors that can heighten risk of negative sexual health outcomes, recommendations are made for increased and tailored sexual health education to religiously identified college students.


Inhibitory potential of Crotalus durissus terrificus venom on measles virus growth.
This paper presents the antiviral activity found in a snake with Crotalus durissus terrificus venom (Cdt), studied by use of microplate inhibition assay, using measles virus (MV). Cdt at concentrations below 100 microg/ml showed no cytotoxicity for Vero cells. This study shows the optimal conditions for cell treatment and infection. Two factors that affect virus binding and infection efficiency were studied: the use of an adsorption step, where infection volume was varied; and the concentration of fetal bovine serum (FBS). The adsorption step, with or without FBS, increased the bound virus percentage, whereas it increased bound virus at equilibrium only in FBS-free until 2.5% FBS. In contrast, the addition of 10% FBS decreased the bound virus percentage. The inhibition of MV replication in Vero cells was observed when Cdt was added either before or during cell infection with virus. Its inhibitory concentration against MV replication was 0.1 until 100 microg/ml, respectively. The anti-MV effect of the Cdt was gradually decreased when it was added before or during infection, and little inhibition was observed when Cdt was added 1 h after infection, suggesting that the MV infection was inhibited at the time of the initial events such as at the moment of adsorption and penetration of the viral cycle. In conclusion, Cdt contains anti-MV effects that may be of potential clinical interest.


Study of immobilized and extracellular aminopeptidases of watermelon.
Watermelon cells after permeabilization in Tween 80 were immobilized by glutaraldehyde without any carrier. Cells immobilized by cross-linking demonstrated significantly lower aminopeptidase activities than untreated cells. Pectate and alginate hydrogels were used successfully for immobilization of watermelon cells which retained activities of some aminopeptidases. A simple and rapid procedure for determination of extracellular aminopeptidases was developed using a synthetic substrate. p-Nitroanilides of amino acids were used as substrates for the determination of the extracellular and intracellular enzymatic activities. The culture medium (without cells) was used for the identification and determination of extracellular enzyme activities, whereas intracellular activities were estimated from the cell suspension.


Use of biotin-labeled monoclonal antibodies and avidin-peroxidase conjugates for the determination of epitope specificities in a solid-phase competitive enzyme immunoassay.
The epitope specificities of monoclonal antibodies against carcinoembryonic antigen (CEA) were determined in a solid-phase, biotin-avidin enzyme immunoassay. Constant amounts of biotin-labeled antibodies were incubated with the immobilized antigen in the presence of decreasing amounts of unlabeled antibodies. The biotinylated antibodies bound to the antigen were then reacted with avidin-peroxidase conjugates. The activity of the bound peroxidase was determined by the use of o-phenylenediamine and hydrogen peroxide.


Using the kalman filter with Arima for the COVID-19 pandemic dataset of Pakistan.
The current pandemic of the Novel Corona virus (COVID-19) has resulted in multifold challenges related to health, economy, and society, etc. for the entire world. Many mathematical epidemiological models have been tried for the available data of the COVID-19 pandemic with the core objective to observe the trend and trajectories of infected cases, recoveries, and deaths, etc. However, these models have their own assumptions and parameters and vary with regional demography. This article suggests the use of a more pragmatic approach of the Kalman filter with the Autoregressive Integrated Moving Average (ARIMA) models in order to obtain more precise forecasts for the figures of prevalence, active cases, recoveries, and deaths related to the COVID-19 outbreak in Pakistan.


Analysis of genetic variation in Theiler's virus during persistent infection in the mouse central nervous system.
The genetic changes occurring in the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) during persistent infection in the mouse central nervous system (CNS) were studied. RNase T1-oligonucleotide fingerprinting of the RNAs of 28 BeAn viruses isolated at various times postinfection (p.i.) demonstrated that mutation occurred throughout the infection. Although plaque-purified BeAn virus was used to inoculate mice intracerebrally, genetically different viruses were recovered from the CNS. One to three oligonucleotide changes were found up to Day 152 p.i., but all three viruses isolated at Day 180 had four to nine oligonucleotide changes. No pattern of oligonucleotide changes occurring in different virus isolates was found, yet three viruses isolated from different animals at Day 180 had the same four new oligonucleotides. Overall, the number of oligonucleotide changes represented a 0.1 to 1.2% change in the virus genome. In addition, the analytical two-dimensional gel technique of P.Z. O'Farrell, H.M. Goodman, and P.H. O'Farrell (Cell 12, 1133-1142, 1977) suggested that mutation occurred in all virus isolates. In nine isolates, one to three proteins were found to have charge changes, and in general, as many nonstructural proteins had charge changes as structural proteins. P20, a nonstructural protein probably equivalent to the protease described for encephalomyocarditis virus, was found to have shifted cathodally in six different viruses. Several virus isolates had doublet patterns, suggesting the possibility that within the CNS, subpopulations existed which had proteins of slightly different charge or that virus-specified proteins had been modified after translation. Finally, antigenic variation of neutralizing site(s) on BeAn virus isolates as a way for virus to evade immune surveillance and thereby maintain the persistent state was studied. The ability of mouse serum to neutralize persisting virus isolates was not significantly different from the ability to neutralize the infecting virus. Therefore, antigenic variation does not appear to be a factor in TMEV persistence.


Topographic distribution and phenotypic heterogeneity of Schlemm's canal endothelium in human donor eyes.
Endothelium phenotype is known to be closely associated with flow shear stress. This study is to determine the topographic distribution of endothelial cells and the phenotype of different quadrants and regions of Schlemm's canal using human donor eyes. This study infers differences in flow dynamics based on cell shape and intracellular structure. The Schlemm's canal from 15 human donor eyes were either perfusion labelled using silver stain or dissected for float labeling with Phalloidin to enable visualization of endothelial cell border and intracellular structure. Data were acquired for endothelial cells from the outer and inner wall of Schlemm's canal and grouped according to quadrant of origin. Measurements included endothelial cell length, width, area, and aspect ratio and compared between quadrants. Endothelial cells are mostly spindle-shape and the cell size on the outer wall are larger and longer than those from the inner wall. Significant differences in endothelial cell size and shape were seen in different quadrants. The endothelial cells have varied shapes and orientations close to large ostia in the outer wall and remarkably long endothelial cells were found in the walls of collector channels. F-actin aggregation was found at all endothelial cell borders, and inside some of the endothelial cytoplasm. The presence of various spindle shapes, significant phenotype heterogeneity and F-actin aggregation of endothelial cells indicates aqueous humor flow likely creates variations in shear stress within Schlemm's canal. Further investigation of the relationship between the phenotype heterogeneity and hydrodynamics of aqueous flow may help us understand the mechanisms of outflow resistance changes in glaucoma.


Characterization of blood flow through intrapulmonary arteriovenous anastomoses and patent foramen ovale at rest and during exercise in stroke and transient ischemic attack patients.
We determined whether stroke and/or TIA subjects have exercise-induced blood flow through intrapulmonary arteriovenous anastomoses (QIPAVA ) and/or patent foramen ovale (QPFO ) and a genetic predisposition for ischemic stroke. Twenty-eight stroke and/or TIA subjects (33-63 years old) underwent transthoracic saline contrast echocardiography concomitant with transcranial Doppler to detect QIPAVA and QPFO at rest and during supine exercise with and without breathing 100% O2 . We also examined genetic polymorphisms in FV Leiden (G1691A; rs6025), factor II (FII) prothrombin (G20210A; rs1799963), methylene tetrahydfropholate reductase (C677T, rs1801133), and plasminogen-activator inhibitor-1 (PAI-1) (4G/5G; rs1799889) and angiotensin-converting enzyme (ACE; I/D, rs4646994) in 24/28 subjects. No subject without PFO had QIPAVA at rest (n=17), but 12/17 did with exercise. All PFO subjects had QPFO at rest (n=11) and 7/11 had either QIPAVA or QPFO with exercise. Breathing 100% O2 during exercise reduced or eliminated left heart contrast in all subjects. Gene analyses revealed that 15/24 patients were either heterozygous or homozygous for methylenetetrahydrofolate reductase gene polymorphism; 4G/4G and 4G/5G genotypes of plasminogen-activator inhibitor-1 were present in 7/24 and 13/24 patients, respectively; polymorphisms of ACE D/D genotype were present in 6/24 and I/D in 14/24 patients. Having both I/D and 4G/4G genotypes was more prevalent in PFO+ subjects (P=.03), and there was a trend (P=.06) for PFO- subjects to have a greater D/D genotype prevalence. Novel genetic predispositions reported here in PFO subjects should be investigated further in larger stroke and/or TIA patient datasets.


The acute skin and heart toxicity of a concurrent association of trastuzumab and locoregional breast radiotherapy including internal mammary chain: a single-institution study.
To evaluate the skin and heart toxicity of a concurrent adjuvant trastuzumab-radiotherapy for breast cancer (BC), especially in the case of internal mammary chain (IMC) irradiation. Prospective study of 106 patients treated between 06/2003 and 03/2007 by concurrent trastuzumab-radiotherapy for non-metastatic BC. Left ventricular ejection fractions (LVEF) was assessed at baseline, before and after radiotherapy and then every 4-6 months. All toxicities were evaluated using CTCAEV3. Median age was 52 years (25-76). Chemotherapy with anthracycline was administered in 92% of patients. All patients received trastuzumab every three weeks (8 mg/kg followed by 6 mg/kg) for a median duration of 12 months (3-40). The IMC was irradiated in 83% of patients. There were: 87 grade 1, 14 grade 2 and 2 grade 3 skin reactions. There were 13 oesophagitis: 9 grade 1; 3 grade 2, and 1 grade 3. Out of 101 patients with assessments after 6 months, late telangiectasia grade 1 occurred in 5 patients, local pain grade 1 in 19 patients and grade 2 in 3 patients, fibrosis grade 1 in 16 patients. A reversible grade ≥2 left ventricular systolic dysfunction occurred in 6 patients. In this prospective study of breast cancer patients treated with trastuzumab-radiotherapy with, in most cases, anthracycline-based chemotherapy and IMC irradiation, both the rate of abnormal LVEF after concurrent trastuzumab-radiotherapy and the skin toxicity were deemed acceptable. Further follow-up is needed.


Agrobacterium tumefaciens pTAR parA promoter region involved in autoregulation, incompatibility and plasmid partitioning.
The locus responsible for directing proper plasmid partitioning of Agrobacterium tumefaciens pTAR is contained within a 1259 base-pair region. Insertions or deletions within this locus can result in the loss of the plasmid's ability to partition properly. One protein product (parA), approximately 25,000 Mr, is expressed from the par locus in Escherichia coli and A. tumefaciens protein analysis systems in vitro. DNA sequence analysis of the locus revealed a single 23,500 Mr open reading frame, confirming the protein data. A 248 base-pair region immediately upstream from the 23,500 Mr open reading frame, containing an array of 12 seven-base-pair palindromic repeats each of which are separated by exactly ten base-pairs of A + T-rich (75%) sequence, not only serves to provide the promoter but is also involved in parA autoregulation. In addition, this region containing a set of 12 seven-base-pair palindromic repeats, is responsible for plasmid-associated incompatibility within Inc Ag-1 and also functions as the cis-acting recognition site at which parA interacts to bring about partitioning. Transcriptional analysis indicated that only the DNA strand responsible for parA is actively transcribed, and that active transcription of the opposite strand of par can inhibit the production of parA, resulting in plasmid destabilization. The presence of the par locus in a plasmid results in stable inheritance within a wide range of members of Rhizobiaceae. Segregation rates of par-defective derivatives can be influenced by the host.


Cost-effectiveness analysis of emtricitabine/tenofovir versus lamivudine/zidovudine, in combination with efavirenz, in antiretroviral-naive, HIV-1-infected patients.
The aim of this study was to compare the cost per unit of effectiveness (successful treatment episode) of 2 highly active antiretroviral therapy combinations-emtricitabine/tenofovir DF + efavirenz (TVD + EFV) and lamivudine/zidovudine + efavirenz (COMB + EFV)-in antiretroviral-naive, HIV-1-infected patients from the perspective of costs to society. This cost-effectiveness analysis was modeled using a decision tree that considered the therapeutic response (successful treatment episode, ie, HIV-1 RNA <400 copies/mL using data obtained directly from a clinical trial) and the switch to rescue therapy in nonresponders. The time horizon was 24 months of treatment. Cost was defined as direct medical costs (drugs, diagnostic and/or laboratory tests, treatment of adverse effects) and indirect medical costs (productivity losses). All data are presented as euro(2005). Sensitivity analysis was 1-factor threshold, adjustment of ex-factory cost, only direct costs, and applying discount rate in the study. The results are presented as incremental costs, success rates, and cost per patient with undetectable viral load or additional success. The expected 48-week cost of the regimen that includes TVD + EFV was euro46,464, and for the regimen that included COMB + EFV, euro56,198. Therefore, savings of euro9734 were achieved for each patient treated with TVD + EFV, as well as a gain of 13% of patients with undetectable viral load after 24 months of treatment. Consequently, treatment with TVD + EFV combination would be dominant in therapy for antiretroviral-naive, HIV-1-infected patients. Sensitivity tests supported the stability of the base-case analysis. The cost-effectiveness ratios were euro619.52 for the TVD + EFV regimen versus euro906.41 for the COMB + EFV regimen. Based on the results of this analysis, patients who started treatment of HIV-1 infection with combination TVD + EFV had significantly lower health care resource utilization and overall treatment costs compared with the COMB + EFV combination.


Skeletal muscle fibres show NADPH diaphorase activity associated with mitochondria, the sarcoplasmic reticulum and the NOS-1-containing sarcolemma.
The subcellular appearance of NADPH diaphorase activity in different rat skeletal muscles has been analyzed. Both a sarcolemma-associated as well as a non-sarcolemma-associated NADPH diaphorase-dependent generation of formazan was observed. The sarcolemma-associated NADPH diaphorase staining appeared regularly in two manifestations: one observed in longitudinal sections as dotted costameres at the cell surface which accordingly appeared in transversal sections as rings surrounding the myofibre surface. At this site, nitric oxide synthase (NOS)-1 was located. The second sarcolemma-associated site of NADPH diaphorase staining was found as bundles of longitudinal-orientated stripes of hitherto unidentified origin. The non-sarcolemma-associated production of formazan was likewise manifested at two sites: the first was found regularly in longitudinal sections as intense sarcomere-like striations occurring parallel to the I-bands and indicating mitochondria. The second non-sarcolemma-associated NADPH diaphorase staining was realized as fine longitudinal filaments of variable occurrence connecting the mitochondria and presumably belonging to the sarcoplasmic reticulum. Attempts to identify single NADPH diaphorase(s) existing in skeletal muscles by incubation with specific inhibitors failed but showed the presence of two different subpopulations of NADPH diaphorases in myofibres: a urea-resistant fraction in the sarcolemma region containing NOS-1 and a non-sarcolemma-associated, urea-sensitive fraction depleted of NOS-1.


Lamivudine for the prevention of hepatitis B virus reactivation in hepatitis B s-antigen seropositive cancer patients undergoing cytotoxic chemotherapy.
For cancer patients receiving cytotoxic chemotherapy, hepatitis B virus (HBV) reactivation is a well described complication resulting in varying degrees of liver damage. The objectives of this study were to assess the efficacy of the antiviral agent lamivudine in reducing the incidence of HBV reactivation and diminishing morbidity and mortality of cancer patients with chronic HBV infection during chemotherapy. Two groups were compared in this nonrandomized study. The prophylactic lamivudine group consisted of 65 patients in a phase II study who were treated with lamivudine before and until 8 weeks after discontinuing chemotherapy. The historical controls consisted of 193 consecutive patients who underwent chemotherapy without prophylactic lamivudine. Significant prognosticators for the development of HBV reactivation were determined based on data from the controls. Potential confounding factors were identified between the two groups. The outcomes were compared. In the controls, lymphoma and anthracycline usage were factors identified to be associated with reactivation. The two groups were comparable in most baseline characteristics, although in the prophylactic lamivudine group, there were significantly more patients with lymphoma and receiving anthracyclines. In the prophylactic lamivudine group, there was significantly less HBV reactivation (4.6% v 24.4% in the controls; P <.001), fewer incidences of hepatitis (17.5% v 44.6%; P <.0001) that were less severe (4.8% v 18.7%; P =.0005), and less disruption of chemotherapy (15.4% v 34.6%; P =.0029). The reduction in overall mortality was not statistically different. Prophylactic lamivudine significantly reduced the incidence of HBV reactivation and the overall morbidity of cancer patients undergoing chemotherapy.


Overcoming constraints on the detection of recessive selection in human genes from population frequency data.
The identification of genes that evolve under recessive natural selection is a long-standing goal of population genetics research that has important applications to the discovery of genes associated with disease. We found that commonly used methods to evaluate selective constraint at the gene level are highly sensitive to genes under heterozygous selection but ubiquitously fail to detect recessively evolving genes. Additionally, more sophisticated likelihood-based methods designed to detect recessivity similarly lack power for a human gene of realistic length from current population sample sizes. However, extensive simulations suggested that recessive genes may be detectable in aggregate. Here, we offer a method informed by population genetics simulations designed to detect recessive purifying selection in gene sets. Applying this to empirical gene sets produced significant enrichments for strong recessive selection in genes previously inferred to be under recessive selection in a consanguineous cohort and in genes involved in autosomal recessive monogenic disorders.


Individual Differences in Judgment and Decision-Making: Novel Predictors of Counterproductive Work Behavior.
The current paper proposed individual differences in judgment and decision-making (JDM)-namely, the skill associated with recognizing social norms, decision-making styles, and risk-benefit perceptions-as a novel set of predictors of counterproductive work behavior (CWB). We hypothesized that the skill associated with recognizing social norms, rational decision-making style, and perceived riskiness of unethical behavior would be related negatively to CWB, whereas the avoidant decision-making style, spontaneous decision-making style, and perceived benefits of unethical behavior would be related positively to CWB. Moreover, we hypothesized that JDM-focused individual differences would exhibit incremental validity above and beyond the traditional individual difference predictors of CWB (personality, trait affect, and cognitive ability). Results from three independent samples provided strong support for the hypotheses. The strongest predictor of CWB was individual differences in perceived benefits of unethical behavior (meta-analytic correlation across the three samples = .487). This result suggests a simple insight, yet one almost completely missing from the existing CWB literature: People who believe unethical behavior is likely to benefit them will tend to enact more CWB than those who do not. Additionally, across the three samples, the novel JDM-focused individual difference predictors performed well in comparison to the traditional individual difference predictors, suggesting their usefulness to research and practice. We therefore suggest several avenues for future research on JDM-focused individual differences as predictors of CWB. Additionally, vis-à-vis practical implications, we discuss the possibility of using JDM-focused individual differences in employee selection and organizational intervention contexts with the aim of reducing CWB.


Correction: ALK Positive Lung Cancer: Clinical Profile, Practice and Outcomes in a Developing Country.
[This corrects the article DOI: 10.1371/journal.pone.0160752.].


Modern atlas of invasive coronary angiography views: a practical approach for fellows and young interventionalists.
Although computed tomographic (CT) assessment of coronary arteries is rapidly becoming a first line imaging technique for the assessment of coronary artery disease (CAD), coronary angiography (CA) still represents the gold standard method, especially for guiding percutaneous coronary artery interventions (PCI). Together with the basic principles of radioprotection and modern radiological equipment's management, the average invasive cardiology should know how to replicate in clinical practice, both the old standard and the new and previously under-used projections and should need to learn their usefulness at both diagnostic and interventional levels. The present article is aimed to present an updated practical overview of modern available angiographic views for fellows and young interventionalists.


Sustainability of community health programme using community-based organizations: a challenge for stakeholders.
A community tuberculosis programme was implemented in Burkina Faso with funding from the Global Fund to fight HIV tuberculosis and malaria. Three years after the end of the funding, it seemed necessary to examine what remains of this innovative programme, which used civil society organizations for implementation. The objective of this study was to assess the factors that influence the capacity for sustainability and the level of sustainability of the programme.Methods The case study approach was used to retrospectively identify the factors that influence the capacity for sustainability and the level of sustainability of the programme. Semi structured interviews were conducted with key informants. The data were analysed according to the theoretical frameworks of Schell and Pluye. Data was analysed using NVivo 12.Results Strong support at the national level enabled the acquisition of funding for this programme, while the instability of financial resources was a drawback to sustainability. The lack of leadership of some associations did not allow the continuation of activities after the end of the funding. The irregularity of funding and the failure to conduct a final evaluation of the programme were the weakest links in the sustainability of the programme. Thus, the analysis of our data showed precarious sustainability at the time of the study.Conclusion A well-designed community programme with a strong capacity for sustainability is not necessarily maintained after funding is withdrawn. The implementation of a community programme must ensure that it is integrated into the existing organizational system. The objectives and operating rules of the host structures must be in line with those of the programme to be implemented.


HDAC2 Regulates Site-Specific Acetylation of MDM2 and Its Ubiquitination Signaling in Tumor Suppression.
Histone deacetylases (HDACs) are promising targets for cancer therapy, although their individual actions remain incompletely understood. Here, we identify a role for HDAC2 in the regulation of MDM2 acetylation at previously uncharacterized lysines. Upon inactivation of HDAC2, this acetylation creates a structural signal in the lysine-rich domain of MDM2 to prevent the recognition and degradation of its downstream substrate, MCL-1 ubiquitin ligase E3 (MULE). This mechanism further reveals a therapeutic connection between the MULE ubiquitin ligase function and tumor suppression. Specifically, we show that HDAC inhibitor treatment promotes the accumulation of MULE, which diminishes the t(X; 18) translocation-associated synovial sarcomagenesis by directly targeting the fusion product SS18-SSX for degradation. These results uncover a new HDAC2-dependent pathway that integrates reversible acetylation signaling to the anticancer ubiquitin response.


Combined congenital diastasis of the inferior tibiofibular joint with contralateral distal femoral bifurcation and hemimelia of the medial structures. A case report.
A case of congenital bilateral lower limb deformities is presented. Diastasis of the distal tibia and fibula has the appearance of a severe clubfoot. Recognition of this condition and early surgical treatment are important. Tibial aplasia is best treated by disarticulation and early mobilization.


Uncertainty, risk, and the role of epidemiology in public policy development.
Risk taking is a concommitant of life--inescapable beyond the inert, sessile state. Accordingly, risk assessment is implicit for almost all human activities, from daily actions, such as crossing a trafficked street to esoteric ones such as landing on the moon.


Enhanced TNF alpha and oxidative stress in patients with heart failure: effect of TNF alpha on platelet O2- production.
Experimental studies have suggested that TNF alpha, a pro-inflammatory cytokine, may contribute to the deterioration of cardiovascular function through various mechanisms, including the generation of reactive oxygen species. It has not yet been demonstrated whether TNF alpha has prooxidant activity in patients with heart failure, and what the mechanism eventually resulting in this effect are. We analyzed 42 patients (38 men and 4 women, aged 26 to 74 years) with heart failure, secondary to idiopathic dilated cardiomyopathy (n=21), coronary artery disease (n=15), and valve disease (n=6), and 20 controls (18 men and 2 women, aged 49 to 67 years). Ten patients were in class I, 9 in class II, 15 in class III and 8 in class IV according to NYHA Classification. Blood samples were obtained from each patient to evaluate basal and collagen-induced platelet O(2)(-) production, and plasma TNF alpha. In vivo results showed increased platelet O(2)(-) production and plasma TNF alpha levels in NYHA class III-IV compared with that in controls or in NYHA I-II (p<0,001); platelet O(2)(-) production correlated significantly (R=0,6; p<0,01) with TNF alpha plasma levels. In vitro studies showed TNF alpha dose-dependently (5-40 pg/ml) induced platelet O(2)(-) production, and that this effect was significantly inhibited by its specific inhibitor, WP9QY (1 microM); aspirin (100 microM), AACOCF(3), a specific PLA(2) inhibitor (14 microM), and DPI, an inhibitor of NADPH oxidase, significantly inhibited TNF alpha-mediated platelet O(2)(-) production. This study suggests that in patients with heart failure, enhanced platelet O(2)(-) production is mediated by TNF alpha via activation of arachidonic acid and NADPH oxidase pathways.


Stress and stability of plate-screw fixation and screw fixation in the treatment of Schatzker type IV medial tibial plateau fracture: a comparative finite element study.
The purpose of this study is to compare the stress and stability of plate-screw fixation and screw fixation in the treatment of Schatzker type IV medial tibial plateau fracture. A three-dimensional (3D) finite element model of the medial tibial plateau fracture (Schatzker type IV fracture) was created. An axial force of 2500 N with a distribution of 60% to the medial compartment was applied to simulate the axial compressive load on an adult knee during single-limb stance. The equivalent von Mises stress, displacement of the model relative to the distal tibia, and displacement of the implants were used as the output measures. The mean stress value of the plate-screw fixation system was 18.78 MPa, which was significantly (P < 0.001) smaller than that of the screw fixation system. The maximal value of displacement (sum) in the plate-screw fixation system was 2.46 mm, which was lower than that in the screw fixation system (3.91 mm). The peak stress value of the triangular fragment in the plate-screw fixation system model was 42.04 MPa, which was higher than that in the screw fixation model (24.18 MPa). But the mean stress of the triangular fractured fragment in the screw fixation model was significantly higher in terms of equivalent von Mises stress (EVMS), x-axis, and z-axis (P < 0.001). This study demonstrated that the load transmission mechanism between plate-screw fixation system and screw fixation system was different and the stability provided by the plate-screw fixation system was superior to the screw fixation system.


Work-related knee injuries treated in US emergency departments.
To characterize work-related knee injuries treated in US emergency departments (EDs). We characterized work-related knee injuries treated in EDs in 2007 and examined trends from 1998 to 2007 by using the National Electronic Injury Surveillance System-occupational supplement. In 2007, 184,300 (± 54,000; 95% confidence interval) occupational knee injuries were treated in US EDs, accounting for 5% of the 3.4 (± 0.9) million ED-treated occupational injuries. The ED-treated knee injury rate was 13 (± 4) injuries per 10,000 full-time equivalent workers. Younger workers and older female workers had high rates. Strains/sprains and contusions/abrasions were common-frequently resulting from falls and bodily reaction/overexertion events. Knee injury rates declined from 1998 through 2007. Knee injury prevention should emphasize reducing falls and bodily reaction/overexertion events, particularly among all youth and older women.


Geography is a better determinant of human genetic differentiation than ethnicity.
Individuals differ genetically in their susceptibility to particular diseases and their response to drugs. However, personalized treatments are difficult to develop, because disease susceptibility and drug response generally have poorly characterized genetic architecture. It is thus tempting to use the ethnicity of patients to capture some of the variation in allele frequencies at the genes underlying a clinical trait. The success of such a strategy depends on whether human populations can be accurately classified into discrete genetic ethnic groups. Despite the heated discussions and controversies surrounding this issue, there has been essentially no attempt so far to quantify the relative power of ethnic groups and geography at predicting the proportion of shared alleles between human populations. Here, we present the first such quantification using a dataset of 51 populations typed at 377 autosomal microsatellite markers, and show that pair-wise geographic distances across landmasses constitute a far better predictor than ethnicity. Allele-sharing between human populations worldwide decays smoothly with increasing physical distance. We discuss the relevance of these patterns for the expected distribution of variants of medical interest. The distribution patterns of gene coding for simple traits are expected to be highly heterogeneous, as most such genes experienced strong natural selection. However, variants involved in complex traits are expected to behave essentially neutrally, and we expect them to fit closely our predictions based on microsatellites. We conclude that the use of ethnicity alone will often be inadequate as a basis for medical treatment.


Access to an online video enhances the consent process, increases knowledge, and decreases anxiety of caregivers with children scheduled for inguinal hernia repair: A randomized controlled study.
There is limited time within the clinical workflow of most pediatric surgeons to obtain a comprehensive, well informed consent. This study evaluates whether ad-lib access to an online video on the consent dialogue enhances the consent process for inguinal hernia repair (IHR) in children. The study was approved by the state ethics board. A 6-min video of a consent speech on IHR was produced and uploaded to a nonpublic online channel, explaining the condition, procedure, complications, and postoperative expectations. A total of 50 families were randomized to conventional, face-to-face consenting in clinic either with (intervention) or without (control) access to the online video. During their child's IHR, the parents were asked to complete the State-Trait-Anxiety Inventory (STAI), a modified Friedlander questionnaire on assessing knowledge sufficient to provide informed consent, and a validated satisfaction survey. Scores of the intervention and control group were statistically compared. The intervention group demonstrated significantly decreased anxiety measured with the STAI (p = 0,026) and increased knowledge (p = 0,016) compared to controls. There was no difference in satisfaction (p = 0,557). Preoperatively providing access to an online consent video regarding IHR reduces anxiety and enhances knowledge without altering satisfaction level. Adjunct online videos are a useful tool to enhance the consent process. Prospective randomized controlled trial. Level I.


Ethical guidance on human embryonic and fetal tissue transplantation: a European overview.
This article presents an overview of regulations, guidelines and societal debates in eight member states of the EC about a) embryonic and fetal tissue transplantation (EFTT), and b) the use of human embryonic stem cells (hES cells) for research into cell therapy, including 'therapeutic' cloning. There appears to be a broad acceptance of EFTT in these countries. In most countries guidance has been developed. There is a 'strong' consensus about some of the central conditions for 'good clinical practice' regarding EFTT. International differences concern, amongst others, some of the informed consent issues involved, and the questions whether an intermediary organisation is necessary, whether the methods of abortion may be influenced by the possible use of EFT, and whether EFTT should only be used for the experimental treatment of rare disorders. The potential use of hES cells for research into cell therapy has given a new impetus to the debate about (human) embryo research. The therapeutic prospects with regard to the retrieval and research use of hES cells appear to function as a catalyst for the introduction of less restrictive regulations concerning research with spare embryos, at least in some European countries. It remains to be seen whether the prospect of treating patients suffering from serious disorders with transplants produced by therapeutic cloning will decrease the societal and moral resistance to allowing the generation of embryos for 'instrumental' use.


Cardiac ischemic score determines the presence of coronary collateral circulation.
The presence of coronary collaterals is of vital importance during acute ischemia, however, marked interindividual variability exists. We examined the extent to which the burden of cardiac ischemia, expressed as a cardiac ischemic score, affects coronary collateral presence. Cross-sectional study in 244 patients, admitted for elective coronary angioplasty. Collaterals were graded with Rentrop's classification. Coronary collateral presence was defined as Rentrop-grade > or =1. The cardiac ischemic score (range 0-4) was calculated by adding 1 point for each of the following four clinical factors present: angina pectoris on exertion, angina pectoris during emotions, previous myocardial infarction, and previous coronary intervention. These four clinical factors were chosen because they can be easily assessed in every patient. We used logistic regression with adjustment for gender, age, hypertension, diabetes mellitus, and hyperlipidemia. The extent of the cardiac ischemic score (odds ratio 1.8 per score-point; 95% confidence interval 1.3-2.5) was strongly associated with coronary collateral presence. Additional adjustment for multivessel coronary disease left the relation essentially unchanged. Also, if the definition of collateral presence was limited to Rentrop-grade 2 and 3, results were effectively the same. The extent of the cardiac ischemic score determines the presence of coronary collaterals, and may provide a new index for simple assessment of collateral vascular development.


microRNA-mediated repression of rolled leaf1 specifies maize leaf polarity.
In both animals and plants, many developmentally important regulatory genes have complementary microRNAs (miRNAs), which suggests that these miRNAs constitute a class of developmental signalling molecules. Leaves of higher plants exhibit a varying degree of asymmetry along the adaxial/abaxial (upper/lower) axis. This asymmetry is specified through the polarized expression of class III homeodomain/leucine zipper (HD-ZIPIII) genes. In Arabidopsis, three such genes, PHABULOSA (PHB), PHAVOLUTA (PHV) and REVOLUTA (REV), are expressed throughout the incipient leaf, but become adaxially localized after primordium emergence. Downregulation of the HD-ZIPIII genes allows expression of the KANADI and YABBY genes, which specify abaxial fate. PHB, PHV and REV transcripts contain a complementary site for miRNA165 and miRNA166, which can direct their cleavage in vitro. Here we show that miRNA166 constitutes a highly conserved polarizing signal whose expression pattern spatially defines the expression domain of the maize hd-zipIII family member rolled leaf1 (rld1). Moreover, the progressively expanding expression pattern of miRNA166 during leaf development and its accumulation in phloem suggests that miRNA166 may form a movable signal that emanates from a signalling centre below the incipient leaf.


Areca nut extracts exert different effects in oral cancer cells depending on serum concentration: A clue to the various oral alterations in betel quid chewers.
Betel quid chewing is associated with various pathologic alterations in oral mucosa. However, the molecular mechanism behind so many contradictory alterations remains unclear. Here we aimed to build a model to facilitate the related studies in cultured cells. In our results, areca nut extract (ANE) was found to exert different effects in oral cells depending on the supplemented serum level. ANE strongly induced DNA damage, necrotic ballooning, and inflammatory cytokines under lower serum concentration while might convert to facilitate deregulated growth of serum-supplemented cells via modulating the activity/expression of factors such as E-cadherin and Snail. Despite ANE significantly activated NF-κB, a mediator critical for inflammation, inhibition of NF-κB did not prevent the activation of IL8 promoter. We further discovered Y705-dephosphorylated STAT3 might enhance IL8 transcription. Since necrosis and the inflammatory cytokines could cause massive inflammation, infiltration of interstitial fluid might potentiate cellular resistance against the acute cytotoxicity of ANE and further support the proliferation of transforming cells. Induction of VEGF and angiogenesis under lower serum condition also paved the way for cell growth and subsequent metastasis. Accordingly, we concluded that in correlation with serum infiltration ANE caused particular effects in oral cells and possibly the various clinicopathological alterations in vivo.


Gas-phase reactivity of [Ca(formamide)]2+ complex: an example of different dynamical behaviours.
In the present contribution, we have summarized our recent work on the comprehension of [Ca(formamide)]2+ complex gas-phase unimolecular dissociation. By using different theoretical approaches, we were able to revise the original (and typical for such kind of problems) understanding given in terms of stationary points on the potential energy surface, which did not provide a satisfactory explanation of the experimentally observed reactivity. In particular, we point out how non-statistical and non-intrinsic reaction coordinate mechanisms are of fundamental importance.This article is part of the themed issue 'Theoretical and computational studies of non-equilibrium and non-statistical dynamics in the gas phase, in the condensed phase and at interfaces'.


Synthesis and inhibitory activity against COX-2 catalyzed prostaglandin production of chrysin derivatives.
A series of chrysin derivatives were prepared and evaluated for their inhibitory activities of cyclooxygenase-2 catalyzed prostaglandin production. Chrysin derivatives were prepared from 2-hydroxyacetophenone, 2,4-dihydroxyacetophenone and 2,6-dihydroxyacetophenone in 2 to 4 steps, respectively. Methxoylated chrysin derivatives were converted to the corresponding hydroxylated chrysin derivatives by the reaction with BBr(3) in good yields. The inhibitory activity of the chrysin derivatives against prostaglandin production from lipopolysaccharide-treated RAW 264.7 cells was measured. We found that chrysin derivatives with 3',4'-dichloro substituents (5e, 6e and 7e) exhibited good inhibitory activity of prostaglandin production.


Adverse drug reactions in hospitalized pediatric patients of Saudi Arabian University Hospital and impact of pharmacovigilance in reporting ADR.
Children are more vulnerable to ADRs, and this susceptibility is compounded due to hospitalization. There is a lack of local data regarding the potential risk of ADRs in hospitalized pediatric patients. Therefore, this study is designed to identify the frequent nature, severity of adverse drug reactions, drugs implicated and factors influencing ADRs. Intensive monitoring study of ADRs was done in hospitalized pediatric patients of King Abdulaziz University Hospital, Jeddah from January to December 2011, with an analogous retrospective study for the preceding year to determine incidence rate, demographic aspects, causality appraisal, polypharmacy, body organs/systems involved and drugs implicated in ADR. Comparison of the two data was done to determine the impact of pharmacovigilance. Incidence rate of ADRs in retrospective study was (4.50%) and (8.2%) in prospective study. ADR was more in patients who received 5-6 drugs, which was (15.5%) in retrospective study and (22.1%) in prospective study. Regarding age, it was the highest in patients of 0-1 year of age which was (40.7%) in retrospective study and (38.8%) in prospective study. Anti-infective agents were the most frequently involved in ADR (40.8%) in prospective study and (48.2%) and retrospective study. This study also demonstrated that, there was high susceptibility of the skin to the ADR which was (37%) in retrospective study and (42.9%) in prospective study. None of the ADRs proved to be fatal. Well premeditated intensive monitoring approach in pharmacovigilance amplifies the ADR detection, which can persuade healthcare providers into more drug safety.


A case of infliximab-induced lupus in a patient with ankylosing spondylitis: is it safe switch to another anti-TNF-α agent?
Anti-TNF-α therapies are the latest class of medications found to be associated with drug-induced lupus, a distinctive entity known as anti-TNF-α-induced lupus (ATIL) (Williams et al., Rheumatology (Oxford) 48:716-20, 2009; De Rycke et al., Lupus 14:931-7, 2005; De Bandt et al., Clin Rheumatol 22:56-61, 2003). With the widespread use of these agents, it is likely that the incidence of ATIL will increase. The onset of ATIL in patients with rheumatoid arthritis and Crohn's disease has been described, but the literature regarding the occurrence of this entity in patients with ankylosing spondylitis (AS) is scarce (De Bandt et al., Clin Rheumatol 22:56-61, 2003; Ramos-Casals et al., Autoimmun Rev 9:188-93, 2010; Perez-Garcia et al., Rheumatology 45:114-116, 2006). To our knowledge, few reports of switching anti-TNF-α therapy after ATIL in AS have been reported (Akgül et al., Rheumatol Int, 2012). Therefore, it is not clear whether the development of ATIL should prohibit switch to another therapy, since patients may respond to another anti-TNF-α agent (Akgül et al., Rheumatol Int, 2012; Bodur et al., Rheumatol Int 29:451-454, 2009; Mounach et al., Clin Exp Rheumatol 26:1116-8, 2008; Williams and Cohen, Int J Dermatol 50:619-625, 2011; Ye et al., J Rheumatol 38:1216, 2011; Wetter and Davis, Mayo Clin Proc 84:979-984, 2009; Cush, Clin Exp Rheumatol 22:S141-147, 2004; Kocharla and Mongey, Lupus 18:169-7, 2009). A lack of published experience of successful anti-TNF-α switching is a cause of concern for rheumatologists faced with this challenging clinical scenario. We report the case of a 69-year-old woman with AS who developed infliximab-induced lupus, which did not recur despite the subsequent institution of etanercept. The authors review and discuss ATIL and the possible implications for subsequent treatment with alternative anti-TNF-α agents.


First-in-man, first-in-class phase I study with the monopolar spindle 1 kinase inhibitor S81694 administered intravenously in adult patients with advanced, metastatic solid tumours.
S81694 is an inhibitor of monopolar spindle 1 kinase, a target expressed in proliferating cells. CL1-81694-001 was the first-in-human study aiming at identifying a safe dosing schedule in solid tumour patients. This trial was based on inter-individual dose-escalation of single agent S81694 in cohorts of ≥3 patients to assess the safety and tolerability and determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and recommended phase II dose (RP2D), with S81694 given on days 1,8,15 of a 28-day cycle as 1-h infusion. 38 patients were treated at doses ranging from 4 to 135 mg/m2/week; 144 cycles were administered (median 2/patient; range 1-32 cycles). Patients discontinued treatment for disease progression (78.9%), adverse events (AE; 18.4%) or withdrawal of consent (2.6%). Treatment modifications occurred in 22 patients (57.9%; 49 cycles). Common treatment-emergent AEs were fatigue (22 patients;57.9%), anaemia (17;44.7%) and nausea (12;31.6%). Haematological toxicity was mild, with Grade 3 anaemia observed in three patients and neutropenia mainly seen at the 135 mg/m2 dose level. Three first cycle DLTs included G3 anaemia (4 mg/m2 dose), G4 hypertension (20 mg/m2), G3 fatigue (135 mg/m2). MTD was not reached due to premature discontinuation of enrolment based on a sponsor decision. Among 35 patients evaluable for response, one (renal cell carcinoma) had a complete response, one (hepatocellular carcinoma) had a transient decrease of target lesions and 13 had stable disease. Seven patients remained on study for ≥6 cycles, two at the 135 mg/m2 dose. S81694 can be administered safely as a single agent in adults with solid tumours on days 1,8,15 of a 28-day cycle up to a dose of 135 mg/m2/week without reaching MTD. The RP2D was not defined due to the prioritization of the use of S81694 in combination with cytotoxic agents, based on emerging preclinical data. EudraCT number: 2014-002023-10; ISRCTN registry ISRCTN35641359.


Preparation and Characterization of Zein-Based Nanoparticles via Ring-Opening Reaction and Self-Assembly as Aqueous Nanocarriers for Pesticides.
Herein, we prepared and compared two water-soluble amphiphilic zein-based nanocarrier systems with avermectin (AVM) payload to enhance pesticide's water-dispersity, foliage wettability, adhesion, anti-UV, and pH-responsive controlled release property. Ethylene glycol diglycidyl ether (EGDE) and diethanolamine (DEA) were utilized to conjugate with hydrophobic zein via a ring-opening reaction and then encapsulated with AVM via a hydrophobic interaction to fabricate a nanopesticide marked as AVM@Zein-EGDE/DEA. For the sake of further improving the nanocarrier's performance, sodium carboxymethyl cellulose (CMC) was grafted with methyl methacrylate (MMA) and 2-hydroxyethyl methacrylate (HEMA) to form a kind of copolymer CMC-g-P(HEMA-MMA), which was applied to conjugate with Zein-EGDE via a ring-opening reaction. Likewise, another nanopesticide system named AVM@Zein-EGDE/CMC-g-P(HEMA-MMA) was obtained through hydrophobic interactions as well as the electrostatic effect. Various techniques were utilized to confirm chemical interaction, thermal behavior, structural characteristics, and stability. The results showed that AVM encapsulated in Zein-EGDE/CMC-g-P(HEMA-MMA) possessed a larger particle size with an average value of 180-254 nm than AVM loaded in Zein-EGDE/DEA with 144-175 nm but had better stability in aqueous solution. Also, AVM loaded in Zein-EGDE/CMC-g-P(HEMA-MMA) enhanced the encapsulation efficiency, and both of them exhibited excellent pH-responsive sustained release behavior. Besides, the former improved wettability on a cucumber leaf surface and enhanced adhesion ability compared to AVM@Zein-EGDE/DEA because of CMC-g-P(HEMA-MMA) with hydrophobic segments. Similarly, anti-UV performance was also enhanced owing to CMC-g-P(HEMA-MMA) as an additional protective layer. More importantly, the encapsulation of Zein-EGDE/DEA and Zein-EGDE/CMC-g-P(HEMA-MMA) as protective barriers for AVM still retained a similar toxicity level. Overall, we demonstrated the proof of concept for the application of amphiphilic zein-based nanomaterials as aqueous nanocarriers for hydrophobic pesticides.


Effect of nevirapine, efavirenz and lopinavir/ritonavir on the therapeutic concentration and toxicity of lumefantrine in people living with HIV at Lagos University Teaching Hospital, Nigeria.
Patients living with HIV in malarial endemic regions may experience clinically significant drug interaction between antiretroviral and antimalarial drugs. Effects of nevirapine (NVP), efavirenz (EFV) and lopinavir/ritonavir (LPVr) on lumefantrine (LM) therapeutic concentrations and toxicity were evaluated. In a four-arm parallel study design, the blood samples of 40 participants, treated with artemether/lumefantrine (AL), were analysed. Lumefantrine Cmax was increased by 32% (p = 0.012) and 325% (p < 0.0001) in the NVP and LPVr arms respectively but decreased by 62% (p < 0.0001) in the EFV-arm. AUC of LM was, respectively, increased by 50% (p = 0.27) and 328% (p < 0.0001) in the NVP and LPVr arms but decreased in the EFV-arm by 30% (p = 0.019). Median day 7 LM concentration was less than 280 ng/mL in EFV-arm (239 ng/mL) but higher in control (290 ng/mL), NVP (369 ng/mL, p = 0.004) and LPVr (1331 ng/mL, p < 0.0001) arms. There were no clinically relevant toxicities nor adverse events in both control and test arms. Artemether/lumefantrine is safe and effective for treatment of malaria in PLWHA taking NVP and LPVr based ART regimen but not EFV-based regimen.


Simultaneous determination of nine endogenous steroids in human urine by polymeric-mixed micelle capillary electrophoresis.
A new CE system based on the use of polymeric-mixed micelles (cholic acid, SDS and the poloxamine Tetronic(®) 1107) was developed for the simultaneous determination of nine steroids in human urine. This method allows the baseline separation and quantitation of cortisol, androstenedione, estriol, dehydroepiandrosterone sulfate, testosterone, dehydroepiandrosterone, estrone, progesterone and estradiol in less than 25 min showing to be sensitive enough to detect low concentrations of these steroids in urine samples (5-45 ng/mL). The optimized electrophoretic conditions were performed using a 50 cm × 75 μm capillary, 18 kV, 25°C, with 44 mM cholic acid, 10 mM SDS, 0.05% w/v tetronic(®) 1107, 2.5% v/v methanol, 2.5% v/v tetrahydrofuran in 5 mM borate - 5 mM phosphate buffer (pH=8.0) as a background electrolyte and a dual 210/254 UV-detection. The method can simultaneously determine 0.1-120 μg/mL, which corresponds to 5-6000 ng/mL of steroids in 2 mL urine. The recoveries ranged between 82.4 and 101.5%. Due to its simplicity, speed, accuracy and reliability, the proposed method could be a potential alternative to the traditional methodologies used with clinical purposes.


"Familial" versus "sporadic" intellectual disability: contribution of subtelomeric rearrangements.
Cryptic subtelomeric rearrangements have been proposed as a significant cause of sporadic intellectual disability (ID) but the role of such aberrations in familial ID has not yet been studied. As positive family history of ID had been proposed as an important and significant predicting factor of subtelomeric rearrangements, it was assumed that the contribution of subtelomeric aberrations in familial ID would be much more than the sporadic ones. Three hundred and twenty two patients from 102 unrelated families with more than two ID patients in the first degree relatives have been investigated. Assessment of subtelomeric rearrangements were carried out using Multiplex Ligation-Dependent Probe Amplification (MLPA) technique. Detected aberrations were then confirmed by Fluorescence in Situ Hybridization (FISH) method. Among the families studied, 27.4% had 4-12, 36.3% had 3 and 36.3% had 2 affected individuals in the first degree relatives. One unbalanced translocation and 4 polymorphic changes were detected. The prevalence of clinically significant subtelomeric rearrangements was 0.98%. This is the first investigation of subtelomeric aberrations in a large sample set of familial ID patients. Our results show that the contribution of subtelomeric rearrangements to familial ID is not as much as what had been determined for sporadic ones in the literature. Moreover, this study shows that the positive family history by alone, cannot be the most important and determining indicator of subtelomeric aberrations while it would be a good predicting factor when associated with dysmorphism or congenital malformations. These findings propose that other cryptic chromosomal abnormalities or even single gene disorders may be the main cause of familial ID rather than subtelomeric aberrations.


Resting-state Functional Magnetic Resonance Imaging in Presurgical Functional Mapping: Sensorimotor Localization.
This article compares resting-state functional magnetic resonance (fMR) imaging with task fMR imaging for presurgical functional mapping of the sensorimotor (SM) region. Before tumor resection, 38 patients were scanned using both methods. The SM area was anatomically defined using 2 different software tools. Overlap of anatomic regions of interest with task activation maps and resting-state networks was measured in the SM region. A paired t-test showed higher overlap between resting-state maps and anatomic references compared with task activation when using a maximal overlap criterion. Resting state-derived maps are more comprehensive than those derived from task fMR imaging.


Birth-related expression of c-fos, c-jun and substance P mRNAs in the rat brainstem and pia mater: possible relationship to changes in central chemosensitivity.
In situ hybridization was used to characterize respiration-related areas of the brainstem activated around the time of birth as well as their postnatal sensitivity to CO2. Levels of mRNA corresponding to the immediate early genes (IEG), c-fos and c-jun, and of substance P precursor, ppt-A, were determined in rat fetuses (E21) and neonatal pups (1 h, 1 day and 6 days after normal birth) and after exposure to hypercapnia (12% CO2 for 1 h). Transient increases in c-fos mRNA were observed in the central chemoreceptor area of the ventral medullary surface (VMS), in the lateral reticular nucleus (LRN), in the nucleus of the solitary tract (NTS), and in the nucleus raphé pallidus (RPA) 1 h after birth. Increased expression of c-fos mRNA in the VMS could also be evoked by hypercapnia and this response was particularly pronounced 1 day after birth. On the other hand, c-jun mRNA could be detected already at E21 in the hypoglossal nucleus (XII) and LRN and these levels were not significantly altered at 1 h after birth. There was, however, an increase in the expression of c-jun mRNA in the pia mater surrounding the brainstem after birth. At 1 day after birth, c-jun mRNA levels had decreased in the LRN and pia mater, and later on (6 days after birth) in XII. Furthermore, the ppt-A mRNA level in NTS increased immediately after birth and remained high 1 and 6 days later. These results suggest that (a) the central chemoreceptor area of the VMS, as well as the NTS, LRN, RPA and pia mater are activated following birth; (b) the VMS, but not the other structures examined, can be activated immediately after birth by hypercapnia; and (c) increased expression of ppt-A mRNA may be related to the transition of respiratory control at birth.