Cerebral small vessel disease and kidney function predict long-term survival in patients with acute stroke.
Cerebral small vessel disease reflected by white matter lesions (WMLs) in MRI and kidney function reflected by estimated glomerular filtration rate (eGFR) is closely associated in patients without stroke. We studied whether eGFR and WMLs predict long-term survival in patients with acute stroke. After exclusion of patients with low eGFR (N=5 [1.3%]; <30 mL/min/1.73 m(2)), consecutive patients with acute stroke (N=378) subjected to MRI and serum creatinine determination were included in the study and prospectively followed-up up to 12 years. Of the patients, 71.2% had died during the follow-up, 152 (40.2%) had moderate (eGFR <60 mL/min/1.73 m(2)), and 226 (59.8%) had normal or mildly impaired eGFR (>or=60 mL/min/1.73 m(2)). Of the patients, 108 (28.6%) had mild, 68 (18.0%) had moderate, and 202 (53.4%) had severe WMLs. In logistic regression analysis adjusted with age and sex, eGFR <60 mL/min/1.73 m(2) was associated with severe WMLs (relative risk 2.77, 95% CI 1.10 to 6.98, P=0.030). In Cox regression survival analysis adjusted with significant covariates, eGFR <60 mL/min/1.73 m(2) (1.30, 95% CI 1.00 to 1.68, P=0.047) and severe WMLs (hazard ratio 1.32, 95% CI 1.02 to 1.71, P=0.033) were associated with poor survival, whereas they were not independent from each other. In further analyses, presence of either eGFR >or=60 mL/min/1.73 m(2) or only mild to moderate WMLs, or both, was associated with improved survival compared with all other combinations. Cerebral small vessel disease is closely associated with kidney function in patients with acute stroke. Cerebral small vessel disease and kidney function are closely associated predictors of poor poststroke survival.


Barriers to blood glucose monitoring in a multiethnic community.
We studied a multiethnic community to determine factors associated with blood glucose monitoring (BGM) and to determine the independent association between barriers to diabetes care and BGM. A total of 323 participants (35.6% European, 32.2% Maori, and 32.2% Pacific Islander) from the South Auckland Diabetes Project (free of major complications by self-report) completed a qualitative survey to determine barriers to diabetes care. Five barriers to diabetes care categories were generated including internal psychological (self efficacy/health beliefs), external psychological (psychosocial environment), internal physical (comorbidities/side effects of treatment), external physical (finance/access to care), and educational (knowledge of diabetes/services) barriers. Characteristics associated with BGM greater than or equal to twice weekly were female sex, HbA(1c) >8%, higher diabetes knowledge scores, and insulin use. Multivariate analyses demonstrated that those reporting external physical barriers (OR 0.47, 95% CI 0.26-0.84), external psychological barriers (0.55, 0.30-1.0), and internal psychological barriers (0.56, 0.32-1.0) were less likely to perform BGM independent of ethnicity, insulin use, age, sex, diabetes knowledge, and glycemic control. Further multivariate analyses demonstrated that those reporting external physical barriers, particularly related to personal finance, were less likely to perform BGM. These data demonstrate that patient-reported barriers to diabetes care are associated with BGM, particularly in relation to financial, psychosocial, and self-efficacy issues. Understanding these barriers and overcoming them within the context of the patient's ethnic environment may lead to increased participation in self-care.


Parabrachial complex processes dura inputs through a direct trigeminal ganglion-to-parabrachial connection.
Migraines cause significant disability and contribute heavily to healthcare costs. Irritation of the meninges' outermost layer (the dura mater), and trigeminal ganglion activation contribute to migraine initiation. Maladaptive changes in central pain-processing regions are also important in maintaining pain. The parabrachial complex (PB) is a central region that mediates chronic pain. PB receives diverse sensory information, including a direct input from the trigeminal ganglion. We hypothesized that PB processes inputs from the dura. Using in vivo electrophysiology recordings from single units in anesthetized rats we identified 58 neurons in lateral PB that respond reliably and with short latency to electrical dura stimulation. After injecting tracer into PB, anatomical examination reveals retrogradely labeled cell bodies in the trigeminal ganglion. Neuroanatomical tract-tracing revealed a population of neurons in the trigeminal ganglion that innervate the dura and project directly to PB. These findings indicate that PB is strategically placed to process dura inputs and suggest that it is directly involved in the pathogenesis of migraine headaches.


Efficacy of two multimodal treatments on physical strength of occupationally subgrouped male with low back pain.
Some occupations are more prone to low back pain (LBP) due to their static work postures and work place design. Multidisciplinary pain programs have shown their effectiveness in the management of LBP in general population but which treatment and which segment of the population will be benefited more was not investigated yet. This study determines the effect of two treatment protocols on five occupationally subgrouped male LBP patients. A total of 102 occupational male, 20-40 yrs of age, with sub-acute or chronic nonspecific LBP were randomized and treated either with conventional treatment a combination of two electrotherapy (ultrasound and short wave diathermy) and one exercise therapy (lumbar strengthening exercises) or dynamic muscular stabilization techniques (DMST) an active approach of stabilizing training. At the end of the treatment, subjects of both the groups were further stratified in five subgroups on the basis of their occupation. The pain was the primary outcome measure while physical strength [back pressure changes (BPC) and abdominal pressure changes (APC)] the secondary. The Pain, BPC and APC of all subgroups improved significantly (P < 0.01) in the both treatments but more in DMST. For each variable, improvement in subgroups differed within and between the treatments. Overall improvement in all assessed variables were evident on Desk workers followed by Shop keepers the most while BPC of Movement job, APC of Others and Pain of Sedentary and Shop keepers improved the least. Study concluded that for the management of occupational LBP, DMST is more effective than conventional treatment. The Pain of Sedentary and Shopkeepers and physical strength of Movement job and Others may need more clinical attention. Findings of this study may be helpful in the management of occupational LBP.


Treatment-seeking behavior of erectile dysfunction patients in Europe: Results of the Erectile Dysfunction Observational Study.
The Erectile Dysfunction Observational Study (EDOS) is a 6-month, pan-European prospective, observational study of health outcomes designed to assess patients' profiles and characteristics and the effectiveness of erectile dysfunction (ED) treatment in routine clinical practice. To present baseline characteristics and treatment-seeking behavior of a large sample of ED patients recruited in real-life clinical settings. Men aged 18 years and older who visited a physician to initiate or change any ED treatment were enrolled in EDOS. They were assessed at baseline, 3 months, and 6 months as part of their normal course of care in nine European countries. Sexual health outcomes using the short form of the Psychological and Interpersonal Relationship Scales. Treatment effectiveness and satisfaction were assessed using the International Index of Erectile Function questionnaire, Global Assessment Questions, and further single-item questions. Of the 8,186 patients enrolled by 904 investigators (69% general practitioners [GPs]) across nine European countries, 8,055 patients were eligible for analysis at baseline; 63.9% were ED treatment-naive. Of the total patient population, mean age was 56.5 years, mean body mass index (BMI) was 27.2 kg/m2, 18.3% were obese (BMI > 30 kg/m2), 42.5% had severe ED, and there was a high frequency of comorbidities and concomitant medication use. A similar proportion of the treatment-naive patients were seen by GPs (62.9%) and specialists (65.8%). In the treatment-naive group, there was a higher frequency of severe ED among ex-smokers, obese patients, and in those who drank no alcohol or excessive amounts of alcohol. Unmet need of treatment in ED is high; 66% of patients had experienced ED symptoms for 1 year or longer when they were looking for treatment. Severity seems to be related to treatment seeking.


Gender Differences in Patient Perceptions of Physicians' Communal Traits and the Impact on Physician Evaluations.
Background: Communal traits, such as empathy, warmth, and consensus-building, are not highly valued in the medical hierarchy. Devaluing communal traits is potentially harmful for two reasons. First, data suggest that patients may prefer when physicians show communal traits. Second, if female physicians are more likely to be perceived as communal, devaluing communal traits may increase the gender inequity already prevalent in medicine. We test for both these effects. Materials and Methods: This study analyzed 22,431 Press Ganey outpatient surveys assessing 480 physicians collected from 2016 to 2017 at a large tertiary hospital. The surveys asked patients to provide qualitative comments and quantitative Likert-scale ratings assessing physician effectiveness. We coded whether patients described physicians with "communal" language using a validated word scale derived from previous work. We used multivariate logistic regressions to assess whether (1) patients were more likely to describe female physicians using communal language and (2) patients gave higher quantitative ratings to physicians they described with communal language, when controlling for physician, patient, and comment characteristics. Results: Female physicians had higher odds of being described with communal language than male physicians (odds ratio 1.29, 95% confidence interval 1.18-1.40, p < 0.001). In addition, patients gave higher quantitative ratings to physicians they described with communal language. These results were robust to inclusion of controls. Conclusions: Female physicians are more likely to be perceived as communal. Being perceived as communal is associated with higher quantitative ratings, including likelihood to recommend. Our study indicates a need to reevaluate what types of behaviors academic hospitals reward in their physicians.


Sexual reproduction of the snow alga Chloromonas fukushimae (Volvocales, Chlorophyceae) induced using cultured materials.
Snow algae are microalgae, growing in melting snowpacks, and are thought to act as primary producers in the snow ecosystem. Chloromonas (Volvocales, Chlorophyceae) contains more than 15 snow-inhabiting species. Although vegetative cells and zygotes, or asexual cysts, of snow species of the genus are frequently collected in the field, sexual reproduction and zygote formation in culture have only been induced in C. tughillensis. Here we describe the sexual reproduction of another snow-inhabiting species, C. fukushimae, which was induced using both previously examined and newly established Japanese strains. Mating of isogamous gametes began after mixing two different strains, implying that C. fukushimae is an outcrossing species. Motile and nonmotile zygotes of the species were also described in this report. The nonmotile zygote of C. fukushimae was distinguishable from those of the other snow-inhabiting species of Chloromonas, based on the zygote shape and the presence of several large lipid bodies within the cell. In addition, C. fukushimae carried out sexual reproduction and produced zygotes even under the nitrogen-sufficient condition.


Human papillomavirus in metastatic squamous carcinoma from unknown primaries in the head and neck: a retrospective 7 year study.
Human Papillomavirus (HPV) is found to be increasingly implicated in head and neck cancers. The objective of this study was to determine the primary site of origin of HPV positive squamous carcinomas metastatic to lymph nodes of the neck. Surgical pathology records from January 1, 2000 to July 31, 2007 were used to identify surgically removed neck lymph nodes with the diagnosis of metastatic squamous carcinoma. Specimens in formalin-fixed, paraffin-embedded blocks were examined for HPV (+) by analyzing sequencing data generated by PCR and immunostaining for the expression of the p16INK biomarker, which is overexpressed if Rb is not present. H & E stained slides were also reviewed for histological classification. The available retrospective demographics were extracted from the charts to determine trends of confounding factors. Of the 43 patient samples, 41 contained adequate DNA to test for HPV. The mean age of the 41 patients was 62 years. All of the patients smoked and 39/41 patients consumed alcohol. The overall HPV (+) incident rate was 27% (11/41) by PCR with strongly diffuse or strong focal p16 staining. 9 of the 34 males and 2 of the 7 females had HPV (+) carcinomas. The average age of the 2 HPV (+) females was 44, compared to the HPV (-) females who averaged 70. The average age of the HPV (+) males was 56 compared with the average age 55 of the HPV (-) males. HPV (+) carcinomas appeared to arise from multiple sites in the oropharynx, particularly the tonsils and tongues, including unknown primaries. By histological exam, most metastatic HPV(+) squamous carcinomas were poorly differentiated (basaloid) microscopically and grossly cystic. The 27% HPV (+) squamous cancers metastatic to neck lymph node originated from multiple sites in the oropharynx. The HPV (+) female population, although a total of only 2, tended to be much younger than the HPV (-) ones, whereas the HPV (+) male population was similar in age to the HPV (-) male population.


Raman spectroscopic analysis of the increase of the carotenoid antioxidant concentration in human skin after a 1-week diet with ecological eggs.
Skin aging is mainly caused by the destructive action of free radicals, produced by the UV light of the sun. The human skin has developed a protection system against these highly reactive molecules in the form of the antioxidative potential. Carotenoids are one of the main components of the antioxidants of the human skin. From former studies, it is known that skin aging is reduced in individuals with high levels of carotenoids. Because most of the antioxidants cannot be produced by the human organism, they must be up taken by nutrition. Using noninvasive Raman spectroscopic measurements it is demonstrated that not only fruits and vegetables but also eggs contain high concentrations of antioxidants including carotenoids, which are even doubled in the case of ecological eggs. After a 1-week diet with ecological eggs performed by six volunteers, it is found that the concentration of the carotenoids in the skin of the volunteers increased by approx. 20%. Our study does not intend to recommend exorbitant egg consumption, as eggs also contain harmful cholesterol. But in the case of egg consumption, ecological eggs from hens kept on pasture should be preferred to also receive a benefit for the skin.


The association of PRNCR1 rs1456315 polymorphism with the risk of colorectal cancer.
A recent meta-analysis found a link between the PRNCR1 rs1456315 polymorphism and cancer risk. In the current study, we further investigated the association of this polymorphism with the risk and clinical stage of colorectal cancer (CRC). A total of 416 CRC patients and 416 healthy individuals were genotyped by Sanger sequencing. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Furthermore, a pooled analysis with 872 CRC cases and 1141 controls was performed by Stata 12.0 software. In both the case-control study and the pooled analysis, there was no significant link between the rs1456315 polymorphism and CRC risk. However, there was a significant link between the rs1456315 polymorphism and the clinical stage of CRC. CRC patients carrying the rs1456315 G allele were more likely to have a high-stage tumor. Further bioinformatics analysis showed that the rs1456315 polymorphism could influence the binding of miRNA to PRNCR1. In conclusion, the findings suggest that the rs1456315 polymorphism is linked to CRC clinical stage and might be used as a biomarker to predict CRC progression.


BmHSP20.8 is Localized in the Mitochondria and has a Molecular Chaperone Function In Vitro.
Heat shock proteins (HSPs) are abundant and ubiquitous in almost all organisms from bacteria to mammals. BmHSP20.8 is a small (sHSP) in Bombyx mori that contains a 561 bp open reading frame that encodes a protein of 186 amino acid residues with a predicted molecular mass of 20.8 kDa. The subcellular localization prediction indicated that BmHSP20.8 is likely distributed in the mitochondria with a 51% probability. To identify the subcellular localization of BmHSP20.8, three recombinant vectors were constructed and used to transfect BmN cells. The cytoplasmic and mitochondrial proteins were extracted 72 h after transfection. The Western blot showed that recombinant BmHSP20.8 exists only in the mitochondria. To locate the mitochondrial localization signal domain of BmHSP20.8 more accurately, we cloned four truncated recombinant vectors. The Western blot analysis of the cytoplasmic and mitochondrial proteins showed that the mitochondrial localization signal domain of BmHSP20.8 is located between amino acids 143 to 186. We constructed the pETduet-HIS-SUMO-BmHSP20.8 vector and a soluble BmHSP20.8 was expressed. In a citrate synthase (CS) thermal aggregation experiment, we found that the recombinant BmHSP20.8 protein can protect CS from aggregating at 43 and 48 °C and thus exhibited molecular chaperone activity. Taken together, the results showed that BmHSP20.8 could be a mitochondrial protein and has a molecular chaperone activity, suggesting an important role in mitochondria.


The 'super nurse' syndrome.
The authors describe the dynamics of the "super nurse" syndrome and provide nurse managers experiencing this syndrome with strategies to assist them. The article discusses the roles of nurse educators, hospital development staff, mentors, and social support networks. The authors hope to prevent the "super nurse" syndrome from affecting new graduates, through proper education of nurse educators, mentors, and nurse managers who assist the new graduates in problem solving and adjusting to being a "real nurse."


Kinetic Characterization of Nitrite Uptake and Reduction by Chlamydomonas reinhardtii.
Kinetics of nitrite uptake and reduction by Chlamydomonas reinhardtii cells growing phototrophically has been studied by means of progress curves and the Michaelis-Menten integrated equation. Both uptake and reduction processes exhibited hyperbolic saturation kinetics, the nitrite uptake system lacking a diffusion component. Nitrite uptake and reduction showed significant differences in K(s) for nitrite at pH 7.5 (1.6 versus 20 micromolar, respectively), optimal pH, activation energy values, and sensitivity toward reagents of sulfhydryl groups. K(s) values for nitrite uptake were halved in cells subjected to darkness or to nitrogen-starvation. Nitrate inhibited nitrite uptake by a partially competitive mechanism. The same inhibition pattern was found for nitrite uptake by C. reinhardtii mutant 305 cells incapable of nitrate assimilation. The results demonstrate that C. reinhardtii cells take up nitrite via a highly specific carrier, probably energy-dependent, kinetically responsive to environmental changes, distinguishable from the enzymic nitrite reduction and endowed with an active site for nitrite not usable for nitrate transport.


Anti-inflammatory effects of essential oils from Chamaecyparis obtusa via the cyclooxygenase-2 pathway in rats.
Essential oils are concentrated hydrophobic liquids containing volatile aromatic compounds from plants. In the present study, the essential oil of Chamaecyparis obtusa (C. obtusa), which is commercially used in soap, toothpaste and cosmetics, was extracted. Essential oil extracted from C. obtusa contains several types of terpenes, which have been shown to have anti-oxidative and anti-inflammatory effects. In the present study, we examined the anti-inflammatory effects of C. obtusa essential oil in vivo and in vitro following the induction of inflammation by lipopolysaccharides (LPS) in rats. While LPS induced an inflammatory response through the production of prostaglandin E2 (PGE2) in the blood and peripheral blood mononuclear cells (PMNCs), these levels were reduced when essential oil was pre-administered. Additionally, the mechanism of action underlying the anti-inflammatory effects of C. obtusa essential oil was investigated by measuring the mRNA expression of inflammation‑associated genes. LPS treatment significantly induced the expression of transforming growth factor α (TNFα) and cyclooxygenase-2 (COX-2) in rats, while C. obtusa essential oil inhibited this effect. Taken together, our results demonstrate that C. obtusa essential oil exerts anti‑inflammatory effects by regulating the production of PGE2 and TNFα gene expression through the COX-2 pathway. These findings suggest that C. obtusa essential oil may constitute a novel source of anti-inflammatory drugs.


First Report of Leaf Spot Caused by Colletotrichum citricola on Cavendish bananas in China.
Cavendish banana (Musa spp. AAA group) is an important tropical and subtropical fruit with significant economic value. It is widely planted in Guangxi, Yunnan, Hainan, Fujian and Guangdong provinces in China. In November 2020, leaf spots were observed on nearly 80% of the plants growing in three Cavendish banana plantations in Chongzuo, Guangxi, China. The symptoms on Cavendish banana leaves initially appeared as small black necrosis spots, which gradually expanded and connected, eventually covered the entire leaf. Three diseased leaves from three plantations were collected, sectioned into small pieces (5 ×5 mm), surface sterilized (10 s in 75% ethanol, followed by 1 min in 1% sodium hypochlorite and rinsed three times in sterile water) and placed on potato dextrose agar (PDA) at 28℃ for 5 days for pathogen isolation. The fungal colonies were white, cottony, while the reverse sides were white, concentric circles with yellowish-brown discoloration in 7-day cultures. The conidia were hyaline, aseptate, cylindrical, oval, measuring 10.3 to 17.71 μm (mean 14.06 ± 1.45 μm; n = 200) in length and 4.48 to 9.57 μm (mean 7.46 ± 0.69 μm; n = 200) in width. Three representative isolates (DX1-5, LZ4-5, and FS1-3) were obtained by monosporic isolation. The partial internal transcribed spacer (ITS) regions, actin (ACT), chitin synthase (CHS-1), glyceraldehydes-3-phosphate dehydrogenase (GAPDH), calmodulin (CAL), and β-tubulin (TUB2) were amplified from genomic DNA for the three isolates (Weir et al. 2012). The sequences of the amplified fragments were deposited in GenBank (accessions OL361844 to OL361858, for GAPDH, CAL, ACT, CHS-1, and TUB2 of isolate DX1-5, LZ4-5 and FS1-3; OL305066 to OL305068 for ITS) and showed over 99% identities with the corresponding sequences of C. citricola. A neighbor-joining phylogenetic tree based on the above six genes of type or ex-type specimens of Colletotrichum (Fu et al. 2019) was constructed with MEGA 5.2 using the concatenation of multiple sequences (Kumar et al. 2016). All three isolates clustered together with the type culture of C. citricola (CBS 134228, CBS 134229, CBS 134230) with 82% bootstrap support in the phylogenetic tree. According to the molecular and morphological characteristics, all three isolates were identified as C. citricola. Pathogenicity tests were conducted on one-month-old primary hardened tissue culture plantlets. Tender, healthy leaves were gently scratched with a sterile needle, and each wound site was inoculated with sterile cotton impregnated with conidial suspension (106 spores/ml) for each isolate. Wounded leaves were treated with sterile cotton impregnated with conidial suspension of C. fructicola as positive controls and sterile water as negative controls. Each isolate was inoculated with three tissue culture plantlets, six inoculated sites on each plantlet, the same as controls. All inoculated tissue culture plantlets were covered with plastic bags to maintain high humidity and placed in a 28℃ growth chamber with constant light. Black necrotic lesions were clearly observed on the inoculated leaves and the positive controls after 7 days, whereas no symptoms appeared on the negative control leaves. The fungus was re-isolated from inoculated leaves, and these isolates matched the morphological and molecular characteristics of the original isolates confirming Koch's postulates. To our knowledge, this is the first report of leaf spot caused by C. citricola on Cavendish banana worldwide.


Role of eruption season in reconciling model and proxy responses to tropical volcanism.
The response of the El Niño/Southern Oscillation (ENSO) to tropical volcanic eruptions has important worldwide implications, but remains poorly constrained. Paleoclimate records suggest an "El Niño-like" warming 1 year following major eruptions [Adams JB, Mann ME, Ammann CM (2003) Nature 426:274-278] and "La Niña-like" cooling within the eruption year [Li J, et al. (2013) Nat Clim Chang 3:822-826]. However, climate models currently cannot capture all these responses. Many eruption characteristics are poorly constrained, which may contribute to uncertainties in model solutions-for example, the season of eruption occurrence is often unknown and assigned arbitrarily. Here we isolate the effect of eruption season using experiments with the Community Earth System Model (CESM), varying the starting month of two large tropical eruptions. The eruption-year atmospheric circulation response is strongly seasonally dependent, with effects on European winter warming, the Intertropical Convergence Zone, and the southeast Asian monsoon. This creates substantial variations in eruption-year hydroclimate patterns, which do sometimes exhibit La Niña-like features as in the proxy record. However, eruption-year equatorial Pacific cooling is not driven by La Niña dynamics, but strictly by transient radiative cooling. In contrast, equatorial warming the following year occurs for all starting months and operates dynamically like El Niño. Proxy reconstructions confirm these results: eruption-year cooling is insignificant, whereas warming in the following year is more robust. This implies that accounting for the event season may be necessary to describe the initial response to volcanic eruptions and that climate models may be more accurately simulating volcanic influences than previously thought.


A dysregulation in CES1, APOE and other lipid metabolism-related genes is associated to cardiovascular risk factors linked to obesity.
The aim of the present study was to investigate the relationship between the differential expression of genes related to lipid metabolism in subcutaneous adipose tissue and metabolic syndrome features in lean and obese subjects with habitual high fat intake. Microarray and RT-PCR analysis were used to analyze and validate differential gene expression in subcutaneous abdominal adipose tissue samples from lean and obese phenotype subjects. Several genes and transcripts involved in lipolysis were down-regulated, such as AKAP1, PRKAR2B, Gi and CIDEA, whereas NPY1R and CES1 were up-regulated, when comparing obese to lean subjects. Similarly, transcripts associated with cholesterol and lipoprotein metabolism showed a differential expression, with APOE and ABCA being decreased and VLDLR being increased in obese versus lean subjects. In addition, positive correlations were found between different markers of the metabolic syndrome and CES1 and NPY1R mRNA expressions, while APOE showed an inverse association with some of them. Different expression patterns in transcripts encoding for proteins involved in lipolysis and lipoprotein metabolism were found between lean and obese subjects. Moreover, the dysregulation of genes such as CES1 and APOE seems to be associated with some physiopathological markers of insulin resistance and cardiovascular risk factors in obesity.


[Postoperative treatment for malignant intracranial tumors--especially concerning intermittent intra-carotid administration of adriamycin].
Seventeen patients, aged 9 to 63 years (mean age 38.2 years), with 6 recurring malignant glioma, 5 malignant meningioma, 4 metastatic brain tumor, one endodermal sinus tumor and one embryonal carcinoma were postoperatively treated with adriamycin (ADM). As a rule, 20 mg of ADM (to 960 mg in a total dosis) were given by means of intra-carotid administration every two weeks (to 250 months in duration). According to Karnofsky's evaluation, 4 of 6 glioblastoma patients(66.7%), 4 of 5 malignant meningioma (80%), 2 of 4 metastatic brain tumor (50%) and one embryonal carcinoma had improvement of clinical condition, at least during two months after the beginning of the treatment, and/or remission of more than 50% of the enhanced area on CT scan. Consequently, allover response rate was 64.7%. Tumor tissue concentration of ADM administered intraoperatively by the same regimen, was estimated by fluorescence assay, twenty times in sixteen patients. The level of the concentration was higher in malignant tumor (3.6 to 6.2 micrograms/g) than in low grade astrocytoma (1.5 microgram/g in maximum) during sixty minutes after ADM administration. On the other hand, when ADM of same dosis was given intravenously, maximum serum level was 2.8 microgram/ml, which was less than half in comparison with tissue level of intracarotid administration. There was a serious myelosuppression in two cases in our series, but no cardiomuscular damage was observed in any cases. In conclusion, ADM concentration of brain tissue such as malignant meningioma, metastatic brain tumor and, even glioblastoma, was highly obtained. Further, intermittent intra-carotid administration of ADM was more effective than intravenous dripping in treating malignant intracranial tumor, although side effects should be carefully avoided.


Characterisation of the aggregation behaviour in a salmeterol and fluticasone propionate inhalation aerosol system.
The nature of the drug-drug aggregation phenomena between salmeterol xinafoate and fluticasone propionate used in a metered-dose inhaler system has been examined. Interactions between the drugs in the solvents 1,1,2-trichlorotrifloroethane (CFC-113) and 1,1,1,2-tetrafluoroethane (HFA-134a) have been characterised using a focused beam reflectance measurement probe by measuring the average floc size of the drug particles individually and in combination as a function of stirrer rate. The floc composition in the CFC-113 system, where the drug particles cream, was determined by high-performance liquid chromatography analysis. The aggregation behaviour of the individual drugs was shown to depend on the physical and chemical properties of both the drug substance and the media. Larger flocs were observed for salmeterol xinafoate compared with fluticasone propionate, while both drugs formed larger aggregates in HFA-134a compared with in CFC-113. The floc composition studies demonstrated that, in the combined formulation in CFC-113, salmeterol xinafoate and fluticasone propionate aggregate together to form hetero-flocs. The interaction between the two drugs was such that they did not separate on creaming, despite having different densities. The average floc size of the combined drug suspension was also found to depend on the dispersion medium.


[Functional anatomy and biomechanics of the carpus].
The wrist is an exceedingly complex structure composed of several joints and a dedicated ligamentous system. Its functional principles allow a wide range of carpal motion and make the wrist remarkably resistant to external stress forces:The proximal carpal row serves as an intercalated link interposed between the static elements of both the forearm and the distal carpal row. Like a flexible place-holder, the proximal row synchronously adapts to the spatial and temporal requirements of the wrist. There are synergistic movement patterns including simultaneous flexion of the proximal row as the wrist is deviated radially and simultaneous extension during ulnar deviation. Together with pronosupination of the radioulnar joints, the combined radial/ulnar inclination and flexion/extension enable spherical, out-of-plane movements of the hand. Carpal function is best explained by the "model of a ring under tension."This review addresses the anatomy and the biomechanics of the wrist and illustrates systematic image analysis by using carpal lines and angles as well as indices of carpal height.


PITX3 and risk for Parkinson's disease: a systematic review and meta-analysis.
Several single nucleotide polymorphisms (SNPs) in the PITX3 gene have been associated with the risk for Parkinson's disease (PD). We conducted a systematic review and a meta-analysis including all the studies published on the risk of PD related with these polymorphisms. The systematic review was done using several databases. Eligible studies were included in the meta-analysis that was carried out using Meta-DiSc 1.1.1 software. Heterogeneity between studies was tested using the Q-statistic. The meta-analysis included eight association studies for the PITX3 rs3758549 SNP (4,052 PD patients, 3,949 controls), eight studies for the PITX3 rs2281983 SNP (4,309 PD patients, 4,287 controls), and six studies for the rs4919621 SNP (2,724 PD patients, 2,285 controls), and the risk for PD, global diagnostic odds ratios (95% confidence intervals) for rs3758549, rs2281983, and rs4919621 were, respectively, 1.00 (0.89-1.12) (p = 0.979), 0.99 (0.91-1.09) (p = 0.896), and 0.98 (0.83-1.16) (p = 0.844) for the total group. The separate analysis in Caucasian and Chinese subjects on the frequency of the minor allele of the three SNPs analyzed did not show significant differences between PD patients and controls in both subgroups. rs2281983 and rs4919621 SNPs were related with early-onset PD risk in Caucasians. The results of the meta-analysis suggest that rs3758549, rs2281983, and rs4919621 SNPs are not major determinants of the risk for PD.


Link worker perspectives of early implementation of social prescribing: A 'Researcher-in-Residence' study.
Social prescribing (SP) is increasing in popularity in the UK and can enable healthcare providers to respond more effectively to a range of non-clinical needs. With the NHS commitment to establish an SP link worker in all GP practices, there is a rapid increase in the number of SP schemes across the country. There is currently insufficient evidence concerning the implementation and acceptability of SP schemes. In this paper, we report our analysis of the descriptions of the experiences of SP link workers, regarding the early implementation of SP link workers in two SP programmes in the South West. Data were gathered using the 'Researcher in Residence' (RiR) model, where the researcher was immersed in the environments in which the SP was managed and delivered. The RiR undertook conversations with 11 SP link workers, 2 SP link worker managers and 1 SP counsellor over six months. The RiR visited seven link workers at their GP practices (service 1) and four at their head office (service 2). The RiR met with the link worker managers at their offices, and the RiR spoke with the SP counsellor on the telephone. Data from these conversations were analysed using Thematic Analysis and six codes were constructed to advance our understanding of the components of early implementation of the SP programmes. Training (particularly around mental health), workforce support, location and SP champions within GP practices were found to be key strategies of SP implementation, link worker involvement acting as a conduit for the impacts of these strategies. This paper suggests that the implementation of SP programmes can be improved by addressing each of these areas, alongside allowing link workers the flexibility and authority to respond to challenges as they emerge.


Unfreezing the behaviour of two orb spiders.
Spider's webs reflect the builders behaviour pattern; yet there are aspects of the construction behaviour that cannot be "read" from the geometry of the finished web alone. Using computerised image analysis we developed an automatic surveillance method to track a spider's path during web-building. Thus we collected data on two orb-weaving spiders--the cribellate Uloborus walckenaerius and the ecribellate Araneus diadematus--for web geometry, movement pattern and time allocation. Representatives of these two species built webs of similar geometry but they used different movement patterns both spatially (which we describe qualitatively) and temporally (which we analyse quantitatively). Most importantly, temporal analysis showed that the two spiders differed significantly in some but not all web-building stages; and from this we deduce that Uloborus--unlike Araneus--was constrained by speed of silk production during the construction of its capture but not its auxiliary spiral.


A sexual dimorphism in hypothalamic arginine vasotocin (AVT) gene expression and AVT plasma levels in the Japanese quail (Coturnix coturnix japonica) in response to water deprivation.
To examine a possible sexual dimorphism in the osmotic control of arginine vasotocin (AVT) release in birds, age-matched male and female Japanese quail were subjected to water deprivation. The observed increased plasma osmolalities were accompanied by increased plasma AVT levels. Plasma mesotocin levels did not change with water deprivation. The sensitivity of the osmotic control of AVT release as determined by the slope of the relationship between plasma AVT levels and plasma osmolalities was significantly (P < 0.05) higher in males than in females. By Northern blot analysis, levels of hypothalamic AVT gene transcripts were increased 2.3 +/- 0.14- and 3.5 +/- 0.13-fold in water-deprived male and female Japanese quail, respectively, compared to normally hydrated birds. Our data suggest gender-related differences in the osmotic control of AVT release and in hypothalamic AVT gene expression in the Japanese quail.


Use of noninvasive electroacupuncture for the treatment of HIV-related peripheral neuropathy: a pilot study.
The main objective of this study was to test the hypothesis that low-voltage non-invasive electroacupuncture will improve the condition of neuropathic human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) patients. A prospective study using HIV/AIDS patients who had antiretroviral drug-induced neuropathy. Eleven patients were enrolled, but complete data was obtained from only 7. Non-invasive skin electrodes were placed on leg acupuncture points BL60, ST36, K1, LIV3, and low-voltage current passed for 20 minutes every day for 30 days. Patients were assessed preintervention and postintervention with MOS-HIV 30-item instrument questionnaire and tibial H-reflex was similarly recorded from the right calf muscle. There was improvement in the condition of all 7 patients. They felt much better and reported feelings of increased physical strength. Outcomes on MOS-HIV 30-item instrument showed significant overall improvement in functional activities (pre 33+/-10, post 38.4+/-9.6, p = 0.02 MANOVA). This was confirmed by postintervention H-reflex parameters; H-max and direct muscle response (M-response) amplitudes were potentiated in relation to pretreatment values (H-max: pre = 1.19+/-1.2, post = 2.68+/-1.9, p<0.05; M-response: pre = 0.93+/-1.1, post = 2.34+/-1.8, p<0.05); M-response latency decreased in relation to pretreatment value (pre = 9.7+/-1.8, post = 7.8+/-1.9, p<0.01). The results support the hypothesis that low-voltage electroacupuncture will improve the condition of the neuropathic HIV/AIDS patient.


Second harmonic imaging of the human brain: the practicability of coronal insonation planes and alternative perfusion parameters.
Second harmonic imaging (SHI) is a novel ultrasound technique that allows the evaluation of brain tissue perfusion. The purpose of this study was to assess normal cerebral echo contrast characteristics in 3 regions of interest (ROIs) in the transverse axial and coronal insonation planes through the temporal bone window. Materials and Methods- SHI examinations were performed in 25 patients without cerebrovascular disease (aged 50+/-19 years) in a transverse axial and a coronal diencephalic insonation plane through the temporal bone window. After intravenous administration of 2.5 g (400 mg/mL) of a galactose-based echo contrast agent, 62 time-triggered images with a transmission rate of 1 frame per 2.5 seconds were recorded for offline analysis. Time-intensity curves, including peak intensity (PI) (dB) and positive gradient (PG) (dB/s), were calculated to quantify ultrasound intensity in 3 different ROIs in both planes of the following sections: the thalamus (ROI(thal)), the lentiform nucleus (ROI(ncl)), and the area supplied by the middle cerebral artery (ROI(mca)). Characteristic time-intensity curves with high PIs and steep PGs were recorded in each ROI. Statistical analysis of the aforementioned parameters showed no significant difference for comparison of the 3 ROIs in the transverse axial versus the coronal insonation plane. Comparison of different ROIs in the transverse axial insonation plane revealed that PI was significantly higher in ROI(thal) than in ROI(mca) (7.8 versus 5.5 dB; P<0.05) and significantly higher in ROI(ncl) than in ROI(thal) (9.3 versus 7.8 dB; P<0.05). In contrast, PG was comparable in ROI(thal) and in ROI(mca) (0.21 versus 0.25 dB/s; P=0.42). SHI is a promising technique for the evaluation of cerebral parenchymal perfusion. Comparison of the transverse axial and coronal insonation planes shows similar time-intensity curves with comparable values for PIs and PGs. Coronal insonation allows the evaluation of perfusion abnormalities near the vertex and skull base, areas that cannot be depicted in the transverse axial plane. Comparison of the different ROIs indicates that the PG is a more robust and reliable parameter than the PI.


Perceived risks of transit use during COVID-19: Correlates and strategies from a case study in El Paso, Texas.
COVID-19 has led to public transportation ridership plummeting and thus created fiscal crises and operational difficulties for transit operators. Although transit services remain essential for people with limited access to alternative transportation modes, the unfavorable public view keeps potential riders from transit. The public transportation industry is in dire need of restoring trust and recovering ridership. In July 2020, we conducted an online survey in El Paso, Texas, to investigate COVID-19 risk perceptions related to transit use. A total of 712 valid responses, consisting of 613 English and 99 Spanish responses, were included in the analyses. Descriptive and bivariate analyses showed many choice transit riders changed their mobility patterns by abandoning public transportation. Survey participants reported that social distancing and cleaning services were very important in encouraging them to return to transit. The free fare policy was also a stimulus for the existing riders to continue their transit use during the pandemic. The multivariable analysis results highlighted that public knowledge plays a vital role in COVID-19 risk perceptions and transit use decisions. Major opportunities exist in terms of public awareness campaigns that inform the public about the COVID-19 related safety measures transit operators are implementing. We further suggest some practical strategies to enhance public communication and help transit operators recover from COVID-19. This study offers timely insights for public policy stakeholders, including transit agencies, to better utilize their resources to protect public health, regain public confidence, and bring passengers back.


Preliminary study on the quantitative analysis of vocal loading effects on vocal fold dynamics using phonovibrograms.
The purpose of the present study was to determine whether high-speed digital imaging with phonovibrogram (PVG) analysis would identify changes in vocal fold vibratory characteristics following prolonged reading (vocal fatigue) in subjects with normal voice to evaluate the voice effects of vocal loading. Three healthy subjects' larynges were examined with an endoscopic high-speed imaging system at 4 different levels of vocal load. Vocal fold dynamics were segmented and processed by PVGs. The PVG images were quantitatively described by a parameter set enabling an individual characterization of vocal fold dynamics. To reveal differences between the subjects, we performed a linear discrimination analysis. Within each subject, the identification of vocal loading effects was performed by statistical analysis (1-way analysis of variance), and 2-tailed paired t-tests were used as a consistency check between left and right vocal fold sides. For each subject, the PVG analysis enabled a precise quantification of the entire range of vocal fold dynamics. Independently of the high-speed videos (vocal loads), each subject could be identified by his or her PVG parameters on linear discrimination analysis. In all subjects, the effect of vocal loading was reflected by alterations of PVG parameters representing the posterior opening and closing dynamics. Evaluation within subjects revealed slight asymmetric vibratory behavior between the left and right vocal folds, confirming earlier assumptions. Within the investigated subjects, vocal loading does affect the vibratory characteristics of the vocal folds. Left-right vocal fold vibratory asymmetries do occur in healthy voices and can be identified by PVGs. High-speed digital imaging in combination with PVG analysis seems to be a promising tool for investigation of vocal fold fatigue and disorders resulting even from small dynamic changes.


First description of an olfactory neuroblastoma in goldfish Carassius auratus: a case report.
An external pinkish growing mass that emerged from the right nostril of an adult goldfish Carassius auratus L. was evaluated by means of light microscopy and immunohistochemistry. The neoplasm presented a well-developed fibrovascular stroma associated with solid cell nests and a large number of Flexner-Wintersteiner rosettes. Myelinated fibres were observed around them. Neoplastic cells showed a prominent degree of nuclear atypia and low mitotic activity. The latter was in agreement with the low reactivity of tumour cells to anti-proliferating cell nuclear antigen antibody. Immunohistochemistry also revealed anti-neuronal nitric oxide synthase, anti-S100 protein, antineuropeptide Y, and anti-cytokeratin immunoreactivity in tumour cells as well as in normal olfactory epithelium of goldfish control sections. Histopathological and immunohistochemical findings strongly suggest a diagnosis of an olfactory neuroblastoma (ONB). To our knowledge this is the first description of ONB in goldfish.


Extracellular calcium protects against verapamil-induced metaphase-II arrest and initiation of apoptosis in aged rat eggs.
Non-specific L-type calcium channel blockers, such as verapamil (> or =50 microM), induce metaphase-II (M-II) arrest and apoptosis in aged rat eggs cultured in Ca(2+)-deficient medium. However, the effects of extracellular Ca(2+) on verapamil-induced M-II arrest and apoptosis have not yet been reported. We have demonstrated that postovulatory aging induced exit from M-II arrest by extruding a second polar body, a morphological sign of spontaneous egg activation (SEA). Verapamil inhibited SEA and induced egg apoptosis in a dose-dependent manner in Ca(2+)-deficient medium. The initiation of apoptotic features was observed at 50 microM of verapamil. Extracellular Ca(2+) (1.80 mM) reduced intracellular H2O2 level, bax protein expression, caspase-3 activity, DNA fragmentation and protected against 50 microM, but not higher concentrations of > or =100 microM in verapamil-induced egg apoptosis. These results suggest that extracellular Ca(2+) ions have a role during SEA and protect against verapamil induced apoptosis in aged rat eggs.


[Microbiological analysis of red octopus in fishing ports of Campeche, Mexico].
In this work we studied the microbiological quality of the red octopus given its important economic and social impact on the region South-Southeast of Mexico. Samples were taken in different areas of capture of the species and analyzed with biochemical tests described in the Mexican official standards, identifying strains belonging to the genus Vibrio, Salmonella and faecal coliforms, and E. coli O157: H7. We used the BAx System for the identification of microorganisms through their bacterial DNA. The results obtained in biochemical and molecular methods were confirmed. Bland-Altman statistical method pointed out that both techniques can be used interchangeably. McNemar test showed that both methods have the same efficacy for the identification of pathogens (value X2=0.5 ρ=0.4795). The microbiological quality of the octopus in the South-Southeast region of Mexico is deficient due to the presence of pathogenic intestinal flora that might represent an epidemiological risk. The indexes established by the regulations suggest the need to apply effective and rapid identification technologies, such as the BAx System.This alternative method of analysis can contribute to the implementation of effective strategies that allow compliance with the minimal sanitary specifications during the processing of fishing products, thus strengthening the control systems to decrease the risks of epidemiological outbreaks in the region.


Nonmetabolic functions of pyruvate kinase isoform M2 in controlling cell cycle progression and tumorigenesis.
Pyruvate kinase catalyzes the rate-limiting final step of glycolysis, generating adenosine triphosphate (ATP) and pyruvate. The M2 tumor-specific isoform of pyruvate kinase (PKM2) promotes glucose uptake and lactate production in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. As recently reported in Nature, PKM2, besides its metabolic function, has a nonmetabolic function in the direct control of cell cycle progression by activating β-catenin and inducing expression of the β-catenin downstream gene CCND1(encoding for cyclin D1). This nonmetabolic function of PKM2 is essential for epidermal growth factor receptor (EGFR) activation-induced tumorigenesis.


Mechanism of the reaction catalyzed by mandelate racemase. 3. Asymmetry in reactions catalyzed by the H297N mutant.
The two preceding papers [Powers, V. M., Koo, C. W., Kenyon, G. L., Gerlt, J. A., & Kozarich, J. W. (1991) Biochemistry (first paper of three in this issue); Neidhart, D. J., Howell, P. L., Petsko, G. A., Powers, V. M., Li, R., Kenyon, G. L., & Gerlt, J. A. (1991) Biochemistry (second paper of three in this issue)] suggest that the active site of mandelate racemase (MR) contains two distinct general acid/base catalysts: Lys 166, which abstracts the alpha-proton from (S)-mandelate, and His 297, which abstracts the alpha-proton from (R)-mandelate. In this paper we report on the properties of the mutant of MR in which His 297 has been converted to asparagine by site-directed mutagenesis (H297N). The structure of H297N, solved by molecular replacement at 2.2-A resolution, reveals that no conformational alterations accompany the substitution. As expected, H297N has no detectable MR activity. However, H297N catalyzes the stereospecific elimination of bromide ion from racemic p-(bromomethyl)mandelate to give p-(methyl)-benzoylformate in 45% yield at a rate equal to that measured for wild-type enzyme; the unreacted p-(bromomethyl)mandelate is recovered as (R)-p-(hydroxymethyl)mandelate. At pD 7.5, H297N catalyzes the stereospecific exchange of the alpha-proton of (S)- but not (R)-mandelate with D2O solvent at a rate 3.3-fold less than that observed for incorporation of solvent deuterium into (S)-mandelate catalyzed by wild-type enzyme. The pD dependence of the rate of the exchange reaction catalyzed by H297N reveals a pKa of 6.4 in D2O, which is assigned to Lys 166.(ABSTRACT TRUNCATED AT 250 WORDS)


Microbial transformation of albendazole.
Screening scale studies were performed to biotransform anthelmintic drug albendazole by using twelve bacterial strains representing six genera and five actinomycetes cultures. Among the cultures studied, Bacillus subtilis MTCC 619, Escherichia coli MTCC 118 and Klebsiella pneumoniae MTCC 109 could transform albendazole to one metabolite whereas, Enterobacter aerogenes NCIM 2695, Klebsiella aerogenes NCIM 2258, Pseudomonas aeruginosa NCIM 2074 and Streptomyces griseus NCIM 2622 could transform albendazole into two metabolites in significant quantities. The transformation of albendazole was identified by HPLC. Based on LC-MS-MS data, the two metabolites were predicted to be albendazole sulfoxide (M1) and albendazole sulfone (M2), the major mammalian metabolites reported previously. Since M1 is active metabolite, the results prove the versatility of microorganisms to perform industrially attractive chemical reactions.


Complementary and alternative medicine in alopecia areata.
Alopecia areata is an unpredictable hair-loss condition. As there is no cure for alopecia areata and no effective conventional therapy, a substantial number of alopecia areata patients resort to complementary and alternative medical remedies and therapies (CAM). This review on the application of CAM in alopecia areata addresses two pertinent aspects. First, it provides a current overview of the published medical literature on CAM used in alopecia areata, and alopecia areata-related studies. Second, it presents a thorough assessment of the considerations and limitations of the use of CAM for the treatment of alopecia areata. A systematic MEDLINE search yielded 13 studies of the clinical use of CAM in the management of alopecia areata, all belonging to one of the five main categories of CAM. Methodological quality was analyzed using objective assessment scores (Wilson and Lawrence scores). Unfortunately, no study was of sufficient internal validity to provide robust evidence of the benefit of CAM. This might be attributable to several specific disease characteristics of alopecia areata, which require an especially solid trial design to properly assess the therapeutic effects of CAM. The review concludes with some recommendations for improving the quality of trials incorporating CAM in the treatment of alopecia areata.


Four-strand hamstring tendon autograft versus LARS artificial ligament for anterior cruciate ligament reconstruction.
This retrospective study compared the results after anterior cruciate ligament (ACL) reconstruction using a four-strand hamstring tendon graft (4SHG) versus Ligament Advanced Reinforcement System (LARS) artificial ligament in 60 patients between January 2003 and July 2004 with a minimum four-year follow-up. The KT-1000 examination, the International Knee Documentation Committee (IKDC) scoring systems and Lysholm knee scoring scale were used to evaluate the clinical results. The mean side-to-side difference was 2.4 +/- 0.5 mm and 1.2 +/- 0.3 mm in the 4SHG group and LARS group, respectively (P = 0.013). Although other results of ACL reconstruction, measured by IKDC evaluation, Lysholm scores and Tegner scores, showed using a LARS graft clinically tended to be superior to using a 4SHG, there were no significant differences calculated. Our results suggest that four years after ACL reconstruction using a LARS ligament or 4SHG dramatically improves the function outcome, while the patients in the LARS group displayed a higher knee stability than those in the 4SHG group.


A simple approach to polymer mixture miscibility.
Polymeric mixtures are important materials, but the control and understanding of mixing behaviour poses problems. The original Flory-Huggins theoretical approach, using a lattice model to compute the statistical thermodynamics, provides the basic understanding of the thermodynamic processes involved but is deficient in describing most real systems, and has little or no predictive capability. We have developed an approach using a lattice integral equation theory, and in this paper we demonstrate that this not only describes well the literature data on polymer mixtures but allows new insights into the behaviour of polymers and their mixtures. The characteristic parameters obtained by fitting the data have been successfully shown to be transferable from one dataset to another, to be able to correctly predict behaviour outside the experimental range of the original data and to allow meaningful comparisons to be made between different polymer mixtures.


Pollen Allergy in a Changing Planetary Environment.
Airborne pollens are one of the common causative and triggering agents of respiratory allergy in a changing planetary environment. A growing number of people worldwide are contracting allergic diseases caused by pollens. The seasonal variations in pollens have occurred everywhere and the sensitization rate to pollens has increased in children as well as in adults. Moreover, allergenic plants, such as ragweed and Japanese hop, grow in soil damaged by human's activities and deforestation with air pollution. It is impossible to avoid plants that cause allergies, because pollens can travel many kilometers in the breeze or wind. Hence, it is essential to survey and forecast pollens for the management of pollen allergy. Weather conditions may alter pollen concentrations. A number of studies have shown that increases in CO2 concentration and atmospheric temperature raise pollen concentration. Hence most of the studies on the impact of climate change on aeroallergens must include the amount and allergenicity of pollens. It is yet unknown whether complex interactions with pollens, meteorological variables, and air pollutants in the changing environment. Considering the effect of climate change on the long-term trends in pollen levels and emerging viral infection, it is crucial to forecast and eliminate the associated risk for human health in future and take appropriate measures to reduce it.


Highly polymorphic microsatellite markers in Pulsatilla vulgaris (Ranunculaceae) using next-generation sequencing.
We developed novel microsatellite markers for the perennial plant Pulsatilla vulgaris (Ranunculaceae) to investigate the effects of fragmentation on gene flow in this imperiled species. We identified microsatellites and developed primers based on 454 shotgun sequences. We identified 14 markers that were polymorphic and produced clean bands. Of these, eight could be analyzed as diploids. Genotyping of 97 individuals across two populations revealed these markers to be highly polymorphic with seven to 17 alleles per locus and observed heterozygosity from 0.41 to 0.83. The markers are highly informative and will be used to test if the reintroduction of shepherding in southern Germany improves genetic connectivity among fragmented populations of P. vulgaris. The combination of diploid and tetraploid markers presented here will be useful in resolving the polyploidization history of this and related species.


Principles of contrast-enhanced MR angiography. Basic and clinical applications.
Contrast-enhanced MR angiography has several advantages in the clinical setting. One advantage is the shortening of T1 because the source of signal increase is resistant to signal losses caused by blood saturation, especially for in-plane flow as encountered in TOF MR angiography and PC MR angiography. This T1 reduction is clearly advantageous in obtaining images of tortuous vessels and stenotic regions. Because the contrast agent Gd-DTPA is well-tolerated and has no nephrotoxic effect, its use in patients with impaired renal function is widely accepted. It is also reported in the literature that the depiction of large aneurysms is markedly more simple with CE-MR angiography than with digital subtraction angiography because filling and subsequent washout of contrast material can be followed over a longer period of time. The main intrinsic advantage of CE-MR angiography compared with TOF and PC-MR angiography is its acquisition speed (because of ultra-short TRs) with comparable gradient performance. Also, the slice orientation can be chosen as the clinical situation dictates and needs rather than being uniformly perpendicular to blood flow, as was often necessary previously. The author considers CE-MR angiography a valuable development for vascular MR imaging. It is currently being compared with alternative methods in studies at several centers.


Polymorphisms associated with the risk of lung cancer in a healthy Mexican Mestizo population: Application of the additive model for cancer.
Lung cancer is the leading cause of cancer mortality in Mexico and worldwide. In the past decade, there has been an increase in the number of lung cancer cases in young people, which suggests an important role for genetic background in the etiology of this disease. In this study, we genetically characterized 16 polymorphisms in 12 low penetrance genes (AhR, CYP1A1, CYP2E1, EPHX1, GSTM1, GSTT1, GSTPI, XRCC1, ERCC2, MGMT, CCND1 and TP53) in 382 healthy Mexican Mestizos as the first step in elucidating the genetic structure of this population and identifying high risk individuals. All of the genotypes analyzed were in Hardy-Weinberg equilibrium, but different degrees of linkage were observed for polymorphisms in the CYP1A1 and EPHX1 genes. The genetic variability of this population was distributed in six clusters that were defined based on their genetic characteristics. The use of a polygenic model to assess the additive effect of low penetrance risk alleles identified combinations of risk genotypes that could be useful in predicting a predisposition to lung cancer. Estimation of the level of genetic susceptibility showed that the individual calculated risk value (iCRV) ranged from 1 to 16, with a higher iCRV indicating a greater genetic susceptibility to lung cancer.


Hospital Privileging Practices for Bedside Procedures: A Survey of Hospitalist Experts.
Many hospitalists are routinely granted hospital privileges to perform invasive bedside procedures, but criteria for privileging are not well described. We conducted a survey of 21 hospitalist procedure experts from the Society of Hospital Medicine Point-of-Care Ultrasound Task Force to better understand current privileging practices for bedside procedures and how those practices are perceived. Only half of all experts reported their hospitals require a minimum number of procedures performed to grant initial (48%) and ongoing (52%) privileges for bedside procedures. Regardless, most experts thought minimums should be higher than those in current practice and should exist alongside direct observation of manual skills. Experts reported that the use of ultrasound guidance was nearly universal for paracentesis, thoracentesis, and central venous catheter placement, but only 10% of hospitals required the use of ultrasound for initial privileging of these procedures.


Nanoparticle-mediated inhibition of survivin to overcome drug resistance in cancer therapy.
The acquired resistance of human cancer cells to apoptosis is one of the defining hallmarks of cancer. Upregulated expression of inhibitors of apoptosis proteins (IAP) has been implicated in drug resistance in several cancers. Survivin (encoded by BIRC5), the smallest member of the IAP family, has been correlated with both the control of cell apoptosis and regulation of cell mitosis in cancer. Owing to its critical role in regulation of cell survival and development of cancer resistance, as well as its distinguishingly high level of expression in many types of cancer, survivin has long been regarded as a promising therapeutic target for cancer therapy. This review first presents an overview of the mechanism by which survivin regulates cell function, followed by a discussion of the current state of survivin-targeted therapies. We focus on the application of nanoparticulate systems to deliver survivin inhibitors, co-delivery of survivin inhibitors with chemotherapeutic agents, synchronous targeting of survivin, other drug resistant molecules, and survivin regulators. We conclude by highlighting the current limitations associated with survivin-targeted therapies and speculating on the future strategies to surmount these impediments.


[Expression of BMP4 mRNA in the in-vivo tissue engineering bone].
This study was aimed to compare the expression of BMP4 mRNA in the in-vivo tissue engineering bone constructed with Ca/P ceramics against the expression of BMP4 mRNA in the naturally healing bone. 20 porous Ca/P ceramics cylinders with Phi 5 mm x 8 mm were made and implanted into the dorsal muscles of 5 dogs. As control, one molar tooth was pulled out from each dog to create bone defect for the naturally healing bone at the same time. The specimens and the naturally healing bone were harvested at 1, 2, 4, 12 and 24 weeks post-implantation. After RNA extraction and reverse transcription, bone morphogenetic protein 4 (BMP4) and GAPDH mRNA were detected by real-time quantitative polymerase chain reaction (PCR) method. The results showed that the expression level of BMP4 mRNA of the in-vivo tissue engineering bone constructed with Ca/P ceramics was higher than that of the naturally healing bone in the period of experiment. However, the in-vivo tissue engineering bone had the same chronological order of BMP mRNA expression that the naturally healing bone did. As a bone substitute analogous to autologous bone, the in-vivo tissue engineering bone constructed with Ca/P ceramics has the potential for clinical application.


Selenium and bone health: a protocol for a systematic review and meta-analysis.
Bone health affects the ability of human body to stay active, and its degradation can cause considerable morbidity and mortality. The factors related to bone health play an important role in preventing osteoporosis and its adverse consequences. However, the risk factors for osteoporosis have not been fully elucidated. Deficiency in the trace element selenium may be one of the risk factors for the development of osteoporosis. Previous studies have investigated the effects of selenium on osteoporosis; however, the results are inconclusive. Therefore, the present study aimed to systematically examine the existing literature on the associations between dietary or serum selenium and bone mineral density (BMD), osteoporosis or osteoporotic fractures, and to quantify such associations through meta-analysis. PubMed, Embase and Cochrane Library will be searched using a specified search strategy to identify relevant studies up to October 2019. Both interventional and observational studies in humans will be included. The outcomes will include BMD and the prevalence or incidence of osteoporosis and osteoporotic fractures. For dietary or serum selenium and BMD, osteoporosis or osteoporotic fractures pooled analyses, estimates will be expressed as the mean difference, and the pooled OR, relative risk, HR or beta coefficient, and corresponding 95% CIs. Heterogeneity of the studies and publication bias will be investigated accordingly. To assess the quality and the risk of bias of the included studies, the Newcastle-Ottawa Quality Scale or the Cochrane risk of bias assessment tool will be used where appropriate. Since no private and confidential patient data will be included in the reporting, approval from an ethics committee is not required. The results will be published in a peer-reviewed journal. The study raises no ethical issues. CRD42019147188.


Polyglutamine aggregates stimulate ER stress signals and caspase-12 activation.
Accumulation of unfolded and malfolded proteins causes endoplasmic reticulum (ER) stress, stimulating unfolded protein response (UPR) and c-Jun N-terminal kinase (JNK) activation and activating caspase-12 located on the ER. Little is known about the relationship between the ER stress and polyglutamine [poly(Q)] aggregates. Poly(Q)72 repeats [poly(Q)(72)] induced the stimulation of ER stress signals such as JNK activation, upregulation of Grp78/Bip and caspase-12 activation in C2C5 cells. We prepared antiserum against the cleavage site of mouse caspase-12 at D(318) (anti-m12D318), and showed that poly(Q)(72) with perinuclear aggregates, cytoplasmic inclusions and nuclear inclusions stimulated JNK activation and anti-m12D318 immunoreactivity, but poly(Q)(72) with dispersed aggregates and small nuclear aggregates showed a significantly less effect. Poly(Q)(72) and poly(Q)(11) dispersed in cytoplasm did not. Anti-m12D318-positive cells showed apoptotic features. Unlike anti-m8D387 immunoreactivity, the anti-m12D318 immunoreactivity was not coaggregated with poly(Q). Ac-IETD-fmk (caspase-8 inhibitor) and Ac-DEVD-CHO (caspase-3 inhibitor) did not prevent the anti-m12D318 immunoreactivity induced by poly(Q)(72) aggregates. Anti-m12D318 immunoreactivity was detected in caspase-8(-/-) and caspase-3(-/-) mouse embryonic fibroblasts expressing poly(Q)(72) aggregates. Thus, caspase-12 was activated by poly(Q)(72) aggregates via a pathway independent of caspase-8 and caspase-3 activation, and caspase-12 activation was closely associated with poly(Q) aggregate-mediated cell death. Stimulation of ER stress signals may be involved in the pathogenesis of neurodegenerative disorders with poly(Q) expansion.


Inflammation and cancer: macrophage migration inhibitory factor (MIF)--the potential missing link.
Macrophage migration inhibitory factor (MIF) was the original cytokine, described almost 50 years ago and has since been revealed to be an important player in pro-inflammatory diseases. Recent work using MIF mouse models has revealed new roles for MIF. In this review, we present an increasing body of evidence implicating the key pro-inflammatory cytokine MIF in specific biological activities related directly to cancer growth or contributing towards a microenvironment favouring cancer progression.


Relationship between time of emergency department admission and adherence to the Surviving Sepsis Campaign bundle in patients with septic shock.
Nighttime hospital admission is often associated with increased mortality risk in various diseases. This study investigated compliance rates with the Surviving Sepsis Campaign (SSC) 3-h bundle for daytime and nighttime emergency department (ED) admissions and the clinical impact of compliance on mortality in patients with septic shock. We conducted an observational study using data from a prospective, multicenter registry for septic shock provided by the Korean Shock Society from 11 institutions from November 2015 to December 2017. The outcome was the compliance rate with the SSC 3-h bundle according to the time of arrival in the ED. A total of 2049 patients were enrolled. Compared with daytime admission, nighttime admission was associated with higher compliance with the administration of antibiotics within 3 h (adjusted odds ratio (adjOR), 1.326; 95% confidence interval (95% CI), 1.088-1.617, p = 0.005) and with the complete SSC bundle (adjOR, 1.368; 95% CI, 1.115-1.678; p = 0.003), likely to result from the increased volume of all patients and sepsis patients admitted during daytime hours. The hazard ratios of the completion of SSC bundle for 28-day mortality and in-hospital mortality were 0.750 (95% CI 0.590-0.952, p = 0.018) and 0.714 (95% CI 0.564-0.904, p = 0.005), respectively. Septic shock patients admitted to the ED during the daytime exhibited lower sepsis bundle compliance than those admitted at night. Both the higher number of admitted patients and the higher patients to medical staff ratio during daytime may be factors that are responsible for lowering the compliance.


The human immunodeficiency virus type 1 transmembrane gp41 protein is a calcium-binding protein and interacts with the putative second-receptor molecules in a calcium-dependent manner.
Fusion is a crucial event in the life cycle of the human immunodeficiency virus (HIV); is is initiated by the high-affinity binding between gp120, the external surface glycoprotein of HIV-1, and the differentiation antigen CD4 and finally results in the insertion of the hydrophobic amino terminus of the gp41 envelope glycoprotein into the plasma membrane of the target cell. Recent results suggest that this process is dependent upon calcium ions, but the mechanism or the proteins involved are not understood. Computer-assisted sequence analysis revealed a putative calcium-binding site within the extracellular part of gp41 that was highly reminiscent of the calcium-binding EF-hand structure. To test this hypothesis, calcium-binding experiments were performed. Binding of a recombinant soluble form of the transmembrane protein (rsgp41) to its putative second-receptor molecules in equilibrium was dependent upon calcium. The affinity was not influenced by calcium, but the maximum binding was increased in a dose-dependent manner. Radioactive calcium bound to rsgp41 covalently attached to Sepharose but not to bovine serum albumin. Binding was inhibited by the addition of nonradioactive calcium, indicating that binding was specific. Neither magnesium nor manganese inhibited the binding of labeled calcium to rsgp41. Binding was dependent on the oxidative state of the rsgp41 molecule, suggesting the functional importance of the correctly folded structure of the rsgp41 protein. In this report, we demonstrate that the HIV-1 transmembrane protein gp41 is a calcium-binding protein and interacts with the putative second-receptor molecules in a calcium-dependent manner.


Loss of vasoreactivity by laser thermal energy or argon laser irradiation.
Vasoreactivity of laser-treated vessels was investigated in two different experimental conditions. The canine left circumflex coronary artery (LCx) was lased under perfusion with Krebs-bicarbonate buffer by means of a thermal laser (hot-tip probe, HT) at 7 W for 6 seconds and an argon laser beam through a 300 microns optical fiber at 3 W (tip power) for 1 second at 12 spots. A nontreated segment of the LCx served as a control. Two 3-mm long segments were obtained from the treated segment: one to measure the results of potassium (K) induced contraction, and another 3, 4 diaminopyridine (DAP; K channel inhibitor) induced contraction. In 11 instances, coronary angiography of the perfused artery showed less than 50% stenosis after laser treatment. The segments were then mounted isometrically with 1 g tension in Krebs-bicarbonate buffer. Contraction was induced either with 30 mM KCI or 10(-2) M DAP and expressed as developed tension (gram; g). KCI induced vasocontraction of 4.15 +/- 0.93 g in the control, 0.33 +/- 0.71 g in laser irradiated segments (P < 0.0001 vs control), and 0.02 +/- 0.06 g in thermally-treated segments (P < 0.0001 vs control). DAP induced vasocontraction of 5.21 +/- 1.32 g in the control, 0.39 +/- 0.83 g in laser irradiated segments (P < 0.0001 vs control), and 0.07 +/- 0.13 g in thermally treated segments (P < 0.001 vs control). In 4 instances, more than 50% stenosis remained and additional balloon dilatation reduced the stenosis to less than 50%. The lesions also showed reduced vasoreactivity. In vivo thermal angioplasty resulted in reduced vasoreactivity compared to control in 4 anesthetized dogs. Thus, laser and thermal angioplasty reduced vasoreactivity induced by either KCI or 3, 4 DAP. Neither acetylcholine at 10(-6) M nor papaverine at 10(-4) M was able to induce relaxation of treated segments. In conclusion, 1) the lased coronary artery loses its vasoreactivity to either a constrictive or relaxing agent, 2) although stenosis may be produced by laser energy, additional balloon dilatation can reduce residual stenosis, and 3) laser thermal or argon laser angioplasty may prevent severe coronary spasm.


Causal connections in the acquisition of an orthographic rule: a test of Uta Frith's developmental hypothesis.
In a longitudinal study we tested Frith's causal hypothesis that children first gain orthographic knowledge through reading and then later, as a consequence, through spelling. Children from Years 2 and 3 were tested three times over two years on their reading and spelling of pseudo-words which conformed to the conditional orthographic rule, the 'final -e' or 'split-digraph' rule. Cross-lagged panel correlation analyses suggested that the children's success in reading split-digraph words was a causal determinant of their learning to use split-digraphs in spelling, in the 7- to 8-year period and, with one year-group but not with the other, in the 8- to 9-year period. In the 9- to 10-year period children's success in reading no longer seemed to affect their spelling. These results strongly support Frith's causal hypothesis about the development of orthographic knowledge.


Extinction of conditioned cues attenuates incubation of cocaine craving in adolescent and adult rats.
Relapse to drug use is often precipitated by exposure to drug associated cues that evoke craving. Cue-induced drug craving has been observed in both animals and humans to increase over the first few weeks of abstinence and remain high over extended periods, a phenomenon known as 'incubation of craving'. As adolescence represents a period of vulnerability to developing drug addiction, potentially due to persistent reactivity to drug associated cues, we first compared incubation of cocaine craving in adolescent and adult rats. Adolescent (P35) and adult (P70) rats were trained to lever press to obtain intravenous cocaine, with each drug delivery accompanied by a light cue that served as the conditioned stimulus (CS). Following acquisition of stable responding, rats were tested for cue-induced cocaine-seeking after either 1 or 30days of abstinence. Additional groups of rats were also tested after 30days of abstinence, however these rats were subjected to a cue extinction session 1week into the abstinence period. Rats were injected with aripiprazole, a dopamine 2 receptor (D2R)-like partial agonist, or vehicle, 30min prior to cue extinction. We found that adolescent and adult rats acquired and maintained a similar level of cocaine self-administration, and rats of both ages exhibited a higher level of cue-induced cocaine-seeking if they were tested after 30days of abstinence compared to 1day. Incubation of cocaine craving was significantly reduced to 1day levels in both adults and adolescents that received cue extinction training. Administration of aripiprazole prior to cue extinction did not further reduce cue-induced drug-seeking. These results indicate that cue extinction training during abstinence may effectively reduce cue-induced relapse at a time when cue-induced drug craving is usually high.


Estrogens and the cardiovascular system: role of estradiol metabolites in hormone replacement therapy.
Estrogen substitution in the postmenopause reduces cardiovascular disease by means of direct and indirect effects of estradiol on the cardiovascular system. Recently, there have been increased indications that estradiol metabolites can also have beneficial effects. In the present short review, the existing experimental data for effects of estradiol metabolites on the blood vessels have been compiled. Results of our own studies, together with those of other research groups, indicate that particularly the catechol estrogens are able to exert a positive influence on the cardiovascular system, and may perhaps play a physiological role there. Attention is drawn to clinical-pharmacological aspects for use of estradiol metabolites for the prevention and treatment of cardiovascular disease.


The effectiveness of drug abuse treatment: a meta-analysis of comparison group studies.
A meta-analysis was conducted on 78 studies of drug treatment conducted between 1965 and 1996. Each study compared outcomes among clients who received drug treatment with outcomes among clients who received either minimal treatment or no treatment. Five methodological variables were significant predictors of effect size. Larger effect sizes were associated with studies with the following characteristics: smaller numbers of dependent variables, significant differences between groups at admission, low levels of attrition in the treatment group, a passive comparison group (no treatment, minimal treatment) as opposed to an active comparison group (standard treatment), and drug use determined by a drug test. Controlling for these methodological variables, further analyses indicated that drug abuse treatment has both a statistically significant and a clinically meaningful effect in reducing drug use and crime, and that these effects are unlikely to be due to publication bias. For substance abuse outcomes, larger effect sizes tended to be found in studies in which treatment implementation was rated high, the degree of theoretical development of the treatment was rated low, or researcher allegiance to the treatment was rated as favorable. For crime outcomes, only the average age of study participants was a significant predictor of effect size, with treatment reducing crime to a greater degree among studies with samples consisting of younger adults as opposed to older adults. Treatment modality and other variables were not related to effect sizes for either drug use or crime outcomes


HIV Disease Severity Is Sensitive to Temporal Changes in Alcohol Use: A National Study of VA Patients With HIV.
Alcohol use influences HIV disease severity through multiple mechanisms. Whether HIV disease severity is sensitive to changes in alcohol use among people with HIV (PWH) is understudied. National Veterans Health Administration. Pairs of AUDIT-C screens within 9-15 months (February 1, 2008-September 30, 2014) were identified among PWH from the Veterans Aging Cohort Study (VACS). Initial and follow-up VACS Index 2.0 pairs obtained 0-270 days after initial and follow-up AUDIT-Cs, respectively, determined change in VACS Index 2.0, a composite HIV severity measure. Change in VACS Index 2.0 was regressed on AUDIT-C change scores (-12 to +12) adjusted for demographics, initial VACS Index 2.0, and days between VACS Index measures. Among 23,297 PWH (76,202 observations), most had no (51%) or low-level (38%) alcohol use initially. Most (54%) had no subsequent change; 21% increased and 24% decreased drinking. Initial VACS Index 2.0 scores ranged from 0 to 134, change scores ranged from -65 to +73, with average improvement of 0.76 points (SD 9.48). AUDIT-C change was associated with VACS Index 2.0 change (P < 0.001). Among those with stable alcohol use (AUDIT-C change ≤ │1│ point), VACS Index 2.0 improvements ranged 0.36-0.60 points. For those with maximum AUDIT-C increase (change from 0 to 12), VACS Index 2.0 worsened 3.74 points (95% CI: -4.71 to -2.78); for those with maximum AUDIT-C decrease (change from 12 to 0), VACS Index 2.0 changed minimally [-0.60 (95% CI: -1.43 to 0.23)]. In this national sample, improvement in HIV severity was generally greatest among those with stable alcohol use (primarily those with no use).


[Syndrome typing based strategies for postoperative gastrointestinal dysfunction in the perioperative phase].
By summarizing the literature and clinical experiences, the author analyzed the pathogenesis of gastrointestinal functions and the diagnosis and treatment progress of Chinese medicine and Western medicine. The author addressed the main reason for gastrointestinal dysfunction was enteroparalysis (lack of motive power). Its pathogenesis was mainly due to deficiency syndrome, or to dominant deficiency syndrome with mingled deficiency and excess. According to the principle of treating different diseases by the same method, syndrome typing based strategies for treating postoperative gastrointestinal dysfunction in the perioperative phase should strengthen body resistance and supplement deficiency, or strengthen body resistance and dispel evil pathogens as the main principal method. Although purgations such as Dachengqi Decoction played a role in promoting gastrointestinal motive power, they were not suitable for major patients with selective surgeries induced gastrointestinal dysfunction. They were mainly suitable for acute abdomen patients with heat accumulation in Fu-organs as main symptoms, or for individual patients with interior heat induced excess syndrome.


Shiga toxin 2 is specifically released from bacterial cells by two different mechanisms.
Shiga toxin 1 (Stx1) is located in the periplasmic fraction, while Stx2 is found in the extracellular fraction, suggesting that enterohemorrhagic Escherichia coli (EHEC) contains a specific Stx2 release system. Both stx(1) and stx(2) are found within the late operons of Stx-encoding phages. Stx2 production is greatly induced by mitomycin C, suggesting that stx(2) can transcribe from the late phage promoter of the Stx2-encoding phage. However, the Stx1 promoter adjacent to stx(1) is a dominant regulatory element in Stx1 production. With the deletion of phage lysis genes of the Stx2-encoding phage, Stx2 remains in the bacterial cells. Further, we demonstrate that the Stx2-encoding phage, but not the Stx1-encoding phage, is spontaneously induced at extremely low rates. These results indicate that spontaneously specific Stx2-encoding phage induction is involved in specific Stx2 release from bacterial cells. Furthermore, to examine whether another system for specific Stx2 release is present in EHEC, we analyze the stx-replaced mutants. As expected, Stx2 derived from the Stx1 promoter is located in both the extracellular and cell-associated fractions, while mutant Stx2 (B subunit, S31N) derived from the Stx1 promoter is found only in the cell-associated fraction. These results indicate that EHEC has another Stx2 release system that strictly recognizes the serine 31 residue of the B subunit. Overall, we present evidence that specific Stx2 release from bacterial cells is involved in both the Stx2-encoding phage induction system and another Stx2 release system.


Divergent effects of intracerebroventricular and peripheral leptin administration on feeding and hypothalamic neuropeptide Y in lean and obese (fa/fa) Zucker rats.
Leptin inhibits feeding and decreases body weight. It may act partly by inhibiting hypothalamic neurons that express neuropeptide Y, a powerful inducer of feeding and obesity. These neuropeptide Y neurons express the Ob-Rb leptin receptor and are overactive in the fatty (fa/fa) Zucker rat. The fa mutation affects the extracellular domain of the leptin receptor, but its impact on leptin action and neuropeptide Y neuronal activity is not fully known. We compared the effects of three doses of leptin given intracerebroventricularly and three doses of leptin injected intraperitoneally on food intake and hypothalamic neuropeptide Y mRNA, in lean and fatty Zucker rats. In lean rats, 4-h food intake was reduced in a dose-related fashion (P<0.01) by all intracerebroventricular leptin doses and by intraperitoneal doses of 300 and 600 microg/kg. Neuropeptide Y mRNA levels were reduced by 28% and 21% after the highest intracerebroventricular and intraperitoneal doses respectively (P<0. 01 for both). In fatty rats, only the highest intracerebroventricular leptin dose reduced food intake (by 22%; P<0. 01). Neuropeptide Y mRNA levels were 100% higher in fatty rats than in lean animals, and were reduced by 18% (P<0.01) after the highest intracerebroventricular leptin dose. Intraperitoneal injection had no effect on food intake and neuropeptide Y mRNA. The fa/fa Zucker rat is therefore less sensitive to leptin given intracerebroventricularly and particularly intraperitoneally, suggesting that the fa mutation interferes both with leptin's direct effects on neurons and its transport into the central nervous system. Obesity in the fa/fa Zucker rat may be partly due to the inability of leptin to inhibit hypothalamic neuropeptide Y neurons.


Phytochrome-mediated cellular photomorphogenesis.
Red light-induced cell elongation and division in intact, etiolated oat (Avena sativa cv Lodi) seedlings have been assessed. The middle of coleoptile was especially responsive in the very low fluence range whereas the region immediately below the coleoptile tip and the two regions just above the coleoptilar node were more responsive than the entire organ in the low fluence range. These responses in the coleoptile are both the result of an increase in cell elongation. Coleoptile cell division is slightly inhibited in the very low and slightly stimulated by red light in the low fluence range.The one-sixth of the mesocotyl closest to the node is more suppressed in its growth than is any other region in the very low fluence range. However, the low fluence response involved the entire mesocotyl equally. In the apical one-sixth of the mesocotyl, a strong suppression of cell division and a weak suppression of cell elongation occurs. In the lower five regions of the mesocotyl, red light in both fluence ranges suppresses only cell elongation. Apparently, the difference between red light-induced oat growth stimulation and suppression primarily involves differences in the response of the cell elongation process.


Pharmacokinetic and pharmacodynamic evaluation of intravenous hydromorphone in cats.
This study describes the pharmacokinetics of intravenous hydromorphone in cats and the simultaneous measurement of antinociceptive pharmacodynamic effects using a thermal threshold testing system. Following establishment of a baseline thermal threshold, six adult cats were administered 0.1 mg/kg of hydromorphone intravenously. Thermal threshold testing and blood collection were conducted simultaneously at predetermined time points. Plasma hydromorphone concentrations were determined by a liquid chromatographic-mass spectral method and pharmacokinetic analysis was performed by nonlinear least squares regression analysis. Plasma hydromorphone concentrations declined rapidly over time, and were below the limit of quantification of the assay (LOQ = 1.0 ng/mL) by 360 min. In contrast, thermal thresholds rose from a pretreatment value of 40.9 +/- 0.65 degrees C (mean +/- SEM) to instrument cut-out (55 degrees C) within 15 min and remained significantly elevated from 15-450 min after treatment. Inspection of the data revealed no direct correlation between plasma hydromorphone concentrations and the antinociceptive effect of this drug in cats. These findings support the importance of conducting pharmacokinetic studies in parallel with objective measurements of drug effect.


Effect of frequency deviance direction on performance and mismatch negativity.
The mismatch negativity (MMN) component of the auditory event-related potential is associated with automatic perceptual inference concerning changes in auditory stimulation. Recent studies have addressed the question whether performance and MMN is affected by the direction of frequency deviance. In the present study, the frequency MMN and performance is investigated during an auditory identification task. Specifically, we examined the effect of positive and negative differences between the present stimulus and the previous response frequencies on performance as well as on the characteristics of stimulus-locked ERPs and brain activation maps. The results show that frequency deviants creating mismatch conditions increase the likelihood of error commission. The decrease in performance achieves statistical significance in the case of positive frequency deviants. In the latter case, ERP amplitude values of the Fz electrode at 164 ms after stimulus onset are statistically larger for mismatch as opposed to no-mismatch condition. This corresponds to significance differences in the activation maps at Brodmann area 11, superior frontal gyrus, and the frontal lobe. The present findings revealed dissociations in behavioral and ERP responses in the processing of positive and negative frequency deviance, lending support to the notion that MMN is more sensitive to increments than to decrements in frequency.


Bayesian calibration of a physiologically based pharmacokinetic/pharmacodynamic model of carbaryl cholinesterase inhibition.
Carbaryl, an N-methyl carbamate (NMC), is a common insecticide that reversibly inhibits neuronal cholinesterase activity. The objective of this work was to use a hierarchical Bayesian approach to estimate the parameters in a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model from experimental measurements of carbaryl in rats. A PBPK/PD model was developed to describe the tissue dosimetry of carbaryl and its metabolites (1-naphthol and "other hydroxylated metabolites") and subsequently to predict the carbaryl-induced inhibition of cholinesterase activity, in particular in the brain and blood. In support of the model parameterization, kinetic tracer studies were undertaken to determine total radioactive tissue levels of carbaryl and metabolites in rats exposed by oral or intravenous routes at doses ranging from 0.8 to 9.2 mg/kg body weight. Inhibition of cholinesterase activity in blood and brain was also measured from the exposed rats. Markov Chain Monte Carlo (MCMC) calibration of the rat model parameters was implemented using prior information from literature for physiological parameter distributions together with kinetic and inhibition data on carbaryl. The posterior estimates of the parameters displayed at most a twofold deviation from the mean. Monte Carlo simulations of the PBPK/PD model with the posterior distribution estimates predicted a 95% credible interval of tissue doses for carbaryl and 1-naphthol within the range of observed data. Similar prediction results were achieved for cholinesterase inhibition by carbaryl. This initial model will be used to determine the experimental studies that may provide the highest added value for model refinement. The Bayesian PBPK/PD modeling approach developed here will serve as a prototype for developing mechanism-based risk models for the other NMCs.


Demonstration of renin mRNA, angiotensinogen mRNA, and angiotensin converting enzyme mRNA expression in the human eye: evidence for an intraocular renin-angiotensin system.
All components necessary for the formation of angiotensin II, the biologically active product of the renin-angiotensin system (RAS), have been demonstrated in ocular tissue or vitreous and subretinal fluid. The tissue concentrations of renin were too high to be explained by admixture of blood. This raises the possibility of an intraocular RAS, independent of the RAS in the circulation. In the present study, gene expression of RAS components in different parts of enucleated human eyes was investigated as evidence for tissue specific production. By using pooled tissue samples renin mRNA could be detected with the RNAse protection assay in retinal pigment epithelium (RPE) choroid, but not in neural retina or sclera. With reverse transcription polymerase chain reaction (RT-PCR), renin mRNA was detected in individual samples of RPE choroid and neural retina, and not anterior uveal tract or sclera. Angiotensinogen and angiotensin converting enzyme (ACE) gene expression could be demonstrated by RT-PCR in individual RPE choroid and neural retina samples and marginally in sclera samples. These results support the concept of intraocular synthesis of angiotensin II, independent of renin, angiotensin, and ACE in the circulation. Since gene expression was highest in ocular parts, which are highly vascularised, local angiotensin II may be involved in blood supply and/or pathological vascular processes such as neovascularisation in diabetic retinopathy.


Plant biomarkers in aerosols record isotopic discrimination of terrestrial photosynthesis.
Carbon uptake by the oceans and by the terrestrial biosphere can be partitioned using changes in the (12)C/(13)C isotopic ratio (delta(13)C) of atmospheric carbon dioxide, because terrestrial photosynthesis strongly discriminates against (13)CO(2), whereas ocean uptake does not. This approach depends on accurate estimates of the carbon isotopic discrimination of terrestrial photosynthesis (Delta; ref. 5) at large regional scales, yet terrestrial ecosystem heterogeneity makes such estimates problematic. Here we show that ablated plant wax compounds in continental air masses can be used to estimate Delta over large spatial scales and at less than monthly temporal resolution. We measured plant waxes in continental air masses advected to Bermuda, which are mainly of North American origin, and used the wax isotopic composition to estimate Delta simply. Our estimates indicate a large (5 6 per thousand) seasonal variation in Delta of the temperate North American biosphere, with maximum discrimination occurring in late spring, coincident with the onset of production. We suggest that the observed seasonality arises from several factors, including seasonal shifts in the proportions of production by C(3) and C(4) plants, and environmentally controlled adjustments in the photosynthetic discrimination of C(3)-plant-dominated ecosystems.


Dissociated horizontal deviation and accommodative esotropia: treatment options when an eso- and an exodeviation co-exist.
Dissociated strabismus includes movements in the vertical, horizontal, and torsional axes. Dissociated vertical deviation (DVD) is an oversimplified label because it implies a purely vertical deviation. When the abducting component of the dissociated strabismus complex is prominent, the term dissociated horizontal deviation (DHD) is used. We present six patients with accommodative esotropia who developed prominent DHD. Only two patients have a prior history of congenital esotropia. Latent nystagmus was observed in five of the patients. With the combination of DHD and esotropia, an esodeviation during active fixation may become an exodeviation when the patient is visually inattentive. Five patients required surgery for DHD. Four options are used and discussed. DHD can be treated alone with lateral rectus muscle recession. DHD can be treated as above, but combined with medial rectus muscle recessions or posterior fixation sutures to simultaneously treat the esotropia. The esotropia can be treated alone, possibly with a reduced surgical dosage. If the patient varies from an esodeviation to an exodeviation, but is straight much of the day, observation without surgical therapy may be advisable. Just as a hypotropia can have an overlying DVD, an esotropia can have an overlying DHD. This combination may masquerade as variable angle esotropia or may present as an esodeviation when the patient is visually attentive and an exodeviation when the patient is visually inattentive.