Active intestinal transport of methyl red isomers.
Transport across the wall of rat jejunum of two isomers of methyl red has been studied. These isomers, meta-methyl red (MMR) and para-methyl red (PMR), are absorbed against a concentration gradient. Uptake consists of three components: rapid adsorption on to the mucosa, a steady uptake proportional to lumen concentration and a reflux which increases exponentially to a limiting value. A substantial part of the uptake is stored in the mucosa, and some of it is metabolized to colourless derivatives. If methyl red is washed out of the lumen after the mucosa has been loaded, there is some reflux into the lumen, but most of the stored methyl red passses into the secretion. The rate of this transport on to the serosal surface is not noticeably diminished until the adverse concentration gradient exceeds 13-14:1. Once the methyl red has been washed out of the lumen there is no further metabolism of methyl red to colourless derivatives. Shifting the lumen pH from 7.4 to 6.4 whilst keeping the tissue fluid pH constant increases the rate of uptake from the lumen by a factor of only 1.68 although the concentration of unionized methyl red is increased approximately 10-fold. It seems that at pH 7.4 about 90% of the uptake is of the ionized form, and that at pH 6.4 this percentage falls to 50. It is concluded that the methyl reds form fresh examples of foreign organic compounds which can be transported actively by the small intestine and that they can be taken up from the lumen into the mucosa in both ionized and unionized states.


The "wider view": André Helleger's passionate, integrating intellect and the creation of bioethics.
This article provides an account of how André Hellegers, founder and first Director of the Kennedy Institute of Ethics at Georgetown University, laid medicine open to bioethics. Helleger's approach to bioethics, as to morality generally and also to medicine and biomedical science, involved taking the "wider view" -- a value-filled vision that integrated and gave meaning to what otherwise was disparate, precarious, and conflicting. This article shows how Helleger's wider view of bioethics was shaped by events in his own life, his resultant sense of the precariousness of life and health, his commitment to religious inclusiveness, his research in fetal medicine, his clinical experience in obstetrics, his role in the struggle to change the teaching of the Roman Catholic Church on fertility control, and his developing concepts of health and disease. Hellegers was committed to and worked toward bioethics as a self-consciously interdisciplinary field in which the contributing disciplines adapt to each other -- rather than sustain themselves as autonomous disciplines -- to create a dynamic and complex intellectual, clinical, and social activity.


[Application of high efficiency promoters in microbial production of 4-hydroxybutyric acid].
4-Hydroxybutyric acid (4HB) is a psychotropic drug used for polymer synthesis such as poly (4-hydroxybutyric acid) (P4HB) and poly (3-hydroxybutyric acid-co-4-hydroxybutyric acid) (P3HB-co-4HB). 1,4-butanediol (BD) can be converted to 4-hydroxybutyric acid by alcohol dehydrogenase (DhaT) and aldehyde dehydrogenase (AldD). In this study, high efficiency promoters including T7 promoter and P(Re) promoter were cloned to increase expression of dhaT and aldD, and thus accelerate the conversion from BD to 4HB. A. hydrophila 4AK4 (pZQ01), the recombinant strain under the control of T7 promoter, produced 6.00 g/L 4HB from 10 g/L BD with the productivity increased by 43.20%. While A. hydrophila 4AK4 (pZQ04), the strain under the control of T7 promoter, produced 4.87 g/L 4HB from 10 g/L BD, and the productivity was increased by 16.23%. Thus, the gene expression was increased by T7 and P(Re) promoters, leading to an accelerated biosynthesis of 4HB.


The Theoretical Highest Frame Rate of Silicon Image Sensors.
The frame rate of the digital high-speed video camera was 2000 frames per second (fps) in 1989, and has been exponentially increasing. A simulation study showed that a silicon image sensor made with a 130 nm process technology can achieve about 1010 fps. The frame rate seems to approach the upper bound. Rayleigh proposed an expression on the theoretical spatial resolution limit when the resolution of lenses approached the limit. In this paper, the temporal resolution limit of silicon image sensors was theoretically analyzed. It is revealed that the limit is mainly governed by mixing of charges with different travel times caused by the distribution of penetration depth of light. The derived expression of the limit is extremely simple, yet accurate. For example, the limit for green light of 550 nm incident to silicon image sensors at 300 K is 11.1 picoseconds. Therefore, the theoretical highest frame rate is 90.1 Gfps (about 1011 fps).


Longitudinal sliding of the median nerve during movements of the upper limb.
An incidental finding during recordings from the median nerve was that the nerve trunk slides longitudinally in its bed when the limb is moved. The amount of movement has been measured in 19 subjects. The observations are discussed with reference to the pathology of entrapment neuropathies and it is suggested that, where longitudinal movement of a peripheral nerve is restricted, continual trauma results from normal movements of the limb.


Association between childhood adversities and premature and potentially avoidable mortality in adulthood: a population-based study.
The association of childhood adversities with mortality has rarely been explored, and even less studied is the question of whether any excess mortality may be potentially preventable. This study examined the association between specific childhood adversities and premature and potentially avoidable mortality (PPAM) in adulthood in a representative sample of the general population. Also, we examined whether the associations were potentially mediated by various adult socioeconomic, psychosocial, and behavioral factors. The study used data from the National Population Health Survey (NPHS-1994) linked to the Canadian Vital Statistics Database (CVSD 1994-2014) available from Statistics Canada. The NPHS interview retrospectively assessed childhood exposure to prolonged hospitalization, parental divorce, prolonged parental unemployment, prolonged trauma, parental problematic substance use, physical abuse, and being sent away from home for doing something wrong. An existing definition of PPAM, consisting of causes of death considered preventable or treatable before age 75, was used. Competing cause survival models were used to examine the associations of specific childhood adversities with PPAM in adulthood among respondents aged 18 to 74 years (rounded n = 11,035). During the 20-year follow-up, 5.4% of the sample died prematurely of a cause that was considered potentially avoidable. Childhood adversities had a differential effect on mortality. Physical abuse (age-adjusted sub-hazard ratio; SHR 1.44; 95% CI 1.03, 2.00) and being sent away from home (age-adjusted SHR 2.26; 95% CI 1.43,3.57) were significantly associated with PPAM. The associations were attenuated when adjusted for adulthood factors, namely smoking, poor perceived health, depression, low perceived social support, and low income, consistent with possible mediating effects. Other adversities under study were not associated with PPAM. The findings imply that the psychological sequelae of childhood physical abuse and being sent away from home and subsequent uptake of adverse health behavior may lead to increased risk of potentially avoidable mortality. The potential mediators identified offer directions for future research to perform causal mediation analyses with suitable data and identify interventions aimed at preventing premature mortality due to potentially avoidable causes. Other forms of adversities, mostly related to household dysfunction, may not be determinants of the distal health outcome of mortality.


A Conceptual Framework for Barriers to the Recruitment and Retention of Rural CVD Participants in Behavior Intervention Trials.
Rural residents diagnosed with cardiovascular disease (CVD) or with CVD-related risks are underrepresented in behavioral intervention trials based on an extensive review of published studies. The low participation rate of rural residents weakens both the internal and external validity of published studies. Moreover, compared to urban residents, limited research exists to describe the unique barriers that limit the participation of rural residents in behavioral intervention trials. The purpose of this review is to identify a conceptual framework (CF) underpinning common barriers faced by rural CVD patients to enroll in behavioral intervention trials. We conducted a literature review using several electronic databases to obtain a representative sample of research articles, synthesized the evidence, and developed a CF to explain the barriers that may affect the research participation rate of rural residents with CVD or related risks. We found our evidence-based CF well explained the barriers for rural CVD patients to take part in behavioral intervention trials. Besides contextual factors (i.e. patient, community and research levels), other common factors impacting rural patients' intent to enroll are lack of awareness and understanding about behavioral trials, limited support from their healthcare providers and social circles, unfavorable attitudes, and the lack of opportunity to participating research. The findings demonstrate the evidence-based model consisting of interlinked multi-level factors may help our understanding of the barriers encountered by rural CVD patients participating interventions to promote behavioral change. The implication for researchers is that identifying and developing strategies to overcome the barriers precedes conducting studies in rural communities.


Acid mucopolysaccharide (glycosaminoglycan) at the epithelial-mesenchymal interface of mouse embryo salivary glands.
Acid mucopolysaccharide (glycosaminoglycan) has been demostrated at the epithelial-mesenchymal interface of mouse embryo submandibular glands by (a) specific staining for polymeric sulfate with Alcian blue 8 GX at various magnesium concentrations, (b) specific staining for polymeric uronic acid by selective oxidation of these residues to Schiff-reactive compounds, (c) electron microscope localization of ruthenium red staining, (d) radioautographic localization of glucosamine-(3)H and (35)SO(4), and (e) by susceptibility of the glucosamine radioactivity at the interface to digestion with protease-free hyaluronidase. Moreover, material labeled with glucosamine-(3)H and (35)SO(4) and with chemical characteristics identical with those of acid mucopolysaccharide were isolated from the glands. Acid mucopolysaccharide is distributed over the entire epithelial surface. The amount of acid mucopolysaccharide, as revealed by the staining procedures, is nearly equivalent at all sites. In contrast, the rate of accumulation of glucosamine-labeled mucopolysaccharide is greater at the surface of the distal ends of the growing and branching lobules. This distribution of newly synthesized acid mucopolysaccharide at the sites of incipient cleft formation suggests that surface-associated acid mucopolysaccharide is involved in the morphogenetic process. A mechanism of branching morphogenesis is proposed which accounts for the distribution of collagen fibers and total and newly synthesized acid mucopolysaccharide at the epithelial surface.


Pulmonary artery stenosis due to external compression by a calcified pericardial band.
A 60-year-old male with exertional dyspnea was referred to our hospital. Right pulmonary artery stenosis due to external compression by a calcified band was diagnosed by echocardiography, computed tomography, and magnetic resonance imaging. Percutaneous transluminal angioplasty was conducted in vain due to vascular recoil and failure of stent delivery. Pulmonary bypass grafting was performed successfully. The surgery indicated a probable etiology of chronic pericarditis. This is an extremely rare case of adult pulmonary artery stenosis without a known history of congenital disease, constrictive pericarditis, tuberculosis, or surgery.


Synthesis of N-acetylglucosamine-modified ara-C and its effect on ovarian cancer cells.
1-beta-D-Arabinofuranosylcytosine (ara-C) was modified by reaction of tetra-N-acetylchitotetraose ((GlcNAc)4) using the transglycosylation activity of thermostable chitinase (EC 18.104.22.168) from Bacillus licheniformis X-7u. The structure of the modified ara-C was determined to be either beta 1-3'- or beta 1-5'-linked GlcNAc-ara-C or (GlcNAc)2-ara-C. The total yield of these glycosylated ara-Cs was about 10%. GlcNAc-ara-C and (GlcNAc)2-ara-C depressed the growth of G-401 cancer cells, while 5-O-beta-D-galactopyranosyl-beta-D-arabinofuranosylcytosine (Gal-ara-C) had no effect on G-401 cells.


The role of antibiotics in Campylobacter pylori associated peptic ulcer disease.
Since the recognition and first culture of Campylobacter pylori (Cp) the hypothesis of a pathogenic role has been strengthened by numerous investigations. Its close association with active chronic gastritis and even active duodenitis, and the disappearance of these pathologic conditions with antimicrobial treatment suggest a pathogenic role for Cp in active chronic gastritis. The close association of antral gastritis with duodenal ulcer (DU) suggests that Cp associated active chronic gastritis may be an important precondition for the development of DU. Therapy studies so far using either bismuth, antibiotics, or a combination of both could demonstrate that the healing of DU ulcer was closely related to the clearance of Cp and healing of gastritis. Relapse of DU was closely associated with reappearance of Cp and active chronic gastritis. At the present state the combination of bismuth salts and antibiotics has achieved the highest eradication rates of Cp and thus lowest relapse rates of DU. Antibiotics therefore seem to be an indispensable factor in the antimicrobial treatment of Cp associated diseases.


[On "the moxibustion shouldn't be applied at Shimen (CV 5) on female"].
The TCM theory "moxibustion shouldn't be applied at Shimen (CV 5) on female" is discussed in this article, which provides theoretical instruction on proper clinical application of Shimen (CV 5). Based on literature study, ancient classics concerning contraindication of "moxibustion shouldn't be applied at Shimen (CV 5) on female" were studied. TCM theory "moxibustion shouldn't be applied at Shimen (CV 5) on female" was explored profoundly through ancient record, physiological relations between Shimen (CV 5) and pregnancy, the relation between the anatomic structure of Shimen (CV 5) and the extra acupoint Jueyun Xue. And the result indicated that as an acupoint with contraindications, Shimen (CV 5) should be attached with great importance in its clinical practice on female patients. Reinforcing manipulation should be given instead of reducing. Moxibustion should be applied with cautiousness on the point, especially during pregnancy.


Multiple needle-stick injuries with risk of human immunodeficiency virus exposure in a primary school.
Twenty children received needle-stick injuries with a risk of exposure to human immunodeficiency virus type 1 during an incident in a primary school playground. All were counseled and offered human immunodeficiency virus postexposure prophylaxis. All 20 children started postexposure prophylaxis, and 19 attended for follow-up testing 3 months later. More than one-half of the children completed the full 4-week course of treatment. None of the 19 children tested seroconverted after the incident.


Bioanalytical method transfer considerations of chromatographic-based assays.
Bioanalysis is an important part of the modern drug development process. The business practice of outsourcing and transferring bioanalytical methods from laboratory to laboratory has increasingly become a crucial strategy for successful and efficient delivery of therapies to the market. This chapter discusses important considerations when transferring various types of chromatographic-based assays in today's pharmaceutical research and development environment.


Complete mitochondrial genome of the Xiangjiang barbel chub Squaliobarbus curriculus: comparative analysis of the genetic variation associated with geographical population.
The barbel chub (Squaliobarbus curriculus), a kind of small commercial fish, is widespread in China. In this study, we sequenced the mitochondrial genome of the barbel chub from the Xiangjiang River. The total length of the mitochondrial genome is 16,619 bp, with the base composition of 31.19% A, 25.01% T, 27.68% C, and 16.12% G. The organization and arrangement of these genes are the same as that found in the teleosts, including 2 ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes, and a major noncoding control region (D-loop region). Compared with the S. curriculus collected from Jiangsu province, there were 29 mutation sites in the mitogenome sequence of Xiangjiang S. curriculus. All the mutation sites were transitions and mainly occurred in protein-coding genes (21/29), two mutation sites occurred in transfer RNA, two occurred in ribosomal RNA, and four occurred in D-loop region. Among the 21 mutation sites in protein-coding genes, 6 mutation sites resulted in amino acid mutation in ND2, ATPase6, COX3, ND4, and Cytb genes, while the others were synonymous substitutions. These results indicated that there was genetic variation in different geographical populations of S. curriculus.


Improved connectivity and cognition due to cognitive stimulation in Alzheimer's disease.
Due to the increasing prevalence of Alzheimer's disease (AD) and the limited efficacy of pharmacological treatment, the interest in non-pharmacological interventions, e.g., cognitive stimulation therapy (CST), to improve cognitive dysfunction and the quality of life of AD patients are on a steady rise. Here, we examined the efficacy of a CST program specifically conceptualized for AD dementia patients and the neural mechanisms underlying cognitive or behavioral benefits of CST. Using neuropsychological tests and MRI-based measurements of functional connectivity, we examined the (neuro-) psychological status and network changes at two time points: pre vs. post-stimulation (8 to 12 weeks) in the intervention group (n = 15) who received the CST versus a no-intervention control group (n = 15). After CST, we observed significant improvement in the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale, cognitive subsection (ADAS-cog), and the behavioral and psychological symptoms of dementia (BPSD) scores. These cognitive improvements were associated with an up-regulated functional connectivity between the left posterior hippocampus and the trunk of the left postcentral gyrus. Our data indicate that CST seems to induce short-term global cognition and behavior improvements in mild to moderate AD dementia and enhances resting-state functional connectivity in learning- and memory-associated brain regions. These convergent results prove that even in mild to moderate dementia AD, neuroplasticity can be harnessed to alleviate cognitive impairment with CST.


Changing pattern of diet in Europe.
The traditional wide range in diet in Europe that was based on climate and geography are slowly being eroded as modern transport and communications bring wider ranges of foods to the markets, and as modern travel cultures are eroding the boundaries of palatability. Tradition and history are still important factors, and the climatic variations are still there. Public education programmes encourage those living in the more northern countries to adopt a diet more similar to that consumed in the Mediterranean area. The programmes are having some success. Unfortunately, however, cultural factors seem to be persuading those living in the south to eat a more northern diet with more meat and animal fat.


Measurement of cholesterol and triglyceride.
As part of a continuing series on how the work of pathology laboratories contribution to patient care, this article looks at the measurement of the concentration of cholesterol and triglyceride in blood. The normal physiological function of cholesterol and triglyceride is described and blood sampling precautions explained. Finally, the causes and clinical consequences of abnormally raised levels are discussed.


An old entity, a new trigger: Post COVID-19 vaccine pityriasis rubra pilaris.
Pityriasis rubra pilaris (PRP) is a rare, acquired, chronic papulosquamous dermatosis which can occur in all ages. PRP can be associated with infection, autoimmunity, drugs and malignancies, and can be idiopathic. PRP following vaccination has been rarely described in the literature. To the best of our knowledge, we report the first case of PRP two weeks following COVID-19 vaccination (Covishield). A 72-year-old male presented to the outpatient dermatology department at All India Institute of Medical Sciences - Bhopal with minimally pruritic superficial plaques since one week. The patient was vaccinated against COVID-19 with Covishield two weeks earlier. The lesions developed as erythematous scaly follicular papules and plaques over axilla that rapidly spread to the trunk in the following weeks and involved palms and soles as well as thickening and fissuring. The clinical features suggested PRP. The histopathology showed epidermal acanthosis with hypergranulosis alternating with parakeratosis and orthokeratosis with broad rete ridges with follicular plugging. The patient had started taking topical corticosteroids and emollients, which proved effective. There was no recurrence after receiving a second dose on follow-up. In patients presenting with new onset PRP in this COVID-19 era, the possibility of vaccine as a trigger should be taken into consideration, and further dosing should be carefully monitored in view of possible recurrence.


[MINIINVASIVE TECHNOLOGIES IN TREATMENT OF POSTOPERATIVE ABDOMINAL HERNIAS].
Methods and results of treatment of 119 patients, suffering postoperative abdominal hernia, were analyzed. There was established, that application of laparoscopic miniinvasive technologies permits to improve the results of treatment in patients in comparison with those after open operative interventions, due to shortening of the operation duration, better visualization during viscerolysis conduction, shortening of rehabilitation period, the patients postoperative quality of life improvement.


Structural basis for binding of the renal carcinoma target hypoxia-inducible factor 2α to prolyl hydroxylase domain 2.
The hypoxia-inducible factor (HIF) prolyl-hydroxylases (human PHD1-3) catalyze prolyl hydroxylation in oxygen-dependent degradation (ODD) domains of HIFα isoforms, modifications that signal for HIFα proteasomal degradation in an oxygen-dependent manner. PHD inhibitors are used for treatment of anemia in kidney disease. Increased erythropoietin (EPO) in patients with familial/idiopathic erythrocytosis and pulmonary hypertension is associated with mutations in EGLN1 (PHD2) and EPAS1 (HIF2α); a drug inhibiting HIF2α activity is used for clear cell renal cell carcinoma (ccRCC) treatment. We report crystal structures of PHD2 complexed with the C-terminal HIF2α-ODD in the presence of its 2-oxoglutarate cosubstrate or N-oxalylglycine inhibitor. Combined with the reported PHD2.HIFα-ODD structures and biochemical studies, the results inform on the different PHD.HIFα-ODD binding modes and the potential effects of clinically observed mutations in HIFα and PHD2 genes. They may help enable new therapeutic avenues, including PHD isoform-selective inhibitors and sequestration of HIF2α by the PHDs for ccRCC treatment.


Pyruvate Kinase Is Required for Sex Pheromone Biosynthesis in Helicoverpa armigera.
Pyruvate kinase (PYK) is a speed-limited enzyme of glycolysis that catalyzes the formation of pyruvate, and plays an important role in acetyl-CoA synthesis. The acetyl-CoA is the precursor of sex pheromone biosynthesis in Helicoverpa armigera. However, the role of PYK in sex pheromone biosynthesis remains elusive. Here, PYK in H. armigera (HaPYK) was found to be highly expressed in the pheromone glands (PGs). The developmental expression profile of HaPYK was consistent with the fluctuation of sex pheromone release. Function analysis revealed that the knockdown of HaPYK led to a decrease in the levels of pyruvic acid and acetyl-CoA in PGs, which in turn caused a significant decrease in cis-11-hexadecenal (Z11-16: Ald) production, female capability to attract males, and mating frequency. Further study demonstrated that sugar feeding (5% sugar) increased the transcription and enzyme activity of HaPYK, thereby facilitating sex pheromone biosynthesis. Moreover, pheromone biosynthesis activating neuropeptide (PBAN) upregulated HaPYK activity through protein kinase C (PKC), as shown by PKC-specific inhibitor analysis. Altogether, our results revealed that PBAN activated HaPYK by Ca2+/PKC, thereby regulating the synthesis of pyruvate and subsequent acetyl-CoA, ensuring the supply of sex pheromone precursor, and finally facilitating sex pheromone biosynthesis and mating behavior.


Defect Detection in Textures through the Use of Entropy as a Means for Automatically Selecting the Wavelet Decomposition Level.
This paper presents a robust method for defect detection in textures, entropy-based automatic selection of the wavelet decomposition level (EADL), based on a wavelet reconstruction scheme, for detecting defects in a wide variety of structural and statistical textures. Two main features are presented. One of the new features is an original use of the normalized absolute function value (NABS) calculated from the wavelet coefficients derived at various different decomposition levels in order to identify textures where the defect can be isolated by eliminating the texture pattern in the first decomposition level. The second is the use of Shannon's entropy, calculated over detail subimages, for automatic selection of the band for image reconstruction, which, unlike other techniques, such as those based on the co-occurrence matrix or on energy calculation, provides a lower decomposition level, thus avoiding excessive degradation of the image, allowing a more accurate defect segmentation. A metric analysis of the results of the proposed method with nine different thresholding algorithms determined that selecting the appropriate thresholding method is important to achieve optimum performance in defect detection. As a consequence, several different thresholding algorithms depending on the type of texture are proposed.


Atrial Septal Aneurysm and Atrial Septal Defect Association - an Uncommon But Well- Recognized Association.
Atrial septal aneurysm (ASA) is an uncommon but wellrecognized cardiac abnormality. This educational text reviews the case of a 54-year-old female presenting an ASA related to a small ostium secundum atrial septal defect. The considerable signs and symptoms, interestingly, have not been justified by the clinical and hemodynamic investigations. So, we opted for a better imaging investigation with cardiac catheterization and transesophageal echocardiography. The surgical process was earlier indicated and performed with aid of cardiopulmonary bypass.


Improved Understanding of the High Shear Wet Granulation Process under the Paradigm of Quality by Design Using Salvia miltiorrhiza Granules.
High shear wet granulation (HSWG) is a shaping process for granulation that has been enhanced for application in the pharmaceutical industry. However, study of HSWG is complex and challenging due to the relatively poor understanding of HSWG, especially for sticky powder-like herbal extracts. In this study, we used Salvia miltiorrhiza granules to investigate the HSWG process across different scales using quality by design (QbD) approaches. A Plackett-Burman experimental design was used to screen nine granulation factors in the HSWG process. Moreover, a quadratic polynomial regression model was established based on a Box-Behnken experimental design to optimize the granulation factors. In addition, the scale-up of HSWG was implemented based on a nucleation regime map approach. According to the Plackett-Burman experimental design, it was found that three granulation factors, including salvia ratio, binder amount, and chopper speed, significantly affected the granule size (D50) of S. miltiorrhiza in HSWG. Furthermore, the results of the Box-Behnken experimental design and validation experiment showed that the model successfully captured the quadratic polynomial relationship between granule size and the two granulation factors of salvia ratio and binder amount. At the same experiment points, granules at all scales had similar size distribution, surface morphology, and flow properties. These results demonstrated that rational design, screening, optimization, and scale-up of HSWG are feasible using QbD approaches. This study provides a better understanding of HSWG process under the paradigm of QbD using S. miltiorrhiza granules.


Intracellular localization of calcium in pancreatic B-cells in relation to insulin secretion by the perfused ob/ob mouse pancreas.
Changes in the distribution of intracellular calcium in B-cells from the perfused ob/ob mouse pancreas in relation to the secretory state of the B-cell were followed using the pyroantimonate technique for calcium precipitation. At the internal surface of the B-cell membrane a highly mobile reservoir of calcium was mobilized during the first 1-3 min of stimulation of the B-cells by glucose as well as by tolbutamide resulting in an increased calcium precipitation in the cytoplasma. During prolonged stimulation of insulin secretion by glucose the calcium precipitation along the internal surface of the B-cell membrane was restored. Concomitantly calcium deposits in the secretory granules and to a lesser extend in the mitochondria increased. Tolbutamide neither restored the membrane-bound pool nor increased the calcium uptake of the secretory granules but decreased mitochondrial calcium. It suggests that this cytoplasmic increase of calcium primarily results from intracellular redistribution.


Factors Influencing Non-albicans Candidemia: A Case-Case-Control Study.
The study identified factors predisposing to non-albicans candidemia with special interest to prior antimicrobial treatment. A retrospective, case-case-control study was performed at the University Hospital of Heraklion, Greece, from November 2007 through September 2011 including adult patients. The study had three groups. The first included 58 patients with non-albicans candidemia, the second 48 with C. albicans candidemia, while the third (control) 104 without candidemia. Each of the two candidemia groups was compared with the control using multivariate logistic regression model. The mean (SD) age of the non-albicans, the albicans and the control patients was 67 (12), 67 (18) and 59 (19) years, respectively. The most common non-albicans Candida spp. isolated were C. parapsilosis in 19 patients (33%), C. glabrata in 17 (29%) and C. tropicalis in 15 (26%). Independent risk factors for non-albicans candidemia were prior treatment with quinolones (p < 0.001), b-lactam-b-lactamase inhibitors (p = 0.011) and presence of central venous catheter (p = 0.05), while for C. albicans candidemia were prior treatment with quinolones (p < 0.001), carbapenems (p = 0.003) along with cardiac disease (p < 0.001). Neither duration of hospitalization nor in-hospital mortality [41% for the non-albicans vs 29% for C. albicans group (p = 0.192)] was significantly different between the two candidemia groups. The study reveals the role of antimicrobial exposure as a risk factor for candidemia caused by different species. Prior treatment with b-lactam-b-lactamase inhibitors was associated with non-albicans, while with carbapenems with C. albicans candidemia. Prior use of quinolones was associated with candidemia in general.


The effects of diethylstilboestrol and castration on the nucleic acid and protein metabolism of rat prostate gland.
1. Implantation of diethylstilboestrol pellets into adult male rats brings about similar biochemical changes in the nucleic acid and protein metabolism to castration. 2. The avidity of the prostate for labelled diethylstilboestrol was greater than that of the other organs examined. 3. Uptake of labelled diethylstilboestrol and testosterone into the nuclei of the rat prostate is greater in castrated rats than in controls. 4. Diethylstilboestrol appeared to be associated with the protein and not with the DNA fraction of the nucleus.


Oxidative stress-CBP axis modulates MOB1 acetylation and activates the Hippo signaling pathway.
Reactive oxygen species (ROS) are constantly produced in cells, an excess of which causes oxidative stress. ROS has been linked to regulation of the Hippo pathway; however, the underlying detailed mechanisms remain unclear. Here, we report that MOB1, a substrate of MST1/2 and co-activator of LATS1/2 in the canonical Hippo pathway, interacts with and is acetylated at lysine 11 by acetyltransferase CBP and deacetylated by HDAC6. MOB1-K11 acetylation stabilizes itself by reducing its binding capacity with E3 ligase Praja2 and subsequent ubiquitination. MOB1-K11 acetylation increases its phosphorylation and activates LATS1. Importantly, upstream oxidative stress signals promote MOB1 acetylation by suppressing CBP degradation, independent of MST1/2 kinase activity and HDAC6 deacetylation effect, thereby linking oxidative stress to activation of the Hippo pathway. Functionally, the acetylation-deficient mutant MOB1-K11R promotes lung cancer cell proliferation, migration and invasion in vitro and accelerates tumor growth in vivo, compared to the wild-type MOB1. Clinically, acetylated MOB1 corresponds to better prediction of overall survival in patients with non-small cell lung cancer. Therefore, as demonstrated, an oxidative stress-CBP regulatory axis controls MOB1-K11 acetylation and activates LATS1, thereby activating the Hippo pathway and suppressing YAP/TAZ nuclear translocation and tumor progression.


Serum independence of transcription from the promoter of an avian retrovirus in v-src-transformed cells is a primary, intracellular effect of increased tyrosine phosphorylation.
We found that transcription from the promoter in the long terminal repeat of Rous sarcoma virus in rat 3Y1 cells is dependent on the presence of serum in the culture. However, this serum dependence of transcription was relieved when 3Y1 cells were transformed by the oncogene v-src. Crossfeeding experiments showed no evidence for the production of a serum-substituting extracellular growth factor by the transformed cells. Using 3Y1 cells transformed with temperature-sensitive Rous sarcoma virus, we showed that the tyrosine kinase activity of pp60v-src was responsible for the serum-sparing effect on the level of RNA expressed from the viral promoter. Sodium orthovanadate, an inhibitor of phosphotyrosine phosphatases that nonspecifically elevates the level of phosphotyrosine-containing proteins in cells, stimulated transcription from the viral promoter. The effects of both pp60v-src and orthovanadate were resistant to cycloheximide. These results suggest that the serum independence of transcription from the viral promoter in v-src-transformed cells was probably due to the constitutive activation of intracellular growth-factor pathways by the tyrosine kinase activity of pp60v-src.


[Controlled study of an abbreviated form of the Hamburg-Wechsler Intelligence Test for Adults (HAWIE, Dahl's WIP) in a heterogenous clinical group].
The "reduzierte Wechsler-Intelligenztest für psychiatrische Kranke (WIP)" by Dahl, a short form of the German version (HAWIE) of the Wechsler-Bellevue Intelligence Scale, comprising the subtests Information, Similarities, Picture Completion and Block Design was applied in a replication study to a heterogeneous group of 420 mental patients. Results show a sufficiently high level of agreement (multiple correlation) between the present test and the HAWIE-IQ. With this result and a sample independence of the correlation, two of the requirements of board clinical application of the WIP are met. On the other hand Dahl's assumption that the WIP represents the optimal (quadruple)combination of subtests of the full scale was not confirmed. Criticisms of the WIP in the literature are discussed. On the basis of previous studies and the present investigations it is held that the WIP is a useful contribution to measurement of general ability in a clinical setting.


Relation between Helicobacter pylori cagA status and risk of peptic ulcer disease.
Although colonization with any Helicobacter pylori strain is associated with peptic ulcer, it is uncertain whether the risk is greater with cagA(+) or cagA(-) strains, which differ in their biology. A nested case-control study was done, based on a cohort of 5,443 Japanese-American men examined on the Hawaiian island of Oahu from 1967 to 1970. A total of 150 men with gastric ulcer, 65 with duodenal ulcer, and 14 with both diseases were identified. The authors matched the 229 cases with 229 population controls and tested their serum for immunoglobulin G antibodies to H. pylori and immunoglobulin G antibodies to the cagA product of H. pylori using enzyme-linked immunosorbent assays. Persons with H. pylori positivity had an odds ratio of 4.0 (95% confidence interval (CI): 1.9, 8.5) for gastric ulcer and 2.5 (95% CI: 0.8, 7.4) for duodenal ulcer. For CagA positivity, the odds ratios were 1.4 (95% CI: 0.9, 2.4) for gastric ulcer and 2.6 (95% CI: 1.1, 5.8) for duodenal ulcer. Subjects who were seropositive for both H. pylori and CagA had an odds ratio of 4.4 (95% CI: 1.8, 10.5) for gastric ulcer and 5.8 (95% CI: 1.1, 30.0) for duodenal ulcer. The results suggest that colonization with a cag(+) H. pylori strain elevates the risk beyond that of a cag(-) H. pylori strain for both gastric and duodenal ulcers.


Probing the Mechanically Stable Solid Electrolyte Interphase and the Implications in Design Strategies.
The inevitable volume expansion of secondary battery anodes during cycling imposes forces on the solid electrolyte interphase (SEI). The battery performance is closely related to the capability of SEI to maintain intact under the cyclic loading conditions, which basically boils down to the mechanical properties of SEI. The volatile and complex nature of SEI as well as its nanoscale thickness and environmental sensitivity make the interpretation of its mechanical behavior many roadblocks. Widely varied approaches are adopted to investigate the mechanical properties of SEI, and diverse opinions are generated. The lack of consensus at both technical and theoretical levels has hindered the development of effective design strategies to maximize the mechanical stability of SEIs. Here, the essential and desirable mechanical properties of SEI, the available mechanical characterization methods, and important issues meriting attention for higher test accuracy are outlined. Previous attempts to optimize battery performance by tuning SEI mechanical properties are also scrutinized, inconsistencies in these efforts are elucidated, and the underlying causes are explored. Finally, a set of research protocols is proposed to accelerate the achievement of superior battery cycling performance by improving the mechanical stability of SEI.


Clinical and Serological Characteristics of a Monocentric Cohort of Patients Affected by Interstitial Pneumonia with Autoimmune Features (IPAF).
Interstitial lung diseases (ILDs) are diseases characterised by excessive deposition of collagen matrices in the pulmonary interstitium. Some of them are considered idiopathic (idiopathic pulmonary fibrosis - IPF), others are related to known pathologies such as connective tissue diseases (CTDs-ILD). Patient affected by ILD and features referable to CTD, not satisfying CTD criteria, are called Interstitial pneumonia with autoimmune features (IPAF) patients. The aim of this report was to investigate clinical and serologic features of a monocentric cohort of patients with IPAF. Another objective was to describe the autoantibody profile, clinical features, High Resolution Computerised Tomography (HRCT) and Nailfold Video Capillaroscopy (NVC) patterns. 36 IPAF patients were consecutively enrolled. Clinical, serological, and morphological features were collected. 36 consecutive IPAF patients were enrolled from January 2021 to January 2022. Raynaud's phenomenon was the most frequent symptom identified. We also described other signs and symptoms not included in IPAF criteria. 36,1% of patients demonstrated a Usual Interstitial Pneumonia (UIP) pattern by HRCT. Pulmonary arterial pressure estimation (PAPs) resulted elevated (≥ 25 mmHg) in 6 patients. Antinuclear antibodies (ANA) ≥ 1/80 was the most frequent autoantibody, followed by anti-Ro, in patients with UIP pattern and Non-Specific Interstitial Pneumonia (NSIP) pattern at HRCT. NVC highlighted non-specific microangiopathy as the most common pattern especially in UIP patients. This paper may contribute to stimulate the interest in better characterisation of clinical, serologic, and instrumental features for IPAF patients by redefining IPAF classification criteria in order to treat them as best as possible.


Failure of unilateral carotid artery ligation to affect pressure-induced interruption of rapid axonal transport in primate optic nerves.
Previous experiments showed that optic nerve axonal transport can be blocked at the level of the lamina cribrosa by elevated intraocular pressure. In an effort to discover if this blockage might be secondary to pressure-induced ischemia, we studied the effect of unilateral common carotid artery ligation upont the pressure-induced interruption of axonal transport. In 13 owl monkeys (Aotus trivirgatus), the right common carotid artery was ligated within the anterior cervical triangle. Three days later, ophtalmodynomometry was performed on all experimental eyes. In nine of the 13 animals, this estimate of ophthalmic artery pressure was 10 to 20 mm Hg less in the right compared to the left eye. Optic nerve axonal transport was studied in right and left eyes during 5 hours of increased intraocular pressure (ocular pressure 35 mm Hg less than mean femoral artery blood pressure). No significant difference in the extent to which the transport mechanisms were interrupted could be demonstrated when comparing right and left eyes of the experimental animals. These observations fail to support a vascular mechanism for this pressure-induced interruption of axonal transport.


[The clinical application of gene diagnosis and genetic counseling on hereditary hearing loss].
Objective:To summarize the clinic procedure and experience about gene diagnosis and genetic counseling on hereditary hearing loss, and explore the strategy and principle about gene diagnosis and genetic counseling on hereditary hearing loss.Method:A retrospective analysis was used on the clinical data of 151 cases who aim at genetic counseling. The all cases were divided into 5 groups according to the purpose of genetic counseling, such as the occurrence risk of hearing loss, the etiological analysis, the choice of the intervention way, the examination guidance, the prevention of hearing loss and the usage requirement of Aminogly cosides drugs. The counseling procedure includes the investigation of the etiology and family history, drawing the family pedigree, general physical examination, auditory examination and genetic analysis. Sanger sequencing analysis and/or Targeted nextgeneration sequencing was utilized to detect the deaf-gene mutations. At last, the genetic counseling, fertility guidance and prenatal diagnosis will be made on the basis of the results of gene detection. Result:There are 33 newborns who did not pass the deafgene screening, 9 of them could be diagnosed definitely as hereditary hearing loss, and the other 24 were the carriers of deafgene mutation. Eighty of 104 deaf patients were diagnosed definitely as hereditary hearing loss and the related gene mutation was found. Six objects in the 10 patients with auditory neuropathy are diagnosed as OTOF or SLC17A8 gene mutations before cochlear implantation. Three of 7 reproductive age objects who had family history were recessive deaf-gene carriers, 2 of them carried the same target gene with the mate who receive our fertility guidance and prenatal diagnose. The other 1 object carried the dominant genetic mutation(incomplete dominant heredity). There were 4 pregnant women who did not pass the deaf-gene screening, 1 of them carry the same target gene with the mate. The populations who want to use Aminoglycosides drugs were not diagnosed as carrying any related mitochondrial gene mutation. We carried out the genetic counseling according to the results of gens detection and clinical phenotype.Conclusion:Genetic counseling is based on the different purpose. The analysis of gene diagnosis should be considered to combine with the clinical phenotype. The principle of choosing the objects to make a gene diagnosis includes: ①the all deaf-genes sequencing was applied for the deaf patients. ② the screening target gene sequencing was used for the newborns who did not pass the deaf-gene screening and the mate whose pregnant wife did not pass the deafgene screening. ③the specific target gene sequencing could be used for the patients who has a clear family history or specific phenotype.


How signaling pathways interact with gene transcription.
Activation of inflammatory cells by extracellular stimuli such as cytokines, viruses, allergens or oxidants lead to stimulation of intracellular amplifying signalling pathways. These activation pathways lead to enhanced inflammatory gene expression through activation of transcription factors such as nuclear factor kappa B (NF-kappa B). Upon activation, NF-kappa B translocates to the nucleus where it binds specific sites in the promoter regions of responsive genes in a time-dependent manner. This leads to the alterations in the structure of the surrounding DNA/chromatin complex resulting in local unwinding of DNA. Changes in chromatin structure occur as a result of recruitment of large, essentially pre-formed, complexes that contain chromatin remodelling factors and histone acetyltransferases (HATs) such as CREB binding protein (CBP). Acetylations of histones are regulated by HATs whose activity is controlled by a number of factors including phosphorylation. Phosphorylation of HATs by signalling pathways, differentiate themselves from those controlling specific transcription factor activation and result in enhanced transcriptional activity as a result of cross-talk between signalling pathways at the level of chromatin modifications.


A form of Jansen's metaphyseal chondrodysplasia with limited metabolic and skeletal abnormalities is caused by a novel activating parathyroid hormone (PTH)/PTH-related peptide receptor mutation.
A novel heterozygous PTH/PTHrP receptor missense mutation (T410R) was identified in a male and his two sons who are all affected by a less severe form of Jansen's metaphyseal chondrodysplasia (JMC). JMC is a rare disorder that is typically characterized by severe growth plate abnormalities that lead to short-limbed dwarfism. Furthermore, affected individuals usually show significant hypercalcemia, despite normal or undetectable levels of PTH and PTHrP. In contrast, the three affected members of this new family showed only mild skeletal dysplasia, comparatively normal stature, and blood calcium concentrations either within or at the upper end of the normal range. However, PTH levels were suppressed, and urinary calcium excretion was elevated, which led to nephrolithiasis in both children. When expressed in COS-7 cells, the PTH/PTHrP receptor with the T410R mutation led to agonist-independent cAMP formation, which was less pronounced than that observed with the previously identified T410P mutant. Our findings indicate that a mild form of JMC has been identified that is characterized by less pronounced skeletal and laboratory abnormalities.


Combined modality therapy for advanced Hodgkin's disease: long-term followup data.
From 1969 to 1979, 155 patients with advanced Hodgkin's disease were treated with a combined modality protocol (combination chemotherapy and irradiation to all sites of disease). The actuarial 10-year survival of all patients who started therapy is 78%, and the relapse-free survival is 67%. Within the group of patients with advanced disease, age greater than 40 years and/or stage IV disease with multiple extranodal sites of involvement adversely affected prognosis. Since 1978, these patients have been treated with MOPP-ABVD and irradiation, with a resulting 3-year survival of 87% compared with 58% for those treated with MVVPP in prior years. A comparison between MVVPP and MOPP, also begun in 1978, has thus far yielded no significant differences. Second malignancies have occurred in four patients apparently cured of their Hodgkin's disease: two patients with acute leukemia and two with non-Hodgkin's lymphoma. Avascular necrosis of bone has developed in nine patients. There have not been other serious long-term complications. This combined modality treatment approach appear to offer a significant survival advantage compared with treatment programs using chemotherapy alone.


Health assessment in child care centers: parent and staff perceptions.
The purpose of this study was to identify preschool children's health needs in child care centers, as perceived by parents and staff. A Health Care Services Assessment was completed by 55 parents and 13 staff in four urban child care centers to identify the health services needed and children's common health problems. The majority (69%) of the parents and staff reported that onsite health services were needed at least once a week. Helpful health services were identified as screening exams for respiratory illnesses (88%), other illnesses (87%), developmental problems (51%), and children with special needs (50%). The most commonly identified child health problems were colds (93%) and ear infections (75%). These findings indicate that efforts to protect the health of preschool children in child care centers might best begin with health services focused on prevention, such as screening children for illnesses and providing information on infection control.


Cochlear implantation in severe traumatic brain-injury and paranoid schizophrenia: two case studies.
In view of the demanding instruction and training requirements associated with cochlear implantation;,patients with cognitive impairments have typically been considered to be poor candidates for this procedure. This presumption persists in part because experience and research in this area are limited. We describe our experience with implanting cochlear devices in 2 patients who had significant psychological impairments; 1 patient had experienced a severe brain injury, and the other had paranoid schizophrenia. Nevertheless, both patients were able to follow the implant training program, and they experienced different degrees of improvement in their hearing. We discuss our preoperative evaluations of these patients and the key factors that led to our decision to proceed with surgery.


Blood Cadmium Is Associated with Osteoporosis in Obese Males but Not in Non-Obese Males: The Korea National Health and Nutrition Examination Survey 2008-2011.
Osteoporosis in males is becoming an important health concern in an aging society. The aim of this study was to investigate the associations between cadmium exposure and osteoporosis by considering the effect of obesity in aged males using a representative sample of the Korean population. Using the fourth and fifth Korea National Health and Nutrition Examination Survey data, 1098 males over 50 years of age were analyzed. The blood cadmium concentration was measured. The bone mineral density in the total hip, femur neck, and lumbar spine was measured using dual-energy X-ray absorptiometry. T-scores to determine the presence of osteoporosis were calculated using a Korean reference. Subjects were stratified into two groups according to obesity status (body mass index <25 kg/m² and ≥25 kg/m²). In comparison with obese subjects with blood cadmium <1.00 μg/L, those with blood cadmium >1.50 μg/L had odds ratios of 4.57 (95% confidence interval [CI] 1.49-14.01) and 5.71 (95% CI 1.99-16.38) at the femur neck and any site, respectively, after adjusting for potential confounders such as age, serum creatinine, vitamin D deficiency, smoking, alcohol drinking, and physical activity level. However, this association was not significant in non-obese males. In conclusion, the effect of cadmium on osteoporosis was different by obesity status in aged males.


Nonaqueous Capillary Electrophoretic Separation of Analogs of (24R)-1,24-Dihydroxyvitamin D3 Derivative as Predicted by Quantum Chemical Calculations.
Nonaqueous capillary electrophoretic (NACE) separation was obtained of analogs of (24R)-1,24-dihydroxyvitamin D3 derivative (calcipotriol) as predicted by quantum chemical calculations supported by the density functional theory (DFT). Among the key electronic properties investigated, absolute values of the dipole polarizability and energy gap between HOMO and LUMO molecular orbitals of the analog molecules differ significantly for particular analogs, and there is a direct relationship with their electrophoretic migration time. These differences and relationships suggest that the structurally related analogs should be separable in the electrostatic field. Indeed, the robust, sensitive, and rapid NACE method was first developed for the identification and determination of the anticancer analog of calcipotriol (coded PRI-2205) and its process-related impurities (coded PRI-2201, PRI-2203, and PRI-2204) in organic and aqueous biological solutions. The direct relation between the calculated electronic properties of the analogs and the experimental electrophoretic migration time could be a promising prospect for theoretically predicting the electrophoretic separations.


Intramedullary sclerosing meningioma: operative video.
Sclerosing meningiomas (SMs) represent a rare histological variant of meningiomas, first described in 1989 as invasive bulking masses of whorling collagen bundles with a minimum percentage of meningothelia-resembling cells, and they are often misdiagnosed. The literature reports only 30 cases of SMs, with only two of them being intramedullary. The authors present the case of a patient with a cervical intramedullary SM who presented with gait disturbances, sensory deficits, weakness in four extremities, and hyperreflexia. The surgery was performed under neurophysiological monitoring and after administration of sodium fluorescein, which allowed us to discriminate the exact myelotomy point. Intramedullary SMs are very rare entities whose correct management may result in a good outcome.


Secondary structure propensity and chirality of the amyloidophilic peptide p5 and its analogues impacts ligand binding - In vitro characterization.
Polybasic helical peptides, such as peptide p5, bind human amyloid extracts and synthetic amyloid fibrils. When radiolabeled, peptide p5 has been shown to specifically bind amyloid in vivo thereby allowing imaging of the disease. Structural requirements for heparin and amyloid binding have been studied using analogs of p5 that modify helicity and chirality. Peptide-ligand interactions were studied using CD spectroscopy and solution-phase binding assays with radiolabeled p5 analogs. The interaction of a subset of peptides was further studied by using molecular dynamics simulations. Disruption of the peptide helical structure reduced peptide binding to heparin and human amyloid extracts. The all-D enantiomer and the β-sheet-structured peptide bound all substrates as well as, or better than, p5. The interaction of helical and β-sheet structured peptides with Aβ fibrils was modeled and shown to involve both ionic and non-ionic interactions. The α-helical secondary structure of peptide p5 is important for heparin and amyloid binding; however, helicity is not an absolute requirement as evidenced by the superior reactivity of a β-sheet peptide. The differential binding of the peptides with heparin and amyloid fibrils suggests that these molecular interactions are different. The all-D enantiomer of p5 and the β-sheet peptide are candidates for amyloid targeting reagents in vivo. Efficient binding of polybasic peptides with amyloid is dependent on the linearity of charge spacing in the context of an α-helical secondary structure. Peptides with an α-helix or β-sheet propensity and with similar alignment of basic residues is optimal.


Attitudes to abortion in the era of reform: evidence from the Abortion Law Reform Association correspondence.
This article examines letters sent by members of the general public to the Abortion Law Reform Association (ALRA) in the decade immediately before the 1967 Abortion Act. It shows how a voluntary organisation, in their aim of supporting a specific cause of unclear legality, called forth correspondence from those in need. In detailing the personal predicaments of those facing an unwanted pregnancy, this body of correspondence was readily deployed by ALRA in their efforts to mobilise support for abortion law reform, thus exercising a political function. A close examination of the content of the letters and the epistolary strategies adopted by their writers reveals that as much as they were a lobbying tool for changes in abortion law, these letters were discursively shaped by debates surrounding that very reform.


A comprehensive review of the therapeutic potential of α-arbutin.
Cosmetic dermatology preparations such as bleaching agents are ingredients with skin-related biological activities for increasing and improving skin beauty. The possibility of controlling skin hyperpigmentation disorders is one of the most important research goals in cosmetic preparations. Recently, cosmetics containing herbal and botanical ingredients have attracted many interests for consumers of cosmetic products because these preparations are found safer than other preparations with synthetic components. However, high-quality trial studies in larger samples are needed to confirm safety and clinical efficacy of phytotherapeutic agents with high therapeutic index. Arbutin (p-hydroxyphenyl-β-d-glucopyranoside) is a bioactive hydrophilic polyphenol with two isomers including alpha-arbutin (4-hydroxyphenyl-α-glucopyranoside) and β-arbutin (4-hydroxyphenyl-β-glucopyranoside). It is used as a medicinal plant in phytopharmacy. Studies have shown that alpha-arbutin is 10 times more effective than natural arbutin. A comparison of IC50 values showed that α-arbutin (with concentration 2.0 mM) has a more potent inhibitory activity on human tyrosinase against natural arbutin (with higher concentration than 30 mM). A review of recent studies showed that arbutin could be beneficial in treatment of various diseases such as hyperpigmentation disorders, types of cancers, central nervous system disorders, osteoporosis, diabetes, etc. This study was designed to describe the therapeutic efficiencies of arbutin.


Sex bias in intergroup conflict and collective movements among social mammals: male warriors and female guides.
Intergroup conflict is a major evolutionary force shaping animal and human societies. Males and females should, on average, experience different costs and benefits for participating in collective action. Specifically, among mammals, male fitness is generally limited by access to mates whereas females are limited by access to food and safety. Here we analyse sex biases among 72 species of group-living mammals in two contexts: intergroup conflict and collective movements. Our comparative phylogenetic analyses show that the modal mammalian pattern is male-biased participation in intergroup conflict and female-biased leadership in collective movements. However, the probability of male-biased participation in intergroup conflicts decreased and female-biased participation increased with female-biased leadership in movements. Thus, female-biased participation in intergroup conflict only emerged in species with female-biased leadership in collective movements, such as in spotted hyenas and some lemurs. Sex differences are probably attributable to costs and benefits of participating in collective movements (e.g. towards food, water, safety) and intergroup conflict (e.g. access to mates or resources, risk of injury). Our comparative review offers new insights into the factors shaping sex bias in leadership across social mammals and is consistent with the 'male warrior hypothesis' which posits evolved sex differences in human intergroup psychology. This article is part of the theme issue 'Intergroup conflict across taxa'.


Nasal obstruction as a complication of pharyngeal flap surgery.
In a series of 85 patients who had pharyngeal flap surgery at Indiana University Medical Center, We found an unusually high incidence of hyponasality with total or near total nasal obstruction. The nasal obstruction was often occult, detected only after careful questioning and examination. Nasal obstruction was associated with peri-operative infection or micrognathia as in the Pierre Robin Anomalad. Flap division or port revision yielded a significant relief of the nasal obstruction and achievement of normal nasal balance.


BIOANALYSIS AND BIOTRANSFORMATION OF OLIGONUCLEOTIDE THERAPEUTICS BY LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY.
Since 2016, eight new oligonucleotide therapies have been approved which has led to increased interest in oligonucleotide analysis. There is a particular need for powerful bioanalytical tools to study the metabolism and biotransformation of these molecules. This review provides the background on the biological basis of these molecules as currently used in therapies. The article also reviews the current state of analytical methodology including state of the art sample preparation techniques, liquid chromatography-mass spectrometry methods, and the current limits of detection/quantitation. Finally, the article summarizes the challenges in oligonucleotide bioanalysis and provides future perspectives for this emerging field. © 2020 John Wiley & Sons Ltd.


Early and late presentation of the ovarian hyperstimulation syndrome: two distinct entities with different risk factors.
This study was designed to identify clinical predictors for early and late ovarian hyperstimulation syndrome (OHSS). A retrospective analysis of all 592 in-vitro fertilization (IVF) cycles from the programme's inception in 1988 up to March 1993 was performed. Six patients (1.0% of cycles) had moderate or severe OHSS presenting 3-7 days post-human chorionic gonadotrophin (HCG), and four patients (0.7% of cycles) had severe OHSS presenting 12-17 days post-HCG. No patient with early OHSS went on to develop late OHSS, and no patient with late OHSS had demonstrated early OHSS. Stepwise logistic regression showed that early OHSS was predicted by the number of oocytes retrieved (range 18-46) (P = 0.0001) and the oestradiol concentration on the day HCG was given (range 12,122-24,454 pmol/l) (P = 0.0003). Late OHSS was predicted by the number of gestational sacs (range 2-3) on ultrasound 4 weeks after embryo transfer (P = 0.0001) but not by the number of oocytes or oestradiol. Early OHSS was an acute effect of the HCG administered prior to egg retrieval in women with high oestradiol and larger numbers of follicles (range 22-51). Late OHSS was induced by the rising serum concentration of HCG produced by the early pregnancy, and in this series of cases it was associated only with multiple gestation.


Imitative behaviors facilitate communicative gaze in children with autism.
Adult imitation of children with autistic spectrum disorders (ASD) is likely to be effective in facilitating their communicative gaze behaviors. This study compared imitative behaviors to contingent, but not-imitative, behaviors in children with ASD and those with typical development (TD). The caretakers were asked to play an imitative role to explore the effects of imitation intervention on parenting. The results indicated that children with ASD gazed longer at imitative behaviors than mere contingent behaviors while children with TD gazed at their mother irrespective of her type of intervention. The present study highlights the benefits of caretakers using imitation while caring for children with ASD. The power of imitation for children with ASD suggests its therapeutic application to home-based intervention by caretakers.


The β-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium.
In the present study, we compared the cardioprotective effects of TRV120023, a novel angiotensin II (ANG II) type 1 receptor (AT1R) ligand, which blocks G protein coupling but stimulates β-arrestin signaling, against treatment with losartan, a conventional AT1R blocker in the treatment of cardiac hypertrophy and regulation of myofilament activity and phosphorylation. Rats were subjected to 3 wk of treatment with saline, ANG II, ANG II + losartan, ANG II + TRV120023, or TRV120023 alone. ANG II induced increased left ventricular mass compared with rats that received ANG II + losartan or ANG II + TRV120023. Compared with saline controls, ANG II induced a significant increase in pCa50 and maximum Ca(2+)-activated myofilament tension but reduced the Hill coefficient (nH). TRV120023 increased maximum tension and pCa50, although to lesser extent than ANG II. In contrast to ANG II, TRV120023 increased nH. Losartan blocked the effects of ANG II on pCa50 and nH and reduced maximum tension below that of saline controls. ANG II + TRV120023 showed responses similar to those of TRV120023 alone; compared with ANG II + losartan, ANG II + TRV120023 preserved maximum tension and increased both pCa50 and cooperativity. Tropomyosin phosphorylation was lower in myofilaments from saline-treated hearts compared with the other groups. Phosphorylation of cardiac troponin I was significantly reduced in ANG II + TRV120023 and TRV120023 groups versus saline controls, and myosin-binding protein C phosphorylation at Ser(282) was unaffected by ANG II or losartan but significantly reduced with TRV120023 treatment compared with all other groups. Our data indicate that TRV120023-related promotion of β-arrestin signaling and enhanced contractility involves a mechanism promoting the myofilament response to Ca(2+) via altered protein phosphorylation. Selective activation of β-arrestin-dependent pathways may provide advantages over conventional AT1R blockers.


Hippocampal volume as an index of Alzheimer neuropathology: findings from the Nun Study.
To determine whether hippocampal volume is a sensitive and specific indicator of Alzheimer neuropathology, regardless of the presence or absence of cognitive and memory impairment. Postmortem MRI scans were obtained for the first 56 participants of the Nun Study who were scanned. The area under receiver operating characteristic curves, sensitivity, specificity, and positive and negative predictive values were used to assess the diagnostic accuracy of hippocampal volume in predicting fulfillment of Alzheimer neuropathologic criteria and differences in Braak staging. Hippocampal volume predicted fulfillment of neuropathologic criteria for AD for all 56 participants (p < 0.001): 24 sisters who were demented (p = 0.036); 32 sisters who remained nondemented (p < 0.001), 8 sisters who remained nondemented but had memory impairment (p < 0.001), and 24 sisters who were intact with regard to memory and cognition at the final examination prior to death (p = 0.003). In individuals who remained nondemented, hippocampal volume was a better indicator of AD neuropathology than a delayed memory measure. Among nondemented sisters, Braak stages III and VI were distinguishable from Braak stages II or lower (p = 0.001). Among cognitively intact individuals, those in Braak stage II could be distinguished from those in stage I or less (p = 0.025). Volumetric measures of the hippocampus may be useful in identifying nondemented individuals who satisfy neuropathologic criteria for AD as well as pathologic stages of AD that may be present decades before initial clinical expression.


Bone marrow dysplasia with basophilic cells in a patient with angiocentric lymphoma.
We report a 46-year-old man suffering from angiocentric lymphoma of the skin. On admission, he had atypical cells rich in basophilic granules in the bone marrow and peripheral blood, in addition to skin eruptions and bone marrow dysplasia. Immediately after diagnosis, the patient was treated with multidrug combination chemotherapy. At first, the chemotherapy markedly relieved the skin eruption and bone marrow dysplasia, and atypical cells in the bone marrow and peripheral blood disappeared rapidly. However, the disease gradually became resistant to chemotherapy, resulting in a gradual deterioration of the skin eruption and bone marrow dysplasia, and reappearance of atypical cells. The levels of serum cytokines such as interleukin-4 and interleukin-6, and of soluble interleukin-2 receptor correlated well with the disease states. These results suggest that the lymphoma cells directly or indirectly induce the production of these cytokines and that a dysregulated cytokine network, which might be caused by lymphoma cells, induces an increase in atypical cells.


Thin and flexible active electrodes with shield for capacitive electrocardiogram measurement.
Capacitive electrocardiogram (ECG) measurement over clothing requires large electrodes that can remain in contact with curved body surfaces to increase the signal-to-noise ratio (SNR). In this article, we propose a new, thin, and flexible active electrode for use as a capacitive ECG measurement electrode. This electrode contains a shielding plate over its surface and it is extremely thin and can bend freely to cover larger body surfaces of the curve-shaped human torso. We evaluated the characteristics of flexible active electrodes under conditions of varying cloth thickness, electrode size, and contacting pressure. Electrodes of two sizes (45 and 12 cm(2)) were attached to a chest belt to measure the ECG from the human torso, and the results obtained for both the sizes were compared. Cloth thickness and electrode size showed a dominant effect on the SNR, whereas contacting pressure had almost no effect. The flexible active electrodes attached to chest belts wrapped closely and uniformly over the curved surface of the torso and SNR was increased with an increase in electrode size. Although the ECG signal became more distorted as the cloth thickness increased, the larger-sized flexible active electrode (45 cm(2)) showed less distortion than the smaller-sized one (12 cm(2)).


Retrotransposition of nonviral RNAs in an avian packaging cell line.
Retroviruses produced from the quail packaging cell line SE21Q1b predominantly contain cellular RNAs instead of viral RNAs. These RNAs can be reverse transcribed and integrated into the genomes of newly infected cells and are thereafter referred to as newly formed retrogenes. We investigated whether retrogene formation can occur within SE21Q1b cells themselves and whether this occurs intracellularly or via extracellular reinfection. By using packaging cell line mutants derived from the SE21Q1b provirus and selectable reporter constructs, we found that the process requires envelope glycoproteins and a retroviral packaging signal. Our results suggest that extracellular reinfection is the primary route of retrotransposition of nonviral RNAs.


Bacteriophage therapy: an alternative to conventional antibiotics.
Bacteriophage therapy is an important alternative to antibiotics in the current era of multidrug resistant pathogens. We reviewed the studies that dealt with the therapeutic use of phages from 1966-1996 and few latest ongoing phage therapy projects via internet. Phages were used topically, orally or systemically in Polish and Soviet studies. The success rate found in these studies was 80-95% with few gastrointeslinal or allergic side effects. British studies also demonstrated significant efficacy of phages against Escherichia coli, Acinetobacter spp., Pseudomonas spp and Staphylococcus aureus. US studies dealt with improving the bioavailability of phage. Problems faced in these studies have also been discussed. In conclusion, phage therapy may prove as an important alternative to antibiotics for treating multidrug resistant pathogens.


A randomized comparison of a single-incision needleless (Contasure-needleless®) mini-sling versus an inside-out transobturator (Contasure-KIM®) mid-urethral sling in women with stress urinary incontinence: 24-month follow-up results.
There is a shortage of reliable data on the efficiency of the under-investigated mini-slings to treat stress urinary incontinence (SUI). We aimed to compare the effectiveness of the single-incision needleless mini-sling (SIMS) with the transobturator inside-out mid-urethral sling (TOT). Two hundred one women with clinically proven SUI were included in this single-center prospective randomized trial. The patients were randomly allocated to the groups. All surgeries were done by the same single surgeon. Examinations were done by one other blinded surgeon. The patients were followed up for 24 months. Objective cure was defined as the absence of SUI and negative cough-stress test. Subjective cure was defined as no stress leakage of urine after surgery in a validated questionnaire. Failure of the surgery was defined as the need for reoperation. Every complaint was categorized by the IUGA/ICS Classification of Prosthesis-related Complications. The objective (85.4% versus 89.9%, p = 0.362) and subjective (87.6% versus 89.9%, p = 0.636) cure rates were similar with the TOT and SIMS at the postoperative month 24, respectively. The mesh exposure ≤ 1 cm rate was 3.4% for both groups, and the mesh exposure > 1 cm rate was 2.2% for both groups. Overall failure rates were 3.4% and 2.2% for the TOT and SIMS group, respectively. No viscus organ perforation was noted. Complications with the SIMS procedure were less painful compared with TOT (p = 0.024). Single-incision needleless mini-slings exhibited similar cure rates as the trans-obturator mid-urethral slings from both the patient and clinician points of view in 24 months of follow-up. Mini-slings resulted in significantly less postoperative pain than trans-obturator mid-urethral slings.


Minimally invasive right lateral thoracotomy without aortic cross-clamping: an attractive alternative to repeat sternotomy for reoperative mitral valve surgery.
The study aim was to determine the safety and benefits of minimally invasive mitral valve surgery without aortic cross-clamping for mitral valve surgery after previous cardiac surgery. Between January 2006 and August 2008, a total of 90 consecutive patients (38 females, 52 males; mean age 66 +/- 9 years) underwent minimally invasive mitral valve surgery after having undergone previous cardiac surgery. Of these patients, 80 (89%) underwent mitral valve replacement and 10 (11%) mitral valve repair utilizing a small (5 cm) right lateral thoracotomy along the 4th or 5th intercostal space under fibrillatory arrest (mean temperature 28 +/- 2 degrees C). The predicted mortality, calculated using the Society of Thoracic Surgeons (STS) algorithm, was compared to the observed mortality. The mean ejection fraction was 45 +/- 13%, mean NYHA class 3 +/- 1, while 66 patients (73%) had previous coronary artery bypass grafting and 37 (41%) had previous valve surgery. Twenty-six patients (29%) underwent non-elective surgery. Cardiopulmonary bypass was instituted through axillary (n = 19), femoral (n = 70) or direct use aortic (n = 1) cannulation. Operative mortality was 2% (2/90), lower than the STS-predicted mortality of 7%. Three patients (3%) developed acute renal failure postoperatively, one patient (1%) required new-onset hemodialysis, and one (1%) developed postoperative stroke. No patients developed postoperative myocardial infarction. The mean postoperative packed red blood cell transfusion requirement at 48 h was 2 +/- 3 units. Minimally invasive right thoracotomy without aortic cross-clamping is an excellent alternative to conventional redo-sternotomy for reoperative mitral valve surgery. The present study confirmed that this technique is safe and effective in reducing operative mortality in high-risk patients undergoing reoperative cardiac surgery.


Clinical utility of antinuclear antibody tests in children.
Antinuclear antibody (ANA) tests are frequently used to screen children for chronic inflammatory diseases such as systemic lupus erythematosus (SLE). However, the diagnostic utility of this test is limited because of the large number of healthy children who have low-titer positive tests. We sought to determine the clinical utility of ANA tests in screening children for rheumatic disease and to determine whether there are specific signs or symptoms that enhance the clinical utility of ANA tests in children. We undertook a retrospective analysis of 509 new patient referrals. Charts of patients referred because of results of ANA testing were selected for further analysis. Children with JRA, SLE, and other conditions were compared using demographic data, chief complaints at the time of presentation, and ANA titers. One hundred ten patients were referred because of an ANA test interpreted as positive. Ten patients were subsequently diagnosed with SLE. In addition, we identified one patient with mixed connective tissue disease, and an additional child with idiopathic Raynaud's phenomenon. Eighteen children of the children referred for a positive ANA test had juvenile rheumatoid arthritis (JRA). Another 80 children with positive ANA tests were identified, the majority of whom (n = 39, 49%) had musculoskeletal pain syndromes. Neither the presence nor the titer of ANA served to distinguish children with JRA from children with other musculoskeletal conditions. Children with JRA were readily identified on the basis of the history and physical examination. Children with SLE were therefore compared with children with positive ANA tests who did not have JRA, designated the "comparison group." Non-urticarial rash was more common in children with SLE than in children without chronic inflammatory disease (p = 0.007). Children with SLE were also older (mean +/- sd = 14.2 +/- 2.5 years) than the comparison group (11.0 +/- 3.6 years; p = 0.001). ANA titer was also a significant discriminator between children with SLE and children without chronic inflammatory disease. The median ANA titer in children with SLE was 1: 1,080 compared with 1:160 for other children (p < 0.0001). ANA titers of >/=1,080 had a positive predictive value for SLE of 1.0 while titers of </=1: 360 had a negative predictive value for lupus of 0.84. Age and ANA titer assist in discriminating children with SLE from children with other conditions. ANA tests are of no diagnostic utility in either making or excluding the diagnosis of JRA.


The impact of follow-up telephone calls to patients after hospitalization.
We studied whether pharmacists involved in discharge planning can improve patient satisfaction and outcomes by providing telephone follow-up after hospital discharge. We conducted a randomized trial at the General Medical Service of an academic teaching hospital. We enrolled General Medical Service patients who received pharmacy-facilitated discharge from the hospital to home. The intervention consisted of a follow-up phone call by a pharmacist 2 days after discharge. During the phone call, pharmacists asked patients about their medications, including whether they obtained and understood how to take them. Two weeks after discharge, we mailed all patients a questionnaire to assess satisfaction with hospitalization and reviewed hospital records. Of the 1,958 patients discharged from the General Medical Service from August 1, 1998 to March 31, 1999, 221 patients consented to participate. We randomized 110 to the intervention group (phone call) and 111 to the control group (no phone call). Patients returned 145 (66%) surveys. More patients in the phone call than the no phone call group were satisfied with discharge medication instructions (86% vs. 61%, P = 0.007). The phone call allowed pharmacists to identify and resolve medication-related problems for 15 patients (19%). Twelve patients (15%) contacted by telephone reported new medical problems requiring referral to their inpatient team. Fewer patients from the phone call group returned to the emergency department within 30 days (10% phone call vs. 24% no phone call, P = 0.005). A follow-up phone call by a pharmacist involved in the hospital care of patients was associated with increased patient satisfaction, resolution of medication-related problems, and fewer return visits to the emergency department.


[From heparin to apixaban: anticoagulants cut both ways?].
Regarding anticoagulant therapies there has been a remarkable shift in recent years. The objective of this brief overview is to provide relevant information and guidelines on the advantages and disadvantages of novel anticoagulants addressing specifically the surgical disciplines. Hitherto, conventional anticoagulant therapy in patients with a high thrombosis risk was largely limited to heparins and vitamin-K antagonists (VKA). Their modes of action, the difficulties in managing VKAs (e.g., bridging therapy) and the risk of HIT (heparin-induced thrombocytopenia) associated with heparins are briefly discussed. Novel anticoagulants supposedly eliminate these obstacles. Fondaparinux (Arixtra®) is a fully synthetic pentasaccharide which acts like a heparin but has an increased half life. Fondaparinux has a diminished risk of HIT. However, no specific antidote is currently available for Fondaparinux. The novel oral anticoagulants (NOAC) dabigatran etexilat (Pradaxa®), rivaroxaban (Xarelto®) and apixaban (Eliquis®), also known as "direct" anticoagulants, act independently from antithrombin by inhibiting thrombin, as in the case of dabigatran, or by inhibiting factor Xa, as in the case of rivaroxaban and apixaban. It is assumed that they are suitable for long-term use and do not require laboratory monitoring. Nevertheless, clinical experience is very limited and caution rather than quick conclusions is necessary. Two major drawbacks are on the one hand the risk of drug accumulation in kidney and/or liver disease and, on the other hand, the lack of specific antidotes. In addition, interactions with other medication may have unexpected effects on serum drug levels. Therefore, the analysis of drug levels in the plasma may become necessary in subgroups of patients. Studies establishing clear recommendations for the desirable and measurable reference range are needed. Similarly, evidence-based recommendations regarding perioperative prevention of thrombosis are required ("bridging": yes or no?). Irrespective of these issues, the authors predict a further expansion of the use of NOACs.


Expression, purification and preliminary crystallographic studies on the catalytic region of the nonreceptor tyrosine kinase Fes.
The proto-oncogene tyrosine protein kinase c-fps/fes encodes a structurally unique protein (Fes) of the nonreceptor protein-tyrosine kinase (PTK) family. Its expression has been demonstrated in myeloid haematopoietic cells, vascular endothelial cells and in neurons. In human-derived and murine-derived cell lines, the activated form of this kinase can induce cellular transformation; moreover, it has been shown that Fes is involved in the regulation of cell-cell and cell-matrix interactions mediated by adherens junctions and focal adhesions. The N-terminus of Fes contains the FCH (Fps/Fes/Fer/CIP4 homology) domain, which is unique to the Fes/Fer kinase family. It is followed by three coiled-coil domains and an SH2 (Src-homology 2) domain. The catalytic region (Fes-CR) is located at the C-terminus of the protein. The successful expression, purification and crystallization of the catalytic part of Fes (Fes-CR) are described.


Perianal Pseudoverrucous Papules and Nodules in an Elderly Patient.
Pseudoverrucous papules and nodules is a reaction to irritation usually associated with urostomies. We report a case of perianal pseudoverrucous papules and nodules in an elderly patient who developed a characteristic diaper dermatitis after infrequent diaper change. The perianal papulonodular lesions improved after saline wet dressing and topical steroid application. These perianal pseudoverrucous papules and nodules indicate a unique type of irritant diaper dermatitis, which can be distinguished from Jacquet erosive diaper dermatitis and granuloma gluteale adultorum. Identifying this condition is important because pseudoverrucous papules and nodules can resemble more serious dermatoses, leading to unnecessary investigations being carried out.


Implementation of a pharmacogenomics education program for pharmacists.
The development, implementation, and evaluation of a pharmacogenomics education program for pharmacists in a large, integrated multicampus health system are described. Pharmacogenomics has been described as tailoring medications to each patient's unique genetic sequence with the goals of minimizing harmful effects and optimizing therapeutic effects. Pharmacists are uniquely trained to lead the implementation of pharmacogenomics in clinical care. After assessment of pharmacists' comfort with pharmacogenomics, different approaches were explored to develop, pilot test, and disseminate pharmacogenomics education across a multicampus academic medical center. Limited success with large-audience, single-lecture didactic education led to development and delivery of targeted, competency-based online modules using the institution's academic virtual learning environment and course management system. Implementation steps included (1) collaboration with the Mayo Clinic Center for Individualized Medicine to create an interprofessional development team and project charter, (2) galvanizing pharmacy leadership support across multiple campuses, (3) development of competency-based interactive modules, and (4) assessment of the quality of and learner satisfaction with the modules. Significant improvements in competency scores were observed with each module and across the multiple campuses. Satisfaction with the education program was assessed at the end of a 4-module series. A pharmacogenomics educational program targeting pharmacists was developed through interprofessional collaboration and provided a novel opportunity to construct an educational infrastructure to support enterprise health-system campuses with limited educational resources.


Impact of dynamin 2 on adenovirus nuclear entry.
The large GTPase dynamin 2 controls both endosomal fission and microtubule acetylation. Here we report that dynamin 2 alters microtubules and regulates the trafficking of human adenovirus type 37. Dynamin 2 knockdown by siRNA in infected cells resulted in accumulation of acetylated tubulin, repositioning of microtubule organizing centers (MTOCs) closer to cell nuclei, increased virus in the cytosol (with a compensatory decrease in endosomal virus), reduced proinflammatory cytokine induction, and increased binding of virus to the nucleoporin, Nup358. These events led to increased viral DNA nuclear entry and viral replication. Overexpression of dynamin 2 generated opposite effects. Therefore, dynamin 2 inhibits adenovirus replication and promotes innate immune responses by the infected cell. MTOC transposition in dynamin 2 knockdown promotes a closer association with nuclear pore complexes to facilitate viral DNA delivery. Dynamin 2 plays a key role in adenoviral trafficking and influences host responses to infection.


The effect of primary and secondary immunization on the lymphoid tissues of the carp, Cyprinus carpio L.
Mirror carp immunized with human gamma globulin (HGG) in Freund's complete adjuvant (FCA) show a proliferative response involving cells whose cytoplasm stains deep red with methyl green-pyronin (pyroninophilic cells). This response occurs particularly in the haemopoietic parenchyma of the pronephros and mesonephros. It peaks at week 3, with the formation of clusters of pyroninophilic cells in the pronephros. Immunization with Aeromonas salmonicida elicited a less intense pyroninophilic response but caused a larger increase in pigment-containing cells. After a secondary immunization with HGG in FCA, a distinct response was observed in the spleen: Pyroninophilic cells collected within the ellipsoid sheaths in large numbers and formed nodules. The reticulum of such nodules acquired spherical proportions and resembled the white pulp reticulum of the tetrapod spleen. The roles of such pyroninophilic cells and the possibility that aggregations of them may be functionally analogous to homoiotherm germinal centres are discussed.


TRPV1 and TRPM8 in Treatment of Chronic Cough.
Chronic cough is common in the population, and among some there is no evident medical explanation for the symptoms. Such a refractory or idiopathic cough is now often regarded as a neuropathic disease due to dysfunctional airway ion channels, though the knowledge in this field is still limited. Persistent coughing and a cough reflex easily triggered by irritating stimuli, often in combination with perceived dyspnea, are characteristics of this disease. The patients have impaired quality of life and often reduced work capacity, followed by social and economic consequences. Despite the large number of individuals suffering from such a persisting cough, there is an unmet clinical need for effective cough medicines. The cough treatment available today often has little or no effect. Adverse effects mostly follow centrally acting cough drugs comprised of morphine and codeine, which demands the physician's awareness. The possibilities of modulating airway transient receptor potential (TRP) ion channels may indicate new ways to treat the persistent cough "without a reason". The TRP ion channel vanilloid 1 (TRPV1) and the TRP melastin 8 (TRPM8) appear as two candidates in the search for cough therapy, both as single targets and in reciprocal interaction.


Healthcare waste management: an interpretive structural modeling approach.
Purpose - The World Health Organization identified infectious healthcare waste as a threat to the environment and human health. India's current medical waste management system has limitations, which lead to ineffective and inefficient waste handling practices. Hence, the purpose of this paper is to: first, identify the important barriers that hinder India's healthcare waste management (HCWM) systems; second, classify operational, tactical and strategical issues to discuss the managerial implications at different management levels; and third, define all barriers into four quadrants depending upon their driving and dependence power. Design/methodology/approach - India's HCWM system barriers were identified through the literature, field surveys and brainstorming sessions. Interrelationships among all the barriers were analyzed using interpretive structural modeling (ISM). Fuzzy-Matrice d'Impacts Croisés Multiplication Appliquée á un Classement (MICMAC) analysis was used to classify HCWM barriers into four groups. Findings - In total, 25 HCWM system barriers were identified and placed in 12 different ISM model hierarchy levels. Fuzzy-MICMAC analysis placed eight barriers in the second quadrant, five in third and 12 in fourth quadrant to define their relative ISM model importance. Research limitations/implications - The study's main limitation is that all the barriers were identified through a field survey and barnstorming sessions conducted only in Uttarakhand, Northern State, India. The problems in implementing HCWM practices may differ with the region, hence, the current study needs to be replicated in different Indian states to define the waste disposal strategies for hospitals. Practical implications - The model will help hospital managers and Pollution Control Boards, to plan their resources accordingly and make policies, targeting key performance areas. Originality/value - The study is the first attempt to identify India's HCWM system barriers and prioritize them.


Association between Bell's palsy in pregnancy and pre-eclampsia.
Previous published case series have suggested an association between the onset of Bell's palsy in pregnancy and the risk of pre-eclampsia and gestational hypertension. To evaluate the period of onset of Bell's palsy in pregnancy and the associated risk of adverse maternal and perinatal events, including the hypertensive disorders of pregnancy. Case series study of consecutive female patients. Women presenting with Bell's palsy during pregnancy or the puerperium were identified by a hospital record review at five Canadian centres over 11 years. Information was abstracted about each woman's medical and obstetrical history, period of onset of Bell's palsy, and associated maternal complications, including pre-eclampsia and gestational hypertension as well as preterm delivery and low infant birth weight (<2500 g). These rates were compared to those previously described for the province of Ontario or for Canada. Forty-one patients were identified. Mean onset of Bell's palsy was 35.4 weeks gestation (SD 3.9). Nine (22.0%, 95%CI 10.8-35.7) were also diagnosed with pre-eclampsia and three (7.3%, 95%CI 1.4-17.1) with gestational hypertension, together (29.3%, 95%CI 16.5-43.9) representing nearly a five-fold increase over the expected provincial/national average. There were three twin births. The observed rates of Caesarean (43.6%) and preterm (25.6%) delivery, as well as low infant birth weight (22.7%), were also higher than expected, although the rate of congenital anomalies (4.5%) was not. The onset of Bell's palsy during pregnancy or the puerperium is probably associated with the development of the hypertensive disorders of pregnancy. Pregnant women who develop Bell's palsy should be closely monitored for hypertension or pre-eclampsia, and managed accordingly.


Electrophoretic study of Clostridium species.
Polyacrylamide gel electrophoretic analysis of soluble cellular proteins (without sodium dodecyl sulfate) of 70 Clostridium species indicated that the procedure was readily applicable to the differentiation of species in the genus. The protein patterns correlated well with the available DNA homology data and with most accepted differential tests. Results indicated that several earlier names for species were synonyms of those of accepted species and that two accepted species may be synonymous.


EmTIP, a T-Cell immunomodulatory protein secreted by the tapeworm Echinococcus multilocularis is important for early metacestode development.
Alveolar echinococcosis (AE), caused by the metacestode of the tapeworm Echinococcus multilocularis, is a lethal zoonosis associated with host immunomodulation. T helper cells are instrumental to control the disease in the host. Whereas Th1 cells can restrict parasite proliferation, Th2 immune responses are associated with parasite proliferation. Although the early phase of host colonization by E. multilocularis is dominated by a potentially parasitocidal Th1 immune response, the molecular basis of this response is unknown. We describe EmTIP, an E. multilocularis homologue of the human T-cell immunomodulatory protein, TIP. By immunohistochemistry we show EmTIP localization to the intercellular space within parasite larvae. Immunoprecipitation and Western blot experiments revealed the presence of EmTIP in the excretory/secretory (E/S) products of parasite primary cell cultures, representing the early developing metacestode, but not in those of mature metacestode vesicles. Using an in vitro T-cell stimulation assay, we found that primary cell E/S products promoted interferon (IFN)-γ release by murine CD4+ T-cells, whereas metacestode E/S products did not. IFN-γ release by T-cells exposed to parasite products was abrogated by an anti-EmTIP antibody. When recombinantly expressed, EmTIP promoted IFN-γ release by CD4+ T-cells in vitro. After incubation with anti-EmTIP antibody, primary cells showed an impaired ability to proliferate and to form metacestode vesicles in vitro. We provide for the first time a possible explanation for the early Th1 response observed during E. multilocularis infections. Our data indicate that parasite primary cells release a T-cell immunomodulatory protein, EmTIP, capable of promoting IFN-γ release by CD4+ T-cells, which is probably driving or supporting the onset of the early Th1 response during AE. The impairment of primary cell proliferation and the inhibition of metacestode vesicle formation by anti-EmTIP antibodies suggest that this factor fulfills an important role in early E. multilocularis development within the intermediate host.


How Changes in Anti-SD Sequences Would Affect SD Sequences in Escherichia coli and Bacillus subtilis.
The 3' end of the small ribosomal RNAs (ssu rRNA) in bacteria is directly involved in the selection and binding of mRNA transcripts during translation initiation via well-documented interactions between a Shine-Dalgarno (SD) sequence located upstream of the initiation codon and an anti-SD (aSD) sequence at the 3' end of the ssu rRNA. Consequently, the 3' end of ssu rRNA (3'TAIL) is strongly conserved among bacterial species because a change in the region may impact the translation of many protein-coding genes. Escherichia coli and Bacillus subtilis differ in their 3' ends of ssu rRNA, being GAUCACCUCCUUA3' in E. coli and GAUCACCUCCUUUCU3' or GAUCACCUCCUUUCUA3' in B. subtilis Such differences in 3'TAIL lead to species-specific SDs (designated SDEc for E. coli and SDBs for B. subtilis) that can form strong and well-positioned SD/aSD pairing in one species but not in the other. Selection mediated by the species-specific 3'TAIL is expected to favor SDBs against SDEc in B. subtilis, but favor SDEc against SDBs in E. coli Among well-positioned SDs, SDEc is used more in E. coli than in B. subtilis, and SDBs more in B. subtilis than in E. coli Highly expressed genes and genes of high translation efficiency tend to have longer SDs than lowly expressed genes and genes with low translation efficiency in both species, but more so in B. subtilis than in E. coli Both species overuse SDs matching the bolded part of the 3'TAIL shown above. The 3'TAIL difference contributes to the host specificity of phages.