On-line assessment of left atrial area and function by echocardiographic automatic boundary detection.
Direct assessment of left atrial (LA) function has not been previously performed by noninvasive techniques; rather, LA function has been evaluated only indirectly via the analysis of transmitral flow velocity by Doppler. The recent development of real-time two-dimensional echocardiographic automatic boundary detection suggests that LA dimensions can be measured instantaneously to provide on-line assessment of its systolic and diastolic functions. We performed echocardiographic assessment of LA dimensions and function with automatic boundary detection in 45 patients by using the apical four-chamber view. Thirty-seven patients had structural or functional cardiac abnormalities, 35 patients were in sinus rhythm, and 10 patients had atrial fibrillation. Moderate to severe mitral regurgitation (MR) was noted in 16 patients. We also studied 10 control subjects to assess normal values of LA cavity area and indexes of function. From the instantaneously derived LA area, we derived indexes of systolic atrial expansion and diastolic atrial emptying. There were excellent correlations between the on-line-derived LA areas and those measured off line from videotaped images of conventional echocardiography (r = .91 for end-diastolic and .93 for end-systolic areas; SEE, 4.0 and 3.8 cm2, respectively). Patients in atrial fibrillation had depressed diastolic emptying index (0.17 +/- 0.05) compared with those in sinus rhythm (0.28 +/- 0.12; P < .02). Furthermore, patients with chronic MR exhibited larger LA cavity areas and depressed systolic and diastolic LA function as compared with those without MR. In addition, the Doppler-determined mitral E/A ratio was related to the ratio of early diastolic-to-late diastolic change in LA cavity area (r = .79; SEE 0.6; n = 35). Instantaneous LA cavity area measurement by echocardiographic automatic boundary detection is accurate and feasible in patients with diverse cardiac disorders. Patients with atrial fibrillation had a depressed diastolic emptying index and those with significant mitral regurgitation had depressed systolic expansion index as well. LA functional indexes in both systole and diastole can be derived providing an approach for quantitative evaluations of left atrial-left ventricular interactions based on geometric assessment noninvasively.


Inflammation and Myeloid Cells in Cancer Progression and Metastasis.
To date, the most immunotherapy drugs act upon T cell surface proteins to promote tumoricidal T cell activity. However, this approach has to date been unsuccessful in certain solid tumor types including pancreatic, prostate cancer and glioblastoma. Myeloid-related innate immunity can promote tumor progression through direct and indirect effects on T cell activity; improved understanding of this field may provide another therapeutic avenue for patients with these tumors. Myeloid cells can differentiate into both pro-inflammatory and anti-inflammatory mature form depending upon the microenvironment. Most cancer type exhibit oncogenic activating point mutations (ex. P53 and KRAS) that trigger cytokines production. In addition, tumor environment (ex. Collagen, Hypoxia, and adenosine) also regulated inflammatory signaling cascade. Both the intrinsic and extrinsic factor driving the tumor immune microenvironment and regulating the differentiation and function of myeloid cells, T cells activity and tumor progression. In this review, we will discuss the relationship between cancer cells and myeloid cells-mediated tumor immune microenvironment to promote cancer progression and immunotherapeutic resistance. Furthermore, we will describe how cytokines and chemokines produced by cancer cells influence myeloid cells within immunosuppressive environment. Finally, we will comment on the development of immunotherapeutic strategies with respect to myeloid-related innate immunity.


Enzymic and molecular characteristics of a new form of monoamine oxidase, distinct from form-A and form-B.
The present study was undertaken to clarify the enzymic and molecular properties of monoamine oxidase (MAO) in carp brain. In particular, its sensitivities to selective MAO inhibitors, kinetic properties and molecular weight were compared with those of the enzyme in carp liver. The selective and potent MAO-A and MAO-B inhibitors FLA 788(+), FLA 336(+), MD 780236 and benzylcyanide caused dose-dependent inhibitions of MAO activity in both carp brain and liver; the inhibition curves were all single-sigmoidal, and the degrees of inhibition of the activities towards 5-hydroxytryptamine (5-HT, selective MAO-A substrate), tyramine (substrate for both forms of MAO) and beta-phenylethylamine (PEA, selective MAO-B substrate) were similar. This was also the case for inhibition of activity in carp brain by the irreversible and selective MAO-A and MAO-B inhibitors clorgyline and I-deprenyl, indicating the presence in both preparations of a single MAO which differs from either form of MAO. Studies on the substrate specificities and Km values for these three substrates and the inhibitory effects of some compounds suggested that the enzymic characters of MAO in carp preparations were similar and that these enzymes might be FAD-containing enzymes, like MAO in various mammals. By labelling the preparations with radioactive pargyline and then subjecting them to sodium dodecyl sulfate electrophoresis, the apparent molecular weights of carp brain and liver MAO were estimated as 60,000 daltons. The same value was also obtained for rat brain and liver mitochondrial MAO-B. These results indicate that by the present definitions of MAO-A and MAO-B, MAO in carp brain and liver is similar to, but distinct from, both these forms of MAO.


Elevated mitochondrial RNA in a Chinese hamster mutant deficient in the mitochondrially encoded subunits of NADH dehydrogenase and cytochrome c oxidase.
In a unique Chinese hamster mutant, Gal-32, the mitochondrially encoded subunits of cytochrome c oxidase (CO I, II, III) and NADH dehydrogenase (ND 1-6) are greatly decreased while other mitochondrially synthesized proteins, such as ATPase subunits 6 and 8, are less affected. Pulse-chase experiments with [35S]methionine demonstrated that the reduced amounts of CO I and ND 5 subunits in Gal-32 are not the result of more rapid protein degradation. No differences in sizes of mtRNAs were detected between wild type and mutant using Northern blotting. The steady state levels of both heavy and light strand mtDNA transcripts were elevated in Gal-32: CO I mRNA was 1.5-fold higher in the mutant than in the wild type; ND 5 mRNA was 1.9-fold higher; ND 6 precursor RNAs were 1.4-fold higher and ATPase 6 and 8 mRNA (a single transcript) was 2.7-fold higher. Thus, the amounts of translation products are roughly correlated with the levels of mRNAs. The reduced levels of mitochondrially synthesized proteins in Gal-32 are the result of decreased translation of specific mRNAs, not increased degradation of mtRNAs.


Enhanced bio-methane production from co-digestion of different organic wastes.
This paper deals with an experimental study aimed at assessing the effect of mixing different organic wastes on the anaerobic digestion process. Livestock manure and organic solid wastes have been taken into account as substrates to verify if their mixing gives rise to higher methane production rates and lower risk of process failure. Bio-methane potential (BMP) tests have been conducted using the following substrates: buffalo manure (BM), poultry manure (PM), organic fraction of the municipal solid waste (OFMSW), greengrocery waste (GW) and two different mixtures composed of BM and OFMSW. Mixing BM with OFMSW resulted in 12% and 30% higher methane volumes after 30 and 15 days from the test start, respectively. Experimental data have been also used to calibrate and validate a mathematical model previously proposed by the authors, showing its capability to reproduce the synergistic effect on methane production promoted by co-digesting BM and OFSMW.


Serogroups and virulence genotypes of Escherichia coli isolated from patients with sepsis.
Sixty strains of Escherichia coli, isolated by hemoculture, from septicemic Brazilian patients were evaluated to determine their serogroup and invasivity to Vero cells. All 60 patients died within 2 days of hospitalization. Furthermore, the molecular study of the following extraintestinal pathogenic E. coli-associated virulence factor (VF) genes was performed by PCR: i) adhesins: type 1 fimbria (fimH), S fimbria (sfaD/E), P fimbria (papC and papG alleles) and afimbrial adhesin (afaB/C); ii) capsule K1/K5 (kpsMTII); iii) siderophores: aerobactin (iucD), yersiniabactin (fyuA) and salmochelin (iroN); iv) toxins hemolysin (hlyA), necrotizing cytotoxic factor type 1 (cnf1) and secreted autotransporter toxin (sat); v) miscellaneous: brain microvascular endothelial cells invasion (ibeA), serum resistance (traT), colicin V (cvaC) and specific uropathogenic protein (usp). Our results showed that isolates are able to invade Vero cells (96.6%), differing from previous research on uropathogenic E. coli (UPEC). The O serogroups associated with UPEC were prevalent in 60% of strains vs 11.7% of other serogroups. The PCR results showed a conserved virulence subgroup profile and a prevalence above 75% for fimH, fyuA, kpsMTII and iucD, and between 35-65% for papC, papG, sat, iroN, usp and traT. The evasion from the immunological system of the host and also iron uptake are essential for the survival of extraintestinal pathogenic E. coli strains. Interestingly, among our isolates, a low prevalence of VF genes appeared. Therefore, the present study contributes to the identification of a bacterial profile for sepsis-associated E. coli.


Survival of Ventilated Extremely Premature Neonates With Severe Intraventricular Hemorrhage.
Severe intraventricular hemorrhage (IVH) is a leading mortality risk factor among extremely premature neonates. Because other life-threatening conditions also occur in this population, it is unclear whether severe IVH is independently associated with death. The existence and potential implications of regional variation in severe IVH-associated mortality are unknown. We performed a retrospective cohort study of mechanically ventilated neonates born at 22 to 29 weeks' gestation who received care in 242 American NICUs between 2000 and 2014. After building groups composed of propensity score-matched and center-matched pairs, we used the Cox proportional hazards analysis to test our hypothesis that severe IVH would be associated with greater all-cause in-hospital mortality, defined as death before transfer or discharge. We also performed propensity score-matched subgroup analyses, comparing severe IVH-associated mortality among 4 geographic regions of the United States. In our analysis cohort, we identified 4679 patients with severe IVH. Among 2848 matched pairs, those with severe IVH were more likely to die compared with those without severe IVH (hazard ratio 2.79; 95% confidence interval 2.49-3.11). Among 1527 matched pairs still hospitalized at 30 days, severe IVH was associated with greater risk of death (hazard ratio 2.03; 95% confidence interval 1.47-2.80). Mortality associated with severe IVH varied substantially between geographic regions. The early diagnosis of severe IVH is independently associated with all-cause in-hospital mortality in extremely premature neonates. Regional variation in severe IVH-associated mortality suggests that shared decision-making between parents and neonatologists is strongly influenced by ultrasound-based IVH assessment and classification.


The alternatively spliced anti-angiogenic family of VEGF isoforms VEGFxxxb in human kidney development.
Vascular endothelial growth factor (VEGF), required for renal development, is generated by alternative splicing of 8 exons to produce two families, pro-angiogenic VEGF(xxx), formed by proximal splicing in exon 8 (exon 8a), and anti-angiogenic VEGF(xxx)b, generated by distal splicing in exon 8 (exon 8b). VEGF(165)b, the first described exon 8b-containing isoform, antagonises VEGF(165) and is anti-angiogenic in vivo. Using VEGF(xxx)b-specific antibodies, we investigated its expression quantitatively and qualitatively in developing kidney, and measured the effect of VEGF(165)b on renal endothelial and epithelial cells. VEGF(xxx)b formed 45% of total VEGF protein in adult renal cortex, and VEGF(165)b does not increase glomerular endothelial cell permeability, it inhibits migration, and is cytoprotective for podocytes. During renal development, VEGF(xxx)b was expressed in the condensed vesicles of the metanephros, epithelial cells of the comma-shaped bodies, invading endothelial cells and epithelial cells of the S-shaped body, and in the immature podocytes. Expression reduced as the glomerulus matured. These results show that the anti-angiogenic VEGF(xxx)b isoforms are highly expressed in adult and developing renal cortex, and suggest that the VEGF(xxx)b family plays a role in glomerular maturation and podocyte protection by regulating the pro-angiogenic pro-permeability properties of VEGF(xxx) isoforms.


Persistent post-COVID-19 neuromuscular symptoms.
Neuromuscular symptoms may develop or persist after resolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Besides residual sensorimotor symptoms associated with acute neuromuscular complications of coronavirus disease-2019 (COVID-19), such as Guillain-Barré syndrome, critical illness neuromyopathy, and rhabdomyolysis, patients may report persistent autonomic symptoms, sensory symptoms, and muscle symptoms in the absence of these acute complications, including palpitations, orthostatic dizziness and intolerance, paresthesia, myalgia, and fatigue. These symptoms may be associated with long COVID, also known as post-COVID-19 conditions or postacute sequelae of SARS-CoV-2 infection, which may significantly impact quality of life. Managing these symptoms represents a challenge for health-care providers. Recent advances have identified small-fiber neuropathy as a potential etiology that may underlie autonomic dysfunction and paresthesia in some long COVID patients. The pathogenic mechanisms underlying myalgia and fatigue remain elusive and need to be investigated. Herein we review the current state of knowledge regarding the evaluation and management of patients with persistent post-COVID-19 neuromuscular symptoms.


Predicting gold-mediated catalytic oxidative-coupling reactions from single crystal studies.
Though metallic gold is chemically inert under ambient conditions, its surface is extremely reactive and selective for many key oxidative chemical transformations when activated by atomic oxygen. A molecular-level understanding of the mechanism of these processes could allow researchers to design "green" catalytic processes mediated by gold-based materials. This Account focuses on the mechanistic framework for oxidative-coupling reactions established by fundamental studies on oxygen-activated Au(111) and the application of these principles to steady-state catalytic conditions. We also discuss the importance of the paradigms discovered both for predicting new oxidative-coupling reactions and for understanding existing literature. The mechanistic framework for the oxidative coupling of alcohols on gold surfaces predicts that new oxidative-coupling reactions should occur between amines and aldehydes and amines and alcohols as well as through alcohol carbonylation. Adsorbed atomic oxygen on the gold surface facilitates the activation of the substrates, and nucleophilic attack and β-H elimination are the two fundamental reactions that propagate the versatile chemistry that ensues. In the self-coupling of primary alcohols, adsorbed atomic oxygen first activates the O-H bond in the hydroxyl group at ∼150 K, which forms the corresponding adsorbed alkoxy groups. The rate-limiting step of the self-coupling reaction is the β-H elimination reaction of alkoxy groups to form the corresponding aldehydes and occurs with an activation barrier of approximately 12 kcal/mol. The remaining alkoxy groups nucleophilically attack the electron-deficient aldehyde carbonyl carbon to yield the adsorbed "hemiacetal". This intermediate undergoes facile β-H elimination to produce the final coupling products, esters with twice the number of carbon atoms as the starting alcohols. This mechanistic insight suggests that cross-coupling occurs between alcohols and aldehydes, based on the logic that the nucleophilic reaction should be independent of the origin of the aldehydes, whether formed in situ or introduced externally. As a further example, adsorbed amides, formed from deprotonation of amines by atomic oxygen, can also attack aldehydes nucleophilically to yield the corresponding amides. Our mechanistic framework can also explain more elaborate gold-mediated chemistry, such as a unique carbonylation reaction via two subsequent nucleophilic attacks. These model studies on well-defined Au(111) at low pressure predict steady-state catalytic behavior on nanoporous gold under practical conditions. The fundamental principles of this research can also explain many other oxygen-assisted gold-mediated reactions observed under ambient conditions.


[Bickerstaff's encephalitis].
The clinical and radiological findings in a case of Bickerstaff encephalitis are described and the relationship with Miller Fisher and Guillain Barré syndromes are discussed. Subsequently to a respiratory infection,a 44-year-old male developed external ophthalmoplegia and cerebellar-like ataxia; his condition deteriorated and he suffered consciousness disturbances and absent tendon reflexes were noted. An MRI scan was performed showing a lesion affecting the brainstem. The cerebrospinal fluid (CSF) revealed albuminocytologic dissociation and the presence of oligoclonal bands. He received high doses of intravenous immunoglobulins and five months later, he had completely recovered. A follow up MRI scan demonstrated complete resolution of the lesion. The initial condition was diagnosed as Bickerstaff brainstem encephalitis (BBE) with overlapping peripheral nervous system semiology. The presence during the acute phase of oligoclonal bands in CSF, which decreased with the clinical improvement, supports the hypothesis than an autoimmune mechanism may function in its pathogenesis. Our case suggests that intravenous immunoglobulins therapy should be considered in patients with BBE.


Formation and properties of in vitro biofilms of ica-negative Staphylococcus epidermidis clinical isolates.
Coagulase-negative Staphylococcus epidermidis has become the leading cause of foreign-body infections due to its biofilm formation on all kinds of medical-device surfaces. The biofilm development of S. epidermidis includes two steps: the initial attachment phase and the accumulative phase. In the accumulative phase, the polysaccharide intercellular adhesin (PIA), encoded by the icaADBC locus, is the major component mediating intercellular adhesion. However, recent studies have revealed the emergence of biofilm-positive/ica-negative staphylococcal clinical isolates. In this report, two ica-negative S. epidermidis clinical strains, SE1 and SE4, exhibited their heterogeneity in biofilm architecture under static and flow conditions, compared with the biofilm-positive/ica-positive RP62A strain. Strains with this type of absence of PIA from biofilms also displayed intermediate resistance to vancomycin. More importantly, the cells of both SE1 and SE4 strains were more tolerant than those of RP62A to exposure to lysostaphin and vancomycin. Based on the results, it is suggested that the biofilm-positive/ica-negative strain represents a newly emergent subpopulation of S. epidermidis clinical strains, arising from selection by antibiotics in the nosocomial milieu, which displays a survival advantage in its host environment. Recent epidemiological data support this suggestion, by showing a tendency towards an increasing proportion of this subpopulation in staphylococci-associated infections.


Focal takotsubo cardiomyopathy with high-dose interleukin-2 therapy for malignant melanoma.
High-dose interleukin-2 (IL-2) is an available treatment option for patients with metastatic melanoma or renal cell carcinoma, and is associated with sustained complete and partial responses in a subset of patients. IL-2, however, is not devoid of toxicities, most of which involve the cardiovascular system and manifest as hypotension, arrhythmias, and cardiomyopathy. This report describes an unusual presentation of takotsubo cardiomyopathy in a postmenopausal woman receiving high-dose IL-2 for metastatic melanoma.


[Clinical evaluation of provitamin B5 drops and gel for postoperative treatment of corneal and conjuctival injuries].
Vitamins B group are important ingredients of coenzymes. Provitamin B5 dexpanthenol is necessary in the processes of reconstruction of epithelium, has regenerative and anti-inflammatory properties. Objective of the study was to determine how the wounds of cornea and/or conjunctiva heal upon the application of D-panthenol/the medicine has been developed in the Faculty of Pharmacy of the Medical University of Gdańsk/. The activity of the medicine was tested in 40 eyes in the test group, a 40 eyes in the control group did not receive D-panthenol. The degree of the objective and subjective symptoms was assessed. The differences between the two groups commenced on the second day following the operation. Better effects were observed in patients receiving D-panthenol. Congestion and oedema of conjunctiva withdrew, the edges of wounds demonstrated smoothness and better adherence. Subjective feelings improved. 1. Provitamin B5 contained in 5% drops and 5% gel of D-panthenol effectively accelerates the processes of healing the wounds of conjunctiva and cornea.


Detection of atherosclerosis by ankle brachial index: evaluation of palpatory method versus ultrasound Doppler technique.
Peripheral Arterial Disease [PAD], a manifestation of systemic atherosclerosis, is highly prevalent both in community studies and in primary care practice. Estimation of ankle brachial index [ABI] by ultrasound Doppler is the standard screening method for the detection of atherosclerosis in PAD patients. A low ABI is associated with increased risk of stroke or transient ischemic attack, ischemic heart disease and lower extremity gangrene. Though prevalence is high, physician and patient awareness of the condition is low. Primary care physicians are not well versed with the use of Doppler. Initial cost of the equipment is another adverse factor in low income countries. Detection of ankle systolic pressure by palpatory method may offer a cheap, simple and useful alternative approach in office care settings for early detection of disease. This may lead to the use of risk reduction strategies to avoid significant future morbidity and mortality. The sample size of 230 participants was identified. Patients were divided into control (100 cases), high risk asymptomatic (100 cases) and symptomatic groups (30 cases). Ankle systolic pressure was measured by digital palpation of foot arteries and by the gold standard Doppler technique in all patients in the three groups. PAD was defined by an ABI of < 0.9. In control group, mean +/- SD value of ABI was 1.0115 +/- 0.08167 by Doppler method versus 0.9923 +/- 0.08609 by palpatory method (p = 0.1), in high risk asymptomatic group, 0.9838 +/- 0.08878 versus 0.9608 +/- 0.10377 (p = 0.13) and in symptomatic group, 0.9302 +/- 0.14064 versus 0.9088 +/- 0.13274 (p = 0.12). Against the more precise Doppler method, palpatory method was equally good in detecting the PAD positive cases. Early diagnosis of PAD in primary care practice by manual palpation of foot arteries is a reliable method to identitfy the population at risk and may lead to aggressive preventive therapies.


Primary prevention research on incontinence in older adults.
Primary prevention research on urinary incontinence in older adults is in its nascent phase. Most clinical research has focused on secondary or tertiary prevention, that is, testing interventions to cure, improve, or manage incontinence. When urinary incontinence is recognized as a public health issue, resources become available to reduce the risk of incontinence and prevent its occurrence. Methodological issues that face nurse researchers desiring to conduct primary prevention research include inadequate theory and outcome development, need for gender and culturally sensitive measurement instruments, and sampling and design issues. Rather than viewing primary prevention as a futile endeavor, nurse researchers must combine the roles of researcher and advocate, articulating the vision for primary prevention, and developing sound clinical studies to prevent urinary incontinence in the older adult population.


Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants.
Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and >100-fold thrombin selectivity. The X-ray structure of one of these inhibitors, 36, demonstrates its unique binding interactions with FXIa. Compound 32 caused a doubling of the activated partial thromboplastin time in human plasma at 2.4 microM and was efficacious in a rat model of venous thrombosis. These data suggest that factor XIa plays a significant role in venous thrombosis and may be a suitable target for the development of antithrombotic therapy.


[Recurrent varices of the lower limbs. Etiologic and clinico-therapeutic study].
The latest findings in varicose relapses of the lower extremities are described, and the most significant bibliographic data discussed. The most frequent causes, the anatomo-topographical distribution and the causal therapy are examined. It is also point out that recurrent varices occur much less frequently than some years ago, the reason being knowledge of the disease's aetiology and hence of the most rational, radical treatment for it. In presenting 25 operations, 15 of them for post-operative recurrence and 10 for recurrences following sclerosing therapy, it is pointed out that out of 518 cases of varicose veins operated on in the Department since 1971, no case of varicose recurrence has ever been encountered. This is attributed to the eclecticism and rigour of the surgical technique. Stress is laid on the words of Martinet and Tubiana in 1950 "...treatment of varicose veins is far from being as simple as many believe...". Treatment must in fact be chosen case by case.


Bioproduction of l- and d-lactic acids: advances and trends in microbial strain application and engineering.
Lactic acid is an important platform chemical used in the food, agriculture, cosmetic, pharmaceutical, and chemical industries. It serves as a building block for the production of polylactic acid (PLA), a biodegradable polymer, which can replace traditional petroleum-based plastics and help to reduce environmental pollution. Cost-effective production of optically pure l- and d-lactic acids is necessary to achieve a quality and thermostable PLA product. This paper evaluates research advances in the bioproduction of l- and d-lactic acids using microbial fermentation. Special emphasis is given to the development of metabolically engineered microbial strains and processes tailored to alternative and flexible feedstock concepts such as: lignocellulose, glycerol, C1-gases, and agricultural-food industry byproducts. Alternative fermentation concepts that can improve lactic acid production are discussed. The potential use of inducible gene expression systems for the development of biosensors to facilitate the screening and engineering of lactic acid-producing microorganisms is discussed.


Potential health benefits of Indian spices in the symptoms of the metabolic syndrome: a review.
Spices used in Indian cooking have a long history of use as medicines to prevent and treat diseases. Many studies have confirmed that spices can be useful medicines, but the major challenge is now to provide scientific evidence and plausible mechanisms for their therapeutic responses. This review focuses on the therapeutic potential of Indian spices to treat multiple symptoms of the metabolic syndrome such as insulin resistance, diabetes, obesity, altered lipid profile and hypertension. The metabolic syndrome is prevalent and has become an important financial burden to the healthcare system in both developed and developing countries. Inflammation and oxidative stress have been proposed as initiators of the metabolic syndrome, especially of insulin resistance. Natural products with anti-inflammatory and anti-oxidant properties are found in spices. Adequate doses of these compounds may be effective in treating the metabolic syndrome. Testing these potential treatments requires adequate animal models, usually rodents, so the limitations of these models are important. Furthermore, this review highlights the need for adequate legislation and regulation to ensure the safety and success of evidence-based functional foods and nutraceuticals. Spices, Diabetes, Cardiovascular disease, Metabolic syndrome, Inflammation, Oxidative stress,


Effects of onapristone, tamoxifen and ICI 182780 on uterine prostaglandin production and luteal function in nonpregnant guinea-pigs.
Onapristone (a progesterone antagonist) or ICI 182780 (an oestrogen antagonist) administered to guinea-pigs on days 11-14 of the cycle significantly reduced uterine PGF2 alpha output on day 15. Concentrations of progesterone in plasma of onapristone-treated and ICI 182780-treated guinea-pigs were still high on day 15 indicating that luteal regression had been prevented. These findings indicate that progesterone and oestradiol are necessary for increased PGF2 alpha production by the uterus towards the end of the cycle, and support the hypothesis that oestradiol acting on a progesterone-primed uterus is the physiological stimulus for increased uterine PGF2 alpha synthesis and release in guinea-pigs. The capacity of the endometrium to synthesize PGF2 alpha on day 15 was reduced by treatment with ICI 182780 and, unexpectedly, by treatment with onapristone, indicating that onapristone may also be antagonizing the release or action of oestradiol in some way. Tamoxifen was an agonist in guinea-pigs since it induced vaginal opening. It had no inhibitory effect on uterine PGF2 alpha output and did not delay luteal regression when administered between days 11 and 14 of the cycle. However, it redirected PG synthesis in homogenates of endometrium and myometrium from PGI2 (as indicated by 6-keto-PGF1 alpha) to PGF2 alpha. The output of 6-keto-PGF1 alpha from the uterus of day 15 guinea-pigs was reduced following tamoxifen treatment, but the high output of PGF2 alpha from the uterus was not affected.


Role of oxidative stress in chemical allergens induced skin cells activation.
Allergic contact dermatitis (ACD) is an important occupational and environmental disease caused by topical exposure to chemical allergens. It describes the adverse effects that may results when exposure to a chemical elicits a T cell-mediated inflammatory skin disease. The ability of contact sensitizers to induce the oxidative stress pathway in keratinocytes and dendritic cells has been confirmed by several authors. Reactive oxygen species (ROS) can serve as essential second messengers mediating cellular responses resulting in immune cells activation. Oxidative stress may be the starter point, as it leads to the activation of transcription factors and signaling pathways, including NF-kB and p38 MAPK, which leads to the release of cytokines and chemokines. ROS are also involved in the activation of the NLRP3/NALP3 inflammasome, which is required to direct the proteolytic maturation of inflammatory cytokines such as IL-1β and IL-18, which are all integral to the process of dendritic cells mobilization, migration and functional maturation. Moreover, emerging evidence correlates ROS to changes in the constitution of the extracellular microenvironment found to facilitate ACD. The purpose of this review is to provide both conceptual and technical frameworks on the role of oxidative stress in chemical allergy.


Expression of human monolysocardiolipin acyltransferase-1 improves mitochondrial function in Barth syndrome lymphoblasts.
The mitochondrial polyglycerophospholipid cardiolipin (CL) is remodeled to obtain specific fatty acyl chains. This is predominantly accomplished by the transacylase enzyme tafazzin (TAZ). Barth syndrome (BTHS) patients with TAZ gene mutations exhibit impaired TAZ activity and loss in mitochondrial respiratory function. Previous studies identified monolysocardiolipin acyltransferase-1 (MLCL AT-1) as a mitochondrial enzyme capable of remodeling CL with fatty acid. In this study, we analyzed what relationship, if any, exists between TAZ and MLCL AT-1 with regard to CL remodeling and whether transfection of BTHS lymphoblasts with an MLCL AT-1 expression construct improves mitochondrial respiratory function. In healthy lymphoblasts, reduction in TAZ expression through TAZ RNAi transfection resulted in a compensatory increase in MLCL AT-1 mRNA, protein, and enzyme activity, but CL mass was unaltered. In contrast, BTHS lymphoblasts exhibited decreased TAZ gene and protein expression but in addition decreased MLCL AT-1 expression and CL mass. Transfection of BTHS lymphoblasts with MLCL AT-1 expression construct increased CL, improved mitochondrial basal respiration and protein leak, and decreased the proportion of cells producing superoxide but did not restore CL molecular species composition to control levels. In addition, BTHS lymphoblasts exhibited higher rates of glycolysis compared with healthy controls to compensate for reduced mitochondrial respiratory function. Mitochondrial supercomplex assembly was significantly impaired in BTHS lymphoblasts, and transfection of BTHS lymphoblasts with MLCL AT-1 expression construct did not restore supercomplex assembly. The results suggest that expression of MLCL AT-1 depends on functional TAZ in healthy cells. In addition, transfection of BTHS lymphoblasts with an MLCL AT-1 expression construct compensates, but not completely, for loss of mitochondrial respiratory function.


Rational use of glucocorticoid during pituitary surgery--a pilot study.
The conventionally used perioperative glucocorticoid replacement protocol in patients with pituitary tumours is far from optimal. In this study we evaluated the validity of a modified protocol for perioperative glucocorticoid replacement in non-functioning pituitary macroadenomas. A total of 24 consecutive patients with non functioning pituitary macroadenomas were included in this interventional study. Patients with a pre-operative 0800 h cortisol of > or = 350 nmol/l (> or = 12.6 microg/dl) did not receive glucocorticoid replacement during perioperative (d(0)-d-(2)) period, while those with < or = 100 nmol/l (< or = 3.6 microg/dl) received glucocorticoid replacement. Those patients with 0800 h cortisol value between > 100-349 nmol/l (> 3.6-12.6 microg/dl) required them to undergo an insulin induced hypoglycaemia (IIH). In response to IIH, patients with a peak cortisol of < 550 nmol/l (< 19.8 microg/dl) received glucocorticoid replacement. Post-operatively, patients on day 3 with 0800 h cortisol of < or = 100 nmol/l (< or = 3.6 microg/dl) received hydrocortisone 10 mg/m(2) per day; those between > 100-449 nmol/l (> 3.6-16 microg/dl) received hydrocortisone replacement only if they had symptoms of adrenal insufficiency (AI) or during stress; while patients with > or = 450 nmol/l (> or = 16.0 microg/dl) did not receive any glucocorticoid replacement. Retesting was done at 12 wk in 23 subjects based on the algorithm. Pre-operatively, 8 (35%) patients were hypocortisolic and received glucocorticoid supplementation, thereby sparing 15 (65%) subjects from glucocorticoid replacement. On d(3) of surgery, 13 (57%) patients were hypocortisolic, but only 6 with serum cortisol of < or = 100 nmol/l (< or = 3.6 microg/dl), had symptoms and were substituted with glucocorticoid. Remaining seven patients, with serum cortisol between >100-349 nmol/l (> 3.6-12.6 microg/dl), were asymptomatic and advised glucocorticoid support only during stress but none required. Overall, 17 (74%) patients were spared from unnecessary glucocorticoid support. At 12 wk, 13 (57%) patients were hypocortisolic and only 6 either with serum cortisol level of < or = 100 nmol/l (< or = 3.6 microg/dl) or symptomatic for AI received glucocorticoids. Post-operative complications including diabetes insipidus and CSF leak remarkably decreased. The protocol used was safe and spared unnecessary use of glucocorticoids peri- and post-operatively. However, more number of patients are to be studied to substantiate the validity of this protocol.


Comparative analysis of iterative reconstruction algorithms with resolution recovery and new solid state cameras dedicated to myocardial perfusion imaging.
New technologies are available in myocardial perfusion imaging. They include new software that recovers image resolution and limits image noise, multifocal collimators and dedicated cardiac cameras in which solid-state detectors are used and all available detectors are constrained to imaging just the cardiac field of view. These innovations resulted in shortened study times or reduced administered activity to patients, while preserving image quality. Many single center and some multicenter studies have been published during the introduction of these innovations in the clinical practice. Most of these studies were lead in the framework of "agreement studies" between different methods of clinical measurement. They aimed to demonstrate that these new software/hardware solutions allow the acquisition of images with reduced acquisition time or administered activity with comparable results (as for image quality, image interpretation, perfusion defect quantification, left ventricular volumes and ejection fraction) to the standard-time or standard-dose SPECT acquired with a conventional gamma camera and reconstructed with the traditional FBP method, considered as the gold standard. The purpose of this review is to provide the reader with a comprehensive understanding of the pro and cons of the different approaches summarizing the achievements reached so far and the issues that need further investigations.


Increased expression of the stefin A cysteine proteinase inhibitor occurs in the myelomonocytic cell-infiltrated tissues of autoimmune motheaten mice.
Mice homozygous for the motheaten (me) and viable motheaten (me) mutations develop a progressively severe inflammatory disease in association with profound disruption of normal hematopoiesis. These mutant mice have been previously shown to manifest abnormally high expression in the bone marrow of cDNAs encoding three members of the stefin family of cysteine proteinase inhibitors. The data reported here reveal that increases in levels of both stefin transcripts and proteins occur in bone marrow, splenic and pulmonary tissues of me and mev mice, and correlate with the abnormal expansion of stefin A-producing myelomonocytic cells in these tissues. Increases in stefin expression are also apparent in me and mev skin and appear to reflect focal hyperplasia of stefin-producing epidermal cells as well as infiltration by stefin-expressing monocytic and granulocytic cells. Because the increases in stefin protein levels occur in the same tissues that are most adversely affected by the me mutation, it appears that overexpression of these proteins may distinguish the cell population responsible for disease pathogenesis and may be relevant to the severe tissue inflammation and damage observed in these mutant mice.


The association of how time is spent during outpatient visits and patient satisfaction: are there racial differences?
Both satisfaction with the physician and how time is spent in the patient-physician outpatient visit have been shown to differ between African-American and Caucasian patients. This study uses structural equation modeling to examine racial differences in the association between time use during the outpatient visit and patient satisfaction. This cross-sectional study employed direct observation of outpatient visits and surveys of 2,502 adult African-American and Caucasian outpatients visiting 138 primary care physicians in 84 family practices in Northeast Ohio. Patient satisfaction was measured using the Medical Outcome Study (MOS) nine-item Visit Rating Scale. Time use was assessed with the Davis Observation Code, which was used to classify every 20 seconds of a visit into 20 behavioral categories. No difference was found between African-American and Caucasian patients in the association between patient satisfaction with a physician and the time the physician spent chatting, planning treatment, providing health education, structuring the interaction, assessing health knowledge or answering patient questions. Patients were generally satisfied with their physicians, and no racial differences between Caucasians and African Americans were observed. Despite racial differences in how physicians spend time in the outpatient visit encounter, these differences are not associated with racial differences in patient satisfaction. Efforts to understand disparities in satisfaction should address areas other than how physicians allocate time in the physician-patient encounter.


Validation of Prostate Imaging Reporting and Data System Version 2 Using an MRI-Ultrasound Fusion Biopsy in Prostate Cancer Diagnosis.
The purpose of our study was to prospectively assess Prostate Imaging Reporting and Data System (PI-RADS) version 2 using an MRI-ultrasound fusion biopsy. This study included 295 consecutive patients with 478 lesions who underwent multiparametric MRI and subsequent MRI-ultrasound fusion biopsy between December 2014 and September 2016. Lesions were assessed by using an overall score of PI-RADS version 2. One radiologist assessed the presence or absence of clinically significant prostate cancer in the whole gland and in subgroups of the peripheral zone and transition zone by using cutoff values of ≥ 4 and ≥ 3. Histologic examination of MRI-ultrasound fusion biopsy specimens was used as the reference standard. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated to assess the utility of PI-RADS version 2 for the diagnosis of clinically significant prostate cancer. The overall PI-RADS version 2 scores showed an accuracy of 82.2% (393/478) for the whole gland, with a cutoff value of ≥ 4 granting sensitivity of 90.0% (90/100), specificity of 80.1% (303/378), PPV of 83.3% (90/108), and NPV of 81.8% (303/370). The overall scores showed accuracies of 84.7% (301/355) in the peripheral zone and 74.7% (92/123) in the transition zone. When we applied an arbitrary overall score of ≥ 3, accuracy was 68.6% (328/478), sensitivity was 94.6% (124/131), specificity was 58.7% (204/347), PPV was 51.6% (124/240), and NPV was 85.7% (204/238). PI-RADS version 2 has an overall good performance for the diagnosis of clinically significant prostate cancer.


Articulation rehabilitation induces cortical plasticity in adults with non-syndromic cleft lip and palate.
In this study, we investigated brain morphological changes in adults with non-syndromic cleft lip and palate (NSCLP) after articulation rehabilitation (AR). High-resolution T1 weighted brain magnetic resonance imaging data were analyzed from 45 adults with NSCLP after palatoplasty: 24 subjects were assessed before AR (bNSCLP) and 21 subjects were assessed after AR (aNSCLP). In addition, there were 24 age and sex matched controls. Intergroup differences of grey matter volume were evaluated as a comprehensive measure of the cortex; cortical thickness and cortical complexity (gyrification and fractal dimensions) were also analyzed. As compared to controls, the bNSCLP subjects exhibited altered indexes in frontal, temporal, and parietal lobes; these morphological changes are characteristic for adults with NSCLP. Importantly, as compared to the bNSCLP and control subjects, the aNSCLP subjects exhibited cortical plasticity in the regions involved in language, auditory, pronunciation planning, and execution functions. The AR-mediated cortical plasticity in aNSCLP subjects may be caused by AR-induced cortical neurogenesis, which might reflect the underlying neural mechanism during AR.


Biofunctional Effects of Thiohemiaminal-Type Dimeric Sesquiterpene Alkaloids from Nuphar Plants.
Dimeric sesquiterpene thioalkaloids from the rhizomes of Nuphar pumilum exhibited immunosuppressive effects using a sheep erythrocyte plaque forming cell (PFC) assay, as well as an anti-metastasis effect, and rapid apoptosis-inducing effects in tumor cell lines. In particular, dimeric sesquiterpene thioalkaloids with a hydroxy group (6-hydroxythiobinupharidine, 6,6'-dihydroxythiobinupharidine, 6-hydroxythionuphlutine B) showed substantial effects, whereas dimeric sesquiterpene thioalkaloids lacking the hydroxy group (thiobinupharidine, thionuphlutine B, 6'-hydroxythionuphlutine B, neothiobinupharidine, thionuphlutine B β-sulfoxide, neothiobinupharidine β-sulfoxide) and monomeric sesquiterpene alkaloids (nupharidine, 7-epideoxynupharidine, nupharolutine) showed weak activity. In this review, we summarize our studies of the biofunctional effects of these alkaloids.


TMPL: a database of experimental and theoretical transmembrane protein models positioned in the lipid bilayer.
Knowing the position of protein structures within the membrane is crucial for fundamental and applied research in the field of molecular biology. Only few web resources propose coordinate files of oriented transmembrane proteins, and these exclude predicted structures, although they represent the largest part of the available models. In this article, we present TMPL (http://www.dsimb.inserm.fr/TMPL/), a database of transmembrane protein structures (α-helical and β-sheet) positioned in the lipid bilayer. It is the first database to include theoretical models of transmembrane protein structures, making it a large repository with more than 11 000 entries. The TMPL database also contains experimentally solved protein structures, which are available as either atomistic or coarse-grained models. A unique feature of TMPL is the possibility for users to update the database by uploading, through an intuitive web interface, the membrane assignments they can obtain with our recent OREMPRO web server.


Image Findings of a Rare Case of Neuroendocrine Tumor Metastatic to Orbital Extraocular Muscle in Gallium-68 DOTANOC Positron Emission Tomography/Computed Tomography and Therapy with Lutetium-177 DOTATATE.
Metastatic tumor is one of several etiologies of space-occupying masses in the orbit that accounts for 1-13% of all orbital masses. In the adult patient population, breast cancer is the most common tumor to metastasize to the orbit, followed by metastasis from the lung, prostate, and gastrointestinal tract. Carcinoid tumors are rare neuroendocrine neoplasms derived from enterochromaffin cells, which are found primarily in the gastrointestinal tract and bronchial tree. Liver metastases are the classic presentation of distant disease. Although rare, metastatic carcinoid to the extraocular muscles (EOMs) has been relatively well described in both retrospective case reports and clinical series in the ophthalmology literature, but not in nuclear medicine. Positron emission tomography/computed tomography (PET/CT) using Ga-68-labeled somatostatin-analogues have shown superiority over other modalities for imaging of Neuroendocrine tumor We describe a case of bilateral EOM metastasis from carcinoid lung in Ga-68 DOTANOC PET/CT and treatment with Lu -177 DOTATATE.


VEGF165-induced vascular permeability requires NRP1 for ABL-mediated SRC family kinase activation.
The vascular endothelial growth factor (VEGF) isoform VEGF165 stimulates vascular growth and hyperpermeability. Whereas blood vessel growth is essential to sustain organ health, chronic hyperpermeability causes damaging tissue edema. By combining in vivo and tissue culture models, we show here that VEGF165-induced vascular leakage requires both VEGFR2 and NRP1, including the VEGF164-binding site of NRP1 and the NRP1 cytoplasmic domain (NCD), but not the known NCD interactor GIPC1. In the VEGF165-bound receptor complex, the NCD promotes ABL kinase activation, which in turn is required to activate VEGFR2-recruited SRC family kinases (SFKs). These results elucidate the receptor complex and signaling hierarchy of downstream kinases that transduce the permeability response to VEGF165. In a mouse model with choroidal neovascularisation akin to age-related macular degeneration, NCD loss attenuated vessel leakage without affecting neovascularisation. These findings raise the possibility that targeting NRP1 or its NCD interactors may be a useful therapeutic strategy in neovascular disease to reduce VEGF165-induced edema without compromising vessel growth.


The Use of Race, Ethnicity, and Social Determinants of Health in Three Pediatrics Journals.
To evaluate how race, ethnicity, and social determinants of health (SDOH) are reported and discussed in 3 pediatrics journals. Bibliometric analysis of original articles that enrolled children as participants between January-June 2021 published in The Journal of Pediatrics, Pediatrics, and JAMA Pediatrics. We recorded in aggregate the inclusion of race, ethnicity, and SDOH data from the methods, results, and discussion sections of each article. We then used χ2 analyses and t tests to compare recording and use of race, ethnicity, and SDOH data on a number of factors. A total of 317 original articles were included with 200 (63.1%) conducted in the US. Researchers presented 116 unique race and ethnicity categories. US studies reported race significantly more frequently than international studies (166/200, 83.0% vs 29/117, 24.8% P < .001), yet only 24.7% (41/166) of US and 10.3% (3/29) of international studies that reported these data interpreted their significance and linked such to their study findings. US federal funding influenced reporting of race and ethnicity but not interpretation. Less than one-half of all studies reported SDOH (147/317, 46.4%), and very few that reported SDOH interpreted the data to study findings in both the US (18/106, 17.0%) and internationally (3/41, 7.3%). Race, ethnicity, and SDOH data are reported without consistent categories, and their significance is not often explained in both US and international articles. Researchers should be more intentional about how and why they collect, report, and interpret these data to help identify health disparities and highlight health inequities.


Social deprivation and hospital admission rates, length of stay and readmissions in emergency medical admissions.
Patients from deprived backgrounds have a higher in-patient mortality following an emergency medical admission. How deprivation relates to the admission or readmission incidence rates, episode length of stay (LOS) and ancillary resource utilization is less clear. All emergency medical admissions (66,861 episodes in 36,214 patients) between 2002 and 2013, categorized by quintile of Irish National Deprivation Index were assessed against admission or readmission incidence rates (/1000 local population by electoral division), LOS and utilization of five ancillary services. Univariate and multi-variable risk estimates (odds ratios (OR) or incidence rate ratios (IRR)) were calculated, using truncated Poisson regression. The deprivation index quintile was strongly correlated with the emergency medical admission rate with IRR (as compared with quintile 1) as follows: Q2 1.99 (95% CI: 1.96, 2.01), Q3 3.45 (95% CI: 3.41, 3.49), Q4 3.27 (95% CI: 3.23, 3.31) and Q5 4.29 (95% CI: 4.23, 4.35). LOS was not influenced by deprivation status; although increasing deprivation resulted in increased utilization of social services (OR 1.04: 95% CI: 1.03, 1.06), with a lower requirement for occupational therapy (OR 0.94: 95% CI: 0.93, 0.96) and speech/language services (OR 0.83: 95% CI: 0.80, 0.86). There was a rather decreased use of ancillary services with increasing deprivation; however, the readmission rate was strongly predicted by deprivation status. Deprivation status strongly influenced the admission and readmission rates for medical patients admitted as emergencies; however, ancillary resource utilization was not increased. Deprivation index will increase demand on hospital resources due to the aggregate effect on both admission and readmission incidence rates.


Fabrication of Addressable Perovskite Film Arrays for High-Performance Photodetection and Real-Time Image Sensing Application.
Patterned growth of periodic perovskite film arrays is essential for application in sensing devices and integrated optoelectronic systems. Herein, we report on patterned growth of addressable perovskite photodetector arrays through an uncured polydimethylsiloxane (PDMS) oligomer-assisted solution-processed approach, in which a periodic hydrophilic/hydrophobic substrate replicating the predesigned patterns of the PDMS stamp was formed due to the migration of uncured siloxane oligomers in the PDMS stamp to the intimately contacted substrate. By using this technique, MAPbI3 film photodetector arrays with neglectable pixel-to-pixel variation, a responsivity of 2.83 A W-1, specific detectivity of 5.4 × 1012 Jones, and fast response speed of 52.7/57.1 μs (response/recovery time) were achieved. An 8 × 8 addressable photodetector array was further fabricated, which functioned well as a real-time image sensor with reasonable spatial resolution. It is believed that the proposed strategy will find potential application in large-scale fabrication of other photodetector arrays, which might be potentially important for future integrated optoelectronic devices.


Phenotypic, chemical and functional characterization of cyclic nucleotide phosphodiesterase 4 (PDE4) as a potential anthelmintic drug target.
Reliance on just one drug to treat the prevalent tropical disease, schistosomiasis, spurs the search for new drugs and drug targets. Inhibitors of human cyclic nucleotide phosphodiesterases (huPDEs), including PDE4, are under development as novel drugs to treat a range of chronic indications including asthma, chronic obstructive pulmonary disease and Alzheimer's disease. One class of huPDE4 inhibitors that has yielded marketed drugs is the benzoxaboroles (Anacor Pharmaceuticals). A phenotypic screen involving Schistosoma mansoni and 1,085 benzoxaboroles identified a subset of huPDE4 inhibitors that induced parasite hypermotility and degeneration. To uncover the putative schistosome PDE4 target, we characterized four PDE4 sequences (SmPDE4A-D) in the parasite's genome and transcriptome, and cloned and recombinantly expressed the catalytic domain of SmPDE4A. Among a set of benzoxaboroles and catechol inhibitors that differentially inhibit huPDE4, a relationship between the inhibition of SmPDE4A, and parasite hypermotility and degeneration, was measured. To validate SmPDE4A as the benzoxaborole molecular target, we first generated Caenorhabditis elegans lines that express a cDNA for smpde4a on a pde4(ce268) mutant (hypermotile) background: the smpde4a transgene restored mutant worm motility to that of the wild type. We then showed that benzoxaborole inhibitors of SmPDE4A that induce hypermotility in the schistosome also elicit a hypermotile response in the C. elegans lines that express the smpde4a transgene, thereby confirming SmPDE4A as the relevant target. The orthogonal chemical, biological and genetic strategies employed identify SmPDE4A's contribution to parasite motility and degeneration, and its potential as a drug target. Transgenic C. elegans is highlighted as a potential screening tool to optimize small molecule chemistries to flatworm molecular drug targets.


[Sequence learning in major depressive disorder].
Major Depressive Disorder (MDD) is one of the most common psychiatric diagnoses, accompanied by several psychological, behavioural and emotional symptoms, and in addition to the symptoms affecting the quality of life, it can lead to severe consequences, including suicide. Sequence learning plays a key role in adapting to the environment, neural plasticity, first language acquisition, social learning and skills, at the same time it defines the behaviour of the patient and also therapeutic possibilities. The aim of this paper is to review sequence learning and its consolidation in MDD. We know little about the effects of mood disorders on sequence learning; the results are contradictory, therefore, further studies are needed to test the effects of MDD on sequence learning and on the consolidation of implicitly acquired sequence knowledge.


Formation and Evolution of Metallocene Single-Molecule Circuits with Direct Gold-π Links.
Single-molecule circuits with group 8 metallocenes are formed without additional linker groups in scanning tunneling microscope-based break junction (STMBJ) measurements at cryogenic and room-temperature conditions with gold (Au) electrodes. We investigate the nature of this direct gold-π binding motif and its effect on molecular conductance and persistence characteristics during junction evolution. The measurement technique under cryogenic conditions tracks molecular plateaus through the full cycle of extension and compression. Analysis reveals that junction persistence when the metal electrodes are pushed together correlates with whether electrodes are locally sharp or blunt, suggesting distinct scenarios for metallocene junction formation and evolution. The top and bottom surfaces of the "barrel"-shaped metallocenes present the electron-rich π system of cyclopentadienyl rings, which interacts with the gold electrodes in two distinct ways. An undercoordinated gold atom on a sharp tip forms a donor-acceptor bond to a specific carbon atom in the ring. However, a small, flat patch on a dull tip can bind more strongly to the ring as a whole through van der Waals interactions. Density functional theory (DFT)-based calculations of model electrode structures provide an atomic-scale picture of these scenarios, demonstrating the role of these bonding motifs during junction evolution and showing that the conductance is relatively independent of tip atomic-scale structure. The nonspecific interaction of the cyclopentadienyl rings with the electrodes enables extended conductance plateaus, a mechanism distinct from that identified for the more commonly studied, rod-shaped organic molecular wires.


[Development of a preoperative criterion to select candidates for nerve-sparing radical prostatectomy at Kyoto University Hospital].
Neurovascular bundle (NVB) preservation is a mandatory procedure to maintain erectile function of localized prostate cancer patients after radical prostatectomy (RP). However, in terms of cancer control, indications to select appropriate patients for nerve-sparing RP are still controversial. In this study, we examined the pathological findings of RP specimens to develop a preoperative criterion for NVB preservation during RP. The study included 76 patients who underwent RP at our institution from 2006 to 2008, and we retrospectively analyzed RP specimens pathologically. The distance between NVB and foci of prostate cancer was measured in 135 prostate sides, and preoperative factors which predict the distance of ≤2 mm was evaluated. Univariate analysis showed that side-specific positive biopsy core rate ≥33.3%, side-specific maximum tumor length in biopsy core ≥5 mm and side-specific tumor involvement rate in biopsy core ≥50% was associated with the risk of the distance of ≤2 mm. Multivariate analysis revealed that side-specific positive biopsy core rate ≥33.3% was the only significant predictor of the ipsilateral NVB-tumor distance ≤2 mm (p = 0.0055, odds ratio 3.49). Based on this study, a nerve-sparing criterion of <33.3% side-specific percent positive biopsy core was developed at our institution. Prospective data on patients who were applied this criterion are needed to evaluate its clinical safety and feasibility.


Externalizing behaviors and cigarette smoking as predictors for use of illicit drugs: a longitudinal study among Finnish adolescent twins.
We examined whether externalizing problem behaviors (hyperactivity-impulsivity, aggressiveness, and inattention) predict illicit drug use independently, or whether their associations with drug use are mediated through cigarette smoking. We used a prospective longitudinal design within the FinnTwin12-17 study among Finnish adolescents with baseline at age 12 and follow-up surveys at ages 14 and 17. Path models were conducted with Mplus and included 1992 boys and 2123 girls. The outcome was self-reported ever use of cannabis or other illicit drugs at age 17. The predictors were: externalizing behaviors (hyperactivity-impulsivity, aggressiveness, and inattention) assessed by teachers and parents (age 12) and self-reported cigarette smoking (age 14). The findings differed across behavior studied. The association of hyperactivity-impulsivity with drug use was mostly mediated through earlier cigarette smoking. Concerning aggressiveness and inattention, the results were different among girls than boys. Among girls no significant mediation occurred, whereas among boys more consistent evidence on mediation was seen. Consistently in all models, the direct association of early cigarette smoking on drug use was strong and highly significant. We conclude that the associations of externalizing problem behaviors with illicit drug use are partially mediated through cigarette smoking. Although interventions targeting externalizing problem behaviors may protect adolescents from early onset smoking and subsequently experimenting with drugs, interventions to prevent cigarette smoking initiation are also important in reducing risk of later drug use.


Integrated Decentralized Training for Health Professions Education at the University of KwaZulu-Natal, South Africa: Protocol for the I-DecT Project.
The Integrated Decentralized Training (i-DecT) project was created to address the current need for health care in South Africa among resource poor climates in rural and periurban settings. The University of KwaZulu-Natal (UKZN) in South Africa has embarked on a program within the School of Health Sciences (SHS) to decentralize the clinical learning platform in order to address this disparity. Framed in a pragmatic stance, this proposal is geared towards informing the roll out of decentralized clinical training (DCT) within the province of KwaZulu-Natal. There currently remains uncertainty as to how the implementation of this program will unfold, especially for the diverse SHS, which includes specialities like audiology, dentistry, occupational therapy, optometry, pharmacy, physiotherapy, speech-language pathology, and sport science. Consequently, there is a need to carefully monitor and manage this DCT in order to ensure that the participating students have a positive learning experience and achieve expected academic outcomes, and that the needs of the communities are addressed adequately. The study aims to explore the factors that will influence the roll-out of the DCT by developing an inclusive and context-specific model that will adhere to the standards set by the SHS for the DCT program at UKZN. Key role players, including but not limited to, the South African Ministry of Health policy makers, clinicians, policy makers at UKZN, clinical educators, academicians, and students of UKZN within the SHS will participate in this project. Once the infrastructural, staffing and pedagogical enablers and challenges are identified, together with a review of existing models of decentralized training, a context-specific model for DCTl will be proposed based on initial pilot data that will be tested within iterative cycles in an Action Learning Action Research (ALAR) process. The study was designed to fit within the existing structures, and emerging framework and memorandum of understanding between the partners of this initiative, namely, the Ministry of Health and UKZN in order to develop health care professionals that are competent and prepared for the changing dynamics of healthcare in a developing world. It is envisioned that this study, the first to include a combination of health professionals in a DCT platform at UKZN, will not only contribute to effective service delivery, but may also serve to promote an interprofessional cooperation within the SHS and tertiary institutions in similar settings.


Effect of surgical trauma on various aspects of the immune response in rats.
The effects of a standard laparotomy on different aspects of the immune response were studied in Wistar R/A rats. When the antigen was administered at the time of operation, antibody synthesis against sheep red blood cells (SRBC), a thymo-dependent antigen was significantly stimulated. The same phenomenon was observed when a soluble antigen extracted from SRBC was injected during the surgical procedure. On the contrary, late antibody production induced by formalinized Salmonella enteritidis or Escherichia coli lipopolysaccharide, two thymo-independent antigens, was reduced in operated animals. Cell-mediated immunity against SRBC was investigated by the radiometric ear index test described by Kostiala in 1977. Surgery did not alter the induction phase but suppressed the expression of the cellular immune response. Carrageenin-induced edema was inhibited in operated rats. These results show that surgical trauma acts differently on the various aspects of the immune response.


Acute Multiple Sclerosis Relapse.
This article discusses acute exacerbations (relapses) of multiple sclerosis (MS). Relapses are a hallmark of MS and are often associated with significant functional impairment and decreased quality of life. This review discusses the proposed pathophysiology of MS relapses, triggering factors, associated markers, variants of clinical presentation, and diagnostic recommendations. Most MS exacerbations are followed by a period of repair leading to clinical remission; however, residual deficits may persist after MS relapse and contribute to the stepwise progression of disability. Treatment of MS relapses is important as it helps to shorten the duration of disability associated with their course. Successful treatment of relapse helps patients with MS obtain a vital sense of being able to gain control over the disease. Patients with relapsing MS who receive treatment report better outcomes than those who are simply observed. This article discusses treatment options for MS relapse, including systemic corticosteroids, adrenocorticotropic hormone, and plasma exchange. Recent findings related to the mechanisms of action of steroids and adrenocorticotropic hormone are also reviewed, and other potential therapies are assessed. A proposed algorithm for MS relapse management is presented, including strategies for steroid-resistant MS exacerbations. MS relapses need to be recognized in a timely manner and treated using recommended therapeutic methods.


Prasugrel in critically ill patients.
While prasugrel is indicated for the treatment of myocardial infarction, its effects in the most severely affected patients requiring intensive care is unknown, so that we measured the antiplatelet effects and sparse pharmacokinetics of prasugrel in critically ill patients. Twenty-three patients admitted to medical intensive care units, who were treated with 10 mg prasugrel once daily, were included in this prospective trial. Critically ill patients responded poorly to daily prasugrel treatment: adenosine diphosphate (ADP)-induced aggregation in whole blood classified 65 % (95 % confidence intervals (CI) 43-84 %) of patients as having high on treatment platelet reactivity, platelet function under high shear rates even 74 % (95 %CI 52-90 %). There was only limited additional inhibition provided 2 hours after the next dose of prasugrel. In contrast, insufficient inhibition of the target was only seen in 26 % (95 %CI 10-48 %) of patients as measured by the vasodilator-stimulated phosphoprotein phosphorylation (VASP-P) assay. Low effective plasma levels of prasugrel active metabolite were measured at trough [0.5 (quartiles 0.5-1.1) ng/ml at baseline], and 2 hours after intake [5.7 (3.8-9.8) ng/ml], but showed coefficients of variation of ~70 %. In sum, inhibition of platelet aggregation by prasugrel is not uniform but highly variable in critically ill patients, similar to clopidogrel in a general population. The pharmacokinetic measurements indicate that poor absorption/metabolism of prasugrel may partly contribute while inflammation induced heightened intrinsic platelet reactivity may also play a role.


Hunting for the beat in the body: on period and phase locking in music-induced movement.
Music has the capacity to induce movement in humans. Such responses during music listening are usually spontaneous and range from tapping to full-body dancing. However, it is still unclear how humans embody musical structures to facilitate entrainment. This paper describes two experiments, one dealing with period locking to different metrical levels in full-body movement and its relationships to beat- and rhythm-related musical characteristics, and the other dealing with phase locking in the more constrained condition of sideways swaying motions. Expected in Experiment 1 was that music with clear and strong beat structures would facilitate more period-locked movement. Experiment 2 was assumed to yield a common phase relationship between participants' swaying movements and the musical beat. In both experiments optical motion capture was used to record participants' movements. In Experiment 1 a window-based period-locking probability index related to four metrical levels was established, based on acceleration data in three dimensions. Subsequent correlations between this index and musical characteristics of the stimuli revealed pulse clarity to be related to periodic movement at the tactus level, and low frequency flux to mediolateral and anteroposterior movement at both tactus and bar levels. At faster tempi higher metrical levels became more apparent in participants' movement. Experiment 2 showed that about half of the participants showed a stable phase relationship between movement and beat, with superior-inferior movement most often being synchronized to the tactus level, whereas mediolateral movement was rather synchronized to the bar level. However, the relationship between movement phase and beat locations was not consistent between participants, as the beat locations occurred at different phase angles of their movements. The results imply that entrainment to music is a complex phenomenon, involving the whole body and occurring at different metrical levels.


Enhancement of aniline hydroxylation in human liver microsomes.
Effects of cyanide, acetone, 2,2'-bipyridine and paraoxon on aniline hydroxylation by human liver microsomes were studied. The activity of aniline hydroxylation was inhibited by cyanide when low concentrations of substrate were used, whereas the activity was increased by the addition of cyanide when higher concentrations of substrate were used. Although there were large variences among different liver samples in the extent of the activation of aniline hydroxylation, acetone, 2,2'-bipyridine and paraoxon also exerted stimulatory effects on aniline hydroxylation in human liver microsomes. The degree of the stimulation was not related with the activities observed in the absence of these compounds.


Computer Scoring of Emotional Awareness in a Nonclinical Population of Young Adults.
The Levels of Emotional Awareness Scale (LEAS; Lane, Quinlan, Schwartz, Walker, & Zeitlin, 1990 ) is an open-ended measure of the ability to describe emotional reactions. Scoring the LEAS by hand is complex and time consuming (Barchard, Bajgar, Leaf, & Lane, 2010 ). Therefore, Program for Open-Ended Scoring (POES; Leaf & Barchard, 2010 ) was designed to score the LEAS quickly and easily. Using 268 undergraduates, this article compares traditional LEAS hand scoring to 6 POES methods, 2 of which are holistic methods that have never before been examined. Based on split-half reliability, correlations with measures of emotional and social intelligence, and partial correlations once response length and vocabulary were partialed out, we recommend 3 of the POES methods when testing nonclinical samples of young adults. Because POES scoring is fast and efficient, it allows more researchers and clinicians to use the LEAS, thus moving away from self-report measures of emotional awareness.


The impact of androgen receptor polymorphism and parental ethnicity on semen quality in young men from Latvia.
Recent studies on young men from the general population have demonstrated geographic and ethnic differences in semen quality. The aim of this study was to investigate whether reported ethnic differences in semen quality might be associated with the maternally derived CAG and GGN polymorphisms in the androgen receptor gene or paternal ethnicity. In total 114 military conscripts from Latvia were included in the study. Information on maternal and parental ethnicity was collected by questionnaires. CAG and GGN repeats were analysed by direct sequencing of leukocyte DNA. Men with Latvian mothers (n = 83) had marginally shorter CAG repeat length (21.6 +/- 2.9) as compared with those with non-Latvian mothers (22.9 +/- 3.2, n = 31), not reaching statistical significance (p = 0.053). Sperm concentration did not differ significantly between these two groups (76 +/- 59 and 70 +/- 52, p = 0.9 respectively). In contrast, significantly higher sperm concentration and total sperm count were found in men with Latvian fathers (n = 77) as compared with men with non-Latvian fathers (n = 37) (80 +/- 61 vs. 62 +/- 48, p = 0.035, for sperm concentration and 225.7 +/- 209 vs. 158.4 +/- 134.4, p = 0.002, for total sperm count respectively). CAG repeat length did not correlate with any semen parameters in the whole population. However, GGN repeat length correlated with semen volume: men with GGN > 23 presented with higher semen volume (3.2 +/- 2.1) as compared with men with GGN = 23 (2.6 +/- 1.3, p = 0.04) or GGN < 23 (2.0 +/- 1.2, p = 0.006). We conclude that GGN repeat length has an impact on semen volume, whereas differences in sperm numbers are associated with the paternal ethnicity.


Efficacy and safety of risankizumab for active psoriatic arthritis: 52-week results from the KEEPsAKE 1 study.
PsA is a chronic disease with heterogeneous clinical manifestations requiring treatment options with long-term efficacy and safety. In this follow-up analysis, the 52-week efficacy and safety of risankizumab 150 mg in patients with active PsA who had previous inadequate response/intolerance to one or more conventional synthetic DMARDs (csDMARD-IR) were evaluated. KEEPsAKE 1 is an ongoing, global, phase 3 study with a 24-week, double-blind, placebo-controlled period (period 1) and an open-label extension period (period 2). In period 1, eligible patients were randomized 1:1 to receive subcutaneous risankizumab 150 mg or placebo at weeks 0, 4 and 16. At week 24 (period 2), all continuing patients received open-label risankizumab 150 mg every 12 weeks through week 208. At week 24, 57.3% of risankizumab-treated patients (n = 483) achieved ≥20% improvement in ACR criteria (ACR20) vs 33.5% of placebo-treated patients (n = 481; P < 0.001). At week 52, 70.0% of patients who were randomized to receive continuous risankizumab therapy and 63.0% of patients who were randomized to receive placebo in period 1 and then receive risankizumab at week 24 achieved ACR20. Similar result trends were observed for other efficacy measures. Risankizumab was well tolerated through 52 weeks of treatment with a consistent safety profile from week 24 through week 52. In patients with active PsA who were csDMARD-IR, continuous risankizumab treatment demonstrated robust long-term efficacy and was well tolerated through 52 weeks of treatment. ClinicalTrials.gov, http://clinicaltrials.gov, KEEPsAKE1, NCT03675308.


Enantioselective phytotoxicity of the herbicide imazethapyr and its effect on rice physiology and gene transcription.
Imazethapyr (IM) is a chiral herbicide and a widely used racemic mixture. This report investigated the enantioselectivity between R- and S-IM in rice and explored its causative mechanism at the physiological and molecular levels. The results suggested that R-IM inhibited acetolactate synthase (ALS) activity to a greater extent than S-IM, which reduced the synthesis of branched-chain amino acids (BCAAs). Additionally, most other amino acids showed enantioselectivity. On the cellular level, R-IM showed stronger toxicity against protoplasts than S-IM. A gene transcription profile analysis showed that gene transcripts in many metabolic pathways, including amino acid metabolism, photosynthesis, starch and sugar metabolism, and the tricarboxylic acid cycle displayed enantioselectivity between the IM enantiomers. R-IM regulated more genes more strongly than S-IM. This study suggested that R-IM has stronger toxicity against plants than S-IM; this toxicity is caused not only by changing targeted enzyme activity and amino acid synthesis, but also by affecting gene transcription in other metabolic pathways directly or indirectly in an enantioselective manner.


Orthostatic systolic hypotension and the reflection pressure wave.
Orthostatic hypotension (OH) is a potent predictor of cardiovascular frailty. Although OH is determined by changes in brachial blood pressure (BP), it has been reported that there are significant differences between central BP and peripheral BP. The prevalence of OH has been reported to be higher in subjects with isolated systolic hypertension. Since an early returning of the reflection pressure wave due to advanced arterial stiffness is one of the underlying mechanisms of systolic hypertension, a significant association between alterations of the reflection pressure wave and OH has been hypothesized. To explore this hypothesis, the orthostatic changes in carotid BP and arterial waveform were evaluated. The study subjects were 155 community residents (69 +/- 7 years old). Carotid and brachial BP were measured simultaneously in the supine position and 1 min after standing using a cuff-oscillometric and tonometric method. The carotid augmentation index (AIx) was obtained from the pressure waveform. The orthostatic decline of BP was more prominent in the carotid artery than the brachial artery. Nine subjects were diagnosed with orthostatic systolic hypotension (OSH) from brachial BP, while 21 subjects were diagnosed from carotid BP (p < 0.001). The orthostatic change in carotid systolic BP was significantly associated with that in carotid AIx (r = 0.361, p < 0.001). The decline of the reflection component of carotid pulse pressure (-4.0 +/- 8.4 mmHg) was more prominent than that of the incident component (-1.2 +/- 9.9 mmHg, p = 0.002). These results indicate that evaluation of brachial BP may not represent the orthostatic changes in central BP. Alteration of the reflection pressure wave could be one of the underlying mechanisms of OSH in the central artery.


Limitations in the current classification systems for dementia.
A brief review of classification in psychiatry from Kraepelin to ICD-10 and DSM-IV reveals that the categorical paradigm inherent in these nosological systems has certain inadequacies when applied to dementia specifically and cognitive impairment in general. There are "outcasts" from these two systems that, with the rapid advances in an understanding of cognitive disorders, expose significant limitations in them. As and when they are revised, serious consideration of a different view, accepting a dimensional paradigm, would contribute to a more inclusive and clinically relevant nosology for dementia and cognitive disorders.


Do women requesting only contraception find attendance at an integrated sexual health clinic more stigmatizing than attendance at a family planning-only clinic?
Both sexually transmitted infections and the genitourinary medicine clinics that patients attend for management of sexually transmitted infections are stigmatized by patients' perceptions. The aim of this study was to assess whether women requesting contraception only find attendance at an integrated sexual health clinic (ISHC) more stigmatizing than attendance at a family planning (FP)-only clinic. Women requesting contraception only were asked to complete a stigma assessment questionnaire in the waiting room of the clinic they attended. Ease of understanding was assessed for each item of the questionnaire prior to commencement of the survey. The questionnaire was given to women attending either an ISHC or a FP-only clinic. One hundred questionnaires that fulfilled the inclusion criteria were returned. The users of FP-only services were generally older than the users of ISHCs and were more likely than the users of ISHCs to classify themselves as UK white. Stigma perception was significantly higher for the ISHC than the FP-only clinic. The results of this research indicate that among women who request contraception only, perceived stigma is higher when they attend an ISHC than when they attend a FP-only clinic. As this survey only enrolled clinic users, the authors were unable to assess whether integration generates sufficient stigma to deter some women from accessing contraception from integrated services. Of all stigma-related issues, disclosure concerns are likely to be the most important to the service user. Stigma is not an issue of overriding concern for most service users.


Evaluation of the Efficacy of Cryosurgery in Patients With Sebaceous Hyperplasia of the Face.
Cryosurgery is an effective treatment for sebaceous hyperplasia, but there have been few clinical studies. The aim of this study was to evaluate the efficacy and safety of cryosurgery in the treatment of sebaceous hyperplasia. Cryosurgery was performed 6 times, at 2-week intervals, with liquid nitrogen, and evaluated in 40 patients with 517 lesions ranging from 2 to 9 mm over the forehead, cheeks, and chin. All of the lesions were measured before and after the treatment. The mean age of the participants was 54.7 ± 8.9 years, and the male/female ratio was 21/19 (1.1). The mean time of the disease duration was 4.2 ± 3.0 years. After 6 cooling cycles, an excellent response (76%-100%) was seen in 341 patients (65.9%), a very good response (51%-75%) was seen in 102 (19.7%), a good response (26%-50%) was seen in 57 (11.1%), a poor response (1%-25%) was seen in 15 (2.9%), and no response (0%) was seen in 2 (0.4%). Age ( P = .004) and sex ( P < .0001) were independent predictors of an excellent response. The excellent response rates were 71.4% for males, 61.8% for females, 70.4% for ages older than 55 years, and 61.8% for ages younger than 55 years. Temporary hyperpigmentation was found in 5 lesions (0.96%), and recurrence was not seen at the 4-month follow-up. The well-aimed and controlled used of cryosurgery is an effective method for treating significant cosmetic disfigurement in patients with sebaceous hyperplasia. It is a low-cost therapy without scarring, hypopigmentation, or recurrence.


Resistance to sevin by DDT- and parathion-resistant houseflies and sesoxane as sevin synergist.
The new carbamate insecticide, Sevin, has a low toxicity against houseflies. However, it is activated effectively by low concentrations of Sesoxane, a pyrethrum synergist. This occurs with normal nonselected flies and also with strains selected for resistance to DDT and Parathion, which have considerable cross resistance to Sevin.


Pre- and postsynaptic ATP-sensitive potassium channels during metabolic inhibition of rat hippocampal CA1 neurons.
Presynaptic and postsynaptic membrane activities during experimental metabolic inhibition were analysed in mechanically dissociated rat hippocampal neurons using nystatin-perforated and conventional whole-cell patch clamp recordings. NaCN, an inhibitor of mitochondrial ATP synthesis, induced an outward current across the postsynaptic soma membrane. This current was blocked by tolbutamide, a sulfonylurea, which blocks ATP-sensitive K+ (KATP) channels. The presynaptic effect of metabolic inhibitors such as NaCN, NaN3, or glucose-free solution was to increase the frequency of GABAergic miniature inhibitory postsynaptic currents (mIPSCs). Tolbutamide had no effect on this increase in mIPSC frequency induced by metabolic inhibition. Diazoxide, a KATP channel opener, evoked a similar somatic outward current in a dose-dependent manner. In addition, diazoxide decreased the frequency of mIPSCs in a dose-dependent fashion. Both these pre- and postsynaptic effects of diazoxide were reversed by tolbutamide, suggesting the existence of KATP channels on both pre- and postsynaptic membranes. These results confirm the presence of KATP channels on both the pre- and postsynaptic membranes but indicate that the channels have significantly different sensitivities to metabolic inhibition.


Induction of drug-metabolizing enzymes by phenobarbitone: structural and biochemical aspects.
Two aspects of the induction of microsomal monooxygenases by phenobarbitone have been investigated. First, structural associations between mitochondria and single cisternae of rough endoplasmic reticulum (mitochondria--RER complexes) may operate as functional units in the biosynthesis of cytochrome P-450. This was deduced from (i) studies on the subcellular distribution of the phenobarbitone-induced incorporation of leucine into microsomal proteins including apocytochromes P-450 and (ii) the incorporation of labelled delta-aminolaevulinic acid into the haem prosthetic group of cytochrome P-450. Secondly, in hepatocytes from chick embryo in primary monolayer culture, induction of cytochrome P-450-haemoproteins was markedly influenced by changes in the proliferative activity of hepatocytes. Inducibility of cytochrome P-450 by phenobarbitone and by beta-naphthoflavone was decreased in cultures with 'spontaneous' or experimentally increased proliferative activity of hepatocytes. Treatment with inhibitors of DNA synthesis increased the induction response.


Changes in Hematological Parameters with Pegylated Interferon in Chronic Hepatitis C Virus Infected Patients.
The liver is one of the most common sites of cancer in the world, hepatocellular carcinoma (HCC) predominating. HCC is the sixth most common cancer and the third leading cause of cancer related death overall. Hepatitis C is a major risk factor and HCV is a rapid spreading virus which has become a problem globally, including in Pakistan. Interferon alpha therapy is used against HCV disease to regulate cell reproduction and to boost the immune system. In minute amounts interferon alpha is produced naturally by the immune system in HCV patients in response to hepatitis C virus and binds to receptors in the target cells and starts transcription of 20-30 genes due to which it develops an antiviral influence. Interferon is also administered artificially to overcome HCV disease and remove the biological effect of the virus from the infected site. The use of interferon or Peg-IFN plus Ribavirin treatment is also associated with adverse effects on body. For the current study, a convenient sample of 156 HCV positive patients of both males and females were taken. To collect blood CP and ALT, a reduction of level data and other important information were collected from the patients at regular intervals. Findings were 11.4 % in the red blood cells (RBC), 9.64 % in the total leukocyte count (WBC), 8.4 % in the hemoglobin levels (HB), 30.3 % in the platelet (Plt) count in both sexes. There was significant reduction in ALT levels due to Pegylated interferon plus ribavirin therapy. Hence strict haemotological monitoring of blood CP and ALT levels is necessary at regular intervals to reduce severe side effects which may lead to morbidity and mortality.


Detection of exon deletions within an entire gene (CFTR) by relative quantification on the LightCycler.
Cystic fibrosis (CF) is associated with at least 1 pathogen point sequence variant on each CFTR allele. Some symptomatic patients, however, have only 1 detectable pathogen sequence variant and carry, on the other allele, a large deletion that is not detected by conventional screening methods. For relative quantitative real-time PCR detection of large deletions in the CFTR gene, we designed DNA-specific primers for each exon of the gene and primers for a reference gene (beta2-microglobulin). For PCR we used a LightCycler system (Roche) and calculated the gene-dosage ratio of CFTR to beta2-microglobulin. We tested the method by screening all 27 exons in 3 healthy individuals and 2 patients with only 1 pathogen sequence variant. We then performed specific deletion screenings in 10 CF patients with known large deletions and a blinded analysis in which we screened 24 individuals for large deletions by testing 8 of 27 exons. None of the ratios for control samples were false positive (for deletions or duplications); moreover, for all samples from patients with known large deletions, the calculated ratios for deleted exons were close to 0.5. In addition, the results from the blinded analysis demonstrated that our method can also be used for the screening of single individuals. The LightCycler assay allows reliable and rapid screening for large deletions in the CFTR gene and detects the copy number of all 27 exons.


Apple Ripening Is Controlled by a NAC Transcription Factor.
Softening is a hallmark of ripening in fleshy fruits, and has both desirable and undesirable implications for texture and postharvest stability. Accordingly, the timing and extent of pre-harvest ripening and associated textural changes following harvest are key targets for improving fruit quality through breeding. Previously, we identified a large effect locus associated with harvest date and firmness in apple (Malus domestica) using genome-wide association studies (GWAS). Here, we present additional evidence that polymorphisms in or around a transcription factor gene, NAC18.1, may cause variation in these traits. First, we confirmed our previous findings with new phenotype and genotype data from ∼800 apple accessions. In this population, we compared a genetic marker within NAC18.1 to markers targeting three other firmness-related genes currently used by breeders (ACS1, ACO1, and PG1), and found that the NAC18.1 marker was the strongest predictor of both firmness at harvest and firmness after 3 months of cold storage. By sequencing NAC18.1 across 18 accessions, we revealed two predominant haplotypes containing the single nucleotide polymorphism (SNP) previously identified using GWAS, as well as dozens of additional SNPs and indels in both the coding and promoter sequences. NAC18.1 encodes a protein that is orthogolous to the NON-RIPENING (NOR) transcription factor, a regulator of ripening in tomato (Solanum lycopersicum). We introduced both NAC18.1 transgene haplotypes into the tomato nor mutant and showed that both haplotypes complement the nor ripening deficiency. Taken together, these results indicate that polymorphisms in NAC18.1 may underlie substantial variation in apple firmness through modulation of a conserved ripening program.


Ileo-ileal knot: a rare case of acute strangulated intestinal obstruction.
Strangulated intestinal obstruction is one of the most common types of acute abdomen and requires urgent surgical treatment. Herein, we report a very rare case of strangulated intestinal obstruction caused by an ileo-ileal knot. An 80-year-old woman was admitted to our hospital with suspicion of strangulation ileus and underwent emergency laparotomy after investigation by exploratory single-port laparoscopy. During surgery, a small bowel gangrene caused by an ileo-ileal knot was found. The gangrenous segment was resected, and primary anastomosis was performed. Post-operative recovery was uneventful except for a minor wound infection. Our extensive search of the literature found only 7 case reports of ileo-ileal knot including ours. An ileo-ileal knot should be considered in the differential diagnosis of acute intestinal obstruction, because this rare phenomenon requires urgent surgical treatment; and some complications should be considered during or after surgery.


Entropy Information of Pulse Dynamics in Three Stages of Pregnancy.
The aim of the present study is to use entropy to explore the change of pulse generated by normal pregnant women with gestational. Firstly, the subjects were divided into early (E), middle (M), and late (L) three stages according to gestational age. Then, pulse signals of the Chi position of 90 pregnant women at different gestational ages were collected. Secondly, the four entropies, namely fuzzy entropy (FuEn), approximate entropy (ApEn), sample entropy (SamEn), and permutation entropy (PerEn), were applied to the analysis of the long-term pulse changes of the pregnancy. Finally, the related information about pulse in different stages of pregnancy is given by the analysis of four kinds of entropy. Furthermore, the statistical tests are conducted for further comparison, and the descriptive statistics and the results are presented. In addition, boxplots are employed to show the distribution of four entropies of pregnancy. This work has studied the changes in pulse during pregnancy from quantitative and qualitative aspects. Our results show that entropy improves the diagnostic value of pulse analysis during pregnancy and could be applied to facilitate noninvasive diagnosis of pregnant women's physiological signals in the future.


Utilization and scope of practice of Nurse Practitioners and physician assistants in Montana.
To explore the licensing, certification, governance and education requirements of nurse practitioners (NPs) and physician assistants (PAs) in the state of Montana. Services provided and privileges retained in employment were also analyzed. This was a descriptive study using a survey of rural hospital administrators (N = 34). Survey results show that 92.5% of PAs in Montana meet their supervision requirement by a telephone contact provision outlined by the state board of medicine. In contrast, 54.2% of NPs, who are autonomous by legal definition, have a telephone supervision requirement imposed on them by their employers. These findings have implications for the current and prospective professionals and the businesses for which they work. Nurse practitioners and their professional organizations need to consider the implications these findings have on the professional image and marketability of all NPs.


The Marshall-Marchetti-Krantz procedure: a critical review.
The success of the Marshall-Marchetti-Krantz procedure is reviewed in 56 articles that were predominantly retrospective analyses. The overall success rate was 86.1 per cent in 2712 cases, with 92.1 per cent in primary and 84.5 per cent in repeat procedures. An overall complication rate of 21.1 per cent was calculated. The frequency of osteitis pubis was 2.5 per cent. Lack of pre- or postoperative urodynamic evaluation in the selection of cases, loss of patients to follow-up in reported series, and the lack of long-term follow-up cases must be considered in appraising this retrospective review.


Stage-specific sampling by pattern recognition receptors during Candida albicans phagocytosis.
Candida albicans is a medically important pathogen, and recognition by innate immune cells is critical for its clearance. Although a number of pattern recognition receptors have been shown to be involved in recognition and phagocytosis of this fungus, the relative role of these receptors has not been formally examined. In this paper, we have investigated the contribution of the mannose receptor, Dectin-1, and complement receptor 3; and we have demonstrated that Dectin-1 is the main non-opsonic receptor involved in fungal uptake. However, both Dectin-1 and complement receptor 3 were found to accumulate at the site of uptake, while mannose receptor accumulated on C. albicans phagosomes at later stages. These results suggest a potential role for MR in phagosome sampling; and, accordingly, MR deficiency led to a reduction in TNF-alpha and MCP-1 production in response to C. albicans uptake. Our data suggest that pattern recognition receptors sample the fungal phagosome in a sequential fashion.


High-resolution DNA melting curve analysis to establish HLA genotypic identity.
High-resolution melting curve analysis is a closed-tube fluorescent technique that can be used for genotyping and heteroduplex detection after polymerase chain reaction. We applied this technique at the HLA-A locus and suggest that this method can be used as a rapid, inexpensive screen between siblings prior to living-related transplantation. At any locus, there are seven general cases of shared alleles among two individuals, ranging from identical homozygous genotypes (all alleles shared) to two heterozygous genotypes that share no alleles. We studied each case using previously typed cell lines to show that identity or non-identity can be determined in all cases by high-resolution melting curve analysis. HLA genotype identity is suggested when two individuals have the same melting curves. Identity is confirmed by comparing the melting curve of a 1:1 mixture with the individual melting curves. Non-identity at the amplified locus changes the heteroduplexes formed in the mixture compared with the original samples and alters the shape of the melting curve. The technique was tested on DNA from a 17-member CEPH family. High-resolution melting curve analysis revealed six different genotypes in the family. The genotype clustering was confirmed by sequence-based typing. Although this technique does not sequence or determine specific HLA alleles, it does rapidly establish identity at highly polymorphic HLA loci. The technique may also prove useful for confirmation of HLA genotypic identity between unrelated individuals prior to allogeneic hematopoietic stem-cell transplantation.