Deletion of the neuropeptide Y Y1 receptor affects pain sensitivity, neuropeptide transport and expression, and dorsal root ganglion neuron numbers.
Neuropeptide Y has been implicated in pain modulation and is substantially up-regulated in dorsal root ganglia after peripheral nerve injury. To identify the role of neuropeptide Y after axotomy, we investigated the behavioral and neurochemical phenotype of neuropeptide Y Y1 receptor knockout mice with focus on dorsal root ganglion neurons and spinal cord. Using a specific antibody Y1 receptor immunoreactivity was found in dorsal root ganglia and in dorsal horn neurons of wild-type, but not knockout mice. The Y1 receptor knockout mice exhibited a pronounced mechanical hypersensitivity. After sciatic nerve axotomy, the deletion of Y1 receptor protected knockout mice from the axotomy-induced loss of dorsal root ganglion neurons seen in wild-type mice. Lower levels of calcitonin gene-related peptide and substance P were identified by immunohistochemistry in dorsal root ganglia and dorsal horn of knockout mice, and the axotomy-induced down-regulation of both calcitonin gene-related peptide and substance P was accentuated in Y1 receptor knockout. However, the transcript levels for calcitonin gene-related peptide and substance P were significantly higher in knockout than in wild-type dorsal root ganglia ipsilateral to the axotomy, while more calcitonin gene-related peptide- and substance P-like immunoreactivity accumulated proximal and distal to a crush of the sciatic nerve. These results indicate that the deletion of the Y1 receptor causes increased release and compensatory increased synthesis of calcitonin gene-related peptide and substance P in dorsal root ganglion neurons. Together, these findings suggest that, after peripheral nerve injury, neuropeptide Y, via its Y1 receptor receptor, plays a key role in cell survival as well as in transport and synthesis of the excitatory dorsal horn messengers calcitonin gene-related peptide and substance P and thus may contribute to pain hypersensitivity.


Metastatic Melanoma to a Neurofibroma.
We present an extraordinary case of metastatic cutaneous melanoma to a pre-existing neurofibroma in a 75-year-old man with a history of primary invasive melanoma in an anatomically close vicinity. Histological examination of the metastatic melanoma showed a well-circumscribed intradermal nodule of frankly malignant epithelioid melanocytes without an intraepidermal component, surrounded and sharply demarcated from a diffuse spindle cell proliferation with morphological features of a neurofibroma. The spindle cell component showed bland cytologic features, with no mitotic activity or lymphocytic inflammation and no features of malignancy. By immunohistochemistry, both components expressed S100, while HMB45 positivity and complete loss of p16 were only observed in the epithelioid cells. The morphologically distinct areas were analyzed by fluorescent in situ hybridization, which demonstrated an abnormal profile (gain of RREB1 and homozygous loss of CDKN2A) in the epithelioid nodule; however, no abnormalities were detected in the spindle cell component. Next-generation sequencing showed somatic NRAS and PTEN mutations in the melanoma cells only. The overall molecular findings supported the immunomorphological diagnosis of metastatic melanoma within a neurofibroma over the potential differential diagnosis of melanoma with a neurofibroma-like spindle/desmoplastic component.


The effects of dietary protein restriction on chronic progressive renal disease.
There have been a large number of clinical trials and two meta-analyses attempting to determine if dietary protein restriction retards the rate of renal disease progression. Indeed, in a systematic search of prospective, controlled trials examining the effects of protein restriction over at least 6 months, we located 23 published between 1980 and 1996. Only 12 of these trials were randomized and controlled. The results of the 23 studies were heterogeneous. Two meta-analyses combined the results of randomized, controlled trials. Although both meta-analyses concluded that dietary protein restriction significantly reduced the number of patients who died or required treatment for end-stage renal disease, the well-known effects of protein restriction on the signs and symptoms of uremia leave open the question of whether protein restriction had a substantial effect on renal disease progression per se. Adding to the uncertainty is the inconclusive result of the largest, best-designed clinical trial, the Modification of Diet in Renal Disease Study. In any case, the effect of protein restriction on the rate of decline in renal function is arguably modest, making it difficult to demonstrate statistical significance, even in large, well-designed clinical trials. All of these trials suggest that we need therapies that are more effective than dietary protein restriction to halt the progression of renal disease.


The Roles of Adolescent Occupational Expectations and Preparation in Adult Suicide and Drug Poisoning Deaths within a Shifting Labor Market.
Research suggests that economic declines contribute to mortality risks from suicide and drug poisoning, but how the economy impacts individuals' risks of these deaths has been challenging to specify. Building on recent theoretical advances, we investigate how adolescent occupational expectations and preparation contribute to suicide and drug poisoning deaths in a shifting economy. We use High School and Beyond data linked to adult mortality records for men that were exposed to a decline in labor market share and wages in predominantly blue-collar occupations during early adulthood. We find that adolescent men who expected these occupations had increased risks of suicide and drug poisoning death as adults net of educational and occupational attainment in early adulthood. Family background and occupational preparation are risk factors for death by drug poisoning but not suicide. Our findings improve our understanding of how labor market uncertainty shapes individuals' vulnerability to suicide and drug poisoning death.


Improvement of Cerebral Glucose Metabolism in Symptomatic Patients With Carotid Artery Stenosis After Stenting.
Neurocognitive performance among patients with carotid artery stenosis or occlusion may deteriorate because of chronic cerebral hypoperfusion. Carotid artery stenting (CAS) has been reported to improve cerebral perfusion and neurocognitive function. The purpose of the study was to evaluate cerebral metabolism using F-fluorodeoxyglucose (FDG) positron emission tomography (PET) after CAS. Nineteen consecutive patients (15 men, 69 ± 13 years) with carotid artery stenosis or occlusion and cerebral ischemia detected on brain perfusion computed tomography (CT) or magnetic resonance imaging (MRI) were enrolled. Four patients had bilateral lesions, and 15 subjects had previous ischemic stroke. Neurocognitive function (NCF) assessments and brain FDG PET scans were performed before and 19 ± 7 (12-31) months after the procedure. The procedural success rate of CAS was 70%. Two patients were excluded from the study because of procedural complications. No new cerebral ischemic events or neurologic deaths occurred during follow-up of 44 ± 11 (15-54) months. Significant improvements were observed in the Mini-Mental State Examination (before, 26.06 ± 3.32 versus after, 28.13 ± 2.8; P = 0.0016), the verbal fluency test (26.81 ± 7.82 versus 30.75 ± 9.58; P = 0.0378), and marginal upgrading in the Alzheimer Disease Assessment Scale-Cognitive Subtest (7.19 ± 7.59 versus 5.63 ± 5.90; P = 0.0523). Six of 9 patients who underwent successful CAS showed improvement of cerebral glucose metabolism. Of the 4 patients with recanalization failure, 2 exhibited decline in ipsilateral glucose metabolism. Cerebral FDG metabolism improved in patients with successful CAS (P = 0.038), although there was a weak correlation between interval change of NCF tests and brain FDG metabolism. Successful CAS may improve long-term cerebral glucose metabolism and neurocognitive function in patients with chronic severe carotid stenosis or occlusion.


Directory of national associations.
Associations have proven to be valuable clearinghouses of information, centers for educational enrichment and switchboards for making connections between practitioners of a given profession. The healthcare central service and materiel management professions are represented by four national associations: the American Society for Healthcare Central Service Personnel (ASHCSP), the International Association of Healthcare Central Service Materiel Management (IAHCSMM), the American Society for Hospital Materials Management (ASHMM), and the Health Care Material Management Society (HCMMS). Within these associations you will find groups of people who have interests and goals similar to yours. Pursue your interests together--join an association!


[Autofluorescent diagnostics of skin and mucosal tumors].
The article discusses the results of a research on fluorescent diagnostics of skin and mucosal tumors carried out by a workgroup of the Research Institute of Eye Diseases of the Russian Academy of Medical Sciences between 2006 and 2012. The main achievement to be mentioned is the development of an easy to perform, noninvasive, safe and economy method of autofluorescent image acquisition and analysis that does not require the use of protoporphyrin IX precusors or exogenous fluorophores. The research workgroup has also devised an original method of tumor probabilistic border estimation which is valuable for assessment of the extent of surgical intervention. Moreover, a comprehensive approach to evaluation of autofluorescent pattern of the region of interest, that ensures high sensitivity and specificity of diagnostics, has been proposed. Obtained results, in authors' opinion, can likely be extrapolated to neoplasms of other, non-ocular localization.


Egg consumption, cardiovascular diseases and type 2 diabetes.
Eggs are rich in nutrients and a source of essential fatty- and amino acids, and the food item with highest cholesterol content. Since the 1970s dietary recommendations have advised limiting egg intake to 2-4 a week for the healthy population, and in those diagnosed with cardiovascular disease (CVD) and type 2 diabetes (T2D) an even more restricted consumption. The aim of the present paper was to assess the recommendation to lower the dietary intake of cholesterol and especially the intake of egg to reduce the risk of CVD and T2D. We performed three web-based literature searches on human studies (observational and interventional) published within the past 10 years during spring 2015. High-quality intervention studies have found nonsignificant effects of increasing the consumption of eggs on risk markers for CVD and T2D in healthy subjects and subjects with T2D. The risk associations found in the observational studies are more likely to be attributed to a dietary pattern often accompanying high egg intake and/or the cluster of other risk factors in people with high egg consumption. Dietary patterns, physical activity and genetics affect the predisposition of CVD and T2D more than a single food item as eggs. In conclusion, up to seven eggs per week can safely be consumed, but in patients with established CVD or T2D only with special emphasis on a healthy lifestyle.


Aldoxime Metabolism Is Linked to Phenylpropanoid Production in Camelina sativa.
Plants produce diverse secondary metabolites. Although each metabolite is made through its respective biosynthetic pathway, plants coordinate multiple biosynthetic pathways simultaneously. One example is an interaction between glucosinolate and phenylpropanoid pathways in Arabidopsis thaliana. Glucosinolates are defense compounds made primarily from methionine and tryptophan, while phenylpropanoids are made from phenylalanine. Recent studies have shown that the accumulation of glucosinolate intermediate such as indole-3-acetaldoxime (IAOx) or its derivatives represses phenylpropanoid production via the degradation of phenylalanine ammonia lyase (PAL) functioning at the entry point of the phenylpropanoid pathway. Given that IAOx is a precursor of other bioactive compounds other than glucosinolates and that the phenylpropanoid pathway is present in most plants, we hypothesized that this interaction is relevant to other species. Camelina sativa is an oil crop and produces camalexin from IAOx. We enhanced IAOx production in Camelina by overexpressing Arabidopsis CYP79B2 which encodes an IAOx-producing enzyme. The overexpression of AtCYP79B2 results in increased auxin content and its associated morphological phenotypes in Camelina but indole glucosinolates were not detected in Camelina wild type as well as the overexpression lines. However, phenylpropanoid contents were reduced in AtCYP79B2 overexpression lines suggesting a link between aldoxime metabolism and phenylpropanoid production. Interestingly, the expression of PALs was not affected in the overexpression lines although PAL activity was reduced. To test if PAL degradation is involved in the crosstalk, we identified F-box genes functioning in PAL degradation through a phylogenetic study. A total of 459 transcript models encoding kelch-motifs were identified from the Camelina sativa database. Among them, the expression of CsKFBs involved in PAL degradation is up-regulated in the transgenic lines. Our results suggest a link between aldoxime metabolism and phenylpropanoid production in Camelina and that the molecular mechanism behind the crosstalk is conserved in Arabidopsis and Camelina.


Clinical characteristics and outcomes of hospitalised patients with COVID-19 treated in Hubei (epicentre) and outside Hubei (non-epicentre): a nationwide analysis of China.
During the outbreak of coronavirus disease 2019 (COVID-19), consistent and considerable differences in disease severity and mortality rate of patients treated in Hubei province compared to those in other parts of China have been observed. We sought to compare the clinical characteristics and outcomes of patients being treated inside and outside Hubei province, and explore the factors underlying these differences. Collaborating with the National Health Commission, we established a retrospective cohort to study hospitalised COVID-19 cases in China. Clinical characteristics, the rate of severe events and deaths, and the time to critical illness (invasive ventilation or intensive care unit admission or death) were compared between patients within and outside Hubei. The impact of Wuhan-related exposure (a presumed key factor that drove the severe situation in Hubei, as Wuhan is the epicentre as well the administrative centre of Hubei province) and the duration between symptom onset and admission on prognosis were also determined. At the data cut-off (31 January 2020), 1590 cases from 575 hospitals in 31 provincial administrative regions were collected (core cohort). The overall rate of severe cases and mortality was 16.0% and 3.2%, respectively. Patients in Hubei (predominantly with Wuhan-related exposure, 597 (92.3%) out of 647) were older (mean age 49.7 versus 44.9 years), had more cases with comorbidity (32.9% versus 19.7%), higher symptomatic burden, abnormal radiologic manifestations and, especially, a longer waiting time between symptom onset and admission (5.7 versus 4.5 days) compared with patients outside Hubei. Patients in Hubei (severe event rate 23.0% versus 11.1%, death rate 7.3% versus 0.3%, HR (95% CI) for critical illness 1.59 (1.05-2.41)) have a poorer prognosis compared with patients outside Hubei after adjusting for age and comorbidity. However, among patients outside Hubei, the duration from symptom onset to hospitalisation (mean 4.4 versus 4.7 days) and prognosis (HR (95%) 0.84 (0.40-1.80)) were similar between patients with or without Wuhan-related exposure. In the overall population, the waiting time, but neither treated in Hubei nor Wuhan-related exposure, remained an independent prognostic factor (HR (95%) 1.05 (1.01-1.08)). There were more severe cases and poorer outcomes for COVID-19 patients treated in Hubei, which might be attributed to the prolonged duration of symptom onset to hospitalisation in the epicentre. Future studies to determine the reason for delaying hospitalisation are warranted.


[Chemotherapy of advanced lymphogranulomatosis. Results of MOPP/COPP treatment at the West German Tumor Center, Essen].
Between 1968 and 1979, a total of 271 patients with advanced Hodgkin's disease received as first systemic chemotherapy MOPP (mechlorethamine [nitrogen mustard], oncovin [vincristine], procarbazine and prednisone) or COPP (as above, but cyclophosphamide instead of nitrogen mustard). In 162 of the 271 patients (60%) full remission was achieved. Demonstration of systemic signs, bioptically confirmed bone-marrow infiltration and suboptimal cytostatic dosage correlated significantly with a lower full-remission rate. A significant trend towards a lower remission rate was demonstrated for stage IV disease, in patients with lymphocyte-poor or unclassified Hodgkin's disease and in those older than 30 years. A five-year recurrence-free period was achieved in 75.5% of patients: stage of the disease and bone-marrow infiltration had a clear influence on recurrence-free survival rate. The results show that 50% of patients with advanced Hodgkin's disease can be cured by chemotherapy.


Cardiometabolic and neuromuscular analyses of the sit-to-stand transition to question its role in reducing sedentary patterns.
To counteract the detrimental health effect of sitting all day long, it has been suggested to regularly break sitting time by standing. However, while the difference in energy expenditure, neuromuscular and/or cardiovascular demand of various postures from lying, sitting, and standing is well documented, little is known regarding the dynamic changes occurring during the sit-to-stand transition itself. The aim of the present study was then to describe the cardiometabolic and neuromuscular responses from sitting to standing and specifically during the time-course of this transition. Twelve healthy young participants were asked to perform standardized raises from sitting posture, while cardiometabolic (cardiorespiratory and hemodynamic variables) and neuromuscular (calf muscles' myoelectrical activity, spinal and supraspinal excitabilities) parameters were monitored. As a result, while there was a rapid adaptation for all the systems after rising, the neuromuscular system displayed the faster adaptation (~ 10 s), then hemodynamic (~ 10 to 20 s) and finally the metabolic variables (~ 30 to 40 s). Oxygen uptake, energy expenditure, ventilation, and heart rate were significantly higher and stroke volume significantly lower during standing period compared to sitting one. In calf muscles, spinal excitability (H-reflexes), was lowered by the sit-to-stand condition, while supraspinal drive (V-wave) was similar, indicating different cortico-spinal balance from sitting to standing. Although very heterogenous among participants in terms of magnitude, the present results showed a rapid adaptation for all the systems after rising and the health benefit, notably in terms of energy expenditure, appears rather modest, even if non negligeable.


Beryllium-10 in australasian tektites: evidence for a sedimentary precursor.
Each of seven Australasian tektites contains about 1 x l0(8) atoms of beryllium-10 (half-life, 1.53 x 10(6) years) per gram. Cosmic-ray bombardment of the australites cannot have produced the measured amounts of beryllium-10 either at the earth's surface or in space. The beryllium-10 contents of these australites are consistent with a sedimentary precursor that adsorbed from precipitation beryllium-10 produced in the atmosphere. The sediments must have spent several thousand years at the earth's surface within a few million years of the tektite-producing event.


[Prevalence and significance of lymphocyte infiltration in papillary carcinoma of the thyroid gland].
We have investigated the prevalence, signification and prognostic value of lymphocytic infiltration associated to differentiated thyroid carcinoma in our series of differentiated carcinoma of the thyroid. We studied the presence of lymphocytic infiltration in 223 patients effected of differentiated thyroid carcinoma, 138 of them were papillary carcinoma. The diagnostic was made with optic microscopy and we studied antithyroid antibodies in these patients. In survival analysis we studied all the variables of the patients and the event used as end point was death due to thyroid carcinoma, summarized in Kaplan-Meir curve and Cox method. We found eight patients with differentiated thyroid carcinoma, six with papillary carcinoma, and lymphocytic thyroiditis and in three cases, antithyroid antibodies were present at low levels. We did not found any difference between the two groups and the survival rate was similar. These data support that in our series the prevalence of lymphocytic infiltration was low and probably without prognostic signification.


A method for the efficient evaluation of substrate-based cholinesterase imaging probes for Alzheimer's disease.
Cholinesterase (ChE) enzymes have been identified as diagnostic markers for Alzheimer disease (AD). Substrate-based probes have been synthesised to detect ChEs but they have not detected changes in ChE distribution associated with AD pathology. Probes are typically screened using spectrophotometric methods with pure enzyme for specificity and kinetics. However, the biochemical properties of ChEs associated with AD pathology are altered. The present work was undertaken to determine whether the Karnovsky-Roots (KR) histochemical method could be used to evaluate probes at the site of pathology. Thirty thioesters and esters were synthesised and evaluated using enzyme kinetic and KR methods. Spectrophotometric methods demonstrated all thioesters were ChE substrates, yet only a few provided staining in the brain with the KR method. Esters were ChE substrates with interactions with brain ChEs. These results suggest that the KR method may provide an efficient means to screen compounds as probes for imaging AD-associated ChEs.


Expression of ERα and PR in Various Morphological Patterns of Abnormal Uterine Bleeding-Endometrial causes in Reproductive Age Group.
Abnormal Uterine Bleeding (AUB) is most common gynaecological problem but its management is not well defined. So FIGO/PALMCOEIN classification was developed to provide clear management options as treatment is different in PALM and AUB-E group. FIGO/PALM-COEIN classification and immunohistochemistry with ERα and PR expression in AUB-E group will be helpful in management of these patients, thus preventing surgical interventions. To study histomorphological classification according to FIGO/PALM-COEIN classification in patients presenting with AUB into PALM and AUB-E group. To study the receptor expression of ERα and PR in AUB-E group. This cross sectional study was performed in patients presenting with AUB in reproductive age group (15-45 years). Six hundred endometrial specimens were stained with H&E for histolomorphological examination and classified as per FIGO/PALM-COEIN classification of AUB in non-gravid women in reproductive age group. Fifty endometrial biopsies were of pregnancy and pregnancy related complications and were excluded from study. A total of 550 samples were evaluated in present study. IHC for quantification of ERα and PR expression was carried out in AUB-E (100) cases and control group endometrium (20) cases due to technical constraints. Unpaired student t-test was performed. p-value ≤ 0.05 was taken as critical level of significance. Endometrial (58.19%) (AUB-E) causes were most common cause of AUB. Most common morphology was AUB-E (Proliferative endometrium), AUB-L (Leiomyoma) and AUB-E (Secretory endometrium) respectively. Statistically significant expression of ERα and PR was found in AUB-E endometrium as compared to control group endometrium. In Non secretory/Proliferative endometrium AUB-E group. Proliferative endometrium and hyperplasia without atypia had significant expression of ERα and PR in glands and stroma when compared with proliferative phase control group endometrium. But disordered proliferative endometrium had only significant PR expression in stroma. When secretory phase endometrium was compared with control group secretory phase significant expression for PR was noted only in stroma. FIGO/PALM-COEIN classification will be helpful in deciding treatment of AUB cases. Study of receptor expression in AUB-E group will help in providing evidence based treatment and prevent from surgical procedures like hysterectomy and endometrial ablation.


Experimental Strategies to Bridge Large Tissue Gaps in the Injured Spinal Cord after Acute and Chronic Lesion.
After a spinal cord injury (SCI) a scar forms in the lesion core which hinders axonal regeneration. Bridging the site of injury after an insult to the spinal cord, tumor resections, or tissue defects resulting from traumatic accidents can aid in facilitating general tissue repair as well as regenerative growth of nerve fibers into and beyond the affected area. Two experimental treatment strategies are presented: (1) implantation of a novel microconnector device into an acutely and completely transected thoracic rat spinal cord to readapt severed spinal cord tissue stumps, and (2) polyethylene glycol filling of the SCI site in chronically lesioned rats after scar resection. The chronic spinal cord lesion in this model is a complete spinal cord transection which was inflicted 5 weeks before treatment. Both methods have recently achieved very promising outcomes and promoted axonal regrowth, beneficial cellular invasion and functional improvements in rodent models of spinal cord injury. The mechanical microconnector system (mMS) is a multi-channel system composed of polymethylmethacrylate (PMMA) with an outlet tubing system to apply negative pressure to the mMS lumen thus pulling the spinal cord stumps into the honeycomb-structured holes. After its implantation into the 1 mm tissue gap the tissue is sucked into the device. Furthermore, the inner walls of the mMS are microstructured for better tissue adhesion. In the case of the chronic spinal cord injury approach, spinal cord tissue - including the scar-filled lesion area - is resected over an area of 4 mm in length. After the microsurgical scar resection the resulting cavity is filled with polyethylene glycol (PEG 600) which was found to provide an excellent substratum for cellular invasion, revascularization, axonal regeneration and even compact remyelination in vivo.


Film forming systems for topical and transdermal drug delivery.
Skin is considered as an important route of administration of drugs for both local and systemic effects. The effectiveness of topical therapy depends on the physicochemical properties of the drug and adherence of the patient to the treatment regimen as well as the system's ability to adhere to skin during the therapy so as to promote drug penetration through the skin barrier. Conventional formulations for topical and dermatological administration of drugs have certain limitations like poor adherence to skin, poor permeability and compromised patient compliance. For the treatment of diseases of body tissues and wounds, the drug has to be maintained at the site of treatment for an effective period of time. Topical film forming systems are such developing drug delivery systems meant for topical application to the skin, which adhere to the body, forming a thin transparent film and provide delivery of the active ingredients to the body tissue. These are intended for skin application as emollient or protective and for local action or transdermal penetration of medicament for systemic action. The transparency is an appreciable feature of this polymeric system which greatly influences the patient acceptance. In the current discussion, the film forming systems are described as a promising choice for topical and transdermal drug delivery. Further the various types of film forming systems (sprays/solutions, gels and emulsions) along with their evaluation parameters have also been reviewed.


Examining Pride Cups as a health promotion resource to address homophobia in Australian men's sport.
Effective interventions are needed to stop homophobic behaviours in sport settings as these behaviours are associated with negative health and social outcomes for individuals who identify as Lesbian, Gay, Bisexual, Transgender, Queer or other diverse genders and sexualities. This paper reports the results of a quasi-experimental study commissioned by a public health agency to explore the benefits of a novel intervention that has been widely adopted by Australian community sport clubs. The 'Pride Cup' intervention includes education for club leaders, sport participants and the hosting of a rainbow-themed 'pride game'. Survey responses of male participants from six randomly selected sport clubs which had received the intervention (n = 148) were compared to responses (n = 137) from six randomly selected comparison clubs (Australian Football, cricket, field hockey, roller derby). Employing a post-test-only design, the study explored differences in homophobic attitudes, behaviours and individual efficacy to react negatively to homophobic behaviours. The study found significant differences (p < 0.001) in self-reported use of homophobic slurs (e.g. fag) in the last 2 weeks by participants in the treatment (11%) versus comparison (31.8%) clubs, and significant differences in the perceived use of these slurs by teammates (25.9% vs. 56.6%) or coaches (7.8% vs. 23.3%). There were also significant differences in efficacy scores, but no differences in homophobic attitudes. These results, combined with evidence of community-driven adoption, support the allocation of public health resources to conduct larger scale trials using pre/post designs to confirm these findings.


Atmospheric versus lithogenic contribution to the composition of first- and second-order stream waters in Seoul and its vicinity.
The spatial variations in the chemistry of first- and second-order stream waters (N = 65) were investigated in the easterly bound of Seoul in order to assess the effects of urban air pollution on surface water chemistry. The sulfate (SO4(2-)) was high (range 3.9-17.8 mg l(-1), mean 11.8 mg l(-1)) within 30 km away from the center of Seoul, compared to the levels (range 1.1-7.7 mg l(-1), mean 4.3 mg l(-1)) observed in remote areas (30-70 km away). Both graphical examination and statistical evaluation (variogram) of sulfate concentration data consistently showed the decrease of sulfate concentration with increasing distance. The results of mass balance modeling also indicate that the concentrations of SO4(2-), Cl- and Na+ may be affected mainly by dry/wet deposition. However, the spatial variations of major cations such as Ca2+ and Na+ are well explained by the reaction of rainwater with diverse rocks in the watercourse. The water type was found to change from Ca(-Na)-SO4) type to Ca(-a)-HCO3 type with the increasing distance. It is thus inferred that the pollutants like SO2 emitted from strong man-made source areas of Seoul are transported to the considerable distance (at least 30 km away) by westerlies and that such mechanism may lead to the changes of the anion composition in surface water. In the remote area (> 30 km away from Seoul), the stream water chemistry appears to be influenced more effectively by the weathering of rock-forming minerals.


Protein Kinase C and Calmodulin Serve As Calcium Sensors for Calcium-Stimulated Endocytosis at Synapses.
Calcium influx triggers and facilitates endocytosis, which recycles vesicles and thus sustains synaptic transmission. Despite decades of studies, the underlying calcium sensor remained not well understood. Here, we examined two calcium binding proteins, protein kinase C (PKC) and calmodulin. Whether PKC is involved in endocytosis was unclear; whether calmodulin acts as a calcium sensor for endocytosis was neither clear, although calmodulin involvement in endocytosis had been suggested. We generated PKC (α or β-isoform) and calmodulin (calmodulin 2 gene) knock-out mice of either sex and measured endocytosis with capacitance measurements, pHluorin imaging and electron microscopy. We found that these knock-outs inhibited slow (∼10-30 s) and rapid (<∼3 s) endocytosis at large calyx-type calyces, and inhibited slow endocytosis and bulk endocytosis (forming large endosome-like structures) at small conventional hippocampal synapses, suggesting the involvement of PKC and calmodulin in three most common forms of endocytosis-the slow, rapid and bulk endocytosis. Inhibition of slow endocytosis in PKC or calmodulin 2 knock-out hippocampal synapses was rescued by overexpressing wild-type PKC or calmodulin, but not calcium-binding-deficient PKC or calmodulin mutant, respectively, suggesting that calcium stimulates endocytosis by binding with its calcium sensor PKC and calmodulin. PKC and calmodulin 2 knock-out inhibited calcium-dependent vesicle mobilization to the readily releasable pool, suggesting that PKC and calmodulin may mediate calcium-dependent facilitation of vesicle mobilization. These findings shed light on the molecular signaling link among calcium, endocytosis and vesicle mobilization that are crucial in maintaining synaptic transmission and neuronal network activity.SIGNIFICANCE STATEMENT Vesicle fusion releases neurotransmitters to mediate synaptic transmission. To sustain synaptic transmission, fused vesicles must be retrieved via endocytosis. Accumulating evidence suggests that calcium influx triggers synaptic vesicle endocytosis. However, how calcium triggers endocytosis is not well understood. Using genetic tools together with capacitance measurements, optical imaging and electron microscopy, we identified two calcium sensors, including protein kinase C (α and β isoforms) and calmodulin, for the most commonly observed forms of endocytosis: slow, rapid, and bulk. We also found that these two proteins are involved in calcium-dependent vesicle mobilization to the readily releasable pool. These results provide the molecular signaling link among calcium, endocytosis, and vesicle mobilization that are essential in sustaining synaptic transmission and neuronal network activity.


Role of trade agreements in the global cereal market and implications for virtual water flows.
Understanding the dynamics of food trade, which involves a corresponding virtual trade in environmental resources, is relevant for its effects on the environment. Among the socioeconomic factors driving the international food market, trade agreements play a significant yet poorly understood role in facilitating access to worldwide trade. Focusing on the global trade of grain from 1993 to 2015, we investigate the role of trade agreements in activating new linkages and increasing traded volumes and their environmental implications. Through a data-driven approach, we show that the activation of a trade agreement among countries induces a more than six-fold increase in the probability of establishing a new link. Also, the presence of a trade agreement over time, not just its activation, relates to a more stable market since it reduces the probability of link deactivation by more than half. The trade links covered by agreements show larger flows and smoother inter-annual fluctuations. Furthermore, trade agreements encourage the development of more water-efficient flows by stimulating the exchange of crops with high water productivity values. The average economic water productivity of crops traded under trade agreements increases by 62% when considering total virtual water and even by 93% when focusing on blue water.


[Radiation risk during radionuclide diagnosis of thyroid diseases].
A cytogenetic study was performed in 2 groups of patients with nodular euthyroid goiter (aged 40 to 50) who underwent radiodiagnostic examination under out-patient conditions. The patients of the 1st group received 0.18 MBq of 131I and then during scanning 1.7-4.0 mBq of 131I. An absorbed dose in the thyroid grew from 8 mSv on the 1st day to 1700 mSv by the 90th day. In the patients of the 2nd group dose exposure was decreased by 1.5-fold. A high cytogenetic toxicity of 131I was revealed: the total number of chromosome aberrations (NCA) increased in parallel with changes in their structure. NCA restoration up to the spontaneous level was undetectable even in 90 days. A decrease in dose exposures did not result in a proportional decrease in a cytogenetic effect of 131I irradiation.


Interactive Effect of Melatonin and UV-C on Phenylpropanoid Metabolite Production and Antioxidant Potential in Callus Cultures of Purple Basil (Ocimum basilicum L. var.s purpurascens).
The present study evaluated the interactive effect of melatonin and UV-C on phenylpropanoid metabolites profile and antioxidant potential of Ocimum basilicum L. Callus was treated with varying concentrations of melatonin and UV-C radiations for different time durations, either alone and/or in combination. Individual treatments of both UV-C and melatonin proved to be more effective than combine treatments. Results indicated that UV-C (10 min) exposure increased rosmarinic acid (134.5 mg/g dry weight (DW)), which was 2.3-fold greater than control. Chichoric acid (51.52 mg/g DW) and anthocyanin (cyanide 0.50 mg/g DW) were almost 4.1-fold, while peonidin was found 2.7-fold higher in UV-C (50 min) exposure. In the case of melatonin, 1.0 mg/L concentrations showed maximum rosmarinic acid (79.4 mg/g DW) accumulation; i.e., 1.4-fold more, as compared to the control. However, 2 mg/L melatonin accumulate chichoric acid (39.99 mg/g DW) and anthocyanin (cyanide: 0.45 mg/g DW and peonidin: 0.22 mg/g DW); i.e., 3.2, 3.7 and 2.0-fold increase, as compared to the control, respectively. On the other hand, melatonin-combined treatment (melatonin (Mel) (4 mg/L) + UV-C (20 min)) was proved to be effective in caffeic acid elicitation, which was 1.9-fold greater than the control. Furthermore, antioxidant potential was evaluated by both in vitro (DPPH, ABTS and FRAP assays) and in cellulo methods. Maximum in vitro antioxidant activity (DPPH: 90.6% and ABTS: 1909.5 µM) was observed for UV-C (50 min)-treated cultures. The highest in vitro antioxidant activity measured with the ABTS assay as compared to the FRAP assay, suggesting the main contribution of antioxidants from basil callus extracts acting through a hydrogen atom transfer (HAT) over an electron transfer (ET)-based mechanism. Cellular antioxidant assay was evaluated by production of ROS/RNS species using yeast cell cultures and further confirmed the protective action of the corresponding callus extracts against oxidative stress. Overall, both melatonin and UV-C are here proved to be effective elicitors since a positive correlation between the induced production of phenolic compounds, and in cellulo antioxidant action of basil callus extracts were observed.


Neutralization-resistant variants of a neurotropic coronavirus are generated by deletions within the amino-terminal half of the spike glycoprotein.
Neuroattenuated variants of mouse hepatitis virus type 4 (MHV-4) selected for resistance to neutralizing monoclonal antibodies (R.G. Dalziel, P.W. Lampert, P. J. Talbot, and M. J. Buchmeier, J. Virol. 59:463-471, 1986) were found to harbor large deletions in both mRNA 3 and its protein product, the 180-kilodalton viron spike (S) glycoprotein. By using antipeptide antibodies directed against selected portions of the chain, deletions were mapped to the middle of the amino-terminal S1 fragment, one of the two posttranslational cleavage products of S, and involved omission of 15 kilodaltons of protein. Deletion mutants could be selected only after multiple passage of virus through cultured cell lines; minimally passaged MHV-4 stocks contained putative point mutants selectable by neutralizing monoclonal antibodies but no deletions. Enhanced growth of deletion mutants relative to wild-type virus was observed in four cell lines used for virus propagation and was attributed to delayed and diminished cytopathic effects that allowed cultures to support virus production for prolonged periods. This hypothesis was reinforced by the finding that no selective advantage for the deletion mutants was observed in two cell lines resistant to virus-induced cytopathic effects. These results indicate that the passaging of MHV-4 in culture generates heterogeneity in S structure and eventually selects for rare neutralization-resistant deletion mutants with decreased virulence properties.


[Dependence of creatine kinase and glycogen synthetase activities of skeletal muscles on state of adenine nucleotide phosphorylation and cAMP metabolism].
Changes in the contents of adenine nucleotides, creatine phosphate, inorganic phosphate, creatine, glucose-6-phosphate and glycogen and the activity of adenylate cyclase, creatine kinase, glycogen phosphorylase 31:51-AMP-phosphodiesterase and glycogen synthetase in muscles and of blood catecholamines were studied in adult rats before loading, immediately after the cessation of the muscular activity, and at rest. Adenine nucleotides are established to play a regulatory role in catabolic and anabolic processes nucleotides are established to play a regulatory role in catabolic and anabolic processes related to the muscular activity. It is established that compensation and supercompensation of the working losses of muscular creatine phosphate and glycogen are due to activation of anabolic processes under conditions of higher phosphorylation of the adenylic system.


An electrically evoked slow potential of the frog's retina. II. Identification with PII component of electroretinogram.
1. To show conclusively that the electrically evoked retinal response (EERG) is in fact an electrically evoked component of the usual ERG, it is necessary to show that the two responses have the same intraretinal pattern of current generators. A method for determining when two responses have the same origin has been developed. This method utilizes measurements from a single microelectrode penetrating the retina. 2. The method was sensitive enough to detect differences in the origins of two responses when they were present. 3. The EERG had the same intraretinal origin as the PII component of the ERG, and thus is the PII component evoked by electricity rather than by light. 4. The hypothesis that electrical stimuli act on the synaptic terminals of the photoreceptor cells predicts that electrical current will evoke components of the ERG. The fact that the EERG is an electrically evoked component of the ERG fulfills that prediction.


Compounds I of catalase and horse radish peroxidase: pi-cation radicals.
Two-electron oxidation of cobaltous octaethylporphyrin [Co(II)(Et)(8)P] yields a stable pi-cation radical [Co(III)(Et)(8)P](2+.), the optical spectrum of which exhibits spectral changes dependent upon the nature of the counterion. Comparison of these spectra with those of Compounds I of horseradish peroxidase and catalase leads us to propose that these Compounds I contain a pi-cation radical of the heme prosthetic group. This proposal explains the oxidation level, optical spectra, and stability of the primary compounds without recourse to properties such as stoichiometric mixtures of special porphyrins, stable Fe(V) porphyrins, or unique conformers of heme porphyrins. Explanations are advanced to account for the missing electron spin resonance signal of Compound I of horseradish peroxidase.


Type-2 diabetes alters hippocampal neural oscillations and disrupts synchrony between hippocampus and cortex.
Type 2 diabetes mellitus (T2DM) increases the risk of neurological diseases, yet how brain oscillations change as age and T2DM interact is not well characterized. To delineate the age and diabetic effect on neurophysiology, we recorded local field potentials with multichannel electrodes spanning the somatosensory cortex and hippocampus (HPC) under urethane anesthesia in diabetic and normoglycemic control mice, at 200 and 400 days of age. We analyzed the signal power of brain oscillations, brain state, sharp wave associate ripples (SPW-Rs), and functional connectivity between the cortex and HPC. We found that while both age and T2DM were correlated with a breakdown in long-range functional connectivity and reduced neurogenesis in the dentate gyrus and subventricular zone, T2DM further slowed brain oscillations and reduced theta-gamma coupling. Age and T2DM also prolonged the duration of SPW-Rs and increased gamma power during SPW-R phase. Our results have identified potential electrophysiological substrates of hippocampal changes associated with T2DM and age. The perturbed brain oscillation features and diminished neurogenesis may underlie T2DM-accelerated cognitive impairment.


Enhanced surveillance of Staphylococcus aureus bacteraemia to identify targets for infection prevention.
Surveillance of Staphylococcus aureus bacteraemia (SAB) in Scotland is limited to the number of infections per 100,000 acute occupied bed-days and susceptibility to meticillin. To demonstrate the value of enhanced SAB surveillance to identify targets for infection prevention. Prospective cohort study of all patients identified with SAB over a five-year period in a single health board in Scotland. All patients were reviewed at the bedside by a clinical microbiologist. In all, 556 SAB episodes were identified: 261 (46.6%) were hospital-acquired; 209 (37.9%) were healthcare-associated; 80 (14.4%) were community-acquired; and in six (1.1%) the origin of infection was not hospital-acquired, but could not be separated into healthcare-associated or community-acquired. These were classified as non-hospital-acquired. Meticillin-resistant S. aureus (MRSA) bacteraemia was associated with hospital-acquired and healthcare-associated infections. In addition, there was a significantly higher 30-day mortality associated with hospital-acquired (31.4%) and healthcare-associated (16.3%) infections compared to community-acquired SAB (8.7%). Vascular access devices were associated with hospital-acquired SAB and peripheral venous cannulas were the source for most of these (43.9%). Community-acquired infections were associated with intravenous drug misuse, respiratory tract infections and skeletal and joint infections. Skin and soft tissue infections were more widely seen in healthcare-associated infections. The data indicate that enhanced surveillance of SAB by origin of infection and source of bacteraemia has implications for infection prevention, empirical antibiotic therapy, and health improvement interventions.


Climate change and mental health: time for action and advocacy.
Climate change poses an existential threat to our planet and our health. We explore the intersections of climate change and mental health which has been under-recognised to date. Climate change can affect mental health directly through the effects of extreme weather events such as heat, drought and flooding, and indirectly through increasing rates of migration and inequality. Vulnerable individuals with neuropsychiatric disorders will be particularly at risk. Emerging evidence is also showing effects of air pollution on brain development. Mitigation efforts related to reducing carbon emissions will have both direct and indirect effects on mental health. A further consideration demonstrated by the COVID-19 pandemic is that the spread of infectious disease can have substantial effects on the mental health of the population. With climate change and biodiversity loss, pandemics could recur in the future with increasing frequency. It is now essential that mental health professionals be equipped as agents for climate action.


Associations of airway inflammation and responsiveness markers in non asthmatic subjects at start of apprenticeship.
Bronchial Hyperresponsiveness (BHR) is considered a hallmark of asthma. Other methods are helpful in epidemiological respiratory health studies including Fractional Exhaled Nitric Oxide (FENO) and Eosinophils Percentage (EP) in nasal lavage fluid measuring markers for airway inflammation along with the Forced Oscillatory Technique measuring Airway resistance (AR). Can their outcomes discriminate profiles of respiratory health in healthy subjects starting apprenticeship in occupations with a risk of asthma? Rhinoconjunctivitis, asthma-like symptoms, FEV1 and AR post-Methacholine Bronchial Challenge (MBC) test results, FENO measurements and EP were all investigated in apprentice bakers, pastry-makers and hairdressers not suffering from asthma. Multiple Correspondence Analysis (MCA) was simultaneously conducted in relation to these groups and this generated a synthetic partition (EI). Associations between groups of subjects based on BHR and EI respectively, as well as risk factors, symptoms and investigations were also assessed. Among the 441 apprentice subjects, 45 (10%) declared rhinoconjunctivitis-like symptoms, 18 (4%) declared asthma-like symptoms and 26 (6%) suffered from BHR. The mean increase in AR post-MBC test was 21% (sd = 20.8%). The median of FENO values was 12.6 ppb (2.6-132 range). Twenty-six subjects (6.7%) had EP exceeding 14%. BHR was associated with atopy (p < 0.01) and highest FENO values (p = 0.09). EI identified 39 subjects with eosinophilic inflammation (highest values of FENO and eosinophils), which was associated with BHR and atopy. Are any of the identified markers predictive of increased inflammatory responsiveness or of development of symptoms caused by occupational exposures? Analysis of population follow-up will attempt to answer this question.


[Role of cytologic examination of smears in vulvovaginal candidiasis].
Cytological examination allows one to reveal various forms of the fungus vegetation in the host, the fungus-epitheliocyte interaction to evaluate morphological state of the epithelium. The method in combination with clinical symptoms allows one to establish a differential diagnosis of genital candidiasis in 87.8% cases and to have an opinion of the disease prognosis.


Farming and incidence of motor neuron disease: French nationwide study.
The association of farming with motor neuron disease (MND) is unclear, with conflicting studies. We performed a French nationwide study of the association of farming with MND incidence, and compared findings with those for Parkinson's disease (PD), which has been shown to be more frequent in farmers. We used the French national health insurance and hospital discharge databases to identify MND/PD incident cases. The Mutualité Sociale Agricole (MSA) guarantees health insurance for farmers and agricultural workers. We compared the incidence of MND (2010-2014) and PD (2011-2012) in MSA farmers, MSA workers and non-MSA affiliates, and estimated relative risks (RRs) and 95% confidence intervals (CIs). Probabilistic sensitivity analyses were used for external smoking adjustment. Analyses relied on 8931 MND (MSA, 9%) and 45 409 PD (MSA,11%) cases. There was a trend towards higher MND incidence in MSA farmers compared with non-MSA affiliates (RR,1.08; 95% CI,0.99-1.18) and MSA workers (RR, 1.13; 95% CI, 0.97-1.31) that strengthened after smoking adjustment (if associated with MND). PD incidence was higher in MSA farmers than non-MSA affiliates (RR, 1.13; 95% CI, 1.08-1.17) and MSA workers (RR, 1.10; 95% CI, 1.02-1.18); this association remained after smoking adjustment (RR, 1.09; 95% CI, 1.05-1.14). This French nationwide study suggested an association between farming and MND, and confirmed higher PD incidence in farmers in France, a country with high pesticide use.


Examining the influence of perceived stress on developmental change in memory and perceptual speed for adopted and nonadopted individuals.
The present study prospectively evaluated cumulative early life perceived stress in relation to differential change in memory and perceptual speed from middle childhood to early adulthood. We aimed to identify periods of cognitive development susceptible to the effects of perceived stress among both adopted and nonadopted individuals. The sample consisted of participants in the Colorado Adoption Project (CAP, N = 690). Structured latent growth curves were fit to 4 memory outcomes as well as 1 perceptual speed outcome, which described nonlinear change between ages 9 and 30. Both adoption status and cumulative perceived stress indices served as predictors of the latent curves. The perceived stress indices were constructed from the Brooks-Gunn Life Events Scale for Adolescents, and reflected "upsettingness" ratings associated with the occurrence of particular life events during middle childhood (ages 9 to 12) and adolescence (ages 13 to 16). For memory and perceptual speed, cumulative perceived stress did not predict differential cognitive gains. However, differences in perceptual speed trajectories between nonadopted and adopted individuals were observed, with adopted individuals showing smaller gains. Although these findings provide no evidence that emergent variability in memory and perceptual speed trajectories by age 30 are explained by cumulative perceptions of stress in childhood and adolescence, further investigations regarding potential vulnerability across the life span are warranted. (PsycINFO Database Record


[Epidemiological characteristics of mpox epidemic in Guangzhou].
Objective: To understand the epidemiological characteristics of mpox epidemic in Guangzhou and provide scientific evidence for the prevention and control of the disease. Methods: Based on the mpox surveillance system in Guangzhou, suspected mpox cases with fever and rash were reported by local hospitals at all levels to centers for disease control and prevention in Guangzhou for sampling, investigation and diagnosis. Descriptive epidemiological analysis was conducted on the clinical characteristics and treatment of the mpox cases and positive detection rate reported in Guangzhou as of 24:00 on June 23. Whole genome sequencing of the virus isolates was performed using Illumina Miniseq high-throughput sequencing platform. Results: The first mpox case in Guangzhou was reported on June 10 in 2023. As of 24:00 on June 23, a total of 25 confirmed mpox cases were reported. All the mpox cases were men with a M(Q1,Q3) of 32 (26, 36) years, the majority of the cases were MSM (96.0%). The main clinical features were rash (100.0%, 25/25), lymphadenectasis (100.0%, 25/25) and fever (52.0%, 13/25). Rash usually occurred near the genitals (88.0%, 22/25). The close contacts, mainly family members (40.4%, 23/57), showed no similar symptoms, such as fever or rash. The positive rate of mpox virus in household environment samples was 30.5%. The analyses on 3 complete gene sequences of mpox virus indicated that the strains belonged to West African type Ⅱb clade, B.1.3 lineage. Conclusions: Hidden transmission of mpox virus had occurred in MSM in Guangzhou. However, the size of affected population is relatively limited, and the possibility of wide spread of the virus is low.


EEG Cortical Source Feature based Hand Kinematics Decoding using Residual CNN-LSTM Neural Network.
Motor kinematics decoding (MKD) using brain signal is essential to develop Brain-computer interface (BCI) system for rehabilitation or prosthesis devices. Surface electroencephalogram (EEG) signal has been widely utilized for MKD. However, kinematic decoding from cortical sources is sparsely explored. In this work, the feasibility of hand kinematics decoding using EEG cortical source signals has been explored for grasp and lift task. In particular, pre-movement EEG segment is utilized. A residual convolutional neural network (CNN) - long short-term memory (LSTM) based kinematics decoding model is proposed that utilizes motor neural information present in pre-movement brain activity. Various EEG windows at 50 ms prior to movement onset, are utilized for hand kinematics decoding. Correlation value (CV) between actual and predicted hand kinematics is utilized as performance metric for source and sensor domain. The performance of the proposed deep learning model is compared in sensor and source domain. The results demonstrate the viability of hand kinematics decoding using pre-movement EEG cortical source data.


The Influence of Gayatri Mantra and Emotional Freedom Technique on Quality of Life of Post-Stroke Patients.
The quality of life in stroke patients is vital for survival. Nowadays, studies that show a decrease in quality of life in post-stroke patients are increasing. Various non-pharmacological modalities were explored in the past to improve rehabilitation. However, the study about the effects of religious mantra and its combination with the modern technique was lacking. Therefore, this study aimed to analyse the effects of Gayatri Mantra and Emotional Freedom Technique (EFT) on quality of life (QOL) of post-stroke patients. A quasi-experimental with pretest and posttest with the control group design was conducted. Forty-six post-stroke subjects with reduced quality of life based on Stroke Specific Quality of Life were consecutively recruited and divided into controls and intervention groups. The intervention group received additional treatment with Gayatri Mantra and EFT. In contrast, the control group attends and adheres only to the standard hospital rehabilitation program. All indicators and the overall score of QOL in the intervention group showed significant improvement after treatment (p<0.05) compared with no improvement in the control group. Overall, a higher QOL score was observed in the intervention group at the end of the study. Mann-Whitney test shows significant differences between the final QOL score in intervention and control groups (p<0.001). Gayatri Mantra and EFT are significantly increasing the quality of life of post-stroke patients.


Microcirculatory and clinical effects of serial percutaneous application of carbon dioxide in primary and secondary Raynaud's phenomenon.
A randomized double-blind monocentric trial was conducted at the spa of Royat, France, in patients with mild Raynaud's phenomenon (one or two attacks a day during the autumn and winter months). Hemodynamic changes were quantified by laser Doppler flow (LDF) and computerized chronothermometric test (CT) during local application of CO2 and compared with the usual clinical parameters. Patients were randomized to 18 days of CO2 (group 1) or 9 days of air + 9 days of CO2 (group 2). The gas was applied at a constant temperature to previously humidified skin on the forearm. Effects of the active treatment were measured by LDF and continuing benefits by computerized chronothermometric test (CT test). Clinical assessment was made on four occasions (before, in the middle and at the end of treatment, and three months afterwards) on the basis of the number of daily attacks and the duration and severity of the attacks. LDF showed a significant increase in digital blood flow (+ 41%) and in vasomotion (+ 42%) during CO2 treatment but no change on placebo treatment. CT test showed a comparable response to cold in the two groups during treatment. Three months later, however, warming time was significantly decreased (by 7 minutes: 25%) and warming rate increased (+ 22.4%) in group 1 (intergroup difference: p = 0.02). There was no difference between groups in the weekly number of attacks during treatment periods. In contrast there was a moderate increase in both groups in the winter months. There was no increase in the severity of the attacks nor in their duration. In this clinical trial, LDF evidenced positive effects of percutaneous application of natural CO2 gas on vasomotricity and vasomotion while CT test showed that patients who had received 18 days of CO2 adapted more easily to exposure to cold. Clinical improvement seems to be masked by winter weather conditions.


Free-floating vitreous cyst in an adult male.
A 50 year-old male patient was referred to our clinic due to a floating mass in the right eye. The uncorrected visual aquity was 10 / 10 in both eyes.The patient did not have any systemic disorder and trauma history. His ophthalmological examination revealed an unremarkable anterior segment with no signs of inflammation. Indirect opthalmoscopy and posterior segment biomicroscopy performed with 90D lens was unremarkable in the left eye, while in the right eye a single oval cyst was identified floating freely in the vitreous. The cyst was partially masking the underlying retinal vasculature. B-scan ultrasound revealed an echo-free, round-shaped cyst that was free from surrounding vitreous strands or retina localised at the posterior vitreous. Fluorescein angiography (FA) ruled out the presence of intra and overlying vascularisation of the cyst. Indeed, FA showed a clear-edged hypofluorescence due to a pre-retinal masking effect. The indirect hemaglutinin tests of the patient for ecinococcus and cysticercosis were negative. Eosinophilia was not detected in the preripheral blood smear. Based on these findings the patient was diagnosed as primary vitreal cyst. The presented case was mild symptomatic so the patient was decided to be followed up without any treatment.


TPCA-1 is a direct dual inhibitor of STAT3 and NF-κB and regresses mutant EGFR-associated human non-small cell lung cancers.
Epidermal growth factor receptor (EGFR) is a clinical therapeutic target to treat a subset of non-small cell lung cancer (NSCLC) harboring EGFR mutants. However, some patients with a similar kind of EGFR mutation show intrinsic resistance to tyrosine kinase inhibitors (TKI). It indicates that other key molecules are involved in the survival of these cancer cells. We showed here that 2-[(aminocarbonyl)amino]-5 -(4-fluorophenyl)-3- thiophenecarboxamide (TPCA-1), a previously reported inhibitor of IκB kinases (IKK), blocked STAT3 recruitment to upstream kinases by docking into SH2 domain of STAT3 and attenuated STAT3 activity induced by cytokines and cytoplasmic tyrosine kinases. TPCA-1 is an effective inhibitor of STAT3 phosphorylation, DNA binding, and transactivation in vivo. It selectively repressed proliferation of NSCLC cells with constitutive STAT3 activation. In addition, using pharmacologic and genetic approaches, we found that both NF-κB and STAT3 could regulate the transcripts of interleukin (IL)-6 and COX-2 in NSCLC harboring EGFR mutations. Moreover, gefitinib treatment only did not efficiently suppress NF-κB and STAT3 activity. In contrast, we found that treatment with TKIs increased phosho-STAT3 level in target cells. Inhibiting EGFR, STAT3, and NF-κB by combination of TKIs with TPCA-1 showed increased sensitivity and enhanced apoptosis induced by gefitinib. Collectively, in this work, we identified TPCA-1 as a direct dual inhibitor for both IKKs and STAT3, whereas treatment targeting EGFR only could not sufficiently repress NF-κB and STAT3 pathways for lung cancers harboring mutant EGFR. Therefore, synergistic treatment of TPCA-1 with TKIs has potential to be a more effective strategy for cancers.


MERMITHID PARASITES OF BLACKFLIES.
Mermithid nematodes parasitize invertebrates only. A general account is given of their parasitism and the consequent mortality of blackflies. The author begins with a review of records of mermithid and blackfly association from different parts of the world and comments on the global distribution of the parasite. He discusses the life-histories of the parasites, stressing their adaptations to the moving environment of the aquatic stages of the blackfly and to the aerial environment of the adult. It is noted that the parasite usually kills its host upon emergence and has a restricted host range. Mermithids must be considered as selective mortality factors against blackfly populations. A survey of European and North American literature leads to conclusions concerning the role of the parasite in the natural regulation of blackflies. The possibility of utilizing these nematodes as biological control agents is discussed.


Dense linkage disequilibrium mapping in the 15q11-q13 maternal expression domain yields evidence for association in autism.
Autism [MIM 209850] is a neurodevelopmental disorder exhibiting a complex genetic etiology with clinical and locus heterogeneity. Chromosome 15q11-q13 has been proposed to harbor a gene for autism susceptibility based on (1) maternal-specific chromosomal duplications seen in autism and (2) positive evidence for linkage disequilibrium (LD) at 15q markers in chromosomally normal autism families. To investigate and localize a potential susceptibility variant, we developed a dense single nucleotide polymorphism (SNP) map of the maternal expression domain in proximal 15q. We analyzed 29 SNPs spanning the two known imprinted, maternally expressed genes in the interval (UBE3A and ATP10C) and putative imprinting control regions. With a marker coverage of 1/10 kb in coding regions and 1/15 kb in large 5' introns, this map was employed to thoroughly dissect LD in autism families. Two SNPs within ATP10C demonstrated evidence for preferential allelic transmission to affected offspring. The signal detected at these SNPs was stronger in singleton families, and an adjacent SNP demonstrated transmission distortion in this subset. All SNPs showing allelic association lie within islands of sequence homology between human and mouse genomes that may be part of an ancestral haplotype containing a functional susceptibility allele. The region was further explored for recombination hot spots and haplotype blocks to evaluate haplotype transmission. Five haplotype blocks were defined within this region. One haplotype within ATP10C displayed suggestive evidence for preferential transmission. Interpretation of these data will require replication across data sets, evaluation of potential functional effects of associated alleles, and a thorough assessment of haplotype transmission within ATP10C and neighboring genes. Nevertheless, these findings are consistent with the presence of an autism susceptibility locus in 15q11-q13.


GOPC-ROS1 Fusion Due to Microdeletion at 6q22 Is an Oncogenic Driver in a Subset of Pediatric Gliomas and Glioneuronal Tumors.
ROS1 is a transmembrane receptor tyrosine kinase proto-oncogene that has been shown to have rearrangements with several genes in glioblastoma and other neoplasms, including intrachromosomal fusion with GOPC due to microdeletions at 6q22.1. ROS1 fusion events are important findings in these tumors, as they are potentially targetable alterations with newer tyrosine kinase inhibitors; however, whether these tumors represent a distinct entity remains unknown. In this report, we identify 3 cases of unusual pediatric glioma with GOPC-ROS1 fusion. We reviewed the clinical history, radiologic and histologic features, performed methylation analysis, whole genome copy number profiling, and next generation sequencing analysis for the detection of oncogenic mutation and fusion events to fully characterize the genetic and epigenetic alterations present in these tumors. Two of 3 tumors showed pilocytic features with focal expression of synaptophysin staining and variable high-grade histologic features; the third tumor aligned best with glioblastoma and showed no evidence of neuronal differentiation. Copy number profiling revealed chromosome 6q22 microdeletions corresponding to the GOPC-ROS1 fusion in all 3 cases and methylation profiling showed that the tumors did not cluster together as a single entity or within known methylation classes by t-Distributed Stochastic Neighbor Embedding.


Partial mechanical long-term support with the CircuLite Synergy pump as bridge-to-transplant in congestive heart failure.
Full mechanical support with a left ventricular assist device (LVAD) is often limited to very sick patients, as the only survival option. This European multicenter study analyzes the effect of partial mechanical support as bridge-to-transplant in a less sick heart failure patient group. The CircuLite Synergy device is implanted via a small right-sided thoracotomy with an inflow cannula in the left atrium and an outflow graft connected to the right subclavian artery without the use of extracorporeal circulation. The pump itself sits in a "pacemaker" pocket subcutaneously in the right clavicular groove. It is able to pump up to 3.0 l/min and partially unload the left ventricle. The device was implanted in 25 patients on the cardiac transplant waiting list (20 males), aged 55.5 +/- 9.6 yrs with an ejection fraction of 21.6 +/- 6.0 %, a mean arterial pressure of 73.5 +/- 8.5 mmHg, a pulmonary capillary wedge pressure of 27.2 +/- 7.8 mmHg and cardiac index of 1.9 +/- 0.4 l/min/m (2). Duration of support ranged from 6 to 238 days. Right heart catheterization showed significant hemodynamic improvement in the short- and intermediate-term after implantation with increases in arterial pressure from 72.6 +/- 11.0 to 79.4 +/- 8.6 mmHg ( P = 0.04) and in cardiac index from 2.0 +/- 0.4 to 2.7 +/- 0.6 l/min/m (2) ( P = 0.003) with a reduction in pulmonary capillary wedge pressure from 28.5 +/- 6.0 to 19.7 +/- 6.9 mmHg ( P = 0.012). The CircuLite Synergy device is a partial support pump, which is easy to implant and which provides hemodynamic benefits in bridging heart failure patients to cardiac transplant.


Intensive care unit syndrome: a dangerous misnomer.
The terms intensive care unit (ICU) syndrome and ICU psychosis have been used interchangeably to describe a cluster of psychiatric symptoms that are unique to the ICU environment. It is often postulated that aspects of the ICU, such as sleep deprivation and sensory overload or monotony, are causes of the syndrome. This article reviews the empirical support for these propositions. We conclude that ICU syndrome does not differ from delirium and that ICU syndrome is caused exclusively by organic stressors on the central nervous system. We argue further that the term ICU syndrome is dangerous because it impedes standardized communication and research and may reduce the vigilance necessary to promptly investigate and reverse the medical cause of the delirium. Directions for future research are suggested.


Theoretical design of solvatochromism switching by photochromic reactions using donor-acceptor disubstituted diarylethene derivatives with oxidized thiophene rings.
We have designed several diarylethene derivatives with oxidized thiophene rings and donor-acceptor substituents, which show the solvatochromism switching by photochromic reactions, using a time-dependent density functional theory (TD-DFT) method using the polarizable continuum model (PCM). It is found that in the UV-vis spectral region examined only the open-ring isomers exhibit the solvatochromism, while the closed-ring isomers do not. The mechanism of the solvatochromism behavior and its switching process are clarified from the viewpoint of the charge-transfer (CT) excitation from the donor to the acceptor substituents. We demonstrate that this CT excitation can be controlled by choosing appropriate pairs of the donor and the acceptor substituents on the basis of the orbital correlation diagram between the diarylethene derivatives and the donor-acceptor substituents, which is constructed from the topologies and the orbital energies of the molecular orbitals primarily contributing to the excitations.


[Basic directions of research of the department of lipid biochemistry].
The review deals with the scientific activity of the Department of Biochemistry of Lipids of the Palladin Biochemistry Institute of the National Academy of Sciences of Ukraine. The estimation of the functional role of some major lipids and of the minor lipid components, namely, N-acylethanolamines (NAE), is the main problem of the scientific investigations of the Department. The role of some lipids in the pathogenesis of diseases accompanied by the oxidative stress was also studied. The Department was the first to find and identify NAE in neuroblastoma C1300 N18 cells. It was shown that NAE with long saturated acyl chains inhibited veratridine-activated fast sodium channels. NAE also activated uterine plasma membrane smooth muscle Ca2+, Mg(2+)-ATPase, and inhibited Fe(2+)-induced free radical oxidation in mitochondria. The results of these investigations served as a basis for development of pharmacological substances with membrane protective properties. It was shown that, at different diseases accompanied by the oxidative stress, a significant change in the lipid composition of cell membranes occurred. Sometimes these changes were adaptive in character, which favored the cell viability adaptation to pathological conditions. The new level of regulation of adaptive reactions can be accompanied by the development of additive injuries of cell viability, which may be caused by the altered level of biologically active cell lipid components. Based on the results of these investigations, the preparation intended for treatment of male infertility was developed. The pharmacological substances intended for treatment of morphine abuse and acute ischemia of myocardium were created.


Designer hydrogels: Shedding light on the physical chemistry of the pancreatic cancer microenvironment.
Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer mortality in the United States, with a 5-year survival of ∼8%. PDAC is characterized by a dense and hypo-vascularized stroma consisting of proliferating cancer cells, cancer-associated fibroblasts, macrophages and immune cells, as well as excess matrices including collagens, fibronectin, and hyaluronic acid. In addition, PDAC has increased interstitial pressures and a hypoxic/acidic tumor microenvironment (TME) that impedes drug delivery and blocks cancer-directed immune mechanisms. In spite of increasing options in targeted therapy, PDAC has mostly remained treatment recalcitrant. Owing to its critical roles on governing PDAC progression and treatment outcome, TME and its interplay with the cancer cells are increasingly studied. In particular, three-dimensional (3D) hydrogels derived from or inspired by components in the TME are progressively developed. When properly designed, these hydrogels (e.g., Matrigel, collagen gel, hyaluronic acid-based, and semi-synthetic hydrogels) can provide pathophysiologically relevant compositions, conditions, and contexts for supporting PDAC cell fate processes. This review summarizes recent efforts in using 3D hydrogels for fundamental studies on cell-matrix or cell-cell interactions in PDAC.


Ability of T cells from patients with rheumatoid arthritis to respond to immunoglobulin G.
The ability of T cells from rheumatoid factor (RF)-positive patients with rheumatoid arthritis (RA) to respond to immunoglobulin G (IgG) was assessed. Peripheral blood mononuclear cells (PBMC) from RA patients and normal individuals were cultured with and without human IgG or Mycobacterium tuberculosis-purified protein derivative (PPD) for 7 days and their proliferative response measured at intervals by their ability to take up tritiated thymidine. PBMC from 14/26 RA patients proliferated in response to IgG (taking a stimulation index of 3 or above as positive). The peak response varied between individuals but usually occurred on day 5, the same day, or 1 day later than the peak response to PPD. By contrast, PBMC from a significantly lower proportion (1/9) of normal individuals and patients with other arthritides (0/6) responded to IgG, although all responded to PPD. PBMC from 9/14 RA patients responded to Fab fragments of IgG but only 3/9 to the Fc fragment. Higher proliferative responses from RA PBMC were elicited by IgG aggregates than the original IgG preparation, but PMBC from 5/5 normal individuals and 5/6 patients with other arthritides failed to respond to the aggregates. The response to IgG was human leucocyte antigen (HLA)-DR restricted and mediated by CD4+ T cells. It is considered that these results advance the hypothesis that IgG-reactive T cells contribute to the initiation or perpetuation of RA.


Serotonergic antidepressant use and morbidity and mortality among older adults with COPD.
We evaluated the relationship between new selective serotonin reuptake inhibitor (SSRI) or serotonin-noradrenaline reuptake inhibitor (SNRI) drug use and respiratory-related morbidity and mortality among older adults with chronic obstructive pulmonary disease (COPD).This was a retrospective population-based cohort study using heath administrative data from Ontario, Canada. Individuals aged ≥66 years, with validated, physician-diagnosed COPD (n=131 718) were included. New SSRI/SNRI users were propensity score matched 1:1 to controls on 40 relevant covariates to minimise potential confounding.Among propensity score matched community-dwelling individuals, new SSRI/SNRI users compared to non-users had significantly higher rates of hospitalisation for COPD or pneumonia (hazard ratio (HR) 1.15, 95% CI 1.05-1.25), emergency room visits for COPD or pneumonia (HR 1.13, 95% CI 1.03-1.24), COPD or pneumonia-related mortality (HR 1.26, 95% CI 1.03-1.55) and all-cause mortality (HR 1.20, 95% CI 1.11-1.29). In addition, respiratory-specific and all-cause mortality rates were higher among long-term care home residents newly starting SSRI/SNRI drugs versus controls.New use of serotonergic antidepressants was associated with small, but significant, increases in rates of respiratory-related morbidity and mortality among older adults with COPD. Further research is needed to clarify if the observed associations are causal or instead reflect unresolved confounding.


Kinetics of DNA methylation by the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in F344 rats.
The carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was injected intravenously (0.41 mmol/kg) into F344 rats. DNA from target organs (lung, liver) and a non-target organ (kidney) was extracted hydrolysed and analysed for methylated guanines by cation-exchange high-performance liquid chromotography-fluorimetry. Levels of O6-methylguanine, a promutagenic lesion, and 7-methylguanine were three to eight times higher in the liver than in the lung. Neither base could be detected in the kidneys. The extent of methylation of hepatic DNA by NNK was 35 times lower than observed with an equimolar dose of NDMA by Swann et al. (1983). The levels of the two methylated guanines in liver and lung DNA increased between 4 and 24 h following NNK injection. NNK is metabolized rapidly in F344 rats to 4-(methylnitrosamino)-1(3-pyridyl)-butan-1-ol (NNA1). The relatively slow methylation of hepatic DNA after injection of NNK could be due to a slow release of methylating species from the major circulating metabolite NNA1. This low but sustained level of O6-methylguanine induced by NNK could, in part, explain its carcinogenic potency.


[Cross-cultural adaptation of the Spanish version of the Child Health and Illness Profile, Child Edition (CHIP-CE)].
To obtain a Spanish version of the CHIP-CE semantically and culturally equivalent to the original version. The methodology used was based on the forward-backward method. Two translations into Spanish were performed. After the first reconciled version, 44 cognitive interviews were carried out with children aged 6-11 years old, selected from two schools in Barcelona. The interviews were recorded and transcribed. A qualitative content analysis of the textual data was carried out. A panel of experts developed the second reconciled version taking into account the children's comments. A back-translation into English was carried out and was compared with the original version. Of a total of 45 items induced in the first reconciled version, 21 were considered equivalent, 23 required changes and 1 was considered not equivalent. Comprehension of abstract concepts differed according to age. Older children differentiated among concepts and gave different examples of experiences related to these concepts, while younger children (6 to 7-year olds) provided similar examples for different concepts. The children's comments were used in the reformulation of the items. An illustrative figure reinforced understanding. Children aged 7 or more started to use an adequate recall period and used the response options correctly. The Spanish version of the CHIP-CE seems appropriate for children aged 6-11 in Spain. The present study shows that children from the age of 6 years onwards are able to describe the health concepts included in the CHIP-CE.


Birth weight, maternal body mass index, and early childhood growth: a prospective birth cohort study in China.
The relations of birth weight and maternal body mass index (BMI) to overweight remain unresolved. We prospectively examined the relations of birth weight with various anthropometric measures at age 3 to 6 years, the effect of maternal BMI, and the patterns of these relations in an analysis using 9 birth weight categories. The subjects were 210 172 singleton infants born alive with a gestational age ≥ 28 weeks between October 1993 and December 1996; the subjects were followed up in 2000. Birth weight, maternal height and weight, and other relevant information were measured or collected prospectively. Overweight and underweight were defined by using National Center for Health Statistics/World Health Organization reference data. Logistic regression models were used to estimate relative risks. Analyses stratified by quartile of maternal BMI were performed to examine the effects of maternal BMI on the associations of birth weight with overweight and underweight. Birth weight was linearly associated with height, weight, and BMI at age 3-6 years. Adjustment for maternal BMI did not alter this association. Birth weight was positively associated with overweight and negatively associated with underweight. The relation curves for both overweight and underweight resembled half of a flat parabolic curve. The associations for overweight and underweight were slightly stronger for the highest and lowest quartiles of maternal BMI, respectively. Higher birth weight is associated with an increased risk for childhood overweight, and lower birth weight with an increased risk for underweight. The associations between birth weight and early childhood anthropometric growth measures could not explained by maternal BMI.


A UoI-Optimal Policy for Timely Status Updates with Resource Constraint.
Timely status updates are critical in remote control systems such as autonomous driving and the industrial Internet of Things, where timeliness requirements are usually context dependent. Accordingly, the Urgency of Information (UoI) has been proposed beyond the well-known Age of Information (AoI) by further including context-aware weights which indicate whether the monitored process is in an emergency. However, the optimal updating and scheduling strategies in terms of UoI remain open. In this paper, we propose a UoI-optimal updating policy for timely status information with resource constraint. We first formulate the problem in a constrained Markov decision process and prove that the UoI-optimal policy has a threshold structure. When the context-aware weights are known, we propose a numerical method based on linear programming. When the weights are unknown, we further design a reinforcement learning (RL)-based scheduling policy. The simulation reveals that the threshold of the UoI-optimal policy increases as the resource constraint tightens. In addition, the UoI-optimal policy outperforms the AoI-optimal policy in terms of average squared estimation error, and the proposed RL-based updating policy achieves a near-optimal performance without the advanced knowledge of the system model.


Aversion to Desflurane and Isoflurane in Sprague-Dawley Rats (Rattus Norvegicus).
Carbon dioxide and isoflurane are widely used for killing rats, yet may not truly achieve "euthanasia", because they elicit aversion. The inhalant anesthetic desflurane is faster acting than isoflurane, representing a potential refinement. Using an aversion-avoidance paradigm, 24 rats were exposed to isoflurane or desflurane (n = 12 per group) at initial exposure. Fourteen rats were then re-exposed to isoflurane or desflurane (n = 7 per group), after a 7 days washout period. Initial exposure: time to recumbency was faster for desflurane than isoflurane (p = 0.0008, 95% CI [-12.9 to 32.6 s]), with 9/12 and 6/12 rats becoming recumbent, respectively. At initial exposure, there was no difference between groups in time to withdrawal (p = 0.714). At re-exposure, all rats withdrew and no rats became recumbent. Time to withdrawal at re-exposure did not differ between treatment groups (p = 0.083). Compared to initial exposure, time to withdrawal during re-exposure was similar for isoflurane (p = 0.228) and faster with desflurane (p = 0.012, 95% CI [19.1 to 49.5 s]). Isoflurane and desflurane are similarly aversive, with aversion increasing at re-exposure. The shorter time from exposure to recumbency with desflurane indicates that any distress is of a shorter duration when compared with isoflurane.


Machine learning vs. traditional regression analysis for fluid overload prediction in the ICU.
Fluid overload, while common in the ICU and associated with serious sequelae, is hard to predict and may be influenced by ICU medication use. Machine learning (ML) approaches may offer advantages over traditional regression techniques to predict it. We compared the ability of traditional regression techniques and different ML-based modeling approaches to identify clinically meaningful fluid overload predictors. This was a retrospective, observational cohort study of adult patients admitted to an ICU ≥ 72 h between 10/1/2015 and 10/31/2020 with available fluid balance data. Models to predict fluid overload (a positive fluid balance ≥ 10% of the admission body weight) in the 48-72 h after ICU admission were created. Potential patient and medication fluid overload predictor variables (n = 28) were collected at either baseline or 24 h after ICU admission. The optimal traditional logistic regression model was created using backward selection. Supervised, classification-based ML models were trained and optimized, including a meta-modeling approach. Area under the receiver operating characteristic (AUROC), positive predictive value (PPV), and negative predictive value (NPV) were compared between the traditional and ML fluid prediction models. A total of 49 of the 391 (12.5%) patients developed fluid overload. Among the ML models, the XGBoost model had the highest performance (AUROC 0.78, PPV 0.27, NPV 0.94) for fluid overload prediction. The XGBoost model performed similarly to the final traditional logistic regression model (AUROC 0.70; PPV 0.20, NPV 0.94). Feature importance analysis revealed severity of illness scores and medication-related data were the most important predictors of fluid overload. In the context of our study, ML and traditional models appear to perform similarly to predict fluid overload in the ICU. Baseline severity of illness and ICU medication regimen complexity are important predictors of fluid overload.


Wheat Leaf Rust: Control by 4-n-Butyl-1,2,4-triazole, a Systemic Fungicide.
Compound 4-n-butyl-1,2,4-triazole was demonstrated as an enduring and selective systemic fungicide for the control of wheat leaf rust by foliar and soil applications. Among several species of rust fungi treated, only wheat leaf rust (Puccinia recondita Rob.) was controlled. Wheat stem rust, for example, was unaffected by either soil or foliar applications.


Genetic polymorphisms in MDR1, CYP3A4 and CYP3A5 genes in a Ghanaian population: a plausible explanation for altered metabolism of ivermectin in humans?
Ivermectin, a substrate of multidrug resistance (MDR1) gene and cytochrome P450 (CYP) 3A4, has been used successfully in the treatment of onchocerciasis in Ghana. However, there have been reports of suboptimal response in some patients after repeated treatment. Polymorphisms in host MDR1 and CYP3A genes may explain the observed suboptimal response to ivermectin. We genotyped relevant functional polymorphisms of MDR1 and CYP3A in a random sample of healthy Ghanaians and compared the data with that of ivermectin-treated patients with a view to exploring the relationship between suboptimal response to ivermectin and MDR1 and CYP3A allelic frequencies. Using PCR-RFLP, relevant polymorphic alleles of MDR1 and CYP3A4 genes were analysed in 204 randomly selected individuals and in 42 ivermectin treated patients. We recorded significantly higher MDR1 (3435T) variant allele frequency in suboptimal responders (21%) than in patients who responded to treatment (12%) or the random population sample (11%). CYP3A4*1B, CYP3A5*3 and CYP3A5*6 alleles were detected at varied frequencies for the sampled Ghanaian population, responders and suboptimal responders to ivermectin. CYP3A5*1/CYP3A5*1 and CYP3A5*1/CYP3A5*3 genotypes were also found to be significantly different for responders and suboptimal responders. Haplotype (*1/*1/*3/*1) was determined to be significantly different between responders and suboptimal responders indicating a possible role of these haplotypes in treatment response with ivermectin. A profile of pharmacogenetically relevant variants for MDR1, CYP3A4 and CYP3A5 genes has been generated for a random population of 204 Ghanaians to address the scarcity of data within indigenous African populations. In 42 patients treated with ivermectin, difference in MDR1 variant allele frequency was observed between suboptimal responders and responders.


The in vivo and in vitro initiation site for transcription of the rRNA operon of Saccharomyces carlsbergensis.
We have performed a detailed analysis of the transcription initiation of the rRNA operon in the yeast Saccharomyces carlsbergensis. Electron microscopic analysis of R-looped pre-rRNA molecules together with a very sensitive S1-nuclease mapping showed the use of only a single transcription start at about 700 bp upstream of the 17S rRNA gene and not of the minor start sites proposed for the very closely related species S. cerevisiae by others [Bayev et al. (5), Swanson and Holland (6)]. The sequence of 730 bp of the initiating region is presented. In vitro transcription in concentrated lysates of yeast spheroplasts in the presence of (gamma-SH)ATP or (gamma-SH)GTP, followed by purification of the in vitro initiated RNA via Hg-agarose, revealed that on the endogenous template exactly the same site is used for transcription initiation as in vivo.


Synthesis of polyacid nanogels: pH-responsive sub-100 nm particles for functionalisation and fluorescent hydrogel assembly.
Nanogels are crosslinked polymer particles with a swollen size between 1 and 100 nm. They are of major interest for advanced surface coatings, drug delivery, diagnostics and biomaterials. Synthesising polyacid nanogels that show triggered swelling using a scalable approach is a key objective of polymer colloid chemistry. Inspired by the ability of polar surfaces to enhance nanoparticle stabilisation, we report the first examples of pH-responsive polyacid nanogels containing high -COOH contents prepared by a simple, scalable, aqueous method. To demonstrate their functionalisation potential, glycidyl methacrylate was reacted with the -COOH chemical handles and the nanogels were converted to macro-crosslinkers. The concentrated (functionalised) nanogel dispersions retained their pH-responsiveness, were shear-thinning and formed physical gels at pH 7.4. The nanogels were covalently interlinked via free-radical coupling at 37 °C to form transparent, ductile, hydrogels. Mixing of the functionalised nanogels with polymer dots enabled covalent assembly of fluorescent hydrogels.


Magnetic resonance enterography compared with ultrasonography in newly diagnosed and relapsing Crohn's disease patients: the METRIC diagnostic accuracy study.
Magnetic resonance enterography and enteric ultrasonography are used to image Crohn's disease patients. Their diagnostic accuracy for presence, extent and activity of enteric Crohn's disease was compared. To compare diagnostic accuracy, observer variability, acceptability, diagnostic impact and cost-effectiveness of magnetic resonance enterography and ultrasonography in newly diagnosed or relapsing Crohn's disease. Prospective multicentre cohort study. Eight NHS hospitals. Consecutive participants aged ≥ 16 years, newly diagnosed with Crohn's disease or with established Crohn's disease and suspected relapse. Magnetic resonance enterography and ultrasonography. The primary outcome was per-participant sensitivity difference between magnetic resonance enterography and ultrasonography for small bowel Crohn's disease extent. Secondary outcomes included sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease extent, and sensitivity and specificity for small bowel Crohn's disease and colonic Crohn's disease presence; identification of active disease; interobserver variation; participant acceptability; diagnostic impact; and cost-effectiveness. Out of the 518 participants assessed, 335 entered the trial, with 51 excluded, giving a final cohort of 284 (133 and 151 in new diagnosis and suspected relapse cohorts, respectively). Across the whole cohort, for small bowel Crohn's disease extent, magnetic resonance enterography sensitivity [80%, 95% confidence interval (CI) 72% to 86%] was significantly greater than ultrasonography sensitivity (70%, 95% CI 62% to 78%), with a 10% difference (95% CI 1% to 18%; p = 0.027). For small bowel Crohn's disease extent, magnetic resonance enterography specificity (95%, 95% CI 85% to 98%) was significantly greater than ultrasonography specificity (81%, 95% CI 64% to 91%), with a 14% difference (95% CI 1% to 27%). For small bowel Crohn's disease presence, magnetic resonance enterography sensitivity (97%, 95% CI 91% to 99%) was significantly greater than ultrasonography sensitivity (92%, 95% CI 84% to 96%), with a 5% difference (95% CI 1% to 9%). For small bowel Crohn's disease presence, magnetic resonance enterography specificity was 96% (95% CI 86% to 99%) and ultrasonography specificity was 84% (95% CI 65% to 94%), with a 12% difference (95% CI 0% to 25%). Test sensitivities for small bowel Crohn's disease presence and extent were similar in the two cohorts. For colonic Crohn's disease presence in newly diagnosed participants, ultrasonography sensitivity (67%, 95% CI 49% to 81%) was significantly greater than magnetic resonance enterography sensitivity (47%, 95% CI 31% to 64%), with a 20% difference (95% CI 1% to 39%). For active small bowel Crohn's disease, magnetic resonance enterography sensitivity (96%, 95% CI 92% to 99%) was significantly greater than ultrasonography sensitivity (90%, 95% CI 82% to 95%), with a 6% difference (95% CI 2% to 11%). There was some disagreement between readers for both tests. A total of 88% of participants rated magnetic resonance enterography as very or fairly acceptable, which is significantly lower than the percentage (99%) of participants who did so for ultrasonography. Therapeutic decisions based on magnetic resonance enterography alone and ultrasonography alone agreed with the final decision in 122 out of 158 (77%) cases and 124 out of 158 (78%) cases, respectively. There were no differences in costs or quality-adjusted life-years between tests. Magnetic resonance enterography and ultrasonography scans were interpreted by practitioners blinded to clinical data (but not participant cohort), which does not reflect use in clinical practice. Magnetic resonance enterography has higher accuracy for detecting the presence, extent and activity of small bowel Crohn's disease than ultrasonography does. Both tests have variable interobserver agreement and are broadly acceptable to participants, although ultrasonography produces less participant burden. Diagnostic impact and cost-effectiveness are similar. Recommendations for future work include investigation of the comparative utility of magnetic resonance enterography and ultrasonography for treatment response assessment and investigation of non-specific abdominal symptoms to confirm or refute Crohn's disease. Current Controlled Trials ISRCTN03982913. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 42. See the NIHR Journals Library website for further project information.


Relation of Pulmonary Diffusing Capacity Decline to HRCT and VQ SPECT/CT Findings at Early Follow-Up after COVID-19: A Prospective Cohort Study (The SECURe Study).
A large proportion of patients exhibit persistently reduced pulmonary diffusion capacity after COVID-19. It is unknown whether this is due to a post-COVID restrictive lung disease and/or pulmonary vascular disease. The aim of the current study was to investigate the association between initial COVID-19 severity and haemoglobin-corrected diffusion capacity to carbon monoxide (DLco) reduction at follow-up. Furthermore, to analyse if DLco reduction could be linked to pulmonary fibrosis (PF) and/or thromboembolic disease within the first months after the illness, a total of 67 patients diagnosed with COVID-19 from March to December 2020 were included across three severity groups: 12 not admitted to hospital (Group I), 40 admitted to hospital without intensive care unit (ICU) admission (Group II), and 15 admitted to hospital with ICU admission (Group III). At first follow-up, 5 months post SARS-CoV-2 positive testing/4 months after discharge, lung function testing, including DLco, high-resolution CT chest scan (HRCT) and ventilation-perfusion (VQ) single photon emission computed tomography (SPECT)/CT were conducted. DLco was reduced in 42% of the patients; the prevalence and extent depended on the clinical severity group and was typically observed as part of a restrictive pattern with reduced total lung capacity. Reduced DLco was associated with the extent of ground-glass opacification and signs of PF on HRCT, but not with mismatched perfusion defects on VQ SPECT/CT. The severity-dependent decline in DLco observed early after COVID-19 appears to be caused by restrictive and not pulmonary vascular disease.


Preparation of GTP sensitive adenylate cyclase from luteinized rat ovaries.
Previous studies have shown that human chorionic gonadotropin stimulation of rat ovarian adenylate cyclase activity is enhanced but not augmented by GTP. Extraction of crude rat luteal membranes with 2M urea induced a GTP augmentation of hCG stimulation of adenylate cyclase activity of 3.5 fold. This augmentation of hormonal stimulation of adenylate cyclase activity by GTP was not accompanied by a decrease in hormone binding such as has been observed with other hormonally stimulated adenylate cyclase.