Hepatic-directed Therapies in Patients with Neuroendocrine Tumors.
Neuroendocrine tumors (NETs) of the gastrointestinal (GI) tract have a propensity for producing hepatic metastases. Most GI NETs arise from the foregut or midgut, are malignant, and can cause severe debilitating symptoms adversely affecting quality of life. Aggressive treatments to reduce symptoms have an important role in therapy. Patients with GI NETs usually present with inoperable metastatic disease and severe symptoms from a variety of hormones and biogenic amines. This article describes intra-arterial hepatic-directed therapies for metastases from NETs, a group of treatments in which the therapeutic and/or embolic agents are released intra-arterially in specific hepatic vessels to target tumors.


Long-term results of accelerated radiation treatment for advanced head and neck cancer.
This report presents long-term follow-up data from a prospective but unrandomized trial of a continuous 3.5-week course of accelerated radiation treatment (ART) used as primary treatment for patients with loco-regionally advanced head and neck cancer. Ninety-three patients in three centres in New Zealand and Australia were treated with ART (59.40 Gy in 33 fractions over 24-25 days). Their disease originated from three anatomical regions (oral cavity, 35 patients; pharynx, 31 patients; larynx, 27 patients). Seventy-nine of these patients had stage III or IV cancers. Follow-up ranged from 68 to 203 months (median 139 months). Loco-regional (LR) failure occurred in 52 patients leading to a 10-year actuarial expectation of LR control of 38%. The actuarial expectation of LR control at 10 years was highly dependent on stage and for stage III, IVA and IVB patients it was 57+/-8.1%, 32+/-1.7% and 7+/-0.5%, respectively. Multivariate analysis could not confirm an independent impact of primary site or histological differentiation on LR failure. Two patients died of acute toxicity of treatment and six patients developed grade 3/4 late complications affecting soft tissues only, yielding an actuarial expectation of complications of this severity at 5 years of 9%. No cases of osteoradionecrosis or myelitis were observed. This ART, which has proved easy to use at a number of large and small centres, has produced encouraging long-term LR control at a cost of limited soft tissue morbidity.


Bursting translation on single mRNAs in live cells.
Stochasticity has emerged as a mechanism of gene regulation. Much of this so-called "noise" has been attributed to bursting transcription. Although bursting transcription has been studied extensively, the role of stochasticity in translation has not been fully investigated due to the lack of enabling imaging technology. In this study, we developed techniques to track single mRNAs and their translation in live cells for hours, allowing the measurement of previously uncharacterized translation dynamics. We applied genetic and pharmacological perturbations to control translation kinetics and found that, like transcription, translation is not a constitutive process but instead cycles between inactive and active states, or "bursts." However, unlike transcription, which is largely frequency-modulated, complex structures in the 5'-untranslated region alter burst amplitudes. Bursting frequency can be controlled through cap-proximal sequences and trans-acting factors such as eIF4F. We coupled single-molecule imaging with stochastic modeling to quantitatively determine the kinetic parameters of translational bursting.


[Use of regional health administrative databases to estimate the prevalence of mental disorders and health service utilization in a Local Health Unit of Tuscany Region (Central Italy)].
prevalence estimation of mental disorders and mental health services (SSM) utilization in 2011, using the administrative regional health databases (hospital discharge records, pharmaceutical prescriptions) and the Regional Database on Mental Health (SIRSM). descriptive population-based study. residents in a Local Health Unit (Florence) of Tuscany Region (Central Italy) who have access to SSM and/or to hospital departments of psychiatry/neuropsychiatry and/ or have psycholeptic/psychoanalectic prescriptions. frequencies; crude and age-standardized prevalence of patients who have access to the SSM or have admission to a hospital psychiatric ward or have psycholeptic/psychoanalectic prescriptions. a high prevalence (11.2%) of residents had at least one contact with health services for mental health problems, mostly (84%) for drug prescriptions only (20% of patients had a unique prescription during 2011). Depression is the most important disease (9.8% of residents had at least one prescription of antidepressants); mood disorders are the most common cause of adult access to SSM (35%-36%) and hospitalization in psychiatric ward (about 36% of admissions). Only a small proportion (about 15%) of patients with mental health problems have access to the SSM, presumably those with more severe diseases. results show that the information of the SIRSM database, together with pharmaceutical prescriptions (psycholeptic/ psychoanalectic) and hospitalisation in psychiatric ward, is a useful tool for assessing the prevalence of mental health problems in a population.


On single-crystal total scattering data reduction and correction protocols for analysis in direct space. Corrigendum.
The name of the third author of the article by Koch et al. [Acta Cryst. (2021). A77, 611-636] is corrected.


Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes.
Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts' body weight, metabolic processing of the drug, malabsorption and/or drug-drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen's physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs.


Growth, respiration, and assimilation of blackfly larvae (Diptera: Simuliidae) in a lake-outlet in Finland.
A field experiment on feeding-rate in blackfly larvae (Diptera: Simuliidae) was conducted in the River Teuronjoki near its origin from Lake Pääjärvi, Finland. Small larvae were seen to feed more rapidly than large larvae.The increase in mean body-tissue weight of the larvae in Teuronjoki was determined and, from this relationship, growth-rate day-1 for the larvae was obtained.In the laboratory, respiration-rate was determined for larvae of known body-tissue weight. Experiments were conducted when animals were feeding to replicate, as closely as possible, the conditions in the field. Respiration costs were higher for small, than for large, larvae.Estimates of assimilation-rate could be obtained by addition of growthrate and respiration-rate for larvae of given body-tissue weight. As the weight of material ingested per unit of time was known it was therefore possible to calculate assimilation efficiency. The values given in this study are the lowest yet recorded for freshwater detritivores.


Effects of the Positive Action Program on Indicators of Positive Youth Development Among Urban Youth.
This study evaluated effects of Positive Action, a school-based social-emotional and character development (SECD) intervention, on indicators of positive youth development (PYD) among a sample of low-income, ethnic minority youth attending 14 urban schools. The study used a matched-pair, cluster-randomized controlled design at the school level. A multiple-measure self-report protocol assessed four key strengths and resources for PYD: self-concept, peer affiliations, ethics, and social skills. Students (n=1170) were assessed from grades 3 to 8, the duration of the intervention, with drop-outs and late entrants included in analyses. Growth curve analyses revealed evidence of favorable program effects on each of the four types of resources. The study contributes to PYD research by providing evidence for school-based interventions in low-income, urban contexts for ethnic minority youth.


[Biochemical indicators of Citrobacter sedlakii].
The authors describe eight strains identified biochemically as a new species of C. sedlakii in clinical material, surface water and the cutting surface of a melon. The majority of strains was isolated in the Czech and Slovak Republic.


Chinese species of Carinostigmus Tsuneki (Hymenoptera, Crabronidae), including three new species and a new record to China.
Three new species of Carinostigmus Tsuneki from the Oriental Region of China are described: Carinostigmus frontirugatus Bashir & Ma, sp. nov., C. latidentatus Bashir & Ma, sp. nov., and C. vesulcatus Bashir & Ma, sp. nov. In addition, ten species are reported, of which Carinostigmus palawanensis (Tsuneki) is recorded in China for the first time. A key to known and new species of the genus Carinostigmus Tsuneki from China is provided.


Medicinal plants: Adjunct treatment to tuberculosis chemotherapy to prevent hepatic damage.
The effectiveness of herbs for the management of chemically induced hepatotoxicity has been discussed by many researchers. However, there is a paucity of compressive literature on the significance of hepatoprotective plants for the management of anti-TB drug induced toxicity. Anti-TB drugs have been reported to causes hepatic damage, due to which, many patients across the globe discontinued the treatment. Medicinal plants have multiple therapeutic effects. The assessment of biological activity of plants against Mycobacterium and its use for hepatic recovery provides an effective treatment approach. Traditionally used medicinal plants are the rich source of phytochemicals and secondary metabolites. These compounds can restore normal function, enzymatic activity and structure of hepatic cells against anti-TB drug induced hepatotoxicity. The present review covers comprehensive details on different hepatoprotective and antimycobacterial plants studied during past few decades so that potential adjuvants can be studied for Tuberculosis chemotherapy.


Modulation of concanavalin A-induced, antigen-nonspecific regulatory cell activity by leu-enkephalin and related peptides.
We have developed a system in which human peripheral blood mononuclear cells (PBMC) stimulated with concanavalin A (Con A) can be examined for regulatory cell activity upon coculture with responder cells undergoing mitogenic proliferation. Low concentrations of Con A resulted in the induction of helper function, while higher concentrations of Con A induced suppressor activity in the PBMC population. However, for each individual donor a particular concentration of Con A can be found at which point no regulatory cell activity is observed. This "balance point" provides a set of conditions under which the ability of an immunomodulator to up-regulate or down-regulate the system can be studied. The ability of leu-enkephalin to positively or negatively regulate an immune response was examined under these circumstances. The addition of leu-enkephalin to cultures stimulated by Con A at this balance point enhanced both suppressor cell (Ts) and helper cell (Th) activity in a concentration-dependent manner. The induction of Ts activity displayed a bimodal response at concentrations between 10(-12) to 10(-13) M and 10(-9) to 10(-10) M, while the induction of Th activity was consistently observed at 10(-11) M. Similar effects were seen with either of the peptides Tyr-Gly and Tyr-Gly-Gly, corresponding to the first two and three amino acids of the N-terminal ends of the enkephalins. Th activity was consistently enhanced at 10(-13) M Tyr-Gly-Gly and 10(-14) M Tyr-Gly. This suggests that leu-enkephalin may either positively or negatively regulate immune responses and that the intact leu-enkephalin molecule is not required for these effects.


Glenoid version and its relationship to glenohumeral instability and labral tears.
Evidence suggests a relationship between glenoid retroversion and posterior instability, but no literature exists comparing glenoid version referencing the scapular body versus the endosteal vault. This study evaluated glenoid version and its relationship to unidirectional instability and labral tears. Glenoid version in patients with unidirectional instability or labral tears was measured with magnetic resonance imaging by either the Friedman method or the Poon and Ting method. Analyses of variance followed by independent t tests were used to compare 3 groups: anterior instability or labral tears (anterior pathology group, n = 33); posterior instability or labral tears (posterior pathology group, n = 34); and stable controls (n = 30). The referencing error for 2-dimensional axial images was evaluated for variance by imaging facility. Interobserver and intraobserver reliability scores were calculated. With the Friedman method, the posterior pathology group (-9°) was more retroverted than the control group (-4°) (P = .0005) and the anterior pathology group (-5°) (P = .0104) but there was no difference between the control group and anterior pathology group (P = .38). The referencing error in the sagittal plane averaged 23° and varied by facility (P = .0365). The coronal-plane error averaged 1° and did not vary by facility (P = .7180). Intraclass correlation coefficient scores showed good to excellent intrarater and inter-rater reliability. The posterior pathology group had 5° more retroversion than controls using the Friedman method. Glenoid version using the Poon and Ting method or the Friedman method did not predict anterior instability or labral tears. Axial magnetic resonance images were constructed with a referencing error in the sagittal plane that varied by magnetic resonance imaging facility and has implications for improving 2-dimensional axial imaging protocols.


Investigation of a deoxyribozyme as a biofuel cell catalyst.
We examined the ability of a previously identified peroxidase deoxyribozyme to be employed as a catalyst in biofuel cells, as a possible replacement for oxidoreductase proteins. We constructed a biocathode using a covalently linked version of the peroxidase deoxyribozyme-hemin complex and successfully paired it with a glucose dehydrogenase-modified bioanode for power production.


Involvement of N-acylethanolamine-hydrolyzing acid amidase in the degradation of anandamide and other N-acylethanolamines in macrophages.
Bioactive N-acylethanolamines including the endocannabinoid anandamide are known to be hydrolyzed to fatty acids and ethanolamine by fatty acid amide hydrolase (FAAH). In addition, we recently cloned an isozyme termed "N-acylethanolamine-hydrolyzing acid amidase (NAAA)", which is active only at acidic pH [Tsuboi, Sun, Okamoto, Araki, Tonai, Ueda, J. Biol. Chem. 285 (2005) 11082-11092]. However, physiological roles of NAAA remained unclear. Here, we examined a possible contribution of NAAA to the degradation of various N-acylethanolamines in macrophage cells. NAAA mRNA as well as FAAH mRNA was detected in several macrophage-like cells, including RAW264.7, and mouse peritoneal macrophages. The homogenates of RAW264.7 cells showed both the NAAA and FAAH activities which were confirmed with the aid of their respective specific inhibitors, N-cyclohexanecarbonylpentadecylamine (CCP) and URB597. As analyzed with intact cells, RAW264.7 cells and peritoneal macrophages degraded anandamide, N-palmitoylethanolamine, N-oleoylethanolamine, and N-stearoylethanolamine. Pretreatment of the cells with CCP or URB597 partially inhibited the degradation, and a combination of the two compounds caused more profound inhibition. In contrast, the anandamide hydrolysis in mouse brain appeared to be principally attributable to FAAH despite the expression of NAAA in the brain. These results suggested that NAAA and FAAH cooperatively degraded various N-acylethanolamines in macrophages.


Glutamine prevents upregulation of NF-kB signaling and caspase 3 activation in ischaemia/reperfusion-induced testicular damage: An animal model.
Testicular ischaemia/reperfusion (I/R) injury is a major consequence of testicular torsion with possible attendant risk of male infertility. Glutamine, on the other hand, is a known antioxidant with anti-inflammatory potential. The present study evaluated whether or not glutamine would improve I/R-induced testicular injury in torsion/detorsion (T/D). The possible associated mechanisms were also investigated. Wistar rats were randomly allotted into four groups (n = 10); sham-operated, glutamine-treated, T/D, and T/D + glutamine. Testicular torsion was induced and reperfusion established after two and a half hour under ketamine/xylazine anaethesia. Glutamine was administered one hour before reperfusion and continued daily for 3 days. At the end of the study, animals were euthanized, blood samples obtained, epididymal sperm suspension collected, and the testes harvested for biochemical and histopathological assays using established methods. Glutamine prevented T/D-driven I/R-induced reduced sperm quality, impaired testicular histoarchitecture, and suppressed circulating testosterone. Also, glutamine abated I/R-induced oxidative stress (evidenced by reduced hydrogen peroxide and MDA generation and enhanced concentrations and activities of antioxidants), inflammation (evidenced by suppression of TNF-α and IL-1β), and apoptosis (evidenced by reduced DNA fragmentation) by down-regulating NF-kB and caspase 3 activity. For the first time, this study demonstrated that glutamine administration improved testicular I/R injury in T/D rat model by maintaining testicular redox balance, and testicular integrity and function via inhibition of I/R-induced upregulation of NF-kB signaling and caspase 3 activation.


Diffusion-weighted imaging on an MRI-linear accelerator to identify adversely prognostic tumour regions in glioblastoma during chemoradiation.
Survival in glioblastoma might be extended by escalating the radiotherapy dose to treatment-resistant tumour and adapting to tumour changes. Diffusion-weighted imaging (DWI) on MRI-linear accelerators (MR-Linacs) could be used to identify a dose escalation target, but its prognostic value must be demonstrated. The purpose of this study was to determine whether MR-Linac DWI can assess treatment response in glioblastoma and whether changes in DWI show greater prognostic value than changes in the contrast-enhancing gross tumour volume (GTV). Seventy-five patients with glioblastoma were treated with chemoradiotherapy, of which 32 were treated on a 1.5 T MRI-linear accelerator (MR-Linac). Patients were imaged with simulation MRI scanners (MR-sim) at treatment planning and weeks 2, 4, and 10 after treatment start. Twenty-eight patients had additional MR-Linac DWI sequences. Cox modelling was used to evaluate the correlation of overall and progression-free survival (OS and PFS) with clinical variables and volumetric changes in the GTV and low-ADC regions (ADC < 1.25 µm2/ms within GTV). In total, 479 MR-Linac DWI and 289 MR-sim DWI datasets were analyzed. MR-Linac low-ADC changes between weeks 2 and 5 inclusive were prognostic for OS (hazard ratio lower limits ≥ 1.2, p-values ≤ 0.02). MR-sim low-ADC changes showed greater correlation with OS and PFS than GTV changes (e.g., OS hazard ratio at week 2 was 3.4 (p <0.001) for low-ADC versus 2.0 (p = 0.022) for GTV). MR-Linac DWI can measure low-ADC tumour volumes that correlate with OS and PFS better than contrast-enhancing GTV. Low-ADC regions could serve as dose escalation targets.


Complete chloroplast genome of Boesenbergia rotunda and a comparative analysis with members of the family Zingiberaceae.
Boesenbergia rotunda (L.) Mansf. is a medically important ginger species of the family Zingiberaceae but its genomic information on molecular phylogeny and identification is scarce. In this work, the chloroplast genome of B. rotunda was sequenced, characterized and compared to the other Zingiberaceae species to provide chloroplast genetic resources and to determine its phylogenetic position in the family. The chloroplast genome of B. rotunda was 163,817 bp in length and consisted of a large single-copy (LSC) region of 88,302 bp, a small single-copy (SSC) region of 16,023 bp and a pair of inverted repeats (IRA and IRB) of 29,746 bp each. The chloroplast genome contained 113 unique genes, including 79 protein-coding genes, 30 transfer RNA (tRNA) genes and four ribosomal RNA (rRNA) genes. Several genes had atypical start codons, while most amino acids exhibited biased usage of synonymous codons. Comparative analyses with various chloroplast genomes of Zingiberaceae taxa revealed several highly variable regions (psbK-psbI, trnT-GGU-psbD, rbcL-accD, ndhF-rpl32, and ycf1) in the LSC and SSC regions in the chloroplast genome of B. rotunda that could be utilized as molecular markers for DNA barcoding and species delimitation. Phylogenetic analyses based on shared protein-coding genes revealed that B. rotunda formed a distinct lineage with B. kingii Mood & L.M.Prince, in a subclade that also contained the genera Kaempferia and Zingiber. These findings constitute the first chloroplast genome information of B. rotunda that could be a reference for phylogenetic analysis and identification of genus Boesenbergia within the Zingiberaceae family. The online version contains supplementary material available at 10.1007/s40415-022-00845-w.


Clinical practice guidelines at an HMO: development and implementation in a quality improvement model.
Harvard Community Health Plan (HCHP) is adapting to clinical medicine the managerial principles and methods of quality improvement theory that were originally developed and successfully applied in industrial settings. An essential step in applying the quality improvement cycle to clinical medicine is the setting of standards or specifications for clinical care. HCHP has chosen to focus its standard-setting efforts on the development of clinical algorithms, which provide an excellent basis for specifying and communicating optimal care processes and for evaluating actual clinical care. When implemented effectively, clinical algorithms may improve quality and decrease costs by guiding clinicians toward more standardized, high-quality, cost-effective clinical strategies and by facilitating more valid measurement of clinical process and outcomes. This article describes the evolution, structure, methods, and future agenda of the Algorithm Based Clinical Quality Improvement Process (ABCQIP) at HCHP.


Desynchronization between Food Intake and Light Stimulations Induces Uterine Clock Quiescence in Female Mice.
Dysmenorrhea is associated with breakfast skipping in young women, suggesting that fasting in the early active phase disrupts uterine functions. To investigate the possible involvement of the uterine clock system in fasting-induced uterine dysfunction, we examined core clock gene expressions in the uterus using a 28-h interval-fed mouse model. Young female mice (8 wk of age) were divided into 3 groups: group I (ad libitum feeding), group II (time-restricted feeding, initial 4 h of the active period every day), and group III (time-restricted feeding for 8 h with a 28-h cycle). Groups II and III have the same fasting interval of 20 h. After analyzing feeding and wheel running behaviors during 2 wk of dietary restriction, mice were sacrificed at 4-h intervals, and the expression profiles of clock genes in the uterus and liver were examined by qPCR. The mice in group I took food mainly during the dark phase and those in group II during the initial 4 h of the dark phase, whereas those in group III delayed feeding time by 4 h per cycle. In all groups, spontaneous wheel running was observed during the dark phase. There was no difference in the quantity of feeding and the amount of running exercise among the 3 groups during the second week. The mRNA expressions of peripheral clock genes, Bmal1, Clock, Per1, Per2, Cry1, Nr1d1, and Dbp and a clock-controlled gene, Fabp1, in the uterus showed rhythmic oscillations with normal sequential expression cascade in groups I and II, whereas their expressions decreased and circadian cycles disappeared in group III. In contrast, liver core clock genes in group III showed clear circadian cycles. Fluctuations in the timing of the first food intake impair the uterine clock oscillator system to reduce clock gene expressions and abolish their circadian rhythms.


Morphology of regressive changes in the kidney following experimental ischaemia.
Total or partial renal ischaemia was studied in rats and pigs in a series of experiments, after total devascularization (ligature of renal vessels and ureter); ligature of isolated renal artery; experimental embolization of renal artery by non-resorbable material; devascularization of a specific renal segment by deep, strangulating sutures. Morphological studies showed that the resulting necrotization is represented most frequently by coagulation necrosis, less frequently by colliquating necrosis. Occlusion of the renal artery by embolization or ligature leads only to partial necrotization or atrophy. Total devascularization of the renal hilus or total devascularization of a specific renal segment by strangulating sutures leads to total destruction of the devascularized (devitalized) tissues. Within 8-12 weeks, the whole organ changes into a small residue of connective tissue. The possibility of the use of the devascularization technique in the treatment of tumours is discussed.


Knowledge and recommendations regarding breast cancer early screening in an upper middle income country: Primary and secondary health care professionals.
To compare the current breast cancer prevention and control Mexican standard with recommendations that health care professionals provide to women for breast self-exams, clinical breast exams and mammography, as well as health care professional knowledge of the risk factors for and main clinical signs of the disease. In 2012, using a cross-sectional design, trained interviewers surveyed health care providers in a sample of 798 medical units, of which 756 corresponded to the first and second levels of medical care. One health care professional from each unit was interviewed for the study. The sampling method was systematic and representative of the national and regional levels. Relative frequencies and 95% confidence intervals (CI) were obtained using the weighting factor assigned to each medical unit. Regarding the indicator about recommendations provided to the population regarding early screening for and risk factors and clinical signs of breast cancer, the average number of health care professional responses in accordance with the Mexican standard was 10.7 (95% CI 10.0-11.4) out of a maximum of 28 points, which corresponds to an average rate of 38.2% of responses (95% CI 35.6-40.8). The percentage of correct answers increased in all areas of breast exam knowledge as training hours in the previous year increased. Health care professionals are unaware of the current standards on breast cancer; therefore, these recommendations are not routinely translated into health care practice, which is a barrier to increasing the coverage of screening programs in health care services.


Successful treatment of long-term unexplained infertility with gonadotropin-releasing hormone agonist analogue and human menopausal gonadotropin.
Thirty-five couples with long-term unexplained infertility were treated in 98 cycles by giving gonadotropin-releasing hormone analogue, human menopausal gonadotropin and human chorionic gonadotropin for induction of superovulation. Pregnancy occurred in 24 cycles (24.5% per cycle and 68.6% per patient). All patients had been treated previously with clomiphene citrate and human menopausal gonadotropin in 110 cycles in conjunction with artificial insemination, but failed to achieve pregnancy. Pituitary suppression with gonadotropin-releasing hormone analogue followed by ovarian stimulation with human menopausal gonadotropin may correct the subtle abnormalities at the hypothalamic hypophyseal level that could be present in cases of unexplained infertility and it should be tried first for these patients before resorting to in vitro fertilization or gamete intrafallopian transfer.


Contralateral decrease of neostriatal dopamine concentration after unilateral pallidal lesion in the rat.
Seven days after unilateral electrolytical and chemical (6-hydroxydopamine (6-OHDA)) lesions in the globus pallidus ipsi- and contralateral neostrial dopamine (DA) concentrations were measured in rats. A definite contralateral DA-decrease was demonstrable, the extent of which was in correlation with ipsilateral decrease.


Relationships between biomarkers of inflammation, ovarian steroids, and age at menarche in a rural Polish sample.
To test the hypothesis that life history trade-offs between maintenance and reproductive effort would be evident through inverse associations between levels of a biomarker of inflammation [C-reactive protein (CRP)], and ovarian hormones. Associations between CRP and age at menarche were also explored. Urinary CRP, salivary progesterone, and estradiol were measured over one menstrual cycle from rural Polish women (n = 25), representing a natural fertility sample. Age of menarche was assessed through interview recall methods. We used minimum second-order Akaike Information Criteria as a means of multiple regression model selection, and repeated measures ANOVA to test cycle-dependent hypotheses. Comparisons of individuals in high and low CRP tertiles revealed that those with high CRP had significantly lower progesterone (luteal P = 0.03, mid luteal P = 0.007) but not estradiol (follicular P = 0.21, luteal P = 0.15) concentrations through the menstrual cycle. However, when the age at menarche was included in the analysis, both age at menarche and urinary CRP were negatively associated with estradiol (R(2) = 0.44, P = 0.0007). Age at menarche and estradiol were the strongest negative predictors of CRP (R(2) = 0.52, P = 0.0001). Inflammation itself may suppress ovarian function, or indicate immune challenges that lead to ovarian suppression. The timing of menarche may also influence adult inflammatory sensitivity and ovarian hormone concentrations. This lends support to existing models of trade-offs between maintenance and reproduction in women.


Successful treatment of a benign solitary rectal ulcer by temporary diverting sigmoidostomy: report of a case.
A rare case of a solitary benign rectal ulcer in which conservative medical therapy was unsuccessful is described. Diversion of the fecal stream by temporary sigmoidostomy resulted in rapid healing of the ulcer. This entity presents diagnostic and therapeutic problems, which are discussed. The use of temporary sigmoidostomy in such cases is recommended.


TSPAN2 is involved in cell invasion and motility during lung cancer progression.
In lung cancer progression, p53 mutations are more often observed in invasive tumors than in noninvasive tumors, suggesting that p53 is involved in tumor invasion and metastasis. To understand the nature of p53 function as a tumor suppressor, it is crucial to elucidate the detailed mechanism of the alteration in epithelial cells that follow oncogenic KRAS activation and p53 inactivation. Here, we report that KRAS activation induces epithelial-mesenchymal transition and that p53 inactivation is required for cell motility and invasiveness. Furthermore, TSPAN2, a transmembrane protein, is responsible for cell motility and invasiveness elicited by p53 inactivation. TSPAN2 is highly expressed in p53-mutated lung cancer cells, and high expression of TSPAN2 is associated with the poor prognosis of lung adenocarinomas. TSPAN2 knockdown suppresses metastasis to the lungs and liver, enabling prolonged survival. TSPAN2 enhances cell motility and invasiveness by assisting CD44 in scavenging intracellular reactive oxygen species.


INCORPORATING A DUAL-TASK ASSESSMENT PROTOCOL WITH FUNCTIONAL HOP TESTING.
Hop tests are commonly used within a testing battery to assess readiness for return to sport after anterior cruciate ligament (ACL) injury, yet athletes still experience a high rate of re-injury. Simultaneous performance of a secondary task requiring cognitive processing or decision-making may test the athlete under more realistic contexts. To examine a clinically feasible, dual-task assessment paradigm applied during functional hop tests in healthy individuals. Repeated measures. Participants performed the crossover triple hop for distance (XHOP) and medial triple hop for distance test (MHOP) under three separate conditions: standard procedures and two dual-task protocols including the backward digit span memory task and a visuospatial recognition task. The visuospatial task involved briefly displaying an image consisting of 18 randomly placed red and blue circles on a screen, where the participant was asked to identify the number of red circles in each image. The backward digit span task was applied by introducing a sequence of random numbers to the participants, who were required to repeat the sequence in reverse order. Each motor and cognitive task was performed independently and simultaneously, in accordance with the dual-task paradigm. Thirty-four healthy participants (age: 24.0 ± 3.9 years) completed testing procedures. No differences in hop distance were observed with the simultaneous application of a cognitive task, with the exception of the backward digit span memory task resulting in decreased hop distance (p = 0.04, d = 0.14). There were no differences in cognitive accuracy according to hop test type, although the effect size was greater for the XHOP (p = 0.08, d = 0.49) compared to the MHOP (p = 1.0, d = 0.07). The dual-task protocol revealed good-excellent within- (ICC3,1 = 0.85 - 0.99) and between-session (ICC3,k = 0.94 - 0.99) intrarater reliability for hop distance across all dual-task conditions. The addition of a cognitive task to the XHOP and MHOP resulted in a lower standard error of measurement and decreased minimal detectable change, as compared to standard testing procedures. The simultaneous application of a cognitive task did not alter hop distance, with the exception of the backward digit span memory task resulting in decreased hop distance with a trivial effect size. There were no differences in cognitive accuracy according to task type (sitting, XHOP, MHOP). All combinations of dual-task assessment demonstrated good-excellent within- and between-session intrarater reliability among healthy individuals, but measurement precision was deficient. 2b.


Stress-induced disturbances of the gastro-intestinal tract in children.
The gastrointestinal tract is particularly sensitive to stress, especially in children. The specificity of the gastric, intestinal and colonic microcirculation explains the high risk of ischemia during septic and hemorrhagic shock. The consequences of digestive ischemia vary from mucosal ulceration to transmural necrosis. Tissue hypoxia, the production of superoxide radicals and luminal factors explain these lesions. Some drugs are proposed which may limit the extent of these ischemic lesions; however to prevent them the author advises, on anticipating stress and complete hemodynamic monitoring of infants at risk.


Antifibrinolytic therapy for prevention of hemorrhage during surgery of the thyroid gland.
The amount of fibrinolytic activity in the thyroid gland equals that of the prostate. In order to examine the effect of the antifibrinolytic drug tranexemic acid on perioperative bleeding saline or tranexemic acid were given randomized double blind to 76 consecutive patients who came for scheduled thyroid surgery. No significant differences were found in perioperative bleeding between patients in the treatment group (n = 39) and control group (n = 37).


Structure and gene cluster of the O-antigen of Escherichia coli O41.
The acidic O-polysaccharide (O-antigen) of Escherichia coli O41 was studied by sugar analysis along with 1D and 2D (1)H and (13)C NMR spectroscopy, and the following structure of the branched hexasaccharide repeating unit was established: This structure is unique among the known structures of bacterial polysaccharides. The O-antigen gene cluster of E. coli O41 was sequenced. The gene functions were tentatively assigned by a comparison with sequences in the available databases and found to be in full agreement with the E. coli O41 O-polysaccharide structure.


A novel superparamagnetic surface molecularly imprinted nanoparticle adopting dummy template: an efficient solid-phase extraction adsorbent for bisphenol A.
Leakage of the residual template molecules is one of the biggest challenges for application of molecularly imprinted polymer (MIP) in solid-phase extraction (SPE). In this study, bisphenol F (BPF) was adopted as a dummy template to prepare MIP of bisphenol A (BPA) with a superparamagnetic core-shell nanoparticle as the supporter, aiming to avoid residual template leakage and to increase the efficiency of SPE. Characterization and test of the obtained products (called mag-DMIP beads) revealed that these novel nanoparticles not only had excellent magnetic property but also displayed high selectivity to the target molecule BPA. As mag-DMIP beads were adopted as the adsorbents of solid-phase extraction for detecting BPA in real water samples, the recoveries of spiked samples ranged from 84.7% to 93.8% with the limit of detection of 2.50 pg mL(-1), revealing that mag-DMIP beads were efficient SPE adsorbents.


Molecular basis for peroxisomal localization of tetrameric carbonyl reductase.
Pig heart peroxisomal carbonyl reductase (PerCR) belongs to the short-chain dehydrogenase/reductase family, and its sequence comprises a C-terminal SRL tripeptide, which is a variant of the type 1 peroxisomal targeting signal (PTS1) Ser-Lys-Leu. PerCR is imported into peroxisomes of HeLa cells when the cells are transfected with vectors expressing the enzyme. However, PerCR does not show specific targeting when introduced into the cells with a protein transfection reagent. To understand the structural basis for peroxisomal localization of PerCR, we determined the crystal structure of PerCR. Our data revealed that the C-terminal PTS1 of each subunit of PerCR was involved in intersubunit interactions and was buried in the interior of the tetrameric molecule. These findings indicate that the PTS1 receptor Pex5p in the cytosol recognizes the monomeric form of PerCR whose C-terminal PTS1 is exposed, and that this PerCR is targeted into the peroxisome, thereby forming a tetramer.


Short and long-term outcomes in children with suspected acute encephalopathy.
The time-dependent changes that occur in children after acute encephalopathy are not clearly understood. Therefore, we assessed changes in brain function after suspected acute encephalopathy over time. We created a database of children admitted to the pediatric intensive care unit at Kobe Children's Hospital because of convulsions or impaired consciousness with fever between 2002 and 2013. Clinical courses and outcomes were reviewed and patients who met the following criteria were included in the study: (1) 6months to 15years of age, (2) no neurological abnormality before onset, (3) treated for suspected acute encephalopathy, and (4) followed after 1 (0-2) month and 12 (10-17) months of onset. Outcomes were assessed using the Pediatric Cerebral Performance Category (PCPC) scale, with a score of 1 representing normal performance; 2, mild disability; 3, moderate disability; 4, severe disability; 5, vegetative state; and 6, brain death. A total of 78 children (32 male) with a median (range) age at onset of 20 (6-172) months were enrolled. Fifty-one cases scored 1 on the PCPC, 13 scored 2, three scored 3, five scored 4, one scored 5, and five cases scored 6 at discharge. Whereas seven of the 13 cases that scored a 2 on the PCPC recovered normal brain function after 12months, none of the nine cases that scored a 3-5 on the PCPC recovered normal function. Our findings suggest moderate to severe disability caused by acute encephalopathy had lasting consequences on brain function, whereas mild disability might result in improved function.


The traceability chain of 131I measurements for nuclear medicine in Cuba.
The national traceability chain for (131)I activity measurements performed in nuclear medicine in Cuba is described. At the highest (primary) level, liquid scintillation counting employing the CIEMAT/NIST method is used; at the secondary level, a secondary standard radionuclide calibrator is utilized that allows for a quick and simple transference of the measurement unit to the tertiary level of end-users' instruments. The equivalence of Cuban standards and the assessment of measurement uncertainties at the end-user level are determined through the results of measurement comparisons.


Statistical Considerations for Trials in Adjuvant Treatment of Colorectal Cancer.
The design of the best possible clinical trials of adjuvant interventions in colorectal cancer will entail the use of both time-tested and novel methods that allow efficient, reliable and patient-relevant therapeutic development. The ultimate goal of this endeavor is to safely and expeditiously bring to clinical practice novel interventions that impact patient lives. In this paper, we discuss statistical aspects and provide suggestions to optimize trial design, data collection, study implementation, and the use of predictive biomarkers and endpoints in phase 3 trials of systemic adjuvant therapy. We also discuss the issues of collaboration and patient centricity, expecting that several novel agents with activity in the (neo)adjuvant therapy of colon and rectal cancers will become available in the near future.


Inhibition of kidney tubule induction by charged polymers.
Charged polymers, known to alter cell surface characteristics, reversibly inhibit the intercellular communication required in kidney tubule induction. This effect seems to be a function of their charge density. It is suggested that this effect is due to the formation of a molecular barrier between the interacting cell surfaces.


Night Cream Containing Melatonin, Carnosine and Helichrysum italicum Extract Helps Reduce Skin Reactivity and Signs of Photodamage: Ex Vivo and Clinical Studies.
Extrinsic factors, such as solar radiation and urban pollution, cause damage that alters the structure, function and appearance of skin. The aim of this study was to determine the ability of a night cream containing melatonin, carnosine and Helichrysum italicum extract (referred to here as Night Cream) to reduce extrinsic skin damage, and to evaluate the efficacy of this Night Cream to reduce clinical signs of age and photodamage under normal conditions of use. Recovery from extrinsic damage was assessed by exposing human skin explants to ultraviolet (UV) A, infrared light, blue light or pollution and then treating the stress-exposed explants with Night Cream. Markers of oxidative stress were examined by immunohistochemistry. Anti-aging and calming properties were determined in four single-center, open-label trials involving 117 individuals. Subjects applied Night Cream to their face once nightly for up to 12 weeks. Improvements in clinical signs of age and photodamage, and reduction of lactic acid-induced stinging were evaluated by investigator assessment and subject self-assessment. Night Cream significantly reduced oxidative stress in human skin ex vivo. Clinically, hydration (+ 64.4%; p < 0.05) and transepidermal water loss (TEWL) values (- 10.0%; p < 0.05) were improved within 1 h of use. Wrinkle counts were reduced by up to 18.9% (p < 0.05), and brown and UV spot numbers by 5.5% (p < 0.05) and 13.2% (p < 0.05), respectively. Lactic acid-induced stinging was significantly reduced within 7 days of use, with 86.7% of subjects reporting that their skin felt calmer. These findings suggest that Night Cream reduces skin damage caused by environmental factors and that its nightly use can improve clinical signs of aging with additional skin calming benefits.


Heat Therapy Can Improve Hepatic Mitochondrial Function and Glucose Control.
This review proposes the novel hypothesis that heat can be used as an alternative therapy to exercise to improve hepatic mitochondrial function and glucose regulation in patients with nonalcoholic fatty liver disease. Although exercise has proven benefits in treating nonalcoholic fatty liver disease, barriers to exercise in the majority of patients necessitate an alternative method of treatment.


High-quality genome sequence and description of Chryseobacterium senegalense sp. nov.
Strain FF12(T) was isolated from the mouth of a West African lungfish (Protopterus annectens) in Senegal. MALDI-TOF-MS did not provide any identification. This strain exhibited a 97.97% 16S rRNA sequence identity with Kaistella flava. Using a polyphasic study including phenotypic and genomic analyses, strain FF12(T) is Gram-negative, aero-anaerobic, oxidase-positive, non-motile, non-spore-forming, and exhibited a genome of 4,397,629 bp with a G+C content of 35.1% that coded 4,001 protein-coding and 55 RNA genes. On the basis of these data, we propose the creation of Chryseobacterium senegalense strain FF12(T).


Artificial liposomes as a model for studying the lipid peroxidation effect of p-phenylene diamine.
The effect of p-phenylene diamine on the peroxidation of liposomized samples of lecithin and peanut oil was studied under optimal conditions. The p-phenylene diamine was found to affect the formation of thiobarbituric acid reactive products of lipid peroxidation and the efficacy of various free radical scavengers.


Theoretical Insights into the Electron Capture Behavior of H₂SO₄···N₂O Complex: A DFT and Molecular Dynamics Study.
Both sulfuric acid (H₂SO₄) and nitrous oxide (N₂O) play a central role in the atmospheric chemistry in regulating the global environment and climate changes. In this study, the interaction behavior between H₂SO₄ and N₂O before and after electron capture has been explored using the density functional theory (DFT) method as well as molecular dynamics simulation. The intermolecular interactions have been characterized by atoms in molecules (AIM), natural bond orbital (NBO), and reduced density gradient (RDG) analyses, respectively. It was found that H₂SO₄ and N₂O can form two transient molecular complexes via intermolecular H-bonds within a certain timescale. However, two molecular complexes can be transformed into OH radical, N₂, and HSO₄- species upon electron capture, providing an alternative formation source of OH radical in the atmosphere. Expectedly, the present findings not only can provide new insights into the transformation behavior of H₂SO₄ and N₂O, but also can enable us to better understand the potential role of the free electron in driving the proceeding of the relevant reactions in the atmosphere.


The telemedicine information exchange: an online resource.
Telemedicine is the use of telecommunications to provide health care services at a distance. It has grown from mostly government-subsidized research initiatives into a fledgling industry. This growth was fueled by decreasing costs of telecommunications and information technologies and fanned by rising health care costs. The telemedicine information exchange (TIE) (http:(/)/tie.telemed.org), developed by the Telemedicine Research Center in Portland, OR, is both a product and a vehicle of this rapid growth. It facilitates collection of telemedicine information from many sources, providing an easy-to-use hypertext format. This article describes the TIE's development, advantages and disadvantages of a web-based online library, and it's codevelopment with a rapidly expanding industry.


Regulation of the hypothalamic-pituitary-adrenocortical system in patients with panic disorder.
Anxiety and depressive disorders are among the most common psychiatric disorders with a high number of hospital admissions and a lifetime prevalence of up to 25%. So far, the pathophysiological mechanisms for anxiety disorders remain to be found. Preclinical studies suggest that changes in hypothalamic-pituitary-adrenocortical (HPA) system function are causally related to the expression of anxiety-related behavior. The findings on HPA system function in patients with anxiety disorders are, however, heterogeneous. Both hypo- and hyperresponsiveness of HPA response in various anxiety disorders under different experimental conditions were found. In order to characterize putative case/control differences in HPA system function, we performed a Dex-CRH test, a widely used test to pick up changes in HPA system regulation with high sensitivity, in 30 patients with panic disorder, 35 patients with major depressive episode and in 30 controls individually matched for ethnicity, age and gender. The results indicate a similar dysregulation of the HPA system response in the Dex-CRH test in both patient groups. This finding further underlines the hypothesis that both, depression and panic disorder, share impaired HPA system regulation, supporting the notion that the impairment is involved in the pathophysiology of these clinical conditions. However, differences in the suppression effects and psychopathological correlation patterns between depressed and panic patients suggest different biological mechanisms of HPA system dysregulation in both disorders.


[22q11.2 microdeletion syndrome: Analysis of the care pathway before the genetic diagnosis].
22q11.2 deletion syndrome (22q11.2DS) is a very broad phenotypic spectrum disorder. It can affect many organs or systems. 22q11.2DS is the most common microdeletion syndrome in humans, with a prevalence ranging from one in every 2000 to one in 4000 newborns. It seems to be more prevalent than reported and under-recognized or undiagnosed because of its inherent clinical variability and heterogeneity. In France, 15,000 patients may be affected by this disease, more than half without knowing it. The aim of this study was to analyze the care pathway before the genetic diagnosis of 22q11.2DS. We conducted a single-center, retrospective analysis of postnatally diagnosed patients recruited by the cytogenetic laboratory of Nancy (France) from January 2000 to December 2015. Clinical data were first collected by consulting the medical files of patients and then by calling them directly. Written informed consent was obtained and the study was approved by local research ethics boards. Data concerned only clinical features before the diagnosis. The cohort consisted of 32 individuals with 22q11.2DS. The average age at diagnosis was 9 years and 2 months and the median age was 2 years and 11 months. Fetal echography was abnormal in 15 pregnancies. During the neonatal period, the most important features were eating difficulties and congenital malformations (n=20), with a majority of complex heart diseases (n=16), dominated by conotruncal malformations (n=6). In case of malformation, the average age at diagnosis decreased to 2 years and 6 months. A congenital heart disease brought the average age of diagnosis down to 2 years and 6 months. Hypocalcemia and dysmorphism were also classical features (n=14). Before the age of 3 years, speech delay occurred in nine patients. After 3 years of age, rhinolalia was predominant (n=11). Academic disabilities were present in all subjects. At least 14 patients had a de novo deletion. Five patients were diagnosed within genetic counseling, with the deletion was inherited from the mother in three out of four cases. One was the monozygotic twin of a patient. Seven patients were diagnosed as adults. Four of them were diagnosed only because of the clinical presentation of their children or fetuses. Retrospectively, all adult patients had clinical signs suggesting the 22q11.2DS diagnosis. Relational disorders affected eight patients. None of them had been referred to the geneticist for this reason. In most cases, the pediatric cardiologist referred patients to the geneticist (n=9). Physiotherapists (n=15) and speech-language pathologists (n=12) were frequently requested but did not participate in the diagnosis. The present study highlights the difficulty of establishing the diagnosis when the major features of the 22q11.2DS are absent during the 1st months of life. This is particularly true when there is no congenital defect. Special attention must be given to speech disorders in childhood and neuropsychological disorders later in life. The association between 22q11.2DS and early-onset parkinson disease implies that adult neurologists should be aware of this diagnosis. For adult patients, familial occurrence is the most frequent cause of diagnosis in spite of clinical signs suggestive of 22q11.2DS. The management of these patients involves better information of medical and paramedical staff in order to refer them to the geneticist earlier in life.


Simultaneous removal of SO2 and NO using a spray dryer absorption (SDA) method combined with O3 oxidation for sintering/pelleting flue gas.
Based on the demand of sintering/pelleting flue gas ultra-low emission, a semi-dry method using a spray dryer absorber (SDA) combined with O3 oxidation was proposed for simultaneous removal of SO2 and NO. Effects of O3 injection site, O3/NO molar ratio, and spray tower temperature on the removal efficiencies were investigated. It was revealed that both desulfurization and denitrification efficiencies could reach to 85% under the conditions of setting O3 injection site inside of tower, O3/NO molar ratio 1.8, spray tower temperature 85°C, Ca/(S + 2 N) molar ratio 2.5 and slurry flow rate 300 mL/hr. CaSO3/Ca(OH)2 mixture slurry was used as absorbent to simulate operating conditions in iron and steel industry. The result shows that the addition of CaSO3 weakens both removal efficiencies. In addition, the reaction mechanism of simultaneous removal of SO2 and NO using SDA combined with O3 oxidation was proposed.


Short-term in vivo morphological changes of amniotic membrane after fibrin glue-assisted pterygium surgery on anterior segment optical coherence tomography: a case presentation.
The evaluations of morphological changes of amniotic membrane (AM), even after successful AM transplantation surgery without complications, may be difficult. Moreover, there was no report regarding morphological changes after fibrin glue-assisted AM transplantation with pterygium excision. Here, we highlight and describe the use of spectral domain optical coherence tomography (OCT) for the evaluation of the morphological features of amniotic membrane (AM) and of associated in vivo structural changes after fibrin glue-assisted pterygium surgery. All three patients underwent cryo-preserved AM transplantation using the permanent inlay technique (epithelial side up) with fibrin glue. In vivo morphological changes of AMs were evaluated using a spectral domain OCT equipped with an anterior segment imaging module (RTVue-100, Optovue, Inc., Fremont, CA, USA). Anterior segment OCT examinations demonstrated morphological changes, that is, re-absorption of fibrin glue or subconjunctival hemorrhage, migration of epithelium, and integration of AM into sclera, of AMs over first postoperative months. Anterior segment OCT might provide additional structural information, including quantitative and qualitative data, on AMs after pterygium surgery as compared with conventional slit-lamp examination.


Cellular transformation by the HTLV-I Tax protein, a jack-of-all-trades.
The human T-cell leukemia virus type I (HTLV-I) is an oncogenic retrovirus that is responsible for adult T-cell leukemia and a neurological disease, HTLV-I-associated myelopathy/tropical spastic paraparesis. HTLV-I encodes an oncogenic protein, Tax, which affects a variety of cellular functions prompting it to be referred to as a jack-of-all trades. The ability of Tax to both transcriptionally regulate cellular gene expression and to functionally inactivate proteins involved in cell-cycle progression and DNA repair provide the basis for Tax-mediated transformation and leukemogenesis. This review will concentrate on the effects of Tax on the dysregulation of the G(1)/S and G(2)/M checkpoints as well as the suppression of DNA damage repair leading to cellular transformation.


Motor Disturbance in ASD: A Pilot Study Showing Hypokinetic Behavior?
Data supporting theoretical models linking autism spectrum disorders (ASD) to motor disturbance are inconclusive. In the present study, children and adolescents with ASD (n = 44) were compared with a matched group of typically developing individuals (n = 49) on both instrumental and observational assessments of motor abnormalities. No group differences were found in the instrumental data. However, more bradykinetic motor behavior was found using an observational scale in the ASD groups. More rigid motor behavior was found in the adolescents with ASD but not in the children. Individuals with ASD show significantly more hypokinetic behavior, which may not be strictly dopaminergic in origin, but may reflect a weak central coherency in neuronal networks related to the motor system in which developmental changes are present.


Non-destructive multibiomarker approach in European quail (Coturnix coturnix coturnix) exposed to the herbicide atrazine.
The effect of orally administered atrazine (25 or 100 mg/kg on days 0, 5, and 10 of the experiment) was studied in European quail (Coturnix coturnix coturnix) on four non-destructive biomarkers: fecal porphyrins, blood glutathione-S-transferase, glutathione reductase, reduced glutathione, and malondialdehyde (MDA). Uroporphyrin I (UPI) and coproporphyrins I and III (CPIII) were the main porphyrins detected in feces. The lowest dose of ATZ caused a significant (P < 0.05) increase in UPI and CPIII at day 5, and the highest dose of ATZ caused an induction of CPI and a significant (P < 0.05) decrease in MDA levels at day 30.


Effects of pancuronium and alcuronium on the changes in arterial pressure and plasma catecholamine concentrations during tracheal intubation.
The changes in the plasma concentrations of noradrenaline, adrenaline and dopamine, during tracheal intubation, were studied in 17 patients. Nine patients received pancuronium and eight alcuronium to produce neuromuscular blockade. In the patients receiving pancuronium, intubation of the trachea was accompanied by an increase in mean arterial pressure, and in the plasma concentrations of noradrenaline and adrenaline. In the alcuronium group, there were no significant changes in the plasma concentrations of any catecholamine, nor any change in mean arterial pressure in response to intubation of the trachea.


Dimethyl sulfoxide delays PrP sc accumulation and disease symptoms in prion-infected hamsters.
PrP(Sc), an aberrantly folded protein, is the only identified component of the prion, an agent causing fatal neurodegenerative diseases such as scrapie and bovine spongiform encephalopathy. Dimethyl sulfoxide (DMSO) has been shown to reduce the accumulation of PrP(Sc) in scrapie-infected (ScN2a) cells, and to inhibit its aggregation in vitro. In humans, DMSO was used successfully in the treatment of various peripheral amyloidotic diseases. Here we show that administration of DMSO to scrapie-infected hamsters significantly prolonged disease incubation time, as well as delayed the accumulation of PrP(Sc) in Syrian hamster brains. Interestingly, administration of DMSO to scrapie sick hamsters resulted in increased clearance of protease-resistant PrP in their urine. We conclude that although DMSO by itself may not be sufficient to cure prion diseases, it may be considered as a component in a 'cocktail' drug approach for these disorders. Also, urine PrP testing should be considered for the assessment of treatment efficacy.


A Study on Myloblastosis Gene (MYB) in Adenoid Cystic Carcinoma Using the New IHC Marker MYB (SZ04-81).
Background and aim: Adenoid cystic carcinoma is one of the most common malignant neoplasms of the salivary gland. It has overlapping histological features with other salivary gland tumors. MYB is a nuclear marker which is known to be expressed in Adenoid cystic carcinoma. In this study we aim to determine the sensitivity and specificity of MYB IHC marker to differentiate Adenoid cystic carcinoma from other benign and malignant salivary gland tumors. Materials and method: This is a retrospective case control study on the paraffin blocks of 78 cases of salivary gland tumors obtained over a period of 5 years. MYB Ser11 monoclonal antibody of clone SZ04-81 IHC, a nuclear marker was done on all cases. The results observed was tabulated and statistical analysis was done to calculate the sensitivity and specificity of the MYB IHC marker. Results: The mean age group of Adenoid cystic carcinoma was 45 years with a female preponderance. 60% of the cases of Adenoid cystic carcinoma were from minor salivary glands spread across various sites. The sensitivity and specificity of the MYB IHC marker were statistically analyzed and found to be 93.9% and 97.8% respectively. Conclusion: The present study shows substantial expression of MYB immunohistochemical marker in Adenoid cystic carcinoma, with a very high sensitivity and specificity obtained using the clone SZ04-81. Thus this marker can be used in the diagnosis of adenoid cystic carcinoma. However, correlation with H & E and FISH studies are required. The online version contains supplementary material available at 10.1007/s12070-023-03471-4.


Retinogeniculate projections in the rabbit: an autoradiographic study.
As shown by autoradiographic techniques, the pattern of retinogeniculate projections in the pigmented rabbit is generally similar to that described in previous studies. Each retina projects bilaterally to the alpha segment of the dorsal lateral geniculate nucleus (LGd) and to the external segment of the ventral lateral geniculate nucleus (LGv). The beta segment of the LGd and internal layer of the LGv receive contralateral inputs only. The alpha segment of the LGd contains an irregularly shaped region which receives overlapping bilateral projections. Within this region the ipsilateral input is continuous and predominant. This pattern of ipsilateral projection can account for both the laminar arrangement perpendicular to the lines of projection and the "hidden lamination" which have been described previously for the rabbit LGd. A separate bilateral projection is identified for a group of cells lying between the LGd and LGv rostrally. Caudally this intergeniculate leaflet extends medial and ventral to the LGv and appears to merge with the zona incerta.


Blue nevus of the uterine cervix.
The clinical, gross pathologic, and light and electron microscopic features of three blue nevi of the endocervix were studied. Immunocytochemical studies for the localization of S-100 protein in the blue nevus cells were performed. A comprehensive review of 47 previously published cases is also presented. Blue nevi of the endocervix appear to be rare incidental lesions; they are often found in hysterectomy specimens from middle-aged women. The lesion is seldom detected clinically or colposcopically. However, it appears in most instances as a blue-black lesion in the posterior wall of the endocervix on gross pathologic examination. The demonstration of S-100 protein in the blue nevus cells before and after bleaching in the present study, along with the ultrastructural observations, supports combined melanocytic and schwannian differentiation of the blue nevus cell.


Adenovirus-associated deaths in US military during postvaccination period, 1999-2010.
Adenoviruses are frequent causes of respiratory disease in the US military population. A successful immunization program against adenovirus types 4 and 7 was terminated in 1999. Review of records in the Mortality Surveillance Division, Armed Forces Medical Examiner System, identified 8 deaths attributed to adenovirus infections in service members during 1999-2010.


Ki-1 large cell lymphoma with regressing lesions in a child.
An 8-year-old boy was seen with a cutaneous Ki-1 anaplastic, large cell lymphoma with multiple lesions. Some of the lesions showed spontaneous regression. During more than seven years of disease no systemic involvement was observed, but recurrent, self-healing lesions did appear. Histopathologic examination of five lesions revealed a variety of findings, from an inflammatory infiltrate to a highly anaplastic pattern. The neoplastic cells expressed Ki-1 and leukocyte common antigens. Ultrastructurally, those cells showed ruffled indentations. The differential diagnosis includes microvillous malignant lymphoma. The patient has had a four-year follow-up without relapses.


'Spirituality' in Health Studies: Competing Spiritualities and the Elevated Status of Mindfulness.
The article investigates discourses of 'spirituality' in the field of Health Studies, among scholarly voices and the voices of the practitioners and patients these studies reflect. It examines current trends in contemporary spirituality as well as links with debates involving science, religion and secularisation. The article argues that, in the public domain, 'spirituality' is beginning to denote a collective practice rather than an individual search for meaning. Furthermore, the article identifies some common understandings of spirituality in the context of Health Studies and health environments, such as it being a tool that can facilitate closeness and emotional exchanges. Finally, it proposes that the success and, as I will show, elevated status of 'mindfulness' in this field points to 'competing spiritualities', despite shared understandings.


A new cytogenetic aspect of polycythemia vera.
The cytogenetic findings in a group of 15 polycythemic patients are reported. G and C banding techniques were used on bone marrow and peripheral blood preparations. Major chromosomal aberrations were found in four out of the 15 patients, an incidence similar to that found in other studies on polymorphism. The most interesting finding concerned the chromosomal polymorphism of the pair 19. A possible relation to the etiology of the disease is discussed.


Blood lead levels of urban and rural Malaysian primary school children.
The objective of this article is to study the influence of exposure and socio-economic variables on the blood lead level of Malaysian school children. Data on respirable lead and blood lead of 346 school children were obtained from Kuala Lumpur (urban), Kemaman (semi-urban) and Setiu (rural). Respirable lead and blood lead were highest for Kuala Lumpur (95 ng/m3 and 5.26 micrograms/dL) followed by Kemaman (27 ng/m3 and 2.81 micrograms/dL) and Setiu (15 ng/m3 and 2.49 micrograms/dL), and the differences were statistically significant. The percentage of school children with excessive blood lead of 10 micrograms/dL or greater was 6.36% overall, and highest for Kuala Lumpur (11.73%). Regression analyses show that urban children are at higher risk of exhibiting excessive blood lead levels. Kuala Lumpur's school children have a 25 times greater risk of having excessive blood lead levels when compared to Kemaman's and Setiu's school children. Respirable and blood lead were correlated (r = 0.999, p = 0.021). Urban school children acquire higher blood lead levels than their rural and semi-urban counterparts, even after controlling for age, sex, parents' education and income levels. In conclusion, it is time that lead in the Malaysian environment and population be monitored closely, especially its temporal and spatial variability. Only then can a comprehensive preventive strategy be implemented.


Advances in understanding and in multi-disciplinary methodology used to assess lipid regulation of signalling cascades from the cancer cell plasma membrane.
The lipid bilayer is a functional component of cells, forming a stable platform for the initiation of key biological processes, including cell signalling. There are distinct changes in the lipid composition of cell membranes during oncogenic transformation resulting in aberrant activation and inactivation of signalling transduction pathways. Studying the role of the cell membrane in cell signalling is challenging, since techniques are often limited to by timescale, resolution, sensitivity, and averaging. To overcome these limitations, combining 'computational', 'wet-lab' and 'semi-dry' approaches offers the best opportunity to resolving complex biological processes involved in membrane organisation. In this review, we highlight analytical tools that have been applied for the study of cell signalling initiation from the cancer cell membranes through computational microscopy, biological assays, and membrane biophysics. The cancer therapeutic potential of extracellular membrane-modulating agents, such as cholesterol-reducing agents is also discussed, as is the need for future collaborative inter-disciplinary research for studying the role of the cell membrane and its components in cancer therapy.


[Perianal precancerous conditions (Bowen disease, Paget disease, Carcinoma in situ, Buschke-Lowenstein tumor)].
Perianal premalignant lesions are rare. Any suspicious perianal lesion or any perianal exanthema, that does not heal by non-surgical treatment has to be biopsied for histology. Many premalignant lesions are diagnosed as an incidental finding after anorectal surgery: any anorectal specimen must be examined by the pathologist. Leukoplakia is a facultative premalignant condition. High-grade anal intraepithelial neoplasia (AIN) is an in situ squamous cell carcinoma, associated with papillomavirus infection. Bowen's disease and Bowenoid papulosis are clinical variations of high-grade AIN. Buschke-Löwenstein tumour (giant condyloma) is a locally destructive tumour, that does not infiltrate or cause metastases. Paget's disease is a premalignant lesion like AIN, associated with other malignancies.


Thieno[3,2-b]thiophene-based conjugated polyfluorene copolymer for efficient polymer solar cell.
We have synthesized and characterized a polyfluorene derivative composed of octyl-substituted thieno[3,2,-b]thiophene and 2,1,3-benzothiadiazole as an acceptor unit. The best power conversion efficiencies of the polymer were showed with 1.63% and 2.31% by using PCBM and PC71BM, respectively.


The effect of pH, electrolytes and temperature on the rhizosphere geochemistry of phytosiderophores.
Graminaceous plants are grown worldwide as staple crops under a variety of climatic and soil conditions. They release phytosiderophores for Fe acquisition (Strategy II). Aim of the present study was to uncover how the rhizosphere pH, background electrolyte and temperature affect the mobilization of Fe and other metals from soil by phytosiderophores. For this purpose a series of kinetic batch interaction experiments with the phytosiderophore 2'-deoxymugineic acid (DMA), a calcareous clay soil and a mildly acidic sandy soil were performed. The temperature, electrolyte concentration and applied electrolyte cation were varied. The effect of pH was examined by applying two levels of lime and Cu to the acidic soil. Fe mobilization by DMA increased by lime application, and was negatively affected by Cu amendment. Mobilization of Fe and other metals decreased with increasing ionic strength, and was lower for divalent than for monovalent electrolyte cations at equal ionic strength, due to higher adsorption of metal-DMA complexes to the soil. Metal mobilization rates increased with increasing temperature leading to a faster onset of competition; Fe was mobilized faster, but also became depleted faster at higher temperature. Temperature also affected biodegradation rates of metal-DMA complexes. Rhizosphere pH, electrolyte type and concentration and temperature can have a pronounced effect on Strategy II Fe acquisition by affecting the time and concentration 'window of Fe uptake' in which plants can benefit from phytosiderophore-mediated Fe uptake.


Study of the effect of polybutylcyanoacrylate nanoparticles and their metabolites on the primary immune response in mice to sheep red blood cells.
Polybutylcyanoacrylate nanoparticles (PBCN) and their metabolites (polycyanoacrylic acid--PCAA, and n-butanol) were compared with respect to their effects on the primary immune response of mice to sheep red blood cells (SRBC). PCAA was synthetized via a Knoevenagel reaction. Antibody production (hemagglutinins) and E-rosette-forming cells (E-RFC) were used to document the induction of antigen-specific immune response to SRBC in all immunized mice. PBCN showed a time- and dose-dependent effect on the immune response, both humoral and cellular. The inductive phase of immune response was affected preferably. The high dose of PBCN (200 mg kg(-1)) tended to suppress the immune response. This was expressed more in mice treated before antigenic stimulation. Lower dose (10 mgkg(-1)) stimulated the immune response. A significant difference was found in the effects of PBCN and their metabolites on the immune response. PCAA and n-butanol administered at doses equivalent (after lysosomal hydrolysis) to the doses applied of intact PBCN did not impair significantly the immune response. A clear time dependence and dose dependence were not observed. The study led to the hypothesis that the greater suppressive effect of PBCN, relative to either PCAA or n-butanol, or a mixture of them, is probably due to the blocking of the immunopresenting function of macrophages instead of some toxicity towards the immunocompetent cells.


Expression of genes related to quality of Longissimus dorsi muscle meat in Nellore (Bos indicus) and Canchim (5/8 Bos taurus × 3/8 Bos indicus) cattle.
This study was performed to compare CAPN1, CAPN2, CAST, TG, DGAT1 and LEP gene expressions and correlate them with meat quality traits in two genetic groups (Nellore and Canchim) in order to assess their expression profile and use their expression profile as genetic markers. We analyzed 30 young bulls (1year old), 15 of each genetic group. Samples of the Longissimus dorsi muscle were collected for analysis of: total lipids (TL) and meat tenderness measured as Warner-Bratzler shear force (SF) and myofibrillar fragmentation (MFI) at day of slaughter and 7days of aging. Gene expression profiles were obtained via RT-qPCR. TL and MFI showed differences between breeds, higher MFI in Canchim and higher TL in Nellore. Calpains showed no differential expression between groups, as did DGAT1, TG, and LEP. CAST was expressed more in the Nellore cattle. The only significant within-breed correlation (0.79) between gene expression and meat traits was found for DGAT1 and MFI in Canchim breed. Although the number of animals used in this study was small, the results indicate that the increased expression of CAST in Nellore may reflect tougher meat, but the lack of correlations with the meat traits indicates it is not a promising genetic marker.


Dual effect of C-C motif chemokine receptor 5 on ischemic stroke: More harm than benefit?
Ischemic stroke involves a series of complex pathological mechanisms, of which neuroinflammation is currently the most widely recognized. C-C motif chemokine receptor 5 (CCR5) has recently been shown to be upregulated after cerebral ischemia. Notably, CCR5 is not only involved in neuroinflammation, but also in the blood-brain barrier, neural structures, and connections. Accumulating experimental studies indicate that CCR5 has a dual effect on ischemic stroke. In the acute phase after cerebral ischemia, the pro-inflammatory and disruptive effect of CCR5 on the blood-brain barrier predominates. However, in the chronic phase, the effect of CCR5 on the repair of neural structures and connections is thought to be cell-type dependent. Interestingly, clinical evidence has shown that CCR5 might be harmful rather than beneficial. CCR5-Δ32 mutation or CCR5 antagonist exerts a neuroprotective effect in patients with ischemic stroke. Considering CCR5 as an attractive potential target, we introduce the current research progress of the entangled relationships between CCR5 and ischemic stroke. Clinical data are still needed to determine the efficacy of activating or inactivating CCR5 in the treatment of ischemic stroke, especially for potential phase- or cell type-dependent treatments in the future.


Expanding role of emergency embolization in the management of severe blunt hepatic trauma.
Emergency embolization using Gelfoam particles alone, or in combination with stainless steel coils or epinephrine, was attempted in 4 patients with severe blunt hepatic trauma complicated by hypovolemic shock to control exsanguinating hemorrhage. Angiography prior to embolization revealed extravasation in all cases. None of the patients rebled or required further intervention. Postembolization course was uneventful in each case. Embolization could become the treatment of choice for more unstable and complicated patients than previously considered.


[Adenocarcinoma of the small intestine: a rare diagnosis--4 case reports].
The authors submit four case-histories of rare primary adenocarcinoma of the small intestine. The poor symptomatology and equivocal results of examinations caused a long delay of the final solution. As compared with data in the literature the submitted cases can be considered typical.


Effect of CDK7 inhibitor on MYCN-amplified retinoblastoma.
Retinoblastoma (RB) is a common malignancy that primarily affects pediatric populations. Although a well-known cause of RB is RB1 mutation, MYCN amplification can also lead to the disease, which is a poor prognosis factor. Studies conducted in various tumor types have shown that MYCN inhibition is an effective approach to impede tumor growth. Various indirect approaches have been developed to overcome the difficulty of directly targeting MYCN, such as modulating the super enhancer (SE) upstream of MYCN. The drug used in this study to treat MYCN-amplified RB was THZ1, a CDK7 inhibitor that can effectively suppress transcription by interfering with the activity of SEs. The study findings confirmed the anticancer activity of THZ1 against RB in both in vitro and in vivo experiments. Therapy with THZ1 was found to affect numerous genes in RB according to the RNA-seq analysis. Moreover, the gene expression changes induced by THZ1 treatment were enriched in ribosome, endocytosis, cell cycle, apoptosis, etc. Furthermore, the combined analysis of ChIP-Seq and RNA-seq data suggested a potential role of SEs in regulating the expression of critical transcription factors, such as MYCN, OTX2, and SOX4. Moreover, ChIP-qPCR experiments were conducted to confirm the interaction between MYCN and SEs. In conclusion, THZ1 caused substantial changes in gene transcription in RB, resulting in inhibited cell proliferation, interference with the cell cycle, and increased apoptosis. The efficacy of THZ1 is positively correlated with the degree of MYCN amplification and is likely exerted by interfering with MYCN upstream SEs.


The Boltzmann equation approach to the shear flow of a granular material.
An exact solution of the Boltzmann equation for the shear flow of granular materials is discussed and compared with some related solutions.


Purification, characterization and bactericidal activities of phospholipase A₂ from the dromedary intestine.
We purified a protein from the dromedary small intestine that displayed potent bactericidal activity against Gram-positive bacteria, and identified it as group-IIA phospholipase A₂ (DrPLA₂-IIA) by NH₂-terminal sequencing and enzymatic measurements. In fact, our findings revealed that the purified PLA₂-IIA was a monomeric protein with a molecular mass of about 14 kDa. Pure enzyme has a specific activity of 329 ± 25 U/mg at optimal conditions (pH 9.5 and 45 °C) in the presence of 6 mM NaDC and 7 mM CaCl₂ with egg yolk emulsion as substrate and binds with a higher affinity to PE than PS and PC. Furthermore, the DrPLA2-IIA activity was dependent on Ca(2+); other cations (Cd(2+), Co(2+), Fe(2+), Mg(2+), Mn(2+), and Zn(2+)) reduced the enzymatic activity notably, suggesting that the arrangement of the catalytic site presents an exclusive structure for Ca(2+). On the other hand, DrPLA2-IIA was highly bactericidal against Gram-positive bacteria with inhibition zones and IC₅₀ values in the range of 21-27 mm and 3.7-8 μg/ml, respectively, whereas Gram-negative bacteria exhibited a much higher resistance. These observations suggest that the main physiological role of DrPLA2-IIA could be the defense of the intestine against bacterial infections.


Missing laboratory results data in electronic health databases: implications for monitoring diabetes risk.
Laboratory test (lab) results may be useful to detect incident diabetes in electronic health record and claims-based studies. Using the Mini-Sentinel distributed database, we assessed the value of lab results added to diagnosis codes and dispensing claims to identify incident diabetes. Inclusion of lab results increased the number of diabetes outcomes identified by 21%. In settings where capture of lab results was relatively complete, the absence of lab results was associated with implausibly low rates of the outcome. Lab results can increase sensitivity of algorithms for detecting diabetes, and missing lab results are associated with much lower rates of diabetes ascertainment regardless of algorithm. Patterns of missing lab results may identify ascertainment bias.


Neck Strength in Coronal and Sagittal Head Movement in Military Pilots and Aircrew With Chronic Neck Pain: A Systematic Review With Meta-Analysis.
This systematic review aimed to assess whether there is a difference in neck strength between military pilots and aircrew with and without chronic neck pain. The PubMed, Embase, and Scopus databases were searched. Two independent reviewers selected relevant full articles comparing neck strength between military pilots and aircrew with and without chronic neck pain. Two independent reviewers extracted the data from the full articles selected. A meta-analysis was used to assess standardized mean differences in neck strength based on a random-effects model. The search returned 3554 results; 5 articles were included in the study. Military pilots and aircrew with chronic neck pain showed no difference in neck strength from military pilots and aircrew without chronic neck pain for flexion and extension, but did show a neck strength reduction for right and left lateral flexion -0.29 (95% confidence interval, -0.52 to -0.06; I² = 3%) and -0.23 (95% confidence interval, -0.45 to 0.00; I² = 0%), respectively. Based on this meta-analysis with a 3a level of evidence, military pilots and aircrew with chronic neck pain have reduced neck strength for coronal head movement, but not sagittal movement compared with military pilots and aircrew without chronic neck pain.


Diastereo- and Enantioselective Reductive Mannich-type Reaction of α,β-Unsaturated Carboxylic Acids to Ketimines: A Direct Entry to Unprotected β2,3,3 -Amino Acids.
Stereoselective construction of unprotected β-amino acids is a significant challenge owing to the lack of methods for the catalytic generation of highly enantioenriched carboxylic acid enolates. In this study, a novel copper-catalyzed diastereo- and enantioselective reductive Mannich-type reaction of α,β-unsaturated carboxylic acids was developed, which provides a direct and scalable synthetic method for enantioenriched β2,3,3 -amino acids with vicinal stereogenic centers. The protocol features in situ generation of transiently protected carboxylic acids by a hydrosilane and their diastereo- and enantioselective reductive coupling with ketimines. The synthetic utility of this process was demonstrated by a gram-scale reaction and the transformation of β-amino acids.


The usefulness of neoadjuvant chemoradiation therapy for locally advanced esophageal cancer with multiple lymph-node metastases.
The prognosis of patients with esophageal squamous-cell cancer (ESCC) and multiple lymph-node metastases is quite poor. We examined whether neoadjuvant chemoradiation therapy (CRT) has a beneficial effect in such patients. A total of 50 consecutive patients with T3-4 tumors and without organ metastases were prospectively enrolled. Of those patients, 20, who had four or more nodal metastases, underwent neoadjuvant CRT (CRT group), and the remaining 30 patients, who had three or fewer nodal metastases, underwent surgery alone (surgery group). CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. The groups' clinical outcomes were compared. Surgery was performed in 48 patients: all enrolled patients except for 2 who had organ metastasis after CRT. In the CRT group, the number of patients with pathological complete response was observed in 8 patients (44 %), mean nodal metastases number was changed from 8.2 to 2.6 and 9 patients had pN0. The 3-year survival rate was 76 % in the CRT group (4 patients relapsed) and 68 % in the surgery group (8 patients relapsed), which is not a statistically significant difference (P = 0.61). Neoadjuvant CRT is beneficial for locally advanced ESCC with four or more lymph-node metastases.


Prediction of the prognosis of patients with bacteremia caused by encapsulated organisms using spleen volume: A retrospective study.
The spleen plays an important role in the immune response, and patients with impaired spleen function are at risk of overwhelming post-splenectomy infection. This study investigated whether the spleen volume could predict the prognosis of patients with bacteremia caused by encapsulated organisms. This was a single-center, retrospective observational study at Tokyo Medical University Hospital. Twenty patients with encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Capnocytophaga canimorsus) detected in blood culture between January 2017 and July 2020 were included in the study and categorized into two groups: survive and nonsurvive groups. We investigated the association between spleen volume (SV), spleen volume index (SVI), and in-hospital mortality. The SVI was defined as: SVI-H, spleen volume cm3/height m; SVI-BW, spleen volume cm3/body weight kg; and SVI-A, spleen volume cm3 × age/100. The number of patients in the survive group was 17, and that of the non-survive group was 3. The SV and SVI were smaller in the nonsurvive group than in the survive group (P < 0.05). The calculated the SV cut-off for the prediction of prognosis was 36 cm3 with a sensitivity of 94.1% and specificity of 66.7% with a positive predictive value of 94.1% and a negative predictive value of 66.7%. The SV and SVI could be used to predict the prognosis of bacteremia caused by encapsulated organisms. If the spleen volume as measured by computed tomography is small, more intensive treatment should be considered.


Advances in methods to characterize ligand-induced ionic lock and rotamer toggle molecular switch in G protein-coupled receptors.
Structural biology of GPCRs has made significant progress upon recently developed technologies for GPCRs expression/purification and elucidation of GPCRs crystal structures. The crystal structures provide a snapshot of the receptor structural disposition of GPCRs itself or with cocrystallized ligands, and the results are congruent with biophysical and computer modeling studies reported about GPCRs conformational and dynamics flexibility, regulated activation, and the various stabilizing interactions, such as "molecular switches." The molecular switches generally constitute the most conserved domains within a particular GPCR superfamily. Often agonist-induced receptor activation proceeds by the disruption of majority of these interactions, while antagonist and inverse agonist act as blockers and structural stabilizers, respectively. Several elegant studies, particularly for the β2AR, have demonstrated the relationship between ligand structure, receptor conformational changes, and corresponding pharmacological outcomes. Thus, it is of great importance to understand GPCRs activation related to cell signaling pathways. Herein, we summarize the steps to produce functional GPCRs, generate suitably fluorescent labeled GPCRs and the procedure to use that to understand if ligand-induced activation can proceed by activation of the GPCRs via ionic lock switch and/or rotamer toggle switch mechanisms. Such understanding of ligand structure and mechanism of receptor activation will provide great insight toward uncovering newer pathways of GPCR activation and aid in structure-based drug design.


Improving Type 2 Diabetes Patient Health Outcomes with Individualized Continuing Medical Education for Primary Care.
This study provided physicians with continuing medical education (CME) related to type 2 diabetes and evaluated the effect on patient health outcomes. Physicians participated in multi-platform CME (live and online programs) and completed a 25 item questionnaire for patient baseline (3-months pre-CME activity) and follow-up visits (≥6-months post-CME activity). Changes in physician knowledge and patient health outcomes were evaluated. 34 physicians completed both phases of the CME curricula and submitted data for 264 patients. Significant improvements were observed in physician knowledge after the live (p < 0.05) and online programs (p < 0.0005). Mean patient glycated hemoglobin (HbA1c) absolute reduction of 1.15% (p < 0.0001) was reported. CME is an effective tool to close established practice gaps and potentially help improve patient health outcomes.


Influence of phenylbutazone on bile flow in the rat.
Phenylbutazone, a well-known enzyme inducer, at a dose of 80 mg . kg-1 once daily for 8 days increases liver weight and bile flow expressed per g of liver (p less than 0.01). The bile salt secretory rate is not increased.


Mechanisms by which lipoprotein lipase alters cellular metabolism of lipoprotein(a), low density lipoprotein, and nascent lipoproteins. Roles for low density lipoprotein receptors and heparan sulfate proteoglycans.
We sought to investigate effects of lipoprotein lipase (LpL) on cellular catabolism of lipoproteins rich in apolipoprotein B-100. LpL increased cellular degradation of lipoprotein(a) (Lp(a)) and low density lipoprotein (LDL) by 277% +/- 3.8% and 32.5% +/- 4.1%, respectively, and cell association by 509% +/- 8.7% and 83.9% +/- 4.0%. The enhanced degradation was entirely lysosomal. Enhanced degradation of Lp(a) had at least two components, one LDL receptor-dependent and unaffected by heparitinase digestion of the cells, and the other LDL receptor-independent and heparitinase-sensitive. The effect of LpL on LDL degradation was entirely LDL receptor-independent, heparitinase-sensitive, and essentially absent from mutant Chinese hamster ovary cells that lack cell surface heparan sulfate proteoglycans. Enhanced cell association of Lp(a) and LDL was largely LDL receptor-independent and heparitinase-sensitive. The ability of LpL to reduce net secretion of apolipoprotein B-100 by HepG2 cells by enhancing cellular reuptake of nascent lipoproteins was also LDL receptor-independent and heparitinase-sensitive. None of these effects on Lp(a), LDL, or nascent lipoproteins required LpL enzymatic activity. We conclude that LpL promotes binding of apolipoprotein B-100-rich lipoproteins to cell surface heparan sulfate proteoglycans. LpL also enhanced the otherwise weak binding of Lp(a) to LDL receptors. The heparan sulfate proteoglycan pathway represents a novel catabolic mechanism that may allow substantial cellular and interstitial accumulation of cholesteryl ester-rich lipoproteins, independent of feedback inhibition by cellular sterol content.


[History of the German Society of Oromaxillofacial Surgery].
The German Society of Oral and Maxillofacial Surgery was founded by Martin Wassmund in 1951. One of the main reasons was the need for scientific representation in the council at a medical convention. The Society, originally composed of 52 members, was first called "The German Society of Maxillofacial Surgery". In 1972, it extended its title to include the term "oral" ("Mund") and currently comprises 620 members. A scientific conference is held annually on a specific topic. The lectures given there have been published since 1954 in "Fortschritte der Kiefer- und Gesichts-Chirurgie" (Progress in Maxillofacial Surgery) by Thieme Verlag; since 1997, they have appeared as a Springer-Verlag supplement. Topics of choice are published in "Mund-, Kiefer- und Gesichtschirurgie" ("Oral and Maxillofacial Surgery"), originally by Hanser in Munich and now by Springer-Verlag in Heidelberg. In this manner, it was possible to completely document the scientific activities and progress in this specialty. Each year since 1957, a prize named after M. Wassmund, has been given for outstanding scientific accomplishment. The presidents, convention locations, topics, and prizewinners are listed in a table. Since the founding of the Society of Oral and Maxillofacial Surgery, close cooperation has existed with the National Association of German Oral and Maxillary-Facial Surgeons (Bundesverband der Deutschen Arzte für Mund-Kiefer-Gesichts-Chirurgie). In order to intertwine scientific and political interests, a fusion of these two organizations is planned for the year 2000.


Tenidap, a novel anti-inflammatory agent, is an opener of the inwardly rectifying K+ channel hKir2.3.
We studied the effect of a novel anti-inflammatory agent, tenidap, on a cloned inwardly rectifying K+ channel, hKir2.3. Tenidap (a) potently potentiated 86Rb+ efflux through hKir2.3 channels expressed in Chinese hamster ovary cells (EC50=402 nM), (b) reversibly and dose-dependently increased whole-cell and macro-patch hKir2.3 currents (maximum whole-cell current response to tenidap was 230+/-27% of control; EC50=1.3 microM.), and (c) caused dose-dependent and Ba2+-sensitive membrane hyperpolarizations and concurrent decreases in input resistance. Potentiation of hKir2.3 by tenidap was unaffected by inhibitors of phospholipase A2, protein kinase C, or arachidonic acid metabolic pathways. The action of tenidap was not intracellular. Tenidap also had little or no effect on currents flowing through hKir2.1, Kv1.5, and micro1 Na+ channels. Our results demonstrate that tenidap is a potent opener of hKir2.3 and suggest that it can serve as a valuable pharmacological tool for studying physiological and pathological processes involving Kir2.3.


Bafibrinase: A non-toxic, non-hemorrhagic, direct-acting fibrinolytic serine protease from Bacillus sp. strain AS-S20-I exhibits in vivo anticoagulant activity and thrombolytic potency.
A non-toxic, direct-acting fibrinolytic serine protease (Bafibrinase) demonstrating thrombolytic and anticoagulant properties was purified from Bacillus sp. strain AS-S20-I. Bafibrinase was monomeric, with a molecular mass of 32.3 kDa. The peptide mass fingerprinting of Bafibrinase revealed only 8.3% sequence coverage, suggesting it was a novel fibrinolytic enzyme. However, two of the tryptic digested de novo peptide sequences of Bafibrinase demonstrated good similarity with endopeptidases possessing serine in their catalytic triad. Further, catalytic activity of Bafibrinase was inhibited by serine protease inhibitor reinforcing this is a subtilisin-like serine protease. The apparent K(m) and V(max) values of Bafibrinase towards fibrin were determined as 0.24 μM and 2.8 μmol/min, respectively. It showed a K(m) value of 0.139 mM towards a chromogenic substrate for plasmin (D-Val-Leu-Lys-p-Nitroanilide dihydrochloride) and optimum activity at physiological conditions (37 °C and pH 7.4). Based on the cleavage pattern of fibrin and fibrinogen, Bafibrinase may be classified as an α,β-fibrinogenase. Bafibrinase could not degrade collagen and was non-cytotoxic to HT29 cells or mammalian erythrocytes. Further, Bafibrinase at a dose of 2 mg/kg was devoid of toxicity as well as hemorrhagic activity on BALB/c mouse model, supporting its suitability for the development of a better and safer thrombolytic drug. Bafibrinase was also superior to human plasmin in degrading in vitro thrombus. The in vivo anticoagulant nature of Bafibrinase is being explored for the treatment and prevention of thrombosis and other cardiovascular diseases.