High-resolution melting curve analysis: a novel method for identification of Mycoplasma species isolated from clinical cases of bovine and porcine respiratory disease.
Mycoplasma species cause wide ranges of infectious diseases in human and animals. The aim of the present study was to evaluate a real-time polymerase chain reaction (RT-PCR) followed by a high-resolution melting curve assay (HRM) for rapid differentiation of Mycoplasma species isolated from clinical cases of bovine and porcine respiratory disease. Lung samples from suspected cases to respiratory infections from cows and pigs were cultured on specific media, and the extracted DNA were tested by conventional polymerase chain reaction (PCR) assays for Mycoplasma. A set of universal primers specific for the 16S ribosomal RNA gene was designed and used for RT-PCR and HRM. The HRM analysis was able to differentiate between five different species of Mycoplasmas, namely, M. hyopneumoniae, M. bovis, M. hyorhinis, M. hyosynoviae and other uncultured Mycoplasma. All results were confirmed based on 16S rRNA gene sequencing. This rapid and reliable assay was as a simple alternative to PCR and sequencing, differentiating bovine and porcine mycoplasmas in species level.


Intravenous immunoglobulin for chronic residual peripheral neuropathy in microscopic polyangiitis: A multicentre randomised double-blind trial.
We conducted a Phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of intravenous immunoglobulin (IVIg) in patients with glucocorticoid-refractory neuropathy associated with microscopic polyangiitis. Patients received immunoglobulin or placebo intravenously for 5 consecutive days at baseline and after 4 weeks. The IVIg and placebo groups received IVIg and placebo, respectively, after 8 weeks. The primary and major secondary end-points were the least squares mean of the change in the manual muscle test (MMT) sum score after 8 and 4 weeks, respectively. A total of 37 patients were randomised into two groups (IVIg [19] and placebo [18]). The least squares mean for the change in the MMT sum score was 9.02 for IVIg and 6.71 for placebo (difference 2.32, 95% confidence interval -2.60 to 7.23, p = .345) after 8 weeks and 6.81 and 2.83 (difference 3.99, 95% confidence interval -1.22 to 9.19, p = .129), respectively, after 4 weeks. There were no new safety concerns for IVIg. MMT sum scores improved with IVIg compared with placebo after 8 weeks of dosing and two courses of treatment, but the differences were not statistically significant, and the results showed no clear efficacy of IVIg in this patient population. No new safety concerns were raised.


Relative judgment in facial identity perception as revealed by sequential effects.
Existing models of facial identity perception often assume that information conveyed by facial stimuli provides the sole basis for identity judgments, largely ignoring the involvement of contextual effects. Capitalizing on sequential effects, the present study investigates whether facial identity is judged relative to a context shaped by stimuli presented in previous trials. When categorizing a sequence of facial identities, our results demonstrated that participants' categorization of current faces varied according to the local sequential context provided by the immediately preceding faces and, to some extent, by the preceding stimuli presented two trials prior to the current trial. Moreover, this variation depended on the relative distance between the preceding and current faces. Notably, the nature of these identity-based sequential effects was qualitatively different between male and female participants. Female participants tended to respond to the current faces with the same category label as on the preceding faces. However, male participants responded with the same label only when the relative distance was small, but responded with a different label when the relative distance was increasingly large. The present study demonstrates that relative information between the preceding and current faces may be used as evidence to inform a judgment. However, this process is multifaceted rather than unitary and depends in part on participant gender.


Hdac1-deficiency affects the cell cycle axis Cdc25-Cdk1 causing impaired G2/M phase progression and reduced cardiomyocyte proliferation in zebrafish.
Zebrafish have the ability to fully regenerate their hearts after injury since cardiomyocytes subsequently dedifferentiate, re-enter cell cycle, and proliferate to replace damaged myocardial tissue. Recent research identified the reactivation of dormant developmental pathways during cardiac regeneration in adult zebrafish, suggesting pro-proliferative pathways important for developmental heart growth to be also critical for regenerative heart growth after injury. Histone deacetylase 1 (Hdac1) was recently shown to control both, embryonic as well as adult regenerative cardiomyocyte proliferation in the zebrafish model. Nevertheless, regulatory pathways controlled by Hdac1 are not defined yet. By analyzing RNA-seq-derived transcriptional profiles of the Hdac1-deficient zebrafish mutant baldrian, we here identified DNA damage response (DDR) pathways activated in baldrian mutant embryos. Surprisingly, although the DDR signaling pathway was transcriptionally activated, we found the complete loss of protein expression of the known DDR effector and cell cycle inhibitor p21. Consequently, we observed an upregulation of the p21-downstream target Cdk2, implying elevated G1/S phase transition in Hdac1-deficient zebrafish hearts. Remarkably, Cdk1, another p21-but also Cdc25-downstream target was downregulated. Here, we found the significant downregulation of Cdc25 protein expression, explaining reduced Cdk1 levels and suggesting impaired G2/M phase progression in Hdac1-deficient zebrafish embryos. To finally prove defective cell cycle progression due to Hdac1 loss, we conducted Cytometer-based cell cycle analyses in HDAC1-deficient murine HL-1 cardiomyocytes and indeed found impaired G2/M phase transition resulting in defective cardiomyocyte proliferation. In conclusion, our results suggest a critical role of Hdac1 in maintaining both, regular G1/S and G2/M phase transition in cardiomyocytes by controlling the expression of essential cell cycle regulators such as p21 and Cdc25.


In vivo trafficking of endogenous opioid receptors.
Several approaches have been taken for these in vivo studies. In many studies, the use of semi-quantitative immuno-electron microscopy is the approach of choice. Endogenous opioid receptors display differential subcellular distributions with mu opioid receptor (MOPR) being mostly present on the plasma membrane and delta-opioid receptor (DOPR) and kappa-opioid receptor (KOPR) having a significant intracellular pool. Etorphine and DAMGO cause endocytosis of the MOPR, but morphine does not, except in some dendrites. Interestingly, chronic inflammatory pain and morphine treatment promote trafficking of intracellular DOPR to the cell surface which may account for the enhanced antinociceptive effects of DOPR agonists. KOPR has been reported to be associated with secretory vesicles in the posterior pituitary and translocated to the cell surface upon salt loading along with the release of vasopressin. The study of endogenous opioid receptors using in vivo models has produced some interesting results that could not have been anticipated in vitro. In vivo studies, therefore, are essential to provide insight into the mechanisms underlying opioid receptor regulation.


Bovine viral diarrhoea virus control in Finland 1998-2004.
The bovine viral diarrhoea virus (BVDV) situation among dairy herds and suckler-cow herds was monitored annually from 1998 to 2004. Bulk-tank milk (BTM) samples from all dairy herds and serum samples from beef animals at slaughter were examined for BVDV antibodies using a commercial indirect ELISA test. New BTM antibody-positive herds and herds with a history of BTM antibodies, but previously untested were sampled individually and tested for evidence of BVDV. The reason for the antibody-positivity or the source of infection was investigated. The percentage of BTM antibody-positive herds ranged from 0.45% in 2000 to 0.15% in 2003. The number of herds with persistently infected (PI) animals ranged from 10 in 2001 to 0 in 2003. The most common cause for a herd to become BTM antibody-positive was the purchase of a seropositive animal or a PI animal or a dam carrying a PI fetus. The new BVD decree of 2004 will be described in brief.


Pulmonary venous obstruction following repair of total anomalous pulmonary venous drainage.
Recurrent pulmonary venous obstruction has been reported as a serious late complication following the initial repair of total anomalous pulmonary venous drainage. It occurs either as true pulmonary venous obstruction or as stenosis of the retrocardiac anastomosis between the left atrium and pulmonary veins. The 2 patients reported herein demonstrated the typical history and course following stenosis of the retrocardiac anastomosis. Reoperation resulted in complete relief of symptoms. Both patients are well 36 and 17 months after reoperation, demonstrating the favorable prognosis of this lesion.


Recent developments in antimalarial activities of 4-aminoquinoline derivatives.
Malaria is the fifth most lethal parasitic infection in the world. Antimalarial medications have played a crucial role in preventing and eradicating malaria. Numerous heterocyclic moieties have been incorporated into the creation of effective antimalarial drugs. The 4-aminoquinoline moiety is favoured in antimalarial drug discovery due to the diverse biological applications of its derivative. Since the 1960s, 4-aminoquinoline has been an important antimalarial drug due to its low toxicity, high tolerability, and rapid absorption after administration. This review focused on the antimalarial efficacy of the 4-aminoquinoline moiety hybridised with various heterocyclic scaffolds developed by scientists since 2018 against diverse Plasmodium clones. It could aid in the future development of more effective antimalarial agents.


Updates in non-alcoholic fatty liver disease (NAFLD).
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in childhood. There is an increase in disease prevalence and diagnoses as it is difficult to diagnose the problem. There are currently no effective medications. Management of NAFLD is a challenge for primary care clinicians and subspecialists. This paper provides guidelines for disease screening, diagnosis, management, and algorithm for subspecialty referral.


Validation of a peptide map for recombinant porcine growth hormone and application to stability assessment.
A reverse-phase HPLC method for the analysis of tryptic digests of recombinant porcine growth hormone (pGH) has been developed and validated. Digestion was performed at 4 degrees C for a 20-hr period with TPCK-treated trypsin at a 1:20 (w/w) trypsin:pGH ratio. Gradient elution HPLC, using an Aquapore RP300 C8 column, was incorporated for separation of the digestion products and peak identification was carried out by mass spectrometry (MS). The digestion procedure and subsequent chromatography were linear in the initial concentration range of 4.55-45.46 microM (100 to 1000 micrograms/mL) pGH. The variability in the fragment retention times was low and the normalized peak area variability was less than 5% for all but three of the fragments. The utility of the trypsin digestion and chromatography procedures has been demonstrated by assessing chemical changes in pGH induced by incubation at elevated pH. Upon incubation of pGH in 0.2 M Tris buffer at pH 9 (ionic strength adjusted to 0.5 with NaCl) and 37 degrees C over a period of 400 hr, significant degradation in the regions corresponding to the digestion fragments T23-T25 (residues 181-182 linked by a disulfide bond to residues 184-191), T9 (residues 96-108), and T5-T18 (residues 43-64 linked by a disulfide bond to residues 158-166) was observed. The disappearance of the peaks corresponding to fragments T23-T25 and T9 both displayed apparent first-order degradation kinetics over the time period investigated with half-lives of 131 and 154 hr, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Retention mechanism of hypoxia selective nuclear imaging/radiotherapeutic agent cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells.
The retention mechanism of the novel imaging/radiotherapeutic agent, Cu-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) in tumor cells was clarified in comparison with that in normal tissue in vitro. With Cu-ATSM and reversed phase HPLC analysis, the reductive metabolism of Cu-ATSM in subcellular fractions obtained from Ehrlich ascites tumor cells was examined. As a reference, mouse brain was used. To determine the contribution of enzymes in the retention mechanisms, and specific inhibitor studies were performed. In subcellular fractions of tumor cells, Cu-ATSM was reduced mainly in the microsome/cytosol fraction rather than in the mitochondria. This finding was completely different from that found in normal brain cells. The reduction process in the microsome/cytosol was heat-sensitive and enhanced by adding exogenous NAD(P)H, an indication of enzymatic reduction of Cu-ATSM in tumor cells. Among the known bioreductive enzymes, NADH-cytochrome b5 reductase and NADPH-cytochrome P450 reductase in microsome played a major role in the reductive retention of Cu-ATSM in tumors. This enzymatic reduction was enhanced by the induction of hypoxia. Radiocopper labeled Cu-ATSM provides useful information for the detection of hypoxia as well as the microsomal bioreductive enzyme expression in tumor.


A gamified augmented reality vocational training program for adults with intellectual and developmental disabilities: A pilot study on acceptability and effectiveness.
The Augmented Reality Games to Enhance Vocational Ability of Patients (REAP) was an augmented reality vocational training program that provided skills training in the context of a psychiatric rehabilitation program. It was implemented over 10 weeks and consisted of gamified augmented reality café training scenarios and bridging group activities to facilitate transfer of learning to the work context. This pilot study aimed to explore the acceptability and effectiveness of the REAP program when carried out with adults with intellectual and developmental disabilities attending work therapy. Its objectives were: (1) to obtain feedback from participants and trainers on their experiences and acceptability of the REAP program and (2) to measure changes in vocational and cognitive skills of participants in the REAP program. This was a pretest-posttest mixed methods study. 15 adults with intellectual and developmental disabilities attending work therapy in a non-profit organization participated in the REAP program and their vocational trainers were involved in assisting in this program. Feasibility Evaluation Checklist (FEC) and the Neurobehavioral Cognitive Status Exam (Cognistat) were administered at baseline, post-training and eight weeks after training. The participants and their trainers also provided user feedback via semi-structured interviews. Majority of the participants and trainers found the REAP program to be useful and interesting. They also found that the augmented reality games were user-friendly and provided a unique opportunity to acquire new skills. Participants who engaged in this program showed a significant improvement in vocational skills and aspects of cognitive skills, which were maintained eight weeks after training. The gamified augmented reality vocational training was feasible and accepted by both adults with intellectual and developmental disabilities and their trainers. When integrated with bridging sessions to facilitate transfer of learning to existing work therapy, participants on the REAP program showed significant improvements in vocational skills and aspects of cognitive skills. Future experimental studies with larger sample size could provide stronger evidence on its effectiveness in improving vocational outcomes.


Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage.
Predictors for cerebral infarction, an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH), were examined. This study used data from the Prospective Registry of Subarachnoid Aneurysms Treatment (PRESAT) cohort, which included 579 patients whose ruptured aneurysms were treated with either clipping or coiling within 12 days of onset. Patient, clinical, radiographic, and treatment variables associated with cerebral infarction were determined. Ruptured aneurysms were clipped in 282 patients and coiled in 297 patients. Cerebral infarction occurred in 162 patients (28.0 %): 101 patients by cerebral vasospasm, 34 patients by clipping, and 33 patients by coiling. Univariate analyses showed that significant factors associated with cerebral infarction development were Fisher computed tomography (CT) group 3 on admission, premature aneurysm rupture during clipping procedure, cerebrospinal fluid drainage, symptomatic vasospasm, endovascular treatment for vasospasm, and shunt-dependent hydrocephalus. Multivariable logistic regression analyses showed that cerebral infarction was significantly associated with Fisher CT group 3 on admission, larger aneurysm dome size, ruptured posterior circulation aneurysms, premature aneurysm rupture during clipping procedure, symptomatic vasospasm, and infection, while endovascular treatment for vasospasm significantly decreased the development of cerebral infarction. The most important potentially treatable factor associated with cerebral infarction was symptomatic vasospasm.


Novel biallelic mutations in TTC29 cause asthenoteratospermia and male infertility.
Multiple morphological abnormalities of the sperm flagella (MMAF), which is characterized as asthenoteratospermia involving absent, short, bent, coiled, and/or irregular-caliber flagella, is a rare recessive inherited disorder associated with male infertility. To date, genetic causes of MMAF cases are not fully explored. Whole-exome sequencing was conducted to identify pathogenic variants in a patient with MMAF. The functional effect of the identified mutations was investigated by immunofluorescence staining and western blotting. Intracytoplasmic sperm injection was used to assist fertilization for the patient with MMAF. We identified novel biallelic mutations, a splicing variant NC_000004.12:g.146937593C>T (c.254+1G>A), and a nonsense mutation NM_001300761.4:c.1185C>G (NP_001287690.1:p.Tyr395*), in TTC29 from an infertile patient. In addition to the typical MMAF phenotype, the patient also presented aberrant morphology of sperm heads. Further functional experiments confirmed the absence of TTC29 expression in the spermatozoa. We also explored the specific expression pattern of TTC29 in human and mouse spermatogenesis. The outcome of intracytoplasmic sperm injection in the patient was unsuccessful, while additional female risk factors should not be excluded. Our study revealed the novel biallelic mutations in TTC29 in a MMAF patient, which findings expand the mutational spectrum of TTC29 and further contribute to the diagnosis, genetic counseling, and prognosis of male infertility.


Racial Differences in Diagnosis of Overweight and Obesity: Results from the National Health and Nutrition Examination Survey (NHANES) 2009-2016.
Diagnostic standards and codes related to excessive weight exist so that clinicians may inform patients that they are overweight: a status which may be a harbinger of more severe obesity and negative health outcomes. Equipped with this knowledge, patients may pursue medical interventions or behavioral changes to reduce their risk. However, diagnoses of overweight are unequally applied in the United States along racial lines. Binary logistic regression was used to analyze National Health and Nutrition Examination Survey (NHANES) 2009-2016 data from 7460 participants to examine the relationship between race of non-Hispanic White and non-Hispanic Black Americans and having ever been told that one is overweight by a clinician when controlling for demographic and socioeconomic factors. The body mass index (BMI) of participants along with obesity-associated comorbidities was then incorporated into the model to see if physical size or disease status mediated the primary relationship. Black Americans are significantly less likely to report being told that they are overweight by a clinician than are White Americans regardless of clinical weight status and weight-associated comorbidities. We find that these racial differences are greatest when respondents' BMIs approach the lower threshold for clinical obesity. Our findings suggest that the lower likelihood of Black Americans to be told they are overweight compared to their White counterparts can result in serious health implications. We posit that implicit biases among clinicians may partly explain this disparity, which may exacerbate health outcome inequalities.


Public Expenditure and Green Total Factor Productivity: Evidence from Chinese Prefecture-Level Cities.
Whilst effective public expenditure policies are essential for transforming the traditional factor-driven economy into a green and innovation-driven economy, the impacts of public expenditure's size and composition on green economic development have not been comprehensively investigated. This paper attempts to fill this research gap. Based on the data of Chinese prefecture-level cities from 2010 to 2018, we first measure green total factor productivity (GTFP), the proxy variable for green development, and briefly analyze its spatial-temporal trends. Then, using the dynamic panel models, dynamic panel mediation models, and dynamic panel threshold models, we evaluate how public expenditure affects GTFP. The main findings are fourfold: (1) there is a significant inverted U-shaped relationship between the expenditure size and GTFP. (2) The expansion of social expenditures and science and technology (S&T) and environmental protection expenditures play an important role in stimulating green growth, while economic expenditures and administrative expenditures have adverse effects. (3) Public expenditure mainly promotes green development through four channels: human capital accumulation, technological innovation, environmental quality improvement, and labor productivity increase. (4) The expenditure composition influences the turning point of the inverted U-shaped relationship. Based on these findings, we propose some targeted policy suggestions to promote green development.


Azobenzene-based unnatural amino acid scaffolds via a Pd(II)-catalyzed C(sp3)-H arylation strategy.
Azobenzene-based unnatural amino acid motifs were synthesized via Pd(II)-catalyzed diastereoselective C(sp3)-H arylation of amino acid carboxamides with iodoacetanilides and Mills azo coupling.


Performance monitoring in cardiac surgery: application of statistical process control to a single-site database.
Graphical Statistical Process Control (SPC) tools have been shown to promptly identify significant variations in clinical outcomes in a range of health care settings. We explored the application of these techniques to quantitatively inform the routine cardiac surgical (CAS) morbidity and mortality (M&M) review processes at a single site. Baseline clinical and procedural data relating to 5265 consecutive cardiac surgical procedures, performed at St Andrew's War Memorial Hospital (SAWMH) between the 1st January 2003 and the 30th April 2012, were retrospectively evaluated. A range of appropriate clinical outcome indicators (COIs) were developed and evaluated using a combination of Cumulative Sum charts, Exponentially Weighted Moving Average charts and Funnel Plots. Charts were updated regularly and discussed at the cardiac surgery unit's bi-monthly M&M meetings. Risk adjustment (RA) for the COIs was developed and validated for incorporation into the charts to improve monitoring performance. Discrete and aggregated measures, including blood product/reoperation, major acute post-procedural complications, cardiopulmonary bypass duration and Length of Stay/Readmission < 28 days have proved to be valuable measures for monitoring outcomes. Instances of variation in performance identified using the charts were examined thoroughly and could be related to changes in clinical practice (e.g. antifibrinolytic use) as well as differences in individual operator performance (in some instances, driven by case mix). SPC tools can promptly detect meaningful changes in clinical outcome thereby allowing early intervention to address altered performance. Careful interpretation of charts for group and individual operators has proven helpful in detecting and differentiating systemic versus individual variation.


Bio-mimicking nano and micro-structured surface fabrication for antibacterial properties in medical implants.
Orthopaedic and dental implants have become a staple of the medical industry and with an ageing population and growing culture for active lifestyles, this trend is forecast to continue. In accordance with the increased demand for implants, failure rates, particularly those caused by bacterial infection, need to be reduced. The past two decades have led to developments in antibiotics and antibacterial coatings to reduce revision surgery and death rates caused by infection. The limited effectiveness of these approaches has spurred research into nano-textured surfaces, designed to mimic the bactericidal properties of some animal, plant and insect species, and their topographical features. This review discusses the surface structures of cicada, dragonfly and butterfly wings, shark skin, gecko feet, taro and lotus leaves, emphasising the relationship between nano-structures and high surface contact angles on self-cleaning and bactericidal properties. Comparison of these surfaces shows large variations in structure dimension and configuration, indicating that there is no one particular surface structure that exhibits bactericidal behaviour against all types of microorganisms. Recent bio-mimicking fabrication methods are explored, finding hydrothermal synthesis to be the most commonly used technique, due to its environmentally friendly nature and relative simplicity compared to other methods. In addition, current proposed bactericidal mechanisms between bacteria cells and nano-textured surfaces are presented and discussed. These models could be improved by including additional parameters such as biological cell membrane properties, adhesion forces, bacteria dynamics and nano-structure mechanical properties. This paper lastly reviews the mechanical stability and cytotoxicity of micro and nano-structures and materials. While the future of nano-biomaterials is promising, long-term effects of micro and nano-structures in the body must be established before nano-textures can be used on orthopaedic implant surfaces as way of inhibiting bacterial adhesion.


Pediatric feeding disorders: a quantitative synthesis of treatment outcomes.
A systematic review of the literature regarding treatment of pediatric feeding disorders was conducted. Articles in peer-reviewed scientific journals (1970-2010) evaluating treatment of severe food refusal or selectivity were identified. Studies demonstrating strict experimental control were selected and analyzed. Forty-eight single-case research studies reporting outcomes for 96 participants were included in the review. Most children presented with complex medical and developmental concerns and were treated at multidisciplinary feeding disorders programs. All studies involved behavioral intervention; no well-controlled studies evaluating feeding interventions by other theoretical perspectives or clinical disciplines met inclusion criteria. Results indicated that behavioral intervention was associated with significant improvements in feeding behavior. Clinical and research implications are discussed, including movement toward the identification of key behavioral antecedents and consequences that promote appropriate mealtime performance, as well as the need to better document outcomes beyond behavioral improvements, such as changes in anthropometric parameters, generalization of treatment gains to caregivers, and improvements in nutritional status.


Sentinel Node Navigation in Gastric Cancer: Where Do We Stand?
Early gastric cancer (EGC) is more common nowadays and is related a to low percentage of lymph node metastasis. For this reason, there is enormous interest to implicate minimally invasive approaches. Recently, special efforts have been made towards a potential intraoperative (real-time) lymph node metastasis (LNM) assessment, as nodal disease status could not be identified with precision before or during surgery. In this direction, accurate prediction of the LNM status through sentinel LN mapping has been attempted, as an approach to the intraoperative detection of sentinel lymph nodes (SLNs). A careful literature search was conducted in order to clarify the potential clinical application of SN biopsy in the gastric cancer field. The real clinical application of SN biopsy in gastric cancer treatment has been more than challenging due to the "complicated" nature of gastric lymphatic drainage and the high possibility of "skip" metastasis phenomenon. Notably, sophisticated technical aspects, such as the preferred tracer used and the potential "ideal" method to verify the presence of metastases in the resected SLNs, made SN biopsy application in gastric cancer field extremely demanding. Assessing the potential role of SN navigation for gastric cancer treatment in the era of advanced technology, where the minimally invasive surgical approaches are in the top of the scientific interest, it has to be highlighted that SN navigation for gastric cancer is a topic that remains highly controversial, and the need for future clinical trials on this topic is obvious.


[Morphofunctional changes in the spinal cord, its meninges and epidural structures in experimental obturation of the epidural veins of the spinal canal].
When the blood flow in the epidural veins of the spinal cord canal is stopped (performed in 24 dogs) by means of paraffin emboli, it results, at early stages, in distrophic and hypoxic changes in neurons and glial cells of the spinal cord. In 2-4 weeks these changes are substituted by certain restorative processes and in 3 months normal structure and function are restored.


Gender Influences on Return to Work After Mild Traumatic Brain Injury.
To examine the influence of gender on the return to work experience of workers who sustained a work-related mild traumatic brain injury (TBI). Qualitative study using in-depth telephone interviews. Community. Purposive sampling was used to recruit participants. Participants were adults (N=12; males, n=6, females, n=6) with a diagnosis of mild TBI sustained through a workplace injury. Not applicable. Not applicable. Our findings suggest that gender impacts return to work experiences in multiple ways. Occupational and breadwinner roles were significant for both men and women after work-related mild TBI. Women in this study were more proactive than men in seeking and requesting medical and rehabilitation services; however, the workplace culture may contribute to whether and how health issues are discussed. Among our participants, those who worked in supportive, nurturing (eg, feminine) workplaces reported more positive return to work (RTW) experiences than participants employed in traditionally masculine work environments. For all participants, employer and coworker relations were critical elements in RTW outcomes. The application of a gender analysis in this preliminary exploratory study revealed that gender is implicated in the RTW process on many levels for men and women alike. Further examination of the work reintegration processes that takes gender into account is necessary for the development of successful policy and practice for RTW after work-related MTBI.


Characterization of a candidate locus for malaria susceptibility in human populations: a (TA)n microsatellite in the promoter region of the CYBB gene, the gp91 phox subunit of the NADPH oxidase.
We have analysed the linkage disequilibrium pattern between the promoter TA microsatellite and Single Nucleotide Polymorphism (SNP) haplotypes for the CYBB gene. None of the CYBB SNPs serve as good surrogates for the microsatellite alleles, previously associated with mild malaria. Thus, the candidate (TA)(n) microsatellite should be directly tested in genetic epidemiology studies.


Effectiveness of computer-assisted perimetry in the diagnosis of pituitary adenomas.
Computer-assisted perimetry (CP) is a new method which quantifies the differential light sensitivity threshold and allows the statistical analysis of the data. It offers advantages as compared with manual methods. This study has been carried out in 27 patients with pituitary adenomas (four males and 23 females; 13 with prolactinomas; six with acromegaly, four with Cushing's disease and four with non-secreting adenomas). A skull X-ray and a computed tomodensitometry (CT), a manual Goldman perimeter and a computer assisted visual field examination were performed in all cases. The presence of a pituitary tumour was suggested by the X-ray and by the CT in 12 and 23 patients respectively out of the 27: the CT scan revealed a suprasellar extension in seven cases. Visual field defects were detected by means of the Goldman perimeter in six patients and by means of the computer-assisted technique in 25/27. The effectiveness of this new technique was proved by the concordance with the CT scan results in 21 cases and by the histological examination of the four adenomas which were not apparent at CT scan. A significant difference was found for both eyes (right eye, chi squared = 258, P less than 0.001; left eye, chi squared = 295.0, P less than 0.001) between patients and controls. No correlation existed between visual defects and the pituitary size apparent at CT scan. Six patients were evaluated with the CT and CP after 1 year of bromocriptine treatment; a slight reduction of size was documented with the CT in four cases, whereas a significant positive change in visual acuity was observed in five patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Therapeutic blood levels of phenytoin in treatment of paroxysmal choreoathetosis.
Eight patients with paroxysmal choreoathetosis received phenytoin therapy, starting from 50 mg of oral phenytoin with a gradual increment of the dose. After successful control of the paroxysmal attacks, blood levels of phenytoin in these patients were measured by enzyme immunoassay. The mean phenytoin blood level was 5.2 +/- 3.2 micrograms/ml, with a range of 1.1-10.9 micrograms/ml. It is proposed that phenytoin can be maintained at a lower level in the treatment of paroxysmal choreoathetosis than in seizure control.


[Construction and characterization of hepatitis B surface antigen "a" epitope virus-like particles].
To construct virus-like particles of hepatitis B core antigen, with HBsAg "a" epitope exposed on the surface. Hepatitis B surface antigen "a" epitope were inserted into the Hepatitis B core antigen, between the 78th (Asp) and the 79th (Pro) amino acids. The gene was synthesized after the codon optimized, then it was ligated to the express vector after been enzyme digest. The virus-like particles were observed by electron microscope and detected by ELISA after been expressed and purified. Immune the rabbits by the VLPs, then detect the antibody. The virus-like particles were confirmed by electron microscope. Its antigenicity and immunogenicity were identified by ELISA. The prokaryotic express plasmid with the fusion gene has been constructed successfully. The virus-like particles have been expressed, purified and identified, which lays the foundation for its application in the further.


Multiple isoforms of beta-TrCP display differential activities in the regulation of Wnt signaling.
The F-box proteins beta-TrCP1 and 2 (beta-transducin repeat containing protein) have 2 and 3 isoforms, respectively, due to alternative splicing of exons encoding the N-terminal region. We identified an extra exon in between the previously known exons 1 and 2 of beta-TrCP1 and beta-TrCP2. Interestingly, sequence analysis suggested that many more isoforms are produced than previously identified, via the alternative splicing of all possible combination of exons II to V of beta-TrCP1 and exons II to IV of beta-TrCP2. Different mouse tissues show specific expression patterns of the isoforms, and the level of expression of the isoform that has been used in most published papers was very low. Yeast two-hybrid assays show that beta-TrCP1 isoforms containing exon III, which are the most highly expressed isoforms in most tissues, do not interact with Skp1. Indirect immunofluorescence analysis of transiently expressed beta-TrCP1 isoforms suggests that the presence of exon III causes beta-TrCP1 to localize in nuclei. Consistent with the above findings, isoforms including exon III showed a reduced ability to block ectopic embryonic axes induced via injection of Wnt8 or beta-catenin in Xenopus embryos. Overall, our data suggest that isoforms of beta-TrCPs generated by alternative splicing may have different biological roles.


Domain-specific interactions between the p185(neu) and epidermal growth factor receptor kinases determine differential signaling outcomes.
We expressed the epidermal growth factor receptor (EGFR) along with mutant p185(neu) proteins containing the rat transmembrane point mutation. The work concerned the study of the contributions made by various p185(neu) subdomains to signaling induced by a heterodimeric ErbB complex. Co-expression of full-length EGFR and oncogenic p185(neu) receptors resulted in an increased EGF-induced phosphotyrosine content of p185(neu), increased cell proliferation to limiting concentrations of EGF, and increases in both EGF-induced MAPK and phosphatidylinositol 3-kinase (PI 3-kinase) activation. Intracellular domain-deleted p185(neu) receptors (T691stop neu) were able to associate with full-length EGFR, but induced antagonistic effects on EGF-dependent EGF receptor down-regulation, cell proliferation, and activation of MAPK and PI 3-kinase pathways. Ectodomain-deleted p185(neu) proteins (TDelta5) were unable to physically associate with EGFR, and extracellular domain-deleted p185(neu) forms failed to augment activation of MAPK and PI 3-kinase in response to EGF. Association of EGFR with a carboxyl-terminally truncated p185(neu) mutant (TAPstop) form did not increase transforming efficiency and phosphotyrosine content of the TAPstop species, and proliferation of EGFR.TAPstop-co-expressing cells in response to EGF was similar to cells containing EGFR only. Thus, neither cooperative nor inhibitory effects were observed in cell lines co-expressing either TDelta5 or TAPstop mutant proteins. Unlike the formation of potent homodimer assemblies composed of oncogenic p185(neu), the induction of signaling from p185(neu).EGFR heteroreceptor assemblies requires the ectodomain for ligand-dependent physical association and intracellular domain contacts for efficient intermolecular kinase activation.


The role of hypoxia inducible factor-1 in cell metabolism--a possible target in cancer therapy.
In many cancer types, intratumoural hypoxia is linked to increased expression and activity of the transcription factor hypoxia-inducible factor (HIF-1alpha), which is associated with poor patient prognosis. This increased the interest in HIF-1alpha as a cancer drug target. Further, HIF-1alpha has also a central role in the adaptive cellular programme responding to hypoxia in normal tissues. Many of the HIF-1alpha-regulated genes encode enzymes of metabolic pathways. Therefore, studying the link and the feedback mechanisms between metabolism and HIF-1alpha is of major importance to find new and specific therapeutic strategies.


Dihydrocapsaicin-induced hypothermia and substance P depletion.
Administration of dihydrocapsaicin to rats resulted in a dose-dependent (0.5-10 mg/kg s.c.) hypothermia. Dihydrocapsaicin was approximately 65% more effective in producing hypothermia than capsaicin. Desensitization and cross-tolerance occurred to the hypothermic effects of both capsaicin and dihydrocapsaicin. Repeated administration of either dihydrocapsaicin or capsaicin resulted in chemogenic antinociception but not marked thermal antinociception. In addition, repeated administration of dihydrocapsaicin, like capsaicin, resulted in depletion of substance P from dorsal root ganglia and dorsal spinal cord but not from the hypothalamus, corpus striatum or ventral spinal cord. These data indicate that dihydrocapsaicin, or radiolabelled dihydrocapsaicin, may be a useful tool for investigating the mechanisms by which capsaicin alters thermoregulation and primary afferent neuron function.


Fetal calf serum-injected F1 mice spontaneously generate specific anti-parental cytotoxic T lymphocytes in in vitro culture.
Spleen cells from adult (BALB/c x AKR/J)F1 mice primed in vivo with fetal calf serum (FCS) can spontaneously generate anti-parental AKR/J cytotoxic T cells (CTL) in a 5-day in vitro culture containing 5% FCS. This response is distinguished by the following features: (i) it is anti-parental but not anti-self, and (ii) it has specificity for the Kk parental determinant as shown by mapping studies on a variety of targets and antiserum-blocking experiments. Although specifically elicited by FCS and mediated by FCS-induced T-helper cells, it is ascertained that this cytotoxicity is not directed against Kk components modified by absorbed FCS as shown by cold-target competition studies. Further experiments involved a comparative investigation of the patterns of lysis of allogenically induced CTL, FCS-induced CTL, and natural killer (NK) cytotoxic activities on tumor cell targets. The resistance of BW 5147 tumor targets to NK- and FCS-induced lysis was found to be dramatically overcome by treatment with mitomycin C, and provides circumstantial evidence for a functional relationship between the FCS-induced anti-parental CTL effectors and NK cells based on the observed similarity in lytic patterns of these two effector types. With reference to the work of other authors, the possibility that hybrid resistance and its possible in vitro counterpart, F1 anti-parental CTL cytotoxicity, and NK activity are mediated by similar or common effector mechanisms is discussed.


High-throughput determination of mono- and di(2-ethylhexyl)phthalate migration from PVC tubing to drugs using liquid chromatography-tandem mass spectrometry.
The risk assessment of di(2-ethylhexyl) phthalate (DEHP) that migrated from polyvinyl chloride (PVC) medical devices is an important issue for hospitalized patients. Many studies have been conducted to determine the level of DEHP migration. A recent report has indicated that DEHP in blood bags was hydrolyzed by esterase to mono(2-ethylhexyl) phthalate (MEHP). Therefore, a method for the simultaneous determination of DEHP and MEHP was developed. The migration of DEHP and MEHP from PVC tubing to drugs was examined. Although we detected MEHP in the drugs, we found no enzymatic activity involved in the migration process. Some reports have indicated that hydrolysis may have occurred during sterilization by autoclaving. However, we did not perform any heat treatment. It is speculated that the MEHP migrated directly from the PVC tubing. The simultaneous determination of DEHP and MEHP is required for risk assessment, as MEHP may be even more toxic than the parent compound.


Birth after preeclamptic pregnancies: association with allergic sensitization and allergic rhinoconjunctivitis in late childhood; a historically matched cohort study.
The development of allergic sensitization and allergic disease may be related to factors during intrauterine life, but the role of maternal preeclampsia is not known.We studied if maternal preeclampsia is associated with long-term allergic sensitization, allergic rhinoconjunctivitis, atopic dermatitis, asthma and with altered lung function in late childhood. 617 children participated in a 1:2 matched and controlled historical cohort study; 230 born after preeclamptic pregnancies and 387 born after normotensive pregnancies. Specific IgE in serum and lung function were measured at the age of 12.8 years and questionnaires on maternal and adolescent data were completed at the ages of 10.8 years (girls) and 11.8 years (boys), and at 12.8 years (both genders). The association between birth after preeclampsia and the main outcome measures allergic sensitization, allergic rhinoconjunctivitis, atopic dermatitis, asthma and lung function in late childhood were analysed with multiple regression analyses, including possible confounders. Severe maternal preeclampsia was associated with high level allergic sensitization (sum of specific IgE in serum ≥ 3.9 kU/l; the 25 percentile for all children being sensitized); odds ratio (OR): 3.79; 95% confidence interval (CI): (1.54, 9.32); p = 0.015 and with allergic rhinoconjunctivitis in offspring; OR: 2.22, 95% CI: (1.19, 4.14), p = 0.047. Preeclampsia was not associated with atopic dermatitis, asthma or altered lung function in late childhood. Maternal preeclampsia was associated with allergic sensitization and allergic rhinoconjunctivitis in offspring in late childhood, but not with other atopic diseases.


Tamoxifen-induced cell death in malignant melanoma cells: possible involvement of the insulin-like growth factor-1 (IGF-1) pathway.
Recent data indicate that the estrogen receptor (ER) blocker tamoxifen (TAM) can induce cell death in malignant melanoma cells. However, as shown in the present study and several other studies melanoma cells usually do not express classical ERs. In the present study we investigated whether the cytotoxic effect of TAM on melanoma cells could depend on interference with the expression or function of the insulin-like growth factor-1 receptor (IGF-1R), a plasma membrane receptor important for cell survival in this tumor cell type. Several melanoma cell lines were included in the analysis. Administration of TAM at a concentration of 15 microm or more resulted in cell death of the melanoma cells within 48 h. TAM treatment was correlated to a slight to moderate inhibition of IGF-1 binding to IGF-1R. Since it has been reported that TAM can increase the release of IGF binding proteins (IGFBPs) we then investigated whether this mechanism could underly the decreased IGF-1 binding. However, we could demonstrate that the amount of released IGFBPs were unchanged or decreased in TAM-treated cells. Whereas TAM did not have any strong effect on IGF-1 binding and the expression of IGF-1R at the cell surface, it was was found to efficently block tyrosine phosphorylation of IGF-1R beta-subunit. Taken together, our data suggest that TAM-induced cytotoxicity of malignant melanoma cells can be due to inactivation of IGF-1R.


Laser navigation combined with XperCT technology-assisted puncture of basal ganglia intracerebral hemorrhage.
Basal ganglia hemorrhage, which is characterized by excessive incapacity charge and high mortality rates, is surgically treated by minimally invasive hematoma puncture and drainage. We aimed at determining the efficacy of laser-guided minimally invasive hematoma puncture and drainage for treatment of basal ganglia hemorrhage. A total of 61 patients with hypertensive basal ganglia hemorrhage were recruited at the Binzhou Medical University Hospital, between October 2019 and January 2021, and their clinical information retrospectively analyzed. Based on the surgical approach used, patients were assigned into either laser navigation or small bone window groups depending on the surgical approach. Then, we compared the operation times, intraoperative blood loss, clinic stay, Glasgow Outcome Score (GOS) rating at 30 days, Barthel index (BI) rating at 6 months, postoperative pneumonia incidences, and intracranial contamination complications between groups. Intraoperative blood loss, operation time, and sanatorium were significantly low in laser navigation group, relative to the small bone window group. At the same time, there were no significant differences between the groups with regard to postoperative hematoma volume, lung contamination, cerebrospinal fluid (CSF) leak, and intracranial contamination, as well as the 6-month BI and 30-day GOS rating. There were no deaths in either group. Compared with the traditional small bone window surgery, laser-guided puncture and drainage is a low-cost, accurate, and safe method for the treatment of basal ganglia hemorrhage, which is suitable for promotion in developing countries and economically underdeveloped areas.


Relationship between alcohol-attributable disease and socioeconomic status, and the role of alcohol consumption in this relationship: a systematic review and meta-analysis.
Studies show that alcohol consumption appears to have a disproportionate impact on people of low socioeconomic status. Further exploration of the relationship between alcohol consumption, socioeconomic status and the development of chronic alcohol-attributable diseases is therefore important to inform the development of effective public health programmes. We used systematic review methodology to identify published studies of the association between socioeconomic factors and mortality and morbidity for alcohol-attributable conditions. To attempt to quantify differences in the impact of alcohol consumption for each condition, stratified by SES, we (i) investigated the relationship between SES and risk of mortality or morbidity for each alcohol-attributable condition, and (ii) where, feasible explored alcohol consumption as a mediating or interacting variable in this relationship. We identified differing relationships between a range of alcohol-attributable conditions and socioeconomic indicators. Pooled analyses showed that low, relative to high socioeconomic status, was associated with an increased risk of head and neck cancer and stroke, and in individual studies, with hypertension and liver disease. Conversely, risk of female breast cancer tended to be associated with higher socioeconomic status. These findings were attenuated but held when adjusted for a number of known risk factors and other potential confounding factors. A key finding was the lack of studies that have explored the interaction between alcohol-attributable disease, socioeconomic status and alcohol use. Despite some limitations to our review, we have described relationships between socioeconomic status and a range of alcohol-attributable conditions, and explored the mediating and interacting effects of alcohol consumption where feasible. However, further research is needed to better characterise the relationship between socioeconomic status alcohol consumption and alcohol-attributable disease risk so as to gain a greater understanding of the mechanisms and pathways that influence the differential risk in harm between people of low and high socioeconomic status.


NK cells play a critical role in the regulation of class I-deficient hemopoietic stem cell engraftment: evidence for NK tolerance correlates with receptor editing.
The role that NK cells play in the rejection of hemopoietic stem cell (HSC) and tolerance induction has remained controversial. In this study, we examined whether NK cells play a direct role in the rejection of HSC. Purified HSC from MHC class II-deficient mice engrafted readily in congenic mice, while HSC from class I-deficient donors (beta(2)-microglobulin(-/-) (beta(2)m(-/-))) failed to engraft. Recipient mice lacking CD8(+), CD4(+), or T cells also rejected HSC from class I-deficient donors, pointing directly to NK cells as the effector in rejection of HSC. Recipients, deficient in or depleted of NK cells, engrafted readily with beta(2)m(-/-) HSC. Expression of the activating Ly-49D and inhibitory Ly-49G2 receptors on recipient NK cells was significantly decreased in these beta(2)m(-/-)-->B6 chimeras, and the proportion of donor NK cells expressing Ly-49D was also significantly decreased. Notably, beta(2)m(-/-) chimeras accepted beta(2)m(-/-) HSC in second transplants, demonstrating that NK cells in the chimeras had been tolerized to beta(2)m(-/-). Taken together, our data demonstrate that NK cells play a direct role in the regulation of HSC engraftment, and down-regulation and/or deletion of specific NK subsets in mixed chimeras can contribute to the induction of NK cell tolerance in vivo. Moreover, our data show that bone marrow-derived elements significantly contribute to NK cell development and tolerance.


Modulatory effects of hard clam (Mercenaria mercenaria) tissue extracts on the in vitro growth of its pathogen QPX.
Quahog parasite unknown (QPX) is a fatal protistan parasite affecting cultured and wild hard clams Mercenaria mercenaria along the northeastern coasts of the USA and maritime Canada. Field investigations and laboratory transmission studies revealed some variations in the susceptibility of different hard clam stocks to QPX infection. In this study, we used in vitro QPX cultures to investigate the effect of plasma and tissue extracts from two different clam stocks on parasite survival and growth. Results demonstrated the presence of factors in clams that significantly modulate QPX growth. Extracts from gills and mantle tissues as well as plasma inhibited in vitro QPX growth, whereas foot and adductor muscle extracts enhanced parasite growth. Investigations of anti-QPX activities in plasma from two clam stocks displaying different susceptibility toward QPX disease in vivo demonstrated higher inhibition of QPX growth by plasma from New York (resistant) clams compared to Florida (susceptible) clams. Some clams appeared to be deficient in inhibitory factors, suggesting that such animals may become more easily infected by the parasite.


Non-viral gene delivery to atelectatic and ventilated lungs.
Three different nonviral vectors and naked DNA were evaluated for in vivo transfer of plasmid DNA to rat lungs through airways in either atelectatic or ventilated lungs. The F344 rats underwent instillation of 300 microg DNA (pCIluc, luciferase) to the left lung. Naked DNA, linear polyethylenimine, branched polyethylenimine, and lipid GL-67 (in either atelectatic or ventilated lungs) were assessed (n = 5 per group). After 24 hours, left lung PaO2 (mm Hg) and luciferase activity (RLU/mg) were measured. The median (range) was given, and the analysis of variance was applied, followed by the planned comparison on log-transformed data. In atelectatic lungs, lipid GL-67 was best (927 [330 to 4112] RLU/mg; p < 0.001 versus other groups of atelectatic lung; p < 0.001 versus all other groups), but highest luciferase activity in all groups was measured in ventilated lungs using linear polyethylenimine (1,240 [922 to 2519] RLU/mg; p < 0.001 versus other groups of ventilated lung; p < 0.001 versus all other groups). In comparison with naked DNA, all nonviral vector systems significantly impaired PaO2 24 hours after airway transfection (p < 0.001; naked DNA versus all other groups). Regardless of transfection technique, PaO2 was worst in lungs transfected by linear polyethylenimine. Highest transfection was achieved with GL-67 in atelectatic lungs and with linear polyethylenimine in ventilated lungs. All gene delivery systems impaired gas exchange of the transduced lung in comparison with naked DNA.


Mutagenic characteristics of formaldehyde on bacterial systems.
The mutagenic characteristics of formaldehyde on bacteria were examined. All the tester strains of Escherichia coli deficient in DNA-repair enzymes tested in the present study were significantly more sensitive to the killing effect of formaldehyde than the corresponding wild-type strain. Among the E. coli B strains, H/r30R (wild-type) and Hs30R (uvrA) were mutable, whereas NG30 (recA) and O16 (polA) were not. There is no appreciable difference in mutation frequency of E. coli B between the wild-type and the uvrA strains in a dose range below 4 mM. However, the mutation frequency of the wild-type strain started to decrease in a higher concentration range, whereas that of the uvrA strain continued to increase linearly. This was confirmed with the E. coli B/r tester strains. The decrease in mutation frequency may be produced by prolongation of the lag period before entering the S-phase so as to give the cells a greater chance for DNA repair through the excision mechanism. In fact, it was evidenced that formaldehyde retarded to a remarkable extent the initiation of DNA synthesis of the cells at the higher dose range used for mutation assay. Some discrepancies found between the results obtained in this study and those previously reported by Nishioka (1973) were pointed out.


Basis and lattice polarization mechanisms for light transmission through nanohole arrays in a metal film.
The extraordinary light transmission through double-hole and elliptical nanohole arrays in a thin gold film is investigated for different orientations of the holes relative to the lattice. Even though these bases have similar symmetry characteristics, the polarization follows the orientation of the basis for the ellipse but remains fixed along a lattice vector for the double holes. Furthermore, the maximum transmitted intensity for linearly polarized light is constant for the ellipse, but decreases for the double holes as they are rotated away from being aligned with the lattice. Finite-difference time-domain simulations agree well with the experimental findings. These experiments show how the basis determines both the coupling into the surface plasmon waves and the evanescent transmission through the nanoholes. Both of these effects need to be considered when designing nanophotonic devices using the extraordinary transmission phenomenon.


Arterial bypass of the descending thoracic aorta with the BioMedicus centrifugal pump.
Bypass of the descending thoracic aorta is frequently advocated as an adjunct for repair of traumatic tears and degenerative aneurysms. Many methods of bypass have been proposed to provide distal perfusion and reduce left ventricular afterload during cross-clamp of the thoracic aorta. We describe a simple method of direct arterial (aortoaortic or aortofemoral) bypass using the BioMedicus centrifugal pump with limited systemic heparinization.


Sex-dependent endozepinergic regulation of ventromedial hypothalamic nucleus glucose counter-regulatory neuron aromatase protein expression in the adult rat.
The hypothalamic brain cell types that produce estradiol from testosterone remain unclear. Aromatase inhibition affects ventromedial hypothalamic nucleus (VMN) glucose-stimulatory nitric oxide (NO) and glucose-inhibitory γ-aminobutyric acid (GABA) transmission during insulin (INS)-induced hypoglycemia (IIH). Pure GABA and NO nerve cell samples acquired by laser-catapult-microdissection from consecutive rostro-caudal segments of the VMN were analyzed by Western blot to investigate whether regional subpopulations of each cell type contain machinery for neuro-estradiol synthesis. Astrocyte endozepinergic signaling governs brain steroidogenesis. Pharmacological tools were used here to determine if the glio-peptide octadecaneuropeptide (ODN) controls aromatase expression in GABA and NO neurons during eu- and/or hypoglycemia. Intracerebroventricular administration of the ODN G-protein coupled-receptor antagonist cyclo(1-8)[DLeu5]OP (LV-1075) decreased (male) or enhanced (female) VMN GABAergic neuron aromatase expression, but increased or reduced this profile in nitrergic neurons in a region-specific manner in each sex. IIH suppressed aromatase levels in GABA neurons located in the middle segment of the male VMN or distributed throughout this nucleus in the female. This inhibitory response was altered by the ODN isoactive surrogate octapeptide (OP) in female, but was refractory to OP in male. NO neuron aromatase protein in hypoglycemic male (middle and caudal VMN) and female (rostral and caudal VMN) rats, but was normalized in OP- plus INS-treated rats of both sexes. Results provide novel evidence that VMN glucose-regulatory neurons may produce neuro-estradiol, and that the astrocyte endozepine transmitter ODN may impose sex-specific control of baseline and/or hypoglycemic patterns of aromatase expression in distinct subsets of nitrergic and GABAergic neurons in this neural structure.


Viral bronchiolitis in children: a common condition with few therapeutic options.
Even though bronchiolitis is a disease that has been recognized for many years, there are still few therapeutic strategies beyond supportive therapies. Bronchiolitis is the most frequent cause of hospital admission in children less than 1 year of age. The incidence is estimated to be about 150° million cases a year worldwide, and 2-3% of these cases require hospitalization. It is acknowledged that viruses cause bronchiolitis, but most of the studies focus on RSV. The RSV causes a more severe form of bronchiolitis in children with risk factors including prematurity, cardiovascular disease and immunodeficiency. Other viruses involved in causing bronchiolitis include RV, hMPV, hBoV and co-infections. The RV seems to be associated with a less severe acute disease, but there is a correlation between the early infection and subsequent wheezing bronchitis and asthma in later childhood and adulthood. The supportive therapies used are intravenous fluids and oxygen supplement administered by nasal cannula or CPAP in most complicated patients. Additional pharmacological therapies include epinephrine, 3% hypertonic saline and corticosteroids. The Epinephrine seems to have the greatest short-term benefits and reduces the need of hospital admission, whereas hypertonic saline and corticosteroids seem to reduce the length of hospital stay. As bronchiolitis is such a prevalent disease in children and RV seems to play an important role, perhaps more studies should center around the RV's contribution to the initial disease and following pathology.


Safety testing of metabolites: Expectations and outcomes.
Metabolites arising from chemical entities, old or new, are often mediators of toxicity. Frequently, metabolites are investigated in test animals, with the expectation that the resultant toxicity or activity will mimic the exposure of their formed counterparts. This communication described observations that showed discrepant kinetics between formed and preformed metabolites in the liver, intestine, and kidney, major drug removal organs. Differences in the observed areas under the curve (AUCs) or the extraction ratios (Es) of formed and preformed metabolites in the liver had been attributed to zonal, enzyme heterogeneity, membrane barriers, or transporters. Preformed and formed metabolite also differed in their handling by the kidney; only the preformed and not the formed metabolite would be filtered. In the intestine, differences in the absorption of the precursor and the metabolite and the flow pattern in the intestine would bring about discrepancy in the time-courses of the formed vs. preformed metabolites. Analytical solutions of the AUCs of the metabolites and extraction ratios, based on physiological modeling of the liver, kidney, and intestine, showed that the AUC of the preformed, administered metabolite was dependent only on metabolite parameters, whereas the AUC of the formed metabolite was modulated additionally by the metabolic, secretory and intestinal absorptive intrinsic clearances of the precursor drug. Hence, administration of the synthetic metabolite would not reflect the toxicity associated with the metabolite formed via bioactivation. However, data on preformed metabolite may be used for simultaneous fitting by a combined model of drug and metabolite. Such a strategy is shown to be successful in risk assessment of environmental chemicals. Upon refinement of the resultant model with data on metabolite transport and handling by modeling and simulations, the resultant model would be more robust to provide improved predictions on metabolite toxicity pursuant to drug administration.


Bioactive Secondary Metabolites with Unique Aromatic and Heterocyclic Structures Obtained from Terrestrial Actinomycetes Species.
Natural products from actinomycetes are important and valuable sources for drug discovery and the development of biological tools. The present review describes our recent study on the isolation of new natural products mainly possessing heterocyclic and aromatic ring structures with biological effects on cancer-related cellular pathways such as tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) and Wnt signaling.


Randomized trial of dacarbazine versus bleomycin, vincristine, lomustine and dacarbazine (BOLD) chemotherapy combined with natural or recombinant interferon-alpha in patients with advanced melanoma.
This randomized phase II study was designed to compare the efficacy and tolerability of dacarbazine (DTIC) and bleomycin, vincristine, lomustine and DTIC (BOLD) combined with natural interferon-alpha (nIFN-alpha) or recombinant interferon-alpha2b (rIFN-alpha2b) in patients with advanced melanoma. The treatment arms were: A, DTIC plus nIFN-alpha; B, BOLD plus nIFN-alpha; C, DTIC plus rIFN-alpha2b; D, BOLD plus rIFN-alpha2b. One hundred and eight patients were randomized, of whom 106 were eligible to be analysed for efficacy. Overall, 56% of patients had abdominal visceral and/or bone involvement. The response rates were 8% (2/25) in arm A, 13% (4/31) in arm B, 12% (3/25) in arm C and 24% (6/25) in arm D. The differences were not statistically significant by the usual chi-squared test. However, when analysed using the Cochran-Armitage trend test, the one-sided P values were close to significant (0.085 and 0.033). All of the eight complete responses occurred in patients with soft tissue and/or lung metastases and the BOLD regimens produced six of them. There were no significant differences in survival (arm A, 11.1 months; arm B, 9.8 months; arm C, 9.1 months; arm D, 7.5 months; P=0.62). BOLD was more toxic than DTIC. With the present sample size, there were no statistically significant differences in efficacy between the arms, but there was a trend towards a higher response rate with BOLD plus rIFN-alpha2b. Patients with soft tissue or lung metastases may achieve more complete responses with BOLD regimens.


On the frontline: pediatric obesity in the emergency department.
Obesity among children is rising at an alarming rate. This study examines pediatric emergency department visits for children aged 2 to 17 years to determine the prevalence of normal, overweight, and obesity as well as to characterize discharge diagnosis and level of service among the different groups. The electronic emergency department medical record and billing service data were used in the review process. Body mass index (BMI) and percentiles were calculated using the Centers for Disease Control formulas with overweight being defined as BMI between 85th and 94th sex- and age-specific percentiles and obesity as greater than 95th sex- and age-specific percentile. The study was reviewed and approved by the institutional review board. Of the 596 patients meeting inclusion criteria, there was a predominance of African American and Hispanic patients. Approximately 53% (313) of patients were classified as normal weight, while 46% (272) of patients were either overweight or obese. The percentages of overweight and obesity were similar across racial/ethnic classifications, with a slight predominance of obesity among minority groups (30% and 35%, respectively, in minority groups vs 28% and 25%, respectively, in nonminority groups). There were no statistically significant differences between discharge diagnosis and level of service among the different weight categories. Rates of overweight and obesity in this predominately minority pediatric population were significantly greater than the published national rates. The impact of the epidemic of childhood obesity mandates the need for innovative strategies of weight control and reduction. Emergency departments routinely treat high-risk pediatric populations and can therefore serve as a resource for screening and early referral that has been previously untapped in combating childhood obesity.


Inhibition of N-methyl-D-aspartate- and kainate-evoked noradrenaline release in human cerebral cortex slices by ethanol.
The effect of ethanol on the release of noradrenaline evoked by various stimuli was investigated in human cerebral cortical slices from patients undergoing neurosurgery. The slices were preincubated with [3H]noradrenaline and then superfused. Tritium overflow was stimulated by exposure to N-methyl-D-aspartate (NMDA; in slices superfused without Mg2+), kainic acid, veratridine or by increasing the K+ concentration. The NMDA-evoked tritium overflow was concentration-dependently inhibited by ethanol; an inhibition by 37% occurred at 48 mmol/l ethanol. This ethanol concentration was not yet effective when kainic acid was used for stimulation, but ethanol 150 mmol/l strongly inhibited the tritium overflow evoked by kainic acid as well. The tritium overflow evoked by veratridine or high K+ was not affected by ethanol in the concentration range investigated. These findings are compatible with the suggestion that the NMDA receptor and, with less susceptibility, the kainate receptor are sites of action underlying the effect of ethanol in the human brain.


[Predictive factors of mortality of the burnt persons: study on 221 adults hospitalized between 2004 and 2009].
The objective of the present study is the evaluation of the predictive factors of mortality to a troop of Moroccan grown-up serious burnt persons. Variables analyzed in the study are: the age, the sex, the localization of the burn, the degree of burn, indicates Total Body Surface Area (TBSA), indicate Unit of Standard Burn (UBS) and the indication of leases, sepsis and the medical histories (tobacco, diabetes). Factors associated significantly to a mortality raised at the burned patients were the female genital organ, the localization of the burn at the level of the head, the sepsis, one TBSA greater or equal to 20%, an UBS greater or equal to 200 and an indication of leases greater or equal to 75. Other factors such as the age, the degree of burn and the histories did not show a significant difference. An evaluation and a good knowledge of factors associated to a high risk of death allow an adequate coverage of this category of patients.


A surface EMG multi-electrode technique for characterizing muscle activation patterns in mice during treadmill locomotion.
In mice a new method for 2x4-channel surface electromyography (EMG) recordings of the vastus lateralis and biceps femoris muscles during locomotion on a treadmill with varying speed is presented. The approach involves high-speed-videography (sampling interval 2.5 ms) in concert with the application of chronically implanted surface EMG multi-electrodes (EMG sampling rate 4000 Hz, frequency range 10-700 Hz). The recordings are started 2 days after surgery and finished 2 weeks after surgery. During the whole investigation period EMG recordings of both muscles have been possible. The monopolar EMG activities recorded by the electrode-arrays and the bipolar EMG signals derived from the monopolar activities permit an evaluation of the extent of myo-electrical activation in larger regions of both muscles and co-ordination between the flexor and extensor muscles. Bipolar EMG signals indicate propagation of activities along the muscle fibers and a slight effect of non-propagating signal components. Thus, the cross talk between these muscles is small and does not influence the evaluation of the EMG results. The resolution of the simultaneously recorded synchronized data allows a precise temporal correlation of kinematic and EMG parameters.


Movement of air bubbles under various liquids using bioinspired conical surfaces.
Gas bubbles are of interest in various applications. The study of their movement is of importance. Gas bubbles are typically formed under liquids. Movement of liquid droplets on bioinspired conical surfaces is known to be facilitated by the Laplace pressure gradient. These conical surfaces, with various wettabilities and shapes, can also be used to move gas bubbles. In this study, effect of various liquids on movement of air bubble under liquid was studied. It was found that liquids with high surface tension and high density are more efficient in moving air bubbles. High surface tension and higher density increases the Laplace pressure gradient force and the buoyancy force, respectively, which drive under liquid air bubbles.


Apgar Scores at 10 Minutes and Outcomes in Term and Late Preterm Neonates with Hypoxic-Ischemic Encephalopathy in the Cooling Era.
To determine the short-term outcomes (abnormal brain magnetic resonance imaging [MRI]/death) in infants born with a 10-minute Apgar score of 0 who received therapeutic hypothermia and compare them with infants with higher scores. This is a retrospective review of 293 neonates (gestational age ≥ 35 weeks) born between November 2006 and October 2015 admitted with hypoxic-ischemic encephalopathy who received therapeutic hypothermia. Results of brain MRIs were assessed by the basal ganglia/watershed scoring system. Short-term outcomes were compared between infants with Apgar scores of 0, 1 to 4, and ≥5 at 10 minutes. Eight of 17 infants (47%) with an Apgar of 0 at 10 minutes survived, having 4 (24%) without abnormalities on the brain MRI and 7 (41%) without severe abnormalities. There was no significant difference in the combined outcomes of "death/abnormal MRI" and "death/severe abnormalities on the MRI" between infants with Apgar scores of 0 and 1 to 4. Follow-up data were available for six of eight surviving infants, and none had moderate or severe neurodevelopmental impairment. In the cooling era, 47% of infants with no audible heart rate at 10 minutes and who were admitted to the neonatal intensive care unit survived; 24% without abnormalities on the brain MRI and 41% without severe abnormalities.


Occult lung carcinoma presenting with dysphagia. The value of computed tomography.
Dysphagia is a relatively uncommon presenting symptom of lung carcinoma that usually occurs in association with mediastinal adenopathy. However, a bronchogenic carcinoma will occasionally involve the esophagus by direct invasion. These central lesions can be difficult to visualize on chest radiographs and may not be detected by esophagoscopy or barium swallow. In such cases, a computed tomography scan of the thorax may suggest the correct diagnosis.


Comparison of Standard and Quadruple-Phase Contrast Material Injection for Artifacts, Image Quality, and Radiation Dose in the Evaluation of Head and Neck Cancer Metastases.
To investigate opacification of head and neck vasculature during computed tomography (CT) of supraclavicular lymph nodes with a quadruple-phase contrast media and saline dual-injection protocol. This retrospective study was institutional review board approved. In 180 consecutive patients, routine head and neck CT was performed with one of two protocols: protocol A, craniocaudal scan direction with 100 mL of contrast material injected intravenously as a single bolus; or protocol B, 100 mL of contrast material injected in four phases (phases 1-2, 60 mL of contrast material and saline injected at 2.5 mL/sec; phases 3-4, 40 mL of contrast material and saline injected at 2.5 mL/sec); both protocols had a fixed scan delay of 70 seconds. Attenuation of supraclavicular arteries and veins was measured with arteriovenous contrast ratio (AVCR) and contrast-to-noise ratio (CNR). Effective dose was calculated. Data were compared with the two-sample t test. Receiver operating characteristic (ROC) and visual grading characteristic analyses were performed. Arterial attenuation was up to 20% higher (P < .05) after protocol B (mean ± standard deviation, 234.5 HU ± 33.2) than protocol A (160.0 HU ± 29.5). Venous system attenuation was significantly lower in protocol B (164.0 HU ± 17.0) than in protocol A (664.0 HU ± 12.0), with up to a 75% reduction (P < .0001). Protocol B generated significant (P < .0001) improvements in AVCR at multiple anatomic sites. At all anatomic levels, mean CNR with protocol B (34.4 HU ± 9.0) was significantly higher than that with protocol A (14.5 HU ± 14.0) (P < .0313). Effective dose was significantly reduced with protocol B (2.6 mSv ± 0.4 vs 3.2 mSv ± 0.8 with protocol A; P < .0041). ROC analysis demonstrated significantly higher area under the ROC curve for protocol B (P < .0022), with interreader agreement increasing from poor to excellent in lymph node visualization. Significant improvement in lymph node visualization at the cervicothoracic junction is achieved with a quadruple-phase contrast media injection protocol.


The multiple forms of brain acetylcholinesterase. II. A suggestion of their functional importance.
The pattern of the multiple forms of the acetylocholinesterase (AChE, E.C. 22.214.171.124) of the rat brain is investigated using polyacrylamide gradient micro-gel electrophoresis with regard to a possible functional importance of this individual forms. The patterns of the AChE-forms of selected regions of the CNS are compared and certain differences could be shown. After increased cholinergic input (into the hippocampus by electrical stimulation of the nc. septi medialis) an aggregation of AChE subunits is detectable. Subletal intoxication with an irreversible inhibitor of AChE is followed by a faster recovery of the smaller forms. A suggestion of a possible functional role of the multiple forms of AChE is discussed.


Stable beta-secretase activity and presynaptic cholinergic markers during progressive central nervous system amyloidogenesis in Tg2576 mice.
We examined presynaptic cholinergic markers and beta-secretase activity during progressive central nervous system amyloidogenesis in Tg2576 Alzheimer mice (transgenic for human amyloid precursor protein Swedish mutation; hAPPswe). At 14, 18, and 23 months of age there were no significant differences between wild-type and transgenic mice in four distinct central nervous system cholinergic indices--choline acetyltransferase and acetylcholinesterase activities, and binding to vesicular acetylcholine transporter and Na(+)-dependent high-affinity choline uptake sites. A novel enzyme-linked immunosorbent assay measuring only the secreted human beta-secretase cleavage product (APPsbetaswe) of APPswe also revealed no change with aging in Tg2576 mouse brain. In contrast, transgenic but not wild-type mice exhibited an age-dependent increase in soluble Abeta40 and Abeta42 levels and progressive amyloid deposition in brain. Thus, aging Tg2576 mice exhibited presynaptic cholinergic integrity despite progressively increased soluble Abeta40 and Abeta42 levels and amyloid plaque density in brain. Older Tg2576 mice may best resemble preclinical or early stages of human Alzheimer's disease with preserved presynaptic cholinergic innervation. Homeostatic APPsbetaswe levels with aging suggest that progressive amyloid deposition in brain results not from increased beta-secretase cleavage of APP but from impaired Abeta/amyloid clearance mechanisms.


Decreasing the ambulatory knee adduction moment without increasing the knee flexion moment individually through modifications in footprint parameters: A feasibility study for a dual kinetic change in healthy subjects.
Gait retraining is gaining in interest to reduce loading associated to knee osteoarthritis (OA) progression. So far, interventions focused on reducing the peak knee adduction moment (pKAM) and it remains unclear if this can be done individually without increasing the peak knee flexion moment (pKFM). Additionally, while modifying foot progression angle (FPA) and step width (SW) is common, little is known about modifications in stride length (SL). This study aimed at characterizing the feasibility of a dual kinetic change, consisting in reducing the pKAM by at least 10% without increasing the pKFM. It also aimed to evaluate the added value of SL modifications in achieving the dual kinetic change. Gait trials with modifications in FPA, SW and SL were recorded for 11 young healthy subjects in a laboratory equipped with an augmented-reality system displaying instruction footprints on the floor. All participants achieved the dual kinetic change with at least one of the modifications. Seven participants achieved it with FPA modification, three with SW modification, and seven with SL modification. In conclusion, this study showed that it is feasible to achieve the dual kinetic change individually through subject-specific modifications in footprint parameters, suggesting that, in the future, gait retraining could aim for more specific kinetic changes than simply pKAM reductions. Modifying SL allowed achieving the dual kinetic change, stressing out the value of this parameter for gait retraining, in addition to FPA and SW. Finally, an augmented-reality approach was introduced to help footprint parameter modifications in the framework of knee OA.


Old and new: recent innovations in vaccine biology and skin T cells.
Memory is the hallmark of the adaptive immune system, and the observation that infectious diseases often lead to lifelong immunity in individuals who survive a first infection became the genesis for the development of vaccines. Immunization, which is the iatrogenic engineering of a protective memory immune response to a pathogen, became a standard part of medical care in the twentieth century, and has had an almost incalculable positive effect on human health and wellness. Vaccines to many, but by no means all, infectious diseases have been developed and are in common use. Smallpox vaccine, arguably the most effective vaccine in human history, was (and still is) delivered through disrupted epidermis in a process called scarification. Virtually all vaccines today are delivered by means of a hypodermic needle and syringe into muscle, in a process that bypasses the epidermis and dermis and their attendant innate and adaptive immune attributes. This article discusses vaccines in the context of the newly appreciated paradigm of tissue-resident memory T cells, and specifically discusses the role of these cells in skin and other epithelial interfaces with the environment in the maintenance of protective immunity.


A novel subtype of sporadic Creutzfeldt-Jakob disease with PRNP codon 129MM genotype and PrP plaques.
The presence of amyloid kuru plaques is a pathological hallmark of sporadic Creutzfeldt-Jakob disease (sCJD) of the MV2K subtype. Recently, PrP plaques (p) have been described in the white matter of a small group of CJD (p-CJD) cases with the 129MM genotype and carrying resPrPD type 1 (T1). Despite the different histopathological phenotype, the gel mobility and molecular features of p-CJD resPrPD T1 mimic those of sCJDMM1, the most common human prion disease. Here, we describe the clinical features, histopathology, and molecular properties of two distinct PrP plaque phenotypes affecting the gray matter (pGM) or the white matter (pWM) of sCJD cases with the PrP 129MM genotype (sCJDMM). Prevalence of pGM- and pWM-CJD proved comparable and was estimated to be ~ 0.6% among sporadic prion diseases and ~ 1.1% among the sCJDMM group. Mean age at onset (61 and 68 years) and disease duration (~ 7 months) of pWM- and pGM-CJD did not differ significantly. PrP plaques were mostly confined to the cerebellar cortex in pGM-CJD, but were ubiquitous in pWM-CJD. Typing of resPrPD T1 showed an unglycosylated fragment of ~ 20 kDa (T120) in pGM-CJD and sCJDMM1 patients, while a doublet of ~ 21-20 kDa (T121-20) was a molecular signature of pWM-CJD in subcortical regions. In addition, conformational characteristics of pWM-CJD resPrPD T1 differed from those of pGM-CJD and sCJDMM1. Inoculation of pWM-CJD and sCJDMM1 brain extracts to transgenic mice expressing human PrP reproduced the histotype with PrP plaques only in mice challenged with pWM-CJD. Furthermore, T120 of pWM-CJD, but not T121, was propagated in mice. These data suggest that T121 and T120 of pWM-CJD, and T120 of sCJDMM1 are distinct prion strains. Further studies are required to shed light on the etiology of p-CJD cases, particularly those of T120 of the novel pGM-CJD subtype.


Cognition and Reward Circuits in Schizophrenia: Synergistic, Not Separate.
Schizophrenia has been studied from the perspective of cognitive or reward-related impairments, yet it cannot be wholly related to one or the other process and their corresponding neural circuits. We posit a comprehensive circuit-based model proposing that dysfunctional interactions between the brain's cognitive and reward circuits underlie schizophrenia. The model is underpinned by how the relationship between glutamatergic and dopaminergic dysfunction in schizophrenia drives interactions between cognition and reward circuits. We argue that this interaction is synergistic: that is, deficits of cognition and reward processing interact, and this interaction is a core feature of schizophrenia. In adopting this position, we undertake a focused review of animal physiology and human clinical data, and in proposing this synergistic model, we highlight dopaminergic afferents from the ventral tegmental area to nucleus accumbens (mesolimbic circuit) and frontal cortex (mesocortical circuit). We then expand on the role of glutamatergic inputs to these dopamine circuits and dopaminergic modulation of critical excitatory pathways with attention given to the role of glutamatergic hippocampal outputs onto nucleus accumbens. Finally, we present evidence for how in schizophrenia, dysfunction in the mesolimbic and mesocortical circuits and their corresponding glutamatergic inputs gives rise to clinical and cognitive phenotypes and is associated with positive and negative symptom dimensions. The synthesis attempted here provides an impetus for a conceptual shift that links cognitive and motivational aspects of schizophrenia and that can lead to treatment approaches that seek to harmonize network interactions between the brain's cognition and reward circuits with ameliorative effects in each behavioral domain.


What do female medical students know about planned oocyte cryopreservation and what are their personal attitudes?
This study aimed to assess medical student knowledge and attitudes regarding oocyte cryopreservation, as well as attitudes regarding future intentions of utilizing this procedure. This cross-sectional web-based survey study was distributed to 873 medical students at the University of Kansas from July through September 2018. The survey was self-reported and female medical student responses were analyzed. Students were surveyed through a variety of multiple-choice questions on demographics, knowledge of oocyte cryopreservation, and factors and attitudes that would impact personal and professional use of oocyte cryopreservation. A total of 122 female responses were collected (30%). A majority of female medical students were aware of oocyte cryopreservation, less than half correctly identified a dramatic drop in female fertility as well as oocyte cryopreservation success and cost-effectiveness. Three-quarters felt pressure to delay childbearing and nearly two-thirds would consider freezing their oocytes. Several factors were found to alter their decision toward oocyte cryopreservation including personal factors, procedure complexity and availability, and outcomes. A majority of female medical students are amenable to the possibility of using oocyte cryopreservation to delay childbearing. Though nearly all knew of oocyte cryopreservation, knowledge regarding fertility and oocyte cryopreservation was low.


Conversion of polycyclic aromatic hydrocarbons by Sphingomonas sp. VKM B-2434.
A versatile bacterial strain able to convert polycyclic aromatic hydrocarbons (PAHs) was isolated, and a conversion by the isolate of both individual substances and PAH mixtures was investigated. The strain belonged to the Sphingomonas genus as determined on the basis of 16S rRNA analysis and was designated as VKM B-2434. The strain used naphthalene, acenaphthene, phenanthrene, anthracene and fluoranthene as a sole source of carbon and energy, and cometabolically oxidized fluorene, pyrene, benz[a]anthracene, chrysene and benzo[a]pyrene. Acenaphthene and fluoranthene were degraded by the strain via naphthalene-1,8-dicarboxylic acid and 3-hydroxyphthalic acid. Conversion of most other PAHs was confined to the cleavage of only one aromatic ring. The major oxidation products of naphthalene, phenanthrene, anthracene, chrysene, and benzo[a]pyrene were identified as salicylic acid, 1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid, o-hydroxyphenanthroic acid and o-hydroxypyrenoic acid, respectively. Fluorene and pyrene were oxidized mainly to hydroxyfluorenone and dihydroxydihydropyrene, respectively. Oxidation of phenanthrene and anthracene to the corresponding hydroxynaphthoic acids occurred quantitatively. The strain converted phenanthrene, anthracene, fluoranthene and carbazole of coal-tar-pitch extract.


Ultraviolet light-resistant primary transfectants of xeroderma pigmentosum cells are also DNA repair-proficient.
In a previous work, an immortal xeroderma pigmentosum cell line belonging to complementation group C was complemented to a UV-resistant phenotype by transfection with a human cDNA clone library. We now report that the primary transformants selected for UV-resistance also acquired normal levels of DNA repair. This was assessed both by measurement of UV-induced [3H]thymidine incorporation and by equilibrium sedimentation analysis of repair-DNA synthesis. Therefore, the transduced DNA element which confers normal UV-resistance also corrects the excision repair defect of the xeroderma pigmentosum group C cell line.


Doxorubicin release is not a prerequisite for the in vitro cytotoxicity of HPMA-based pharmaceuticals: in vitro effect of extra drug-free GlyPheLeuGly sequences.
A systematic study was designed to elucidate differences in cytostatic activity in vitro between HPMA-based doxorubicin conjugates synthesized using different polymerization techniques and differing in peptidyl side chain. A polymer-drug conjugate containing doxorubicin (DOX) bound to HPMA copolymer backbone through the enzymaticaly non-cleavable sequence GlyGly shows low but significant cytotoxicity in vitro in seven cancer cell lines of mouse (EL4, 38C13, 3T3, BCL1) and human (SW620, Raji, Jurkat) origin. The low cytotoxicity can be considerably increased by the presence of additional drug-free GlyPheLeuGly side chains. P1 conjugate, i.e. non-targeted HPMA copolymer bearing doxorubicin bound via a biodegradable GlyPheLeuGly sequence, synthesized by direct copolymerization of HPMA with monomeric doxorubicin and thus without additional drug-free GlyPheLeuGly sequences is less effective compared to PK1 synthesized by polymer analogous reaction and thus containing extra drug-free GlyPheLeuGly sequences. Significant activity-enhancing effect was not seen with other amino acid/oligopeptide sequences (e.g., Gly or GlyGly). The activity-enhancing effect of GlyPheLeuGly sequences is more obvious in the conjugate containing doxorubicin bound to HPMA through GlyGly sequence. Derivatization of the terminal carboxyl group of the extra GlyPheLeuGly side chains (amide, N-substituted amide, free carboxyl) does not significantly influence the cytotoxicity of the conjugates. The presence of the GlyPheLeuGly sequence in the conjugate structure increases its rate of intracellular accumulation. Normal cells (Balb/c splenocytes) accumulate less polymer-doxorubicin conjugate compared to cancer cells (T cell lymphoma EL4, B cell lymphoma Raji and T cell leukemia JURKAT).


Effects of long-term vigabatrin on somatosensory-evoked potentials in epileptic patients.
Vigabatrin (gamma vinyl GABA, GVG) has been shown to be an effective antiepileptic agent. GVG specifically and irreversibly inhibits GABA-transaminase (GABA-T). Long-term animal toxicology studies have demonstrated that GVG can induce nonprogressive, reversible intramyelinic edema in central white matter tracts. The response to GVG varies among species, with rodents being the most dramatic and monkeys showing an equivocal effect even at high doses. The response in dogs is marked and measurable. The detection of these subtle findings requires the use of sophisticated technology. Evoked potentials are becoming reliable and sensitive tools in clinical neurology. This study, involving 54 patients for 11 months, was undertaken to assess the effect and safety of GVG in humans with refractory epilepsy. No data from this investigation indicate prolongation of neuronal conduction time in CNS pathways, suggesting that this agent is safe in humans.


Multi-temporal Landsat imagery and MSAVI index for monitoring rangeland degradation in arid ecosystem, case study of Biskra (southeast Algeria).
The Algerian Saharan rangelands are an arid ecosystem characterized by limited soil, water, and vegetation resources, which make it very susceptible to degradation. This research focuses on the diachronic assessment and multi-temporal mapping of the degradation of steppe vegetation in the south of Biskra during the period 1987-2019, using remote sensing data (MSAVI index), for extracting spatiotemporal data to monitor the rangeland vegetation dynamics. We examined demographic evolution, number of livestock, and land use from quantitative data. The results show that during this period, the landscape of the region changed considerably. The area of rangelands decreased from 19,939 ha (1987) to 3605 ha (2019), where 58% of the pre-existing vegetation was transformed into bare soil. This study confirmed that the rangeland vegetation health is closely related to climate, and its degradation is mainly due to the recurrence, duration, severity, and magnitude of drought events. Manmade activities were also a determinant factor of long-term degradation of the rangeland, such as the expansion of new land development areas that increased from 3754 ha (1987) to 24,410 ha (2019). This trend was found throughout the region, including predominantly pastoral regions such as Oumache and El Haouch, leading to overgrazing with a loss of about 2% of vegetation cover. All these factors have led to a severe and continuous degradation of pastoral resources in a vulnerable environment. The preservation of these limited resources requires appropriate management of the ecosystem and a rational exploitation of its vegetation, soil, and water resources.


Catalytic mechanism of S-adenosylhomocysteine hydrolase: roles of His 54, Asp130, Glu155, Lys185, and Aspl89.
S-adenosylhomocysteine hydrolase (AdoHcyase) catalyzes the hydrolysis of S-adenosylhomocysteine (AdoHcy) to form adenosine and homocysteine. The crystal structure of the K185N mutated enzyme, which has weak catalytic activity (0.1%), has been determined at 2.8 A resolution and supports the previously predicted mechanism [Takata, Y., Yamada, T., Huang, Y., Komoto, J., Gomi, T., Ogawa, H., Fujioka, M., & Takusagawa, F. (2002). Catalytic mechanism of S-adenosylhomocysteine hydrolase. Site-directed mutagenesis of Asp-130, Lys-185, Asp-189, and Asn-190. J. Biol. Chem. 277, 22670-22676]. The mutated enzyme has an intermediate structure between the open and closed conformation, observed in the substrate-free enzyme and in the inhibitor complexes, respectively. H54, H300, and H352 were mutated to asparagine, respectively, to identify the roles of the histidine residues in catalysis. The kinetic data of H54N, H300N, and H354N mutated enzymes suggest that H54 is the amino acid residue that acts as a general acid/base to cleave the C5'-S(D) bond of AdoHcy. The E155Q mutated enzyme retained a large portion of the catalytic activity (31%), while the E155D mutated enzyme lost most of it (0.3%). The NADH accumulation measurements of the mutated enzymes indicated that the C3'-oxidation and the C4'-proton abstraction are a concerted event and the C5'-S(D) bond cleavage is an independent event. The C4'-proton exchange measurements indicate that the enzyme has an open conformation when AdoHcy is converted to 3'-keto-4', 5'-dehydro-Ado in the active site. With the results of this study and those of the previous studies, a detailed catalytic mechanism of AdoHcyase is described. K185 facilitates the C3'-oxidation, D130 abstracts the C4'-proton, D189, and E155 act as a communicator between the concerted C3'-oxidation and C4'-proton abstraction, and H54 plays as a general acid to cleave the C5'-S(D) bond of AdoHcy.