[The expansion of vector-borne diseases and the implications for blood transfusion safety: The case of West Nile Virus, dengue and chikungunya].
Arbovirus infections are increasing in prevalence worldwide. This presents new risks for blood transfusion. This article describes the epidemiology and surveillance of West Nile Virus, dengue and chikungunya and their role in the risk management of transfusions. Arboviruses are RNA viruses and very adaptable by nature. The majority of arbovirus infections are zoonoses. The risk of transmission is multifactorial and concerns the virus, vectors, animal reservoirs, the environment and human behaviour. In recent years, West Nile Virus has become established and widespread in North America, the number of cases of dengue worldwide has increased dramatically, and major epidemics of chikungunya have occurred in the Indian Ocean and Asia. The transmission of dengue and chikungunya is demonstrated in temperate zones. All arboviruses are potentially transmissible by transfusion due to their capacity to induce an asymptomatic viremic phase. The risk of West Nile Virus transmission via transfusion is recognised and prevention measures are well established. The risk of transmission via transfusion of dengue and chikungunya is real but difficult to quantify and the optimum prevention strategy is currently the subject of research. Access to up-to-date epidemiological data is an essential aid to decision-making, especially for donors returning from endemic areas to Europe. The challenge is to define and implement appropriate measures in unpredictable situations.


[CENTER FOR PUBLIC HEALTH AND MEDICAL PREVENTION IN MOSCOW: ISSUES OF FORMATION AND DEVELOPMENT PROSPECTS].
The authors have identified the priorities of the CPHMC based on the results of the Center's work in 2021 and the trends in the development of public health in Moscow. Along with this, the preferred directions for the development of the public health system in the city of Moscow are highlighted. Scientific research in the areas of work of the Center for Medical Health Care allows using reliable and up-to-date scientific information in the work of health care in Moscow, which makes it possible to improve not only the quality, but also the volume of work performed, projects of management decisions in the field of public health. As part of the activities of the CPHMC, it is planned to expand the range of activities related to the formation of the health of labor collectives and to draw the attention of employers to corporate public health programs to the maximum.


Sequential studies of pre-S2 antigenemia and anti-pre-S2 antibodies in relation to viral replication in acute hepatitis B followed from the early incubation phase.
To determine the time sequence of expression of pre-S2 peptide (120-150) during the presymptomatic phase of acute hepatitis B, we used a monoclonal antibody radioimmunoassay in five subjects followed from 30 to 70 days before the onset of liver damage. Pre-S2 peptide was present in serum at low levels from the early incubation phase and started to increase immediately after the first detection of HBV-DNA in serum, in parallel with the increase in HBsAg levels. During the symptomatic phase, levels of pre-S2 peptide declined rapidly; it was no longer detectable after recovery. Anti-pre-S2 antibodies were detected, in four patients, only in the recovery phase. These results demonstrate that expression of pre-S2 peptide occurs very early in the incubation phase of acute HBV infection and is cleared in parallel with HBsAg. Anti-pre-S2 antibodies seem to play no role in viral clearance in these patients.


Human IM-9 lymphoblasts as a model of the growth hormone-insulin-like growth factor axis: gene expression, and interactions of ligands with receptors and binding proteins.
Human IM-9 lymphoblasts bind growth hormone (hGH) and insulin-like growth factors (IGFs). We have systematically examined the IM-9 cells as a valuable model of the interaction of hGH and the IGFs at the cellular level. Cells were cultured in medium with 10% serum and for a subset of experiments cultured in serum-free medium. Binding of [125I]hGH and [125I]IGF-I and -II to intact IM-9 cells was measured: unlabeled hGH inhibited binding of [125I]hGH (half max. 20 ng/ml). Binding of [125I]IGF-I was inhibited by IGF-I (half max. 7.5 ng/ml), IGF-II (half max. 60 ng/ml), and insulin and anti IGF-I receptor antibody (alpha IR3). [125I]IGF-II was inhibited by IGF-II (half max. 15 ng/ml), IGF-I (half max. 500 ng/ml), insulin (half max. 250 ng/ml) but not by alpha IR3. Crosslinking experiments with [125I]IGF-II and DSS as the crosslinking agent and analysis of radioligand-receptor complexes by SDS-PAGE under reducing conditions revealed that [125I]IGF-II bound to a 250 kDa and a 135 kDa receptor species. The latter possibly represents an insulin-type receptor whereas the 250 kDa species had the characteristics of the IGF-II/M6P receptor. When IM-9 cell conditioned medium was analyzed in ligand blotting experiments with either [125I]IGF-I or -II a 30 kDa IGFBP species was detected on the autoradiographs. Also, IGF-II immunoreactivity (approx. 1 ng/ml medium) was measured in the cell conditioned medium using an IGF-BP blocked RIA employing [125I]IGF-II. In a subset of experiments IM-9 cells were homogenized in 4 M guanidinium-thiocyanate and RNA extracted in 5.7 M CsCl. Denatured RNA was electrophoresed on 0.8% agarose gels and transferred to a nylon membrane, fixed and the blots hybridized with cDNA probes. Probes were labeled with [32P]dCTP using a random prime labeling procedure: a Pst I 700 bp fragment of the human IGF-I cDNA, a 554 bp Pst I-Sal I fragment of the IGF-II cDNA, a 614 bp Pst I fragment of the IGF-I receptor cDNA and a 663 bp Pst I fragment of the IGF-II/M6P receptor. Autoradiographs of Northern blots showed specific hybridization with the IGF-I probe at 3.7 kb and with the IGF-II probe at 5.3 kb. No signal was detected with the IGF-I receptor cDNA probe. Hybridization with the IGF-II/M6P receptor probe yielded a 9 kb RNA species.(ABSTRACT TRUNCATED AT 400 WORDS)


Morphological and immunohistochemical analysis in ovaries and fallopian tubes of tamoxifen, letrozole and clomiphene-treated rats.
Ovarian and tubal dysplasia may be precursors to ovarian cancer. The goal of this study was to check whether these histopathological lesions would be found after ovulation induction using tamoxifen, clomiphene citrate and letrozole. Seventy-two rats were divided into four groups. In the first group, 24 rats received normal saline. The second group (16 rats) received clomiphene citrate for six cycles. The third group, divided into two sub-groups of eight rats each, were stimulated with tamoxifen for six cycles, with a dosage, respectively, of 0.4 and 0.8 mg/kg/day. In the last group, eight rats received letrozole 0.1 mg/kg/day and eight other rats received letrozole 0.5 mg/kg/day, for six cycles. Once the six cycles had been completed the rats were killed in order to remove ovaries and tubes for histopathological analysis (morphological, p53 and Ki67 immunohistochemical assessment). Histopathological lesions were found in both ovaries and tubes. The mean ovarian dysplasia score was significantly higher in the tamoxifen group whatever the dosage (p = 0.006 and 0.0002) and in the letrozole group with 0.5 mg/kg/day (p = 0.0002) compared with the control group. The mean tubal dysplasia score was significantly higher in all groups that received drug treatment compared with the control group, whatever the dosage used. The proliferation index (Ki67) was significantly higher in the tamoxifen and letrozole groups while no significant difference was found for apoptosis marker p53. Ovulation induction may induce histopathological abnormalities in ovaries and tubes with a different immunohistochemical profile in comparison with salpingo-oophorectomies for genetic risk.


Depressive symptoms as a novel risk factor for recurrent venous thromboembolism: a longitudinal observational study in patients referred for thrombophilia investigation.
Increasing evidence suggests that psychosocial factors, including depression predict incident venous thromboembolism (VTE) against a background of genetic and acquired risk factors. The role of psychosocial factors for the risk of recurrent VTE has not previously been examined. We hypothesized that depressive symptoms in patients with prior VTE are associated with an increased risk of recurrent VTE. In this longitudinal observational study, we investigated 271 consecutive patients, aged 18 years or older, referred for thrombophilia investigation with an objectively diagnosed episode of VTE. Patients completed the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). During the observation period, they were contacted by phone and information on recurrent VTE, anticoagulation therapy, and thromboprophylaxis in risk situations was collected. Clinically relevant depressive symptoms (HADS-D score ≥ 8) were present in 10% of patients. During a median observation period of 13 months (range 5-48), 27 (10%) patients experienced recurrent VTE. After controlling for sociodemographic and clinical factors, a 3-point increase on the HADS-D score was associated with a 44% greater risk of recurrent VTE (OR 1.44, 95% CI 1.02, 2.06). Compared to patients with lower levels of depressive symptoms (HADS-D score: range 0-2), those with higher levels (HADS-D score: range 3-16) had a 4.1-times greater risk of recurrent VTE (OR 4.07, 95% CI 1.55, 10.66). The findings suggest that depressive symptoms might contribute to an increased risk of recurrent VTE independent of other prognostic factors. An increased risk might already be present at subclinical levels of depressive symptoms.


Combination therapy with Bosentan and Sildenafil improves Raynaud's phenomenon and fosters the recovery of microvascular involvement in systemic sclerosis.
The aim of this study was to evaluate in systemic sclerosis (SSc) retrospectively the effect of Bosentan and Sildenafil and their combination on Raynaud's phenomenon (RP), function, and capillaroscopic patterns. One hundred and twenty-three SSc patients (mean age ± sd, 57.69 ± 14.07 years) were retrospectively evaluated and divided into two groups according to American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification score: group 1 score < 10, group 2 score > 10. Each group was divided into three subgroups according to treatment: Bosentan, Sildenafil, and Bosentan + Sildenafil. Nailfold videocapillaroscopy (NVC), Scleroderma Health Assessment Questionnaire (SHAQ) and Raynaud Condition Score (RCS) were performed at baseline and after 3 and 6 months. In Bosentan (29 patients: 12, group 1; 17, group 2), NVC changed significantly in both groups, after 3 and 6 months (p = 0.00439, group 1; p = 0.00035, group 2). In group 1, the "active" and the "late" patterns reduced, and the "aspecific" increased. In group 2, there was a reduction of late patterns, a worsening of SHAQ (p < 0.005) and an improvement of RCS (p = 0.00014). In Sildenafil (63 patients: 35, group 1; 28, group 2), after 3 months, NVC patterns changed significantly in both groups(p = 0.042 group 1, p = 0.00089 group 2). In group 1, the late and early patterns increased, and the aspecific decreased. In group 2, a significant change of NVC pattern was observed also after 6 months (p = 0.00089): the late pattern increased while the active one reduced. After 6 months, SHAQ was significantly reduced in group 1 (p = 0.00027) and in group 2 (p = 0.0043). RCS improved in both groups (p = 0.0042, group 1; p = 0.0016, group 2). Combination therapy (Bosentan + Sildenafil) (31 patients: 14, group 1; 17, group 2) induced significant changes on NVC only in group 1 after 3 (p = 0.00256) and 6 months (p = 0.000349) with a reduction of the late and active patterns and an increase of the early pattern. In both groups, after 6 months, SHAQ (p < 0.05, group 1; p = 0.00049, group 2) and RCS significantly reduced (group 1, p = 0.00024; group 2, p = 0.0021). Patients treated with Bosentan + Sildenafil show a significant improvement of RCS and NVC. This combination therapy may exert a vascular activity achieving an amelioration of the structure of microvasculature in SSc.


Haplotype-controlled analysis of the association of a non-synonymous single nucleotide polymorphism at DBH (+ 1603C --> T) with plasma dopamine beta-hydroxylase activity.
The DBH locus controls plasma dopamine beta-hydroxylase activity (pDbetaH). A 5'-upstream single nucleotide polymorphism (SNP) at DBH (-1021C --> T) explains approximately 45% of the variance in pDbetaH, and a non-synonymous SNP in exon 11 (+ 1603C --> T) an additional 2%. However, that regression result underestimates the effect of + 1603C --> T because of its low minor allele frequency. We estimated the biological effect of + 1603C --> T on pDbetaH by comparing subjects of identical -1021CgammaT genotype, in a diagnostically heterogeneous group of subjects of European origin (N = 367). + 1603C --> T genotype associated with pDbetaH within groups of identical genotype at -1021 C --> T, accounting for 5%-16% of the variance. There was no significant linkage disequilibrium between -1021C --> T and + 1603C --> T (D = 0.0058, D' = 0.4774, d(2) = 0.0011, P > 0.05), confirming the validity of assessing the two polymorphisms independently. These results suggest that altered homospecific activity of the enzyme can contribute to variation in pDbetaH. This conclusion informs how associations between DBH and psychiatric disorders should be approached. (c) 2005 Wiley-Liss, Inc.


Logistic ridge regression to predict bipolar disorder using mRNA expression levels in the N-methyl-D-aspartate receptor genes.
It is hypothesized that demographic variables and mRNA expression levels in the N-methyl-D-aspartate receptor (NMDAR) genes can be employed as potential biomarkers to predict bipolar disorder using artificial intelligence and machine learning approaches. To determine bipolar status, we established a logistic ridge regression model resulting from the analysis of age, gender, and mRNA expression levels in 7 NMDAR genes in the blood of 51 bipolar patients and 139 unrelated healthy individuals in the Taiwanese population. The NMDAR genes encompasses COMT, GCAT, NRG1, PSAT1, SHMT2, SLC1A4, and SRR. We also compared our approach with various state-of-the-art algorithms such as support vector machine and C4.5 decision tree. The analysis revealed that the mRNA expression levels of COMT, GCAT, NRG1, PSAT1, SHMT2, SLC1A4, and SRR were associated with bipolar disorder. Moreover, the logistic ridge regression model (area under the receiver operating characteristic curve = 0.922) performed maximally among predictive models to infer the complicated relationship between bipolar disorder and biomarkers. Additionally, the results for the age- and gender-matched cohort were similar to those of the unmatched cohort. The cross-sectional study design limited the predictive value. This is the first study demonstrating that the mRNA expression levels in the NMDAR genes may be altered in patients with bipolar disorder, thereby supporting the NMDAR hypothesis of bipolar disorder. The study also indicates that the mRNA expression levels in the NMDAR genes could serve as potential biomarkers to distinguish bipolar patients from healthy controls using artificial intelligence and machine learning approaches.


Molecular analysis of expression and function of hFcgammaRIIbl and b2 isoforms in myeloid cells.
The inhibitory receptor FcgammaRIIb becomes tyrosine phosphorylated and associates with the inositol phosphatase SHIP to downregulate phagocytosis. The two splice variants of FcgammaRIIb, b1 and b2, are differentially expressed in hematopoetic cells. Both isoforms of FcgammaRIIb are expressed in human myeloid cells although FcgammaRIIb2 predominates. In murine B cells FcgammaRIIb2 associates with clathrin-coated pits and undergoes endocytosis, whereas FcgammaRIIbl is excluded from the coated pits, indicating that the two isoforms serve partially differing functions. In humans, there are conflicting reports with regard to the ability of FcgammaRIIb2 to become tyrosine phosphorylated, and the functional capacities of the two isoforms are poorly understood. We, and others, have previously reported that the expression of FcgammaRIIb is upregulated in human monocytes by the anti-inflammatory cytokine IL-4. Here, we extend these findings to demonstrate that the IL-4-induced upregulation of FcgammaRIIb is synergistically enhanced by the addition of IL-10, both at the protein and the mRNA level. The upregulated receptors are functional as assessed by their ability to become tyrosine phosphorylated and to downregulate phagocytosis. Interestingly, both b1 and b2 isoforms are upregulated by anti-inflammatory cytokines. Transfection experiments expressing human FcgammaRIIbl or b2 in Raw 264.7 murine macrophage cells revealed that both isoforms are tyrosine phosphorylated and promote SHIP phosphorylation. Finally, both b1 and b2 isoforms of FcgammaRIIb downregulate phagocytosis to a similar extent. Thus we conclude that FcgammaRIIbl and b2 are both functional inhibitory receptors in the phagocytic process.


The site-directed mutation I(L177)H in Rhodobacter sphaeroides reaction center affects coordination of P(A) and B(B) bacteriochlorophylls.
To explore the influence of the I(L177)H single mutation on the properties of the nearest bacteriochlorophylls (BChls), three reaction centers (RCs) bearing double mutations were constructed in the photosynthetic purple bacterium Rhodobacter sphaeroides, and their properties and pigment content were compared with those of the correspondent single mutant RCs. Each pair of the mutations comprised the amino acid substitution I(L177)H and another mutation altering histidine ligand of BChl P(A) or BChl B(B). Contrary to expectations, the double mutation I(L177)H+H(L173)L does not bring about a heterodimer RC but causes a 46nm blue shift of the long-wavelength P absorbance band. The histidine L177 or a water molecule were suggested as putative ligands for P(A) in the RC I(L177)H+H(L173)L although this would imply a reorientation of the His backbone and additional rearrangements in the primary donor environment or even a repositioning of the BChl dimer. The crystal structure of the mutant I(L177)H reaction center determined to a resolution of 2.9Å shows changes at the interface region between the BChl P(A) and the monomeric BChl B(B). Spectral and pigment analysis provided evidence for β-coordination of the BChl B(B) in the double mutant RC I(L177)H+H(M182)L and for its hexacoordination in the mutant reaction center I(L177)H. Computer modeling suggests involvement of two water molecules in the β-coordination of the BChl B(B). Possible structural consequences of the L177 mutation affecting the coordination of the two BChls P(A) and B(B) are discussed. This article is part of a Special Issue entitled: Photosynthesis Research for Sustainability: from Natural to Artificial.


Varietal diversity as a lever for cassava variety development: exploring varietal complementarities in Cameroon.
Cassava is an important crop for the survival of smallholder farmers in Cameroon. However, the cassava sector has a low production per unit area compared to the technological potential in this country. In this context, breeders have developed varieties based mainly on their potential in terms of yield and disease resistance. These varieties have been widely disseminated in Cameroon within the framework of development projects. However, these releases have not achieved the expected adoption and yield levels at the national level. Therefore, it appears important to rethink the determinants of dissemination with a broader examination of the cassava production system. This paper analyses varietal complementarity as a key strategy in support of optimizing the experimental and continuous use of cassava varieties by farmers in the Central and Eastern regions of Cameroon. These two regions account for 50% of the country's production. A total of 111 semi-structured interviews were conducted with farmers selected through purposive sampling in four villages in Central and Eastern Cameroon where improved varieties have been disseminated. The research revealed four types of complementarity, related to use, crop management, risk management and cultural complementarity. Our results argue for considering varietal complementarities practiced by farmers, within research and development programs to develop more effective breeding and dissemination approaches. © 2023 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.


Development of a Support Vector Machine-Based System to Predict Whether a Compound Is a Substrate of a Given Drug Transporter Using Its Chemical Structure.
The aim of this study was to develop an in silico prediction system to assess which of 7 categories of drug transporters (organic anion transporting polypeptide [OATP] 1B1/1B3, multidrug resistance-associated protein [MRP] 2/3/4, organic anion transporter [OAT] 1, OAT3, organic cation transporter [OCT] 1/2/multidrug and toxin extrusion [MATE] 1/2-K, multidrug resistance protein 1 [MDR1], and breast cancer resistance protein [BCRP]) can recognize compounds as substrates using its chemical structure alone. We compiled an internal data set consisting of 260 compounds that are substrates for at least 1 of the 7 categories of drug transporters. Four physicochemical parameters (charge, molecular weight, lipophilicity, and plasma unbound fraction) of each compound were used as the basic descriptors. Furthermore, a greedy algorithm was used to select 3 additional physicochemical descriptors from 731 available descriptors. In addition, transporter nonsubstrates tend not to be in the public domain; we, thus, tried to compile an expert-curated data set of putative nonsubstrates for each transporter using personal opinions of 11 researchers in the field of drug transporters. The best prediction was finally achieved by a support vector machine based on 4 basic and 3 additional descriptors. The model correctly judged that 364 of 412 compounds (internal data set) and 111 of 136 compounds (external data set) were substrates, indicating that this model performs well enough to predict the specificity of transporter substrates.


Laminar origins of spinal projection neurons to the periaqueductal gray of the rat.
Attempts were made to determine the cells of origin of the spinal projections to the PAG using retrograde axoplasmic transport techniques of HRP and fluorescent markers. Following injections limited to the lateroventral subnucleus of the PAG, labels were transported to the contralateral laminae I, III, V, VII and X primarily. A striking number of labeled neurons were found in the lumbosacral region. Discussion followed on the possible dichotomic axonal projections of the labeled spinal neurons.


Biomechanical changes, acceptance, and usability of a passive shoulder exoskeleton in manual material handling. A field study.
Occupational exoskeletons contribute to diminish the biomechanical load during manual work. However, familiarization to the use of exoskeletons is rarely considered, which may lead to failure of acceptance and implementation. In this study, ten logistic workers underwent a 5-week progressive familiarization to a passive shoulder exoskeleton, while ten workers acted as controls. Tests pre and post the familiarization applied measurements of muscle activity and kinematics of back, neck, and shoulder, perceived effort, and usability-ratings of the exoskeleton. Exoskeleton use resulted in lower muscle activity of anterior deltoid (13-39%) and upper trapezius (16-60%) and reduced perceived effort. Additionally, it induced an offset in shoulder flexion and abduction during resting position (8-10°). No conclusions on familiarization could be drawn due to low adherence to the protocol. However, the emotions of the workers towards using the exoskeleton decreased making it questionable whether the shoulder exoskeleton is suitable for use in the logistics sector.


Knowledge, Attitude and Practice Around Breast Cancer and Mammography Screening Among Jordanian Women.
Breast cancer is the most common occurring cancer in women worldwide. To guide current breast cancer screening program, the level of knowledge about breast cancer should be evaluated. This study aims to ascertain the level of breast cancer knowledge including risk factors, signs and symptoms, and early detection methods, especially mammography screening. The study was conducted among 1353 Jordanian women from the public using a self-administered questionnaire. Responses to the knowledge test were summed for an overall knowledge score. Comparisons between socio-demographics and knowledge, attitude and practice were also measured using a Chi-square test. About 76% of participants were aware that breast cancer is the most common cancer among women in Jordan. About 53.7% of our participants were rated as having an intermediate level of knowledge regarding risk factors, and 44% were rated as having a good to an excellent level of knowledge about breast cancer signs and symptoms. The participants' level of education was the main factor identified as influencing the participants' knowledge of the risk factors, signs and symptoms, and knowledge of early detection methods of breast cancer. The study sample was rated as having an intermediate level of knowledge regarding mammography screening; however, their participation in this screening method was low. Although Jordanian women had an acceptable level of knowledge of breast cancer, the screening rates for mammography were low. These findings suggest that there is a need to provide extra awareness programs for Jordanian women to improve their breast cancer knowledge and practice.


Epidermal growth factor (EGF) increases the renal amino acid transport capacity in amino acid loaded rats.
In anaesthetized adult female rats, the influence of epidermal growth factor (EGF) on renal amino acid handling was investigated in glutamine, arginine (both 50 mg/100 g b.wt. per hour), or alanine (90 mg/100 g b.wt. per hour) loaded animals. Continuous infusions of the three amino acids were followed by an increase in the fractional excretion (FE) of the administered amino acids as well as of the other endogenous amino acids. Under load conditions (alanine, arginine or glutamine), EGF pretreatment (8 micrograms/100 g b.wt. subcutaneously for 8 days, twice daily 8 a.m. and 4 p.m.) was followed by a stimulation of renal amino acid reabsorption. The increase in the fractional excretion of the administered amino acids was significantly lower than in non-EGF-treated rats. These changes in amino acid transport were connected with a significant reduction of GFR after EGF pretreatment (0.96 +/- 0.10 vs. 0.62 +/- 0.07 ml/min x 100 g b.wt.) and a distinct increase in sodium excretion (2.98 +/- 0.55 vs. 4.97 +/- 0.71 muval/100 g b.wt. x 20 min). After loading with p-aminohippurate (PAH; 200 mg/100 g b.wt.), PAH excretion in EGF rats was increased by about 20%, whereas urinary protein excretion was lower in EGF pretreated rats (control: 0.45 +/- 0.04 vs. EGF: 0.18 +/- 0.03 mg/100 g b.wt. x 20 min). The PAH load reduced amino acid reabsorption as a sign of overloading of renal tubular transport capacity, but in EGF pretreated animals the amino acid excretion was only slightly increased under these conditions. Furthermore, EGF pretreatment depressed normal kidney weight gain significantly (874 +/- 18 vs. 775 +/- 32 mg/100 g b.wt.). EGF can improve the renal tubular transport capacity, but, compared to well-known stimulators of renal transport like dexamethasone or triiodothyronine, its effect is only of a moderate degree.


Methimazole as a protectant against cisplatin-induced nephrotoxicity using the dog as a model.
The protective effect of methimazole, a commonly used antithyroid drug, on cisplatin-induced nephrotoxicity was studied. Eight dogs received 80 mg/m2 cisplatin i.v. without saline prehydration. Dogs were randomized into two groups of four dogs each: one group received 40 mg/kg methimazole i.p. at 30 min prior to and 4 h after cisplatin delivery, and the other group received saline placebo i.p. Methimazole protected dogs against the in vivo nephrotoxicity elicited by cisplatin as evidenced by clinicopathologic and histopathologic indices. Protection was not complete, as methimazole-treated animals developed mild histopathologic renal changes. Measures of renal oxidative stress did not differ between the two groups at day 5 following cisplatin treatment. No difference was noted for serum thyroxine concentrations before or after therapy in either group; however, serum levels of 3,5,3'-triiodothyronine were significantly higher on day 5 in both groups of dogs receiving cisplatin, regardless of whether they received methimazole or not. Methimazole as used in this study was found to be well tolerated in dogs over the short term, with no significant clinical or clinicopathologic toxicity being observed. The results of this study support the additional evaluation of methimazole as a protectant against cisplatin-induced nephrotoxicity using the dog as a model.


Cerebrospinal fluid monoamine metabolites in patients with infantile spasms.
We measured CSF levels of homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) by high-performance liquid chromatography in seven children with infantile spasms and in a group of age- and sex-matched controls. The mean concentration of the serotonin metabolite 5-HIAA was 40% (p less than 0.01) lower in the infantile spasms group as compared with controls; HVA levels were similar in both groups. The data provide additional evidence that serotonin metabolism is abnormal in patients with infantile spasms.


Impact of blood pressure dysregulation on health-related quality of life in persons with spinal cord injury: development of a conceptual model.
To identify medically relevant aspects of blood pressure dysregulation (BPD) related to quality of life in individuals with spinal cord injury (SCI), and to propose an integrated conceptual framework based on input from both individuals with SCI and their clinical providers. This framework will serve as a guide for the development of a patient-reported outcome (PRO) measure specifically related to BPD. Three focus groups with individuals with SCI and 3 groups with SCI providers were analyzed using grounded-theory based qualitative analysis to ascertain how blood pressure impacts health-related quality of life (HRQOL) in individuals with SCI. Focus groups were conducted at 2 Veterans Affairs medical centers and a research center. Individuals with SCI (n=27) in 3 focus groups and clinical providers (n=25) in 3 focus groups. Not applicable. Not applicable. Qualitative analysis indicated that all focus groups spent the highest percentage of time discussing symptoms of BPD (39%), followed by precipitators/causes of BPD (16%), preventative actions (15%), corrective actions (12%), and the impact that BPD has on social or emotional functioning (8%). While patient/consumer focus groups and provider focus groups raised similar issues, providers spent more time discussing precipitators/causes of BPD and preventative actions (38%) than patient/consumer groups (24%). These results suggest that BPD uniquely and adversely impacts HRQOL in persons with SCI. While both individuals with SCI and their providers highlighted the relevant symptoms of BPD, the SCI providers offered additional detailed information regarding the precipitators/causes and what can be done to prevent/treat BPD. Further, the results suggest that persons with SCI are aware of how BPD impacts their HRQOL and are able to distinguish between subtle signs and symptoms. These findings exemplify the need for a validated and sensitive clinical measurement tool that can assess the extent to which BPD impacts HRQOL in patients with SCI.


QbD based Eudragit coated Meclizine HCl immediate and extended release multiparticulates: formulation, characterization and pharmacokinetic evaluation using HPLC-Fluorescence detection method.
This study is based on the QbD development of extended-release (ER) extruded-spheronized pellets of Meclizine HCl and its comparative pharmacokinetic evaluation with immediate-release (IR) pellets. HPLC-fluorescence method was developed and validated for plasma drug analysis. IR drug cores were prepared from lactose, MCC, and PVP using water as granulating fluid. Three-level, three-factor CCRD was applied for modeling and optimization to study the influence of Eudragit (RL100-RS100), TEC, and talc on drug release and sphericity of coated pellets. HPLC-fluorescence method was sensitive with LLOQ 1 ng/ml and linearity between 10 and 200 ng/ml with R2 > 0.999. Pharmacokinetic parameters were obtained by non-compartmental analysis and results were statistically compared using logarithmically transformed data, where p > 0.05 was considered as non-significant with a 90% CI limit of 0.8-1.25. The AUC0-t and AUC0-∞ of ER pellets were not significantly different with geometric mean ratio 1.0096 and 1.0093, respectively. The Cmax of IR pellets (98.051 ng/ml) was higher than the ER pellets (84.052 ng/ml) and the Tmax of ER pellets (5.116 h) was higher than the IR pellets (3.029 h). No significant food effect was observed on key pharmacokinetic parameters of ER pellets. Eudragit RL100 (6%) coated Meclizine HCl pellets have a potential therapeutic effect for an extended time period.


Social media and online hate.
Social media host alarming degrees of hate messages directed at individuals and groups, threatening victims' psychological and physical well-being. Traditional approaches to online hate often focus on perpetrators' traits and their attitudes toward their targets. Such approaches neglect the social and interpersonal dynamics that social media afford by which individuals glean social approval from like-minded friends. A theory of online hate based on social approval suggests that individuals and collaborators generate hate messages to garner reward, for their antagonism toward mutually hated targets, by providing friendship and social support that enhances perpetrators' well-being as it simultaneously deepens their prejudices. Recent research on a variety of related processes supports this view, including notions of moral grandstanding, political derision as fun, and peer support for interpersonal violence.


Metastatic melanoma of the gallbladder: report of two cases and a review of the literature.
Melanoma is one of the most aggressive and highly metastatic cancers. The most common sites of distant metastases are soft tissues, lung, liver, skin and brain, whereas only few patients develop gastrointestinal metastases. Metastatic involvement of the gallbladder is rare and more often part of a widespread disease than a solitary lesion. The "gold-standard" treatment of metastatic melanoma of the gallbladder remains unclear. We report two cases of patients with past history of cutaneous melanoma who developed visceral metastases. The first patient was asymptomatic and had a widespread disease with metastatic involvement of both the spleen and the gallbladder. The second patient had an isolated metastasis of the gallbladder and complained of upper abdominal pain. The chosen treatment was open cholecystectomy (and splenectomy) in the first case and laparoscopic cholecystectomy in the second. A review of the literature is provided.


Sex differences in choice behaviour: the object-person dimension.
When viewing two conflicting stimuli in a stereoscope, males reported seeing objects significantly more often than human figures. The opposite effect was observed in females.


Robust signaling networks of the adipose secretome.
Type 2 diabetes is a prototypical complex systems disease that has a strong hereditary component and etiologic links with a sedentary lifestyle, overeating and obesity. Adipose tissue has been shown to be a central driver of type 2 diabetes progression, establishing and maintaining a chronic state of low-level inflammation. The number and diversity of identified endocrine factors from adipose tissue (adipokines) is growing rapidly. Here, I argue that a systems biology approach to understanding the robust multi-level signaling networks established by the adipose secretome will be crucial for developing efficient type 2 diabetes treatment. Recent advances in whole-genome association studies, global molecular profiling and quantitative modeling are currently fueling the emergence of this novel research strategy.


Isolation and identification of oxidation products of guaiacol from brines and heated meat matrix.
In this study we investigated the formation of the oxidation products of guaiacol in brines and heated meat matrix: 6-nitrosoguaiacol, 4-nitroguaiacol and 6-nitroguaiacol. For this purpose we applied a newly developed HPLC-UV and LC-MS method. For the first time, 6-nitrosoguaiacol was determined in brine and meat (containing guaiacol and sodium nitrite), which had been heated to 80°C and subsequently subjected to simulated digestion. Application of 500mg/L ascorbic acid to the brines reduced guaiacol degradation at pH3 and simultaneously inhibited the formation of 6-nitrosoguaiacol compared to brines containing only 100mg/L of ASC. The oxidation products were isolated with a new extraction method from meat samples containing 400mg/kg sodium nitrite at pH3.6 following simulated digestion. When oxygen was added, 6-nitrosoguaiacol was determined even at legally allowed levels (150mg/kg) of the curing agent. Finally, we developed a new LC-MS method for the separation and qualitative determination of the four main smoke methoxyphenols.


Adhesion to fibronectin via alpha4 integrin (CD49d) protects B cells from apoptosis induced by serum deprivation but not via IgM or Fas/Apo-1 receptors.
Apoptosis is a regulated event crucial to the development and proliferation of normal and malignant B cells. We have studied the role of signals delivered via alpha4 integrin on apoptosis triggered by three different pathways on these cells. For apoptosis induced by serum deprivation, culturing B cells on the recombinant fibronectin fragment H89, a known ligand for alpha4beta1 integrin, resulted in statistically significant (P < 0.005) higher viability values (68%, 65% and 67%) for Ramos, Nalm-6 and EHEB cells, respectively, than culturing cells on poly lysine (42%, 42% and 48%). An antialpha4 MoAb reverted the protecting effect, thus confirming that it was due specifically to alpha4 engagement. Similarly, cells cultured on FN-III4-5, a recently identified fibronectin region which binds activated alpha4 integrin, also showed statistically significant higher viability than poly lysine cultures. Alpha4 engagement however, did not prevent apoptosis induced on Ramos cells via surface IgM. Adhesion of IM-9 cells, a myeloma cell line carrying functional Fas receptors, to the H89 fragment neither increased cell viability upon triggering apoptosis via Fas when compared to poly lysine. These results indicate that alpha4 signalling may overcome B cell apoptosis induced by the lack of growth factors but does not seem to affect the IgM or Fas apoptotic pathways, thus suggesting different intracellular mechanisms for these processes.


Can the state of cancer chemotherapy resistance be reverted by epigenetic therapy?
Transcriptome analysis shows that the chemotherapy innate resistance state of tumors is characterized by: poorly dividing tumor cells; an increased DNA repair; an increased drug efflux potential by ABC-transporters; and a dysfunctional ECM. Because chemotherapy resistance involves multiple genes, epigenetic-mediated changes could be the main force responsible of this phenotype. Our hypothesis deals with the potential role of epigenetic therapy for affecting the chemotherapy resistant phenotype of malignant tumors. Recent studies reveal the involvement of DNA methylation and histone modifications in the reprogramming of the genome of mammalian cells in cancer. In this sense, it can be hypothesized that epigenetic reprogramming can participate in the establishment of an epigenetic mark associated with the chemotherapy resistant phenotype. If this were correct, then it could be expected that agents targeting DNA methylation and histone deacetylation would by reverting the epigenetic mark induce a global expression profile that mirror the observed in untreated resistant cells. It is proposed to perform a detailed analysis using all the available databases where the gene expression of primary tumors was analyzed and data correlated with the therapeutic outcome to determine whether a transcriptome profiling of "resistance" is observed. Assuming an epigenetic programming determines at some level the intrinsic resistant phenotype, then a similar pattern of gene expression dictated by an epigenetic mark should also be found in cell acquiring drug resistance. If these expectations are meet, then it should be further investigated at the genomic level whether these phenotypes are associated to certain patterns of DNA methylation and chromatin modification. Once confirmed the existence of an epigenetic mark associated to either the intrinsic or acquired chemotherapy resistant phenotype, then a causal association should be investigated. These preclinical findings should also be tested in a clinical setting. Our hypothesis on the ability of epigenetic therapy to revert the epigenetic changes leading to a transcritome profile that defines the resistant state will eventually be a more rational and effective way to treat malignant tumors.


Efficacy of constraint-induced movement therapy and electrical stimulation on hand function of children with hemiplegic cerebral palsy: a controlled clinical trial.
The purpose of this study is to compare the efficacy of constraint therapy, constraint therapy plus electrical stimulation, and occupational therapy in the treatment of hand dysfunction. Sixty-eight children with hemiplegic cerebral palsy were randomly allocated to constraint therapy, constraint therapy plus electrical stimulation, and occupational therapy group. Three groups received 2 weeks of treatment. All participants were measured at baseline and 2 weeks, 3 and 6 months after treatment using measures of active ROM, grip strength, nine-peg hole test, upper extremity functional test, Peabody developmental motor scales (PDMS), globe rating scale, and social life ability scale. Three groups improved significantly (p < 0.05). The mean improvements between baseline and the end of follow-up were respectively 12.4, 11.4 and 11.3 degrees for active ROM; 12.8, 10.5 and 8.8 mmHg for grip strength; -22.3, -30.7 and -14.0 s for nine-peg hole test; 15.3, 10.3 and 10.4 for upper extremity functional test scores; 2.2, 1.8 and 1.8 for grasping scores of PDMS; 5.8, 3.7 and 2.8 for visual-motor integration scores of PDMS; 2.0, 2.5 and 0.9 for globe rating scale scores; 7.7, 5.7 and 5.3 for social life ability scale scores in constraint therapy plus electrical stimulation, constraint therapy, and occupational therapy group. The constraint therapy plus electrical stimulation group showed greater rate of improvement in upper extremity functional test scores (p < 0.05) and visual-motor integration scores of PDMS (p < 0.05) than the other two groups after treatment for 6 months. Constraint therapy plus electrical stimulation is likely to be best in improving hand performance in children with hemiplegic cerebral palsy.


Nanotechnology in Auditory Research: Membrane Electromechanics in Hearing.
The soft, thin membranes that envelop all living cells are 2D, nanoscale, fluid assemblies of phospholipids, sterols, proteins, and other molecules. Mechanical interactions between these components facilitate membrane function, a key example of which is ion flow mediated by the mechanical opening and closing of channels. Hearing and balance are initiated by the modulation of ion flow through mechanoreceptor channels in stereocilia membranes. Cochlear amplification by the outer hair cell involves modulation of ion movement by the membrane protein prestin. Voltage-gated ion channels shape the receptor potential in hair cells and are responsible for the initiation of action potentials that are at the heart of sensory processing in the brain. All three processes require a membrane and their kinetics are modulated by the mechanical (i.e., material) properties of the membrane. This chapter reviews the methodology for measuring the mechanics of cellular membranes and introduces a method for examining membrane electromechanics. The approach allows examination of electromechanically mediated interactions between the different molecular species in the membrane that contribute to the biology of hearing and balance.


High speed Deans switch for low duty cycle comprehensive two-dimensional gas chromatography.
A new high-speed valve-based modulator has been designed and tested for use in comprehensive two-dimensional gas chromatography (GC×GC). The modulator is a Deans switch constructed from two micro-volume fittings and a solenoid valve. Modulator performance was characterized over a wide range of device settings including the magnitude of the switching flow, the gap between the tips of the primary and secondary column, the primary column flow rate, and the carrier gas identity. Under optimized conditions, the modulator was found to be capable of generating narrow pulses (<50ms) of primary effluent with a 2mL/min secondary column flow. This capability will ultimately allow the modulator to be used with GC×GC separations employing a wide range of detectors and secondary column geometries. The main disadvantage of this modulator is that it employs a low sampling duty cycle, and thus it produces separations with sensitivities that are lower than those produced with thermal modulators or differential flow modulators. The efficacy of the new high-speed Deans switch modulator was demonstrated through the GC×GC separation of a hydrocarbon standard and gasoline. Precise quantitation of individual components was possible provided the modulation ratio was kept greater than 2.0.


Dual donor-acceptor covalent organic frameworks for hydrogen peroxide photosynthesis.
Constructing photocatalytically active and stable covalent organic frameworks containing both oxidative and reductive reaction centers remain a challenge. In this study, benzotrithiophene-based covalent organic frameworks with spatially separated redox centers are rationally designed for the photocatalytic production of hydrogen peroxide from water and oxygen without sacrificial agents. The triazine-containing framework demonstrates high selectivity for H2O2 photogeneration, with a yield rate of 2111 μM h-1 (21.11 μmol h-1 and 1407 μmol g-1 h-1) and a solar-to-chemical conversion efficiency of 0.296%. Codirectional charge transfer and large energetic differences between linkages and linkers are verified in the double donor-acceptor structures of periodic frameworks. The active sites are mainly concentrated on the electron-acceptor fragments near the imine bond, which regulate the electron distribution of adjacent carbon atoms to optimally reduce the Gibbs free energy of O2* and OOH* intermediates during the formation of H2O2.


Hypocholesterolemic activity of a novel inhibitor of cholesterol absorption, SCH 48461.
The amount of cholesterol that circulates in the plasma as lipoproteins can be affected by the balance of cholesterol metabolism within and between the intestines and liver. In the present report, we describe a novel hypocholesterolemic agent and document its pharmacological effects in animal models of hypercholesterolemia. The oral administration of (3R,4S)-1,4-bis-(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone (SCH 48461) reduced plasma cholesterol concentrations in cholesterol-fed hamsters, rats and rhesus monkeys with ED50s of 1, 2 and 0.2 mg/kg per day, respectively, SCH 48461 was also highly effective in reducing hepatic cholesteryl ester accumulation in cholesterol-fed hamsters and rats after 7 days of treatment. In one 3 week study, rhesus monkeys were fed a 0.25% cholesterol/22% saturated fat diet with or without SCH 48461. At the end of the 3 week period the control group's VLDL + LDL-cholesterol increased to 180 Mg/dl from a baseline of approximately 65 mg/dl while plasma apolipoprotein B levels had doubled. Animals treated daily with 1 mg/kg SCH 48461 maintained their baseline levels of VLDL + LDL-cholesterol, HDL-cholesterol, and plasma apolipoproteins B and A-I. After 3 weeks the diets of the two groups were switched. Within 1 week SCH 48461 (1 mg/kg per day) rapidly reversed the elevated VLDL + LDL-cholesterol levels of the previous control group to near baseline values. SCH 48461 exerted its hypocholesterolemic effect through the inhibition of cholesterol absorption. A dose of 10 mg/kg per day inhibited cholesterol absorption in cholesterol-fed hamsters by 68% while a similar reduction was achieved in chow-fed monkeys with 3 mg/kg per day. This latter dose inhibited cholesterol absorption in cholesterol-fed monkeys by 95%. Treatment of cholesterol-fed monkeys with 10 mg/kg per day SCH 48461 significantly increased fecal neutral sterol excretion (52 vs. 32 mg/kg) but had no effect on acidic sterol excretion. Using a 2-h absorption model in cholesterol-fed hamsters, SCH 48461 caused a 46% inhibition of unesterified [14C]cholesterol accumulation in the intestinal wall and a 90% inhibition of cholesteryl ester formation at a dose of 10 mg/kg. Similar data were observed when the plasma radioactivity was assessed, indicating inhibition of both free (61%) and esterified (85%) cholesterol appearance. In contrast, CI-976, a potent acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, did not affect the uptake of free cholesterol into the intestines while inhibiting cholesterol esterification (98% inhibition).(ABSTRACT TRUNCATED AT 400 WORDS)


[Stabilization-alleviation method for cementing the stem in total hip replacement].
A modified method of the Weller stem fixation into the femoral bone has been presented. Clinical results of 106 arthroplasties in 101 patients have been reviewed and it was found out, that this method contributes to greater longevity of the total hip replacement.


Role ambiguity as an amplifier of the association between job stressors and workers' psychological ill-being: Evidence from an occupational survey in Japan.
We aim to examine the extent to which role ambiguity modifies the association between job stressors and workers' psychological ill-being. We used data from 41 962 observations from 13 811 individuals (10 269 males and 3542 females) who participated in three to eight waves of an occupational survey conducted in Japan. We estimated fixed-effects models to explain psychological distress (defined by Kessler 6 score ≥13) by role ambiguity. Four types of job stressors (i.e., high job demands, low job control, high effort, and low reward), and their interactions were examined along with potential confounders. We repeated a similar analysis for job dissatisfaction. The fixed-effects models showed that role ambiguity as well as the four job stressors were positively associated with psychological distress, albeit somewhat more modestly than the results of the pooled cross-sectional models. More notably, we found that role ambiguity substantially amplified the association between job stressors and psychological distress; for example, a combination of high job demands and high role ambiguity added to the risk of psychological distress by 3.5% (95% confidence interval [CI]: 2.5%-4.5%), compared with 1.4% (95% CI: 0.4%-2.3%) for a combination of high job demands and low role ambiguity. In contrast, we did not find a modifying effect of role ambiguity on the association between low job control and psychological distress. Similar results were observed for job dissatisfaction. The results underscore the importance of reducing role ambiguity to mitigate the adverse impact of job stressors on workers' psychological ill-being.


The effect of quantitative and qualitative antiepileptic drug changes on cognitive recovery after epilepsy surgery.
Epilepsy surgery is associated with a risk of cognitive deterioration, but improvement has also been reported. Improvements have mostly been attributed to seizure control, neglecting changes in drug treatment during the observation period. We evaluated whether changes of antiepileptic treatment affect cognitive outcome one year after epilepsy surgery. This retrospective study evaluated the impact of quantitative and qualitative antiepileptic drug changes on postoperative outcome on cognition (executive functions, episodic memory) and mood in 116 epilepsy surgery patients, controlling the results for seizure outcome (seizure free yes/no) and site of surgery (87 temporal lobe, 29 extratemporal lobe resections). At baseline, 60% of all patients showed impairment in executive functions, 54% in memory, 49% in mood. Postoperatively, 65% of the patients were seizure free. Executive functions, memory, and mood improved in 22%, 10%, and 32%, respectively, and deteriorated in 15%, 21%, and 11%. Drugs were changed quantitatively (change of drug load) and qualitatively (optimization in regard to side effect profiles). According to MANCOVA and individual level analyses, executive functions changed significantly with altered drug load. This was confirmed by partial correlations when controlling for seizure outcome. Memory outcome was more strongly determined by site of surgery. Mood improved non-specifically. However, qualitative drug change had some positive effect on postoperative memory and mood. The data highlight the relevance of AED changes for cognitive outcome after epilepsy surgery. Drug load reduction and selection of drugs with favorable side effect profiles significantly release cognitive functions thereby supporting recovery after epilepsy surgery.


Primary intestinal-type adenocarcinoma of the vulva. A case report and review of the literature.
Primary non-squamous cell carcinomas of the vulva are rare entities including various tumor types. Among these, primary vulvar intestinal-type adenocarcinoma (vPITA) is extremely rare. Until 2021, less than twenty-five cases have been reported in the literature. We report a case of vPITA in a 63 years old woman with a histopathological diagnosis of signet-ring cell intestinal type adenocarcinoma at vulvar biopsy. Accurate clinical and pathological work-up excluded secondary metastatic localization, and vPITA was diagnosed. The patient was treated with radical vulvectomy and bilateral inguinofemoral dissection. Adjuvant chemo-radiotherapy was performed because of a positive lymph node. At 20 months follow-up the patient was alive and free of disease. The prognosis of this very rare disease is unclear and optimal treatment is not well established. About 40% of clinical early-stage diseases reported in literature had positive inguinal nodes, more than in vulvar squamous cell carcinomas. A proper histopathologic and clinical diagnosis is mandatory to exclude secondary disease and to recommend an adequate treatment.


Parkinson's disease: A risk factor for osteoporosis.
Parkinson's disease is the most common neurodegenerative disease after Alzheimer's disease. On the long term, it may be complicated by various musculoskeletal problems, such as osteoporotic fractures, that have significant socioeconomic consequences. Indeed, patients suffering from Parkinson's disease have a higher fracture risk, particularly hip fracture risk, than other subjects of the same age because of both a higher risk of falls and lower bone mineral density. Bone loss in Parkinson's disease may be associated with the severity and duration of the disease. We review here the different suspected mechanisms of accelerated bone loss in Parkinson's disease, amongst which weight loss and reduced mobility appear to play key roles. Antiparkinsonian drugs, particularly levodopa, may also be associated with decreased bone mineral density as a result of hyperhomocysteinaemia. We discuss the role of other nutritional deficiencies, such as vitamin B12, folate or vitamin K. In conclusion, it seems necessary to screen for and treat osteoporosis in this at-risk population, while actions to prevent falls are still disappointing. A better understanding of the factors explaining bone loss in this population would help implementing preventive actions.


MicroRNAs modulating nutrient homeostasis: a sustainable approach for developing biofortified crops.
During their lifespan, sessile plants have to cope with bioavailability of the suboptimal nutrient concentration and have to constantly sense/evolve the connecting web of signal cascades for efficient nutrient uptake, storage, and translocation for proper growth and metabolism. However, environmental fluctuations and escalating anthropogenic activities are making it a formidable challenge for plants. This is adding to (micro)nutrient-deficient crops and nutritional insecurity. Biofortification is emerging as a sustainable and efficacious approach which can be utilized to combat the micronutrient malnutrition. A biofortified crop has an enriched level of desired nutrients developed using conventional breeding, agronomic practices, or advanced biotechnological tools. Nutrient homeostasis gets hampered under nutrient stress, which involves disturbance in short-distance and long-distance cell-cell/cell-organ communications involving multiple cellular and molecular components. Advanced sequencing platforms coupled with bioinformatics pipelines and databases have suggested the potential roles of tiny signaling molecules and post-transcriptional regulators, the microRNAs (miRNAs) in key plant phenomena including nutrient homeostasis. miRNAs are seen as emerging targets for biotechnology-based biofortification programs. Thus, understanding the mechanistic insights and regulatory role of miRNAs could open new windows for exploring them in developing nutrient-efficient biofortified crops. This review discusses significance and roles of miRNAs in plant nutrition and nutrient homeostasis and how they play key roles in plant responses to nutrient imbalances/deficiencies/toxicities covering major nutrients-nitrogen (N), phosphorus (P), sulfur (S), magnesium (Mg), iron (Fe), and zinc (Zn). A perspective view has been given on developing miRNA-engineered biofortified crops with recent success stories. Current challenges and future strategies have also been discussed.


A generalized model of a resource-population system : I. General properties.
A basic structure [Eqs. (5), (6), (3), (12), (30)] for mathematical models of resource-population systems is presented. This basic structure may be specified in order to include different alternative hypotheses and it represents, therefore, a family of particular models. The study of one of its particular realizations [Eqs. (31) and (39)] shows that its behavior agrees qualitatively with what should be expected from biological considerations.Even when the system of nonlinear differential equations could not be solved explicitly, important information has been obtained, by studying its properties in the limiting cases, its sensitivity to changes in the parameters, and the results of computer simulation.The proposed model, duplicating some of the basic features of a population living under resource limitation, and allowing a coupling with a predator population, is intended to be used as an elementary component in food web or ecosystem theoretical studies. The studies need not include detailed descriptions of the population variables, but rather only its essential, gross features, in order to explore the properties that characterize the complete systems.


Structure and expression of human alpha-interferon genes.
cDNA was prepared from induced leukocyte poly(A) RNA and cloned in Escherichia coli. Interferon (IFN)-alpha cDNA clones were isolated by subculture cloning using a translation hybridization assay. Definitive identification of the clones was based on the production of an interferon-like protein by the transformed bacteria. Different IFN-alpha cDNAs, with characteristic target cell specificities, were identified. The cloned cDNAs typically encode a mature polypeptide of 166 (or, in the case of IFN-alpha 2, 165) amino acids and a signal sequence of 23 amino acids.


Patterns of Biologics Utilization and Discontinuation Before and During Pregnancy in Women With Autoimmune Diseases: A Population-Based Cohort Study.
To characterize patterns of biologics use and discontinuation before and during pregnancy in women with autoimmune diseases in British Columbia, Canada. Women with ≥1 autoimmune diseases, as identified by International Classification of Diseases Ninth/Tenth Revision codes, who had pregnancies ending in deliveries between January 1, 2002, and December 31, 2012, and had ≥1 prescription for a biologic drug 1 year before pregnancy or during pregnancy, were included. Secular trends, patterns of biologics use, and risk of biologics discontinuation before and during pregnancy were examined. Associations between drug discontinuations and various factors were investigated using multilevel logistic regression models, fitted with binomial generalized estimating equations. Of 6,218 women (8,431 pregnancies) with autoimmune diseases, 131 women (144 pregnancies) were exposed to a biologic before or during pregnancy. The use of biologics in this cohort increased from 0% in 2002 to 5.7% by 2012 (P < 0.001). Within the first trimester of pregnancy, 31% of women (34/110) discontinued their biologic treatment, and 38% (30/79) discontinued use in the second trimester, while 98% of those receiving treatment in the second trimester (50/51) continued treatment in the third trimester. Women with rheumatoid arthritis had three times higher odds (odds ratio 3.40 [95% confidence interval 1.33-8.71]) of discontinuing biologics during pregnancy, compared to those with inflammatory bowel disease. Given the increased use of biologics and high odds of discontinuation during pregnancy in certain populations, more research is needed to improve our understanding of the risks and benefits of biologics for fetal and maternal health.


Real-time comprehension of wh- movement in aphasia: evidence from eyetracking while listening.
Sentences with non-canonical wh- movement are often difficult for individuals with agrammatic Broca's aphasia to understand (, inter alia). However, the explanation of this difficulty remains controversial, and little is known about how individuals with aphasia try to understand such sentences in real time. This study uses an eyetracking while listening paradigm to examine agrammatic aphasic individuals' on-line comprehension of movement sentences. Participants' eye-movements were monitored while they listened to brief stories and looked at visual displays depicting elements mentioned in the stories. The stories were followed by comprehension probes involving wh- movement. In line with previous results for young normal listeners [Sussman, R. S., & Sedivy, J. C. (2003). The time-course of processing syntactic dependencies: evidence from eye movements. Language and Cognitive Processes, 18, 143-161], the study finds that both older unimpaired control participants (n=8) and aphasic individuals (n=12) showed visual evidence of successful automatic comprehension of wh- questions (like "Who did the boy kiss that day at school?"). Specifically, both groups fixated on a picture corresponding to the moved element ("who," the person kissed in the story) at the position of the verb. Interestingly, aphasic participants showed qualitatively different fixation patterns for trials eliciting correct and incorrect responses. Aphasic individuals looked first to the moved-element picture and then to a competitor following the verb in the incorrect trials. However, they only showed looks to the moved-element picture for the correct trials, parallel to control participants. Furthermore, aphasic individuals' fixations during movement sentences were just as fast as control participants' fixations. These results are unexpected under slowed-processing accounts of aphasic comprehension deficits, in which the source of failed comprehension should be delayed application of the same processing routines used in successful comprehension. This pattern is also unexpected if aphasic individuals are using qualitatively different strategies than normals to comprehend such sentences, as under impaired-representation accounts of agrammatism. Instead, it suggests that agrammatic aphasic individuals may process wh- questions similarly to unimpaired individuals, but that this process often fails to facilitate off-line comprehension of sentences with wh- movement.


Associations Between Parental and Grandparental Marijuana Use and Child Substance Use Norms in a Prospective, Three-Generation Study.
Using prospective longitudinal data from three generations, this study seeks to test whether and how parent and grandparent marijuana use (current and prior) predicts an increased likelihood of child cigarette, alcohol, and marijuana use. Using multilevel modeling of prospective data spanning three generations (n = 306 families, children ages 6-22), this study tested associations between grandparent (G1) and parent (G2) marijuana use and child (G3) past-year cigarette, alcohol, and marijuana use. Analyses tested whether G3 substance-related norms mediated these associations. Current G1 and G2 marijuana use was examined, as was G2 high school and early adult use and G1 marijuana use when G2 parents were in early adolescence. Controls included G2 age at G3 birth, G2 education and depression, and G3 gender. G2 current marijuana use predicted a higher likelihood of G3 alcohol and marijuana use but was not related to the probability of G3 cigarette use. G3's perceptions of their parents' norms and G2 current marijuana use both contributed independently to the likelihood of G3 alcohol and marijuana use when included in the same model. G3 children's own norms and their perceptions of friends' norms mediated the link between G2 current marijuana use and G3 alcohol and marijuana use. Results are discussed in light of the growing trend toward marijuana legalization. To the extent that parent marijuana use increases under legalization, we can expect more youth to use alcohol and marijuana and to have norms that favor substance use.


Wenxin Keli diminishes Ca2+ overload induced by hypoxia/reoxygenation in cardiomyocytes through inhibiting INaL and ICaL.
An increase in the late sodium current (INaL ) causes intracellular Na+ overload and subsequently intracellular Ca2+ ([Ca2+ ]i ) overload via the stimulated reverse Na+ -Ca2+ exchange (NCX). Wenxin Keli (WXKL) is an effective antiarrhythmic Chinese herb extract, but the underlying mechanisms are unclear. The INaL , NCX current (INCX ), L-type Ca2+ current (ICaL ), and action potentials were recorded using the whole-cell patch-clamp technique in rabbit ventricular myocytes. Myocyte [Ca2+ ]i transients were measured using a dual excitation fluorescence photomultiplier system. WXKL decreased the enhanced INaL , reverse INCX , diastolic [Ca2+ ]i , and the amplitude of Ca2+ transients induced by sea anemone toxin II (ATX II, a specific INaL channel opener) in a concentration-dependent manner. Hypoxia increased INaL , INCX , and diastolic [Ca2+ ]i , and decreased amplitude of [Ca2+ ]i transients. Hypoxia-reoxygenation aggravated these changes and induced spontaneous [Ca2+ ]i transients and hypercontraction in 86% cells (6/7). The application of WXKL during hypoxia or reoxygenation periods decreased the increased INaL , INCX , and diastolic [Ca2+ ]i , and prevented those events in 82% cells (9/11) under hypoxia-reoxygenation conditions. WXKL also inhibited the ICaL in a dose-dependent manner. Furthermore, WXKL shortened the action potential duration and completely abolished ATX II-induced early afterdepolarizations from 9/9 to /9. In isolated heart electrocardiogram recordings, WXKL inhibited ischemia-reperfusion induced ventricular premature beats and tachycardia. WXKL attenuated [Ca2+ ]i overload induced by hypoxia-reoxygenation in ventricular myocytes through inhibiting INaL and ICaL and prevents arrhythmias. This could, at least partly, contribute to the antiarrhythmic effects of WXKL.


Risk of colorectal adenocarcinoma in men receiving androgen deprivation therapy for prostate cancer; a nationwide cohort study.
To assess whether androgens play a role in explaining the sex related differences in the incidence of colorectal cancer (CRC). A nationwide matched cohort study was conducted employing the Prostate Cancer data Base Sweden (PCBaSe) 4.0 during the study period 2006-2016. Prostate cancer (PC) patients receiving androgen deprivation therapy (ADT) were treated as exposed. Prostate cancer-free men from the general population were randomly selected and matched to the index case by birth year and county of residence, forming the unexposed group. All were followed until a diagnosis of CRC, death, emigration, or end of the study period. The risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men was calculated using a flexible parametric survival model and expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). There was an increased risk of CRC among ADT exposed PC patients compared to unexposed cancer-free men (HR 1.27 [95% CI 1.15-1.41]), in particular an increased risk of adenocarcinoma of the colon (HR 1.33 [95% CI 1.17-1.51]) and more specifically an increased risk of adenocarcinoma of the distal colon (HR 1.53 [95% CI 1.26-1.85]). Examination of latency effects yielded significantly decreased HRs over time for CRC (p = 0.049 for trend). This population-based study found an increased risk of CRC among PC patients exposed to ADT, specifically adenocarcinoma of the distal colon, which indicates an increased association between ADT (PC + ADT) and CRC but not a positive dose-response trend questioning a true causal effect.


A role for G-proteins in the epidermal growth factor stimulation of phospholipase A2 in rat kidney mesangial cells.
We have previously demonstrated phospholipase C (PLC) independent activation of phospholipase A2(PLA2) by epidermal growth factor (EGF) in glomerular mesangial cells in culture. In the current study using glass beads to permeabilize [3H]- or [14C]-arachidonate labelled mesangial cells we demonstrate that guanine nucleotides modulate the EGF-mediated stimulation of arachidonic acid release (75% inhibition with 100 microM GDP beta S and 108% augmentation with 100 microM GTP gamma S). GTP gamma S alone stimulated both the release of free arachidonic acid and production of diacylglycerol (DAG), while EGF itself neither stimulated DAG nor augmented the DAG response to GTP gamma S. These findings suggest the intermediacy of a G-protein in PLC-independent stimulation of PLA2 by a growth factor, and provide a model system for determining the relationship between G-protein intermediacy and the intrinsic tyrosine kinase activity of the growth factor receptor.


Complication rates of diagnostic cerebral arteriography in children.
Cerebral arteriography (CA) remains the gold standard in delineating both intra- and extracranial vascular anatomy. Most data relating to the safety of CA are drawn from studies of adult patients in whom the practicalities of the procedure, range of potential pathologies and comorbid factors are different from those in children. To evaluate the current local and neurological complication rates of paediatric CA in the setting of a tertiary level children's hospital in the UK. Data from patients who had undergone CA between January 1998 and July 2003 were reviewed. The medical, anaesthetic and nursing records, and angiography reports were reviewed for all identified patients. The following parameters were extracted and entered into a proforma: gender, age, ethnicity, diagnosis, cerebrovascular diagnosis, referral source, date of CA, number of vessels catheterized and local and neurological complications. A total of 176 CA studies were undertaken in 150 patients (median age 7.3 years, range neonate to 19 years; 83 males, 67 females) during the 5.5-year study period. The majority of referrals originated from the neurology (58%) and neurosurgery services (27.8%). No neurological complications or deaths occurred. Local complications occurred in eight children (4.5%). Five children had a groin haematoma and two had bleeding at the puncture site. A single child had a reduced pedal pulse distal to the site of catheterization, but Doppler imaging was normal. CA has a continuing role in the evaluation of cerebrovascular pathologies in children. Neurological complications are rare and local complications are not uncommon (around 5%), but are not usually serious.


Proof-of-Mechanism Study of the Phosphodiesterase 10 Inhibitor RG7203 in Patients With Schizophrenia and Negative Symptoms.
Reduced activation of dopamine D1 receptor signaling may be implicated in reward functioning as a potential driver of negative symptoms in schizophrenia. Phosphodiesterase 10A (PDE10A), an enzyme that is highly expressed in the striatum, modulates both dopamine D2- and D1-dependent signaling. We assessed whether augmentation of D1 signaling by the PDE10 inhibitor RG7203 enhances imaging and behavioral markers of reward functions in patients with schizophrenia and negative symptoms. In a 3-period, double-blind, crossover study, we investigated the effects of RG7203 (5 mg and 15 mg doses) and placebo as adjunctive treatment to stable background antipsychotic treatment in patients with chronic schizophrenia with moderate levels of negative symptoms. Effects on reward functioning and reward-based effortful behavior were evaluated using the monetary incentive delay task during functional magnetic resonance imaging and the effort-cost-benefit and working memory reinforcement learning tasks. Patients (N = 33; 30 male, mean age ± SD 36.6 ± 7.0 years; Positive and Negative Syndrome Scale negative symptom factor score 23.0 ± 3.5 at screening) were assessed at three study centers in the United States; 24 patients completed the study. RG7203 at 5 mg significantly increased reward expectation-related activity in the monetary incentive delay task, but in the context of significantly decreased overall activity across all task conditions. In contrast to our expectations, RG7203 significantly worsened reward-based effortful behavior and indices of reward learning. The results do not support the utility of RG7203 as adjunctive treatment for negative symptoms in patients with schizophrenia.


Modeling the role of lateral membrane diffusion in AMPA receptor trafficking along a spiny dendrite.
AMPA receptor trafficking in dendritic spines is emerging as a major postsynaptic mechanism for the expression of plasticity at glutamatergic synapses. AMPA receptors within a spine are in a continuous state of flux, being exchanged with local intracellular pools via exo/endocytosis and with the surrounding dendrite via lateral membrane diffusion. This suggests that one cannot treat a single spine in isolation. Here we present a model of AMPA receptor trafficking between multiple dendritic spines distributed along the surface of a dendrite. Receptors undergo lateral diffusion within the dendritic membrane, with each spine acting as a spatially localized trap where receptors can bind to scaffolding proteins or be internalized through endocytosis. Exocytosis of receptors occurs either at the soma or at sites local to dendritic spines via constitutive recycling from intracellular pools. We derive a reaction-diffusion equation for receptor trafficking that takes into account these various processes. Solutions of this equation allow us to calculate the distribution of synaptic receptor numbers across the population of spines, and hence determine how lateral diffusion contributes to the strength of a synapse. A number of specific results follow from our modeling and analysis. (1) Lateral membrane diffusion alone is insufficient as a mechanism for delivering AMPA receptors from the soma to distal dendrites. (2) A source of surface receptors at the soma tends to generate an exponential-like distribution of receptors along the dendrite, which has implications for synaptic democracy. (3) Diffusion mediates a heterosynaptic interaction between spines so that local changes in the constitutive recycling of AMPA receptors induce nonlocal changes in synaptic strength. On the other hand, structural changes in a spine following long term potentiation or depression have a purely local effect on synaptic strength. (4) A global change in the rates of AMPA receptor exo/endocytosis is unlikely to be the sole mechanism for homeostatic synaptic scaling. (5) The dynamics of AMPA receptor trafficking occurs on multiple timescales and varies according to spatial location along the dendrite. Understanding such dynamics is important when interpreting data from inactivation experiments that are used to infer the rate of relaxation to steady-state.


Lack of association of a functional single nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with susceptibility to biopsy-proven giant cell arteritis.
To assess the possible association between PTPN22 1858C(R)T polymorphism and susceptibility to giant cell arteritis (GCA) and to determine if this polymorphism is implicated in the clinical expression of this vasculitis. Ninety-six patients with biopsy-proven GCA and 229 ethnically matched controls from the Lugo region of Northwest Spain were studied using molecular methods. All individuals were of Spanish Caucasian origin. Genotyping of PTPN22 gene 1858C(R)T polymorphism was performed by real time polymerase chain reaction technology, using TaqMan 5' allelic discrimination assay. No significant differences in allele or genotype frequencies for PTPN22 polymorphism were observed between patients with GCA and controls or when patients were stratified by presence of polymyalgia rheumatica (n = 38) or severe ischemic manifestations (n = 47). Our results do not support potential involvement of PTPN22 gene polymorphism in the susceptibility or clinical expression of GCA.


Polytope vaccines for the codelivery of multiple CD8 T-cell epitopes.
Vaccines against a number of diseases, including HIV, Epstein Barr virus, malaria and several cancers, are believed to require the coinduction of multiple alphabeta CD8+ cytotoxic T-lymphocyte responses that are directed towards a number of different target antigens. The difficulties associated with making large recombinant vaccines that contain numerous antigens has led to the development of alphabeta CD8+ cytotoxic T-lymphocyte polyepitope or polytope vaccine approach, where multiple (usually 8-10 amino acids long) alphabeta CD8+ cytotoxic T-lymphocyte epitopes, derived from several antigens are conjoined into single artificial constructs. Such polytope constructs can be delivered using a number of different vaccine vector modalities with each epitope in the construct emerging as individually immunogenic.


Nano-Raman mapping of a porous glass-ceramic SERS substrate in collection mode.
Porous glass-ceramics is an extremely important material to be used in combination with metallic nanolayers as a Surface-Enhanced Raman Scattering (SERS) substrate for biological and chemical analysis, demonstrating excellent biocompatibility and chemical inertness. These materials show their own Raman background signal lateral distribution, mostly from crystalline skeleton, which has to be considered. A nano-Raman setup using the optical fibre of a Scanning Near-Field Optical Microscope (SNOM), working in collection mode, is described and applied for mapping of such glass-ceramic. The collected Raman signal of Ti and P containing phase distribution in this near-field geometry reaches spatial resolution around 50 nm.


Constitutive modeling of the stress-strain behavior of F-actin filament networks.
The central role of the cytoskeleton in both healthy and diseased cellular functions makes it a compelling subject for detailed three-dimensional (3D) micromechanical modeling. Microstructural features of the cytoskeleton govern the cell's mechanical behavior in many of the regulating cellular functions including cell division, adhesion, spreading, migration, contraction, and other mechanotransductive effects which influence biochemical processes. Actin microfilaments (AF) combine to form one of the predominant cytoskeletal networks important to these biological processes. Here, the AF cytoskeletal microstructure and stress-strain behavior is modeled via a microstructurally-informed continuum mechanics approach. The force-extension behavior of the individual filaments is captured using the MacKintosh derivation of the worm-like chain (WLC) constitutive relationship for short chains where a new and direct analytical expression for the filament force as a function of filament extension is developed in this paper. The filament force-extension behavior is then used in conjunction with the Arruda-Boyce eight-chain network model to capture the 3D multiaxial stress-strain behavior of the network. The resulting 3D cytoskeletal network constitutive model provides the ability to track microstructural stretch and orientation states during 3D macroscopic stretching conditions. The non-affine nature of the network model effectively accommodates the imposed macroscopic shear strain through filament rotation and a relatively small amount of filament stretch. These characteristics enable the network model, using physically realistic material properties, to capture the initial stiffness of the AF network as well as the nonlinear strain stiffening observed at large stresses. The network model predictions compare favorably with published microrheological data of in vitro AF networks.


Using Bayesian state-space models to understand the population dynamics of the dominant malaria vector, Anopheles funestus in rural Tanzania.
It is often assumed that the population dynamics of the malaria vector Anopheles funestus, its role in malaria transmission and the way it responds to interventions are similar to the more elaborately characterized Anopheles gambiae. However, An. funestus has several unique ecological features that could generate distinct transmission dynamics and responsiveness to interventions. The objectives of this work were to develop a model which will: (1) reconstruct the population dynamics, survival, and fecundity of wild An. funestus populations in southern Tanzania, (2) quantify impacts of density dependence on the dynamics, and (3) assess seasonal fluctuations in An. funestus demography. Through quantifying the population dynamics of An. funestus, this model will enable analysis of how their stability and response to interventions may differ from that of An. gambiae sensu lato. A Bayesian State Space Model (SSM) based on mosquito life history was fit to time series data on the abundance of female An. funestus sensu stricto collected over 2 years in southern Tanzania. Prior values of fitness and demography were incorporated from empirical data on larval development, adult survival and fecundity from laboratory-reared first generation progeny of wild caught An. funestus. The model was structured to allow larval and adult fitness traits to vary seasonally in response to environmental covariates (i.e. temperature and rainfall), and for density dependency in larvae. The effects of density dependence and seasonality were measured through counterfactual examination of model fit with or without these covariates. The model accurately reconstructed the seasonal population dynamics of An. funestus and generated biologically-plausible values of their survival larval, development and fecundity in the wild. This model suggests that An. funestus survival and fecundity annual pattern was highly variable across the year, but did not show consistent seasonal trends either rainfall or temperature. While the model fit was somewhat improved by inclusion of density dependence, this was a relatively minor effect and suggests that this process is not as important for An. funestus as it is for An. gambiae populations. The model's ability to accurately reconstruct the dynamics and demography of An. funestus could potentially be useful in simulating the response of these populations to vector control techniques deployed separately or in combination. The observed and simulated dynamics also suggests that An. funestus could be playing a role in year-round malaria transmission, with any apparent seasonality attributed to other vector species.


Pilot Project: Heart Chargers-A Successful Model for a Home-Based Physical Activity Program Utilizing Telemedicine for Fontan Patients.
Fontan patients have decreased exercise capacity which further declines throughout adolescence. A positive exercise capacity trajectory in children predicts better adult Fontan outcomes. Hospital-based physical activity programs improve exercise capacity and attenuate the age-expected decline in Fontan patients. The purpose of this project was to investigate the feasibility and safety of a partially reimbursable 12-month, home-based, individualized physical activity program (Heart Chargers) for Fontan patients utilizing telemedicine. The Heart Chargers team included a cardiologist, nurse coordinator, and exercise physiologists. Eligible participants with a Fontan completed a baseline cardiopulmonary exercise test (CPET) and consented to participate in Heart Chargers, a 12-month home-based exercise prescription. The individualized exercise prescription focused on skeletal and respiratory muscle strength training and aerobic activities. Participants received a Garmin© device to monitor adherence. Telephone check-ins ranged from weekly to monthly as participants gained independence. Pre- and post-program CPET and informal surveys of physical activity self-efficacy were completed. Nine participants have completed the Heart Chargers program. There was no pre-post difference in maximal or submaximal oxygen consumption (VO2), peak heart rate, or oxygen saturation. There was a significant pre-post increase in systolic blood pressure (p-value 0.004) and minute ventilation (p-value 0.012) at peak exercise. Per subjective report, exercise-related self-efficacy increased after program completion. There were no adverse events. At present, 7 participants remain actively enrolled in the program. Heart Chargers, a novel, home-based, partially reimbursable, 12-month individualized exercise program using telemedicine was successfully implemented in Fontan patients with no adverse events. The lack of decline in exercise capacity for participants is encouraging.


Rapid procedure for coupling protein antigens to red cells to be used in plaque assays, by prewashing in chromium chloride.
A rapid and efficient procedure is described for the coupling of proteins (protein A, ovalbumin, albumin and chicken gamma globulin) to sheep red blood cells (SRBC) to be used in antigen-specific or protein A plaque assays. This modification of the original procedure has three distinct features: prewash of the red cells with a low concentration of essentially freshly prepared CrCl3, use of a relatively high concentration of CrCl3 in the reaction mixture and a coupling time of only 4 min. Protein A plaque assays performed with such target cells have the same sensitivity as those employing red cells coupled with protein A according to the original procedure. Studies with hybridomas secreting antibody specific for a protein antigen showed that antigen-specific plaque assays employing target red cells coupled with the protein antigen according to the modified procedure have the same sensitivity as the protein A plaque assay. The modified procedure greatly facilitates cellular studies on antibody formation after immunization with protein antigens.


A weekly 35,000 IU vitamin D supplementation improves bone turnover markers in vitamin D deficient Saudi adolescent females.
This study examined the effects of weekly 35,000 IU vitamin D supplementation for 4 weeks on bone turnover markers (BTMs). There was improvement in the levels of parathyroid hormone (PTH), osteocalcin, and carboxy-terminal telopeptides of crosslinks of type 1 collagen (βCTX) which paralleled the increase in vitamin D levels. The effects of vitamin D supplementation on bone turnover markers (BTMs) have been inconsistent. This study examined the effects of weekly 35,000 IU vitamin D supplementation for 1 month on BTMs. Sixty-eight vitamin D deficient adolescent females were given 35,000 IU of vitamin D3 for 4 weeks. Pre and post intervention blood samples were taken for 25(OH) D, PTH, osteocalcin and βCTX. There was a significant increase in serum 25 (OH) D in the post intervention period which was accompanied by a significant decrease in PTH, osteocalcin and βCTX (P < 0.001). We concluded that weekly 35,000 IU vitamin D supplementation for 4 weeks results in significant improvement of BTMs.


Current state of apheresis technology and its applications.
Apheresis is at the forefront of therapeutic approaches for an increasing number of indications caused by formation of pathologic antibodies treated by therapeutic plasma exchange, or through the use of red cell exchanges to overcome complications secondary to sickle cell crises. Likewise, the number of hematopoietic stem cell transplants has continued to grow annually and this is the direct result of the expansion of apheresis collections. Over the years a number of apheresis platforms have been utilized, but as one of the oldest and most widely used systems, the COBE Spectra, has ceased to be used therapeutically and at blood centers for donations there is an active search to find suitable systems that will replace it and have the versatility to perform as many procedures as possible. Computer innovations have made it possible with current apheresis technology to obtain more real-time information of the procedure which permits the operator to adjust parameters not only to optimize the specific procedure but also to safeguard against potential adverse events. The focus of this review is to go over available clinical data describing the operation, outcomes and applications of apheresis platforms, and discuss those systems that are likely to meet clinical demands and those of blood donation centers.


Disproportionate presentation of high risk prostate cancer in a safety net health system.
Most prostate cancer research is based on relatively homogenous cohorts of men, often with comparatively high socioeconomic status. We describe prostate cancer characteristics in men treated in a public health system and hypothesize a disproportionate burden of high risk disease in this population. We created a clinical registry from a review of the medical records of 377 men diagnosed with prostate cancer in the San Francisco General Hospital system, which provides care to underserved, uninsured populations. We compared sociodemographic data and cancer characteristics with those in 2 large prostate cancer databases from a community (CaPSURE™) and an academic (University of California-San Francisco tumor registry) setting to assess differences in risk distribution using the D'Amico and Cancer of the Prostate Risk Assessment scoring systems. Compared to men in CaPSURE or the University of California-San Francisco tumor registry those in the San Francisco General Hospital cohort were nonwhite (76%), insured under Medicaid (31%) or uninsured (8%) and had adverse clinical characteristics, including median prostate specific antigen greater than 10 ng/ml at diagnosis and higher Gleason grade. In addition, the majority of patients (67%) had intermediate or high risk disease based on the D'Amico classification and a higher mean Cancer of the Prostate Risk Assessment score. Using ANOVA for continuous variables and the chi-square test for categorical variables, all comparisons were statistically significant (p <0.001). Men in the San Francisco General Hospital public health system bear a substantially higher burden of high risk disease that those in an academic or a community setting. Populations such as this would benefit most from targeted efforts for early detection and treatment to decrease prostate cancer morbidity and mortality.


Reelin as a putative vulnerability factor for depression: examining the depressogenic effects of repeated corticosterone in heterozygous reeler mice.
We examined a potential two-hit murine animal model of depression by assessing whether a genetic deficit in reelin increases vulnerability to the depressogenic effects of the stress hormone corticosterone. Stress is an identified risk factor for the onset of depressive symptoms, but depression also has a significant genetic component, suggesting that environmental factors and genetic background likely interact in the etiology of depression. Previous results have revealed that reelin levels are decreased in post-mortem hippocampal tissue from patients with schizophrenia, bipolar disorder and depression, and also in an animal model of depression. Therefore, we hypothesized that heterozygous reeler mice (HRM), with approximately 50% normal levels of reelin, would be more sensitive to the depressogenic effects of corticosterone than wild-type mice (WTM). Mice received subcutaneous injections of either vehicle or 5 mg/kg, 10 mg/kg, or 20 mg/kg of corticosterone for 21 consecutive days, and then they were assessed for changes in depression-like behavior, hippocampal reelin expression, and hippocampal neurogenesis. Corticosterone produced dose-dependent increases in depression-like behavior and decreases in reelin expression, neurogenesis, and cell maturation regardless of mouse genotype. There were no differences between the vehicle-injected HRM and WTM in these measures. However, the effects of CORT on behavior, the number of reelin-positive cells in the subgranular zone or hilus, and hippocampal neurogenesis were more pronounced in the HRM than in the WTM, providing support for the idea that mice with impaired reelin signaling may be more vulnerable to the deleterious effects of glucocorticoids. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.


[Therapy of Buried Bumper Syndrome via NOTES - A Case Report].
Mucosal overgrowth and migration of the inner bumper into or even through the gastric wall (= buried bumper syndrome) is a possible complication of percutaneous endoscopic gastrostomy (PEG). In this case report we describe the successful endoscopic recovery of an intraabdominally migrated inner bumper as well as reestablishment of PEG using NOTES (Natural Orifice Translumenal Endoscopic Surgery). This practical application of the NOTES technique via the preexisting transgastric approach (PEG) can therefore be a reasonable alternative to a surgical-laparoscopic therapy of the severe buried bumper.


Selective use of low frequency stimulation in Parkinson's disease based on absence of tremor.
High frequency stimulation (HFS) of the subthalamic nucleus is one of the most effective treatments for advanced Parkinson's disease (PD). HFS has provided beneficial improvements in the cardinal features of PD, but has not been proven as effective for addressing the axial predominant levodopa resistant symptoms, such as speech disturbances, gait disturbances, and postural instability. Recent studies have suggested that changes in stimulation parameters may influence differing PD symptoms. The purpose of this study was to compare the effects of low frequency stimulation (LFS) versus HFS on the Unified Parkinson's Disease Rating Scale (UPDRS), gait, balance, and verbal fluency. Eight tremor dominant and nine non-tremor dominant participants with bilateral deep brain stimulation of the subthalamic nucleus were tested off stimulation, during LFS, and during HFS. Results revealed that HFS significantly reduced UPDRS tremor score in the tremor dominant group; however no differences emerged within the non-tremor dominant group. No differences between groups or stimulation conditions were found for gait, balance, and verbal fluency measures. These results may suggest that HFS is better than LFS for reducing tremor in tremor dominant patients. However, patients with mild or no tremor show no acute differences in benefit from LFS as compared to HFS.


Cellular assay for measuring anti-erythrocyte antibody responses.
Splenocytes from mice immunized with sheep red cells (SRC) or donkey red cells (DRC) were able to lyse radiolabeled SRC or DRC respectively. The cytotoxic effect was mediated by the active supernatant which was released from the immune splenocytes and which was characterized as antibody. This cellular cytotoxic response was found to be a very reliable, efficient, rapid and objective assay for measuring anti-erythrocyte antibody responses.


Patient-Specific Instrumentation for Medial Closing Wedge Distal Femoral Osteotomy With Patellar Osteochondral Allograft.
The primary indications for performing a medial closing wedge distal femoral osteotomy are valgus knee malalignment, lateral knee compartment overload, lateral meniscus insufficiency, and/or lateral compartment osteoarthritis or cartilage damage. Without correction of this malalignment, there is an increased risk for chondral damage in the lateral and patellofemoral compartment of the knee. The optimal candidates for this procedure are young, active individuals with moderate to severe arthritis in the lateral compartment. Recently, preoperative planning for high tibial and distal femoral osteotomies (HTOs and DFOs) using 3-dimensional (3D) patient-specific instrumentation (PSI) has increased in popularity. Successful patient outcomes have been reported using this technique. This Technical Note illustrates our preferred technique that uses 3D PSI in addition to a patellar OCA transplant when treating a symptomatic cartilage lesion associated with genu valgum.