The glomerulus: the sphere of influence.
The glomerulus, the filtering unit of the kidney, is a unique bundle of capillaries lined by delicate fenestrated endothelia, a complex mesh of proteins that serve as the glomerular basement membrane and specialized visceral epithelial cells that form the slit diaphragms between interdigitating foot processes. Taken together, this arrangement allows continuous filtration of the plasma volume. The dynamic physical forces that determine the single nephron glomerular filtration are considered. In addition, new insights into the cellular and molecular components of the glomerular tuft and their contribution to glomerular disorders are explored.


Similarity preserving principal curve: an optimal 1-d feature extractor for data representation.
This paper discusses the problem of what kind of learning model is suitable for the tasks of feature extraction for data representation and suggests two evaluation criteria for nonlinear feature extractors: reconstruction error minimization and similarity preservation. Based on the suggested evaluation criteria, a new type of principal curve-similarity preserving principal curve (SPPC) is proposed. SPPCs minimize the reconstruction error under the condition that the similarity between similar samples are preserved in the extracted features, thus giving researchers effective and reliable cognition of the inner structure of data sets. The existence and properties of SPPCs are analyzed; a practical learning algorithm is proposed and high dimensional extensions of SPPCs are also discussed. Experimental results show the virtues of SPPCs in preserving inner structures of data sets and discovering manifolds with high nonlinearity.


CASK, the Soluble Glomerular Permeability Factor, Is Secreted by Macrophages in Patients With Recurrent Focal and Segmental Glomerulo-Sclerosis.
Introduction: Focal and segmental glomerulosclerosis (FSGS) is a frequent form of glomerulonephritis that may be caused by a soluble permeability factor and regulated by the immune system. We previously described a soluble form of calcium/calmodulin-dependent serine/threonine kinase (CASK) acting as a permeability factor in patients with recurrent FSGS (rFSGS). Here, we aimed to identify the immune cells associated with CASK secretion in patients with rFSGS. Methods: FACS, western blotting and immunoprecipitation were performed to detect CASK in peripheral blood mononuclear cells, including CD3+, CD20+, and CD14+subsets, from patients with rFSGS, healthy donors, transplant patients and patients with nephrotic syndrome due to diabetes mellitus, and in KHM2 cells. Results: CASK was produced mostly by monocytes in patients with rFSGS but not by T or B lymphocytes. It was not detectein cells from control patients. CASK was also produced and secreted by M2 polarized macrophages and KMH2 cells, but not by M1 polarized macrophages. CASK secretion was not not inhibited by brefeldin A, suggesting an absence of classical secretion pathway involvement. Within cells, CASK was partly colocalized with ALIX, a molecule involved in exosome development, and these two molecules were coprecipitated from M2 macrophages. Moreover, exosomes derived from M2 macrophages induced podocyte cytoskeleton alterations and increased podocyte motility. Conclusion: These results suggest that the soluble permeability factor CASK is secreted by monocytes and M2 macrophages, via exosomes, to alter the glomerular filtration barrier in rFSGS.


Video See-Through Pipelines for Virtual Reality Headsets and their Impact on Gait.
This study investigated the impact of different video see-through pipelines in virtual reality on gait. A mobility task was conducted with healthy participants to evaluate the gait adaptions using different video see-through pipelines. The gait parameters observed for this study were stride length, maximum toe clearance and walking speed. The results showed an impact on gait where the gait parameters were reduced when participants used a high latency and restricted field of view pipeline. However, when participants used a pipeline with low latency and a field of view closer to normal vision, less impact on gait was achieved. As virtual reality poses a promising future for gait rehabilitation in patients with Parkinson's disease, this result highlights the need to carefully consider the video see-through pipeline and display characteristics when considering its use for gait rehabilitation or mobility studies in general.Clinical relevance- This study demonstrates the impact of virtual reality systems on gait using different video see- through pipelines during a mobility task. This may be useful for clinicians who use virtual reality in gait rehabilitation and aid them in choosing the most suitable virtual reality system for therapy.


Coolsense® versus EMLA® for peripheral venous cannulation in adult volunteers: A randomised crossover trial.
Peripheral venous cannulation (PVC) is a commonly performed invasive medical procedure. Topical treatments such as the eutectic mixture of local anaesthetics (EMLA®, Aspen Pharmacare Australia Pty Ltd, St Leonards, NSW) attenuate the associated pain, but are limited by requiring up to one hour of application before becoming effective. The Coolsense® (Coolsense Medical Ltd., Tel Aviv, Israel) pain numbing applicator is a new device using a cryoanalgesic means to anaesthetise skin within seconds. Coolsense is being increasingly used for cannulation, but comparative studies are lacking. We recruited 64 healthy adult volunteers to this open-label two sequence, two period randomised crossover trial. Participants had two 20 gauge venous cannulae inserted, one on the dorsum of each hand. Each cannulation attempt was preceded by treatment with Coolsense or an EMLA patch containing 2.5% lidocaine and 2.5% prilocaine. The primary outcome was participant pain using the 0-10 numerical pain rating scale. Secondary outcomes were participant satisfaction scores on a 0-10 scale, treatment preference, and failed cannulation attempts. Participants were randomly assigned to either the Coolsense EMLA (n = 32) or EMLA Coolsense (n = 32) sequence. All participants completed the trial. The pooled mean paired difference of the numerical pain rating scale was -1.84 (95% confidence intervals -1.28 to -2.41; P < 0.001) in favour of EMLA. The pooled mean paired difference for satisfaction score was 2.26 (95% confidence intervals 1.46 to 3.07; P < 0.001) higher with EMLA. Most participants preferred EMLA over Coolsense (P < 0.001). There was no significant difference regarding failed cannulation between the two treatments (P = 0.14). Among healthy individuals undergoing elective PVC, EMLA was associated with reduced pain, increased satisfaction, and was the preferred treatment compared to Coolsense.


The Life Course, Cohort Dynamics, and International Differences in Aging Trajectories.
In recent years, population health research has focused on understanding the determinants of later-life health. Two strands of that work have focused on (1) international comparisons of later-life health and (2) assessing the early-life origins of disease and disability and the importance of life course processes. However, the less frequently examined intersection of these approaches remains an important frontier. The present study contributes to the integration of these approaches. We use the Health and Retirement Study family of data sets and a cohort dynamic approach to compare functional health trajectories across 12 high-income countries and to examine the role of life course processes and cohort dynamics in contributing to variation in those trajectories. We find substantial international variation in functional health trajectories and an important role of cohort dynamics in generating that variation, with younger cohorts often less healthy at comparable ages than the older cohorts they are replacing. We further find evidence of heterogeneous effects of life course processes on health trajectories. The results have important implications for future trends in morbidity and mortality as well as public policy.


Immunodominant minor histocompatibility antigen peptides recognized by cytolytic T lymphocytes primed by indirect presentation.
Indirect presentation of minor histocompatibility antigens (HA) as revealed by cross-priming of H2 heterozygous recipients effectively primes minor HA-specific cytolytic T lymphocytes (CTLs). However, it is not known if indirect priming generates CTLs specific for the same set of immunodominant minor HA recognized by CTLs primed by direct spleen cell injections. In order to indirectly prime minor HA-specific CTLs, we implanted (C57BL/6 x B6.C-H2d)F1 recipients with BALB.B and BALB/c splenocytes loaded into immunoisolation devices that effectively preclude direct donor:host contact. Responder spleen cells from these recipients were stimulated in vitro to expand BALB.B- and BALB/c-specific CTLs to reveal classical cross-priming. Tests of CTL specificity using (1) CXB recombinant inbred strain targets that express different arrays of BALB/c minor HA and (2) high-performance liquid chromatography fractions of peptides from BALB.B Kb and Db molecules revealed that anti-BALB.B CTLs were specific for two previously identified dominant peptides, CTT-2 and CTT-5, presented by Kb molecules. Variation of responders and priming cells resulted in CTL responses to additional dominant peptides that had been identified previously with CTLs generated by direct priming with spleen cell injections. Indirect priming was not limited to this set of peptides recognized by CTLs in vitro because devices loaded with cells devoid of the CTL-detected peptides primed for accelerated skin allograft rejection. Indirect presentation of minor HA in vivo stimulates the generation of CTLs specific for a subset of dominant minor HA peptides recognized by CTLs primed by direct presentation.


Examining ventral and dorsal prefrontal function in bipolar disorder: a functional magnetic resonance imaging study.
Several lines of research suggest both dorsal and ventral prefrontal cortical dysfunction in bipolar disorder (BD). We used functional magnetic resonance imaging to compare patterns of brain activation in remitted BD patients and controls whilst performing tasks selected for their relative specificity in engaging either the dorsal (n-back sequential-letter working memory task) or ventral (gambling task) PFC. Seven BD patients were selected from participants of the Maudsley Bipolar Disorder Project on the basis of clinical remission, absence of cognitive deficits, and monotherapy with mood stabilisers. Subjects were individually matched by gender, age, and IQ to an equal number of healthy controls. In the n-back task, group differences were only present in response to increasing memory load. Patients did not show the predicted dynamic response in the dorsal PFC, but had increased activation in the parietal cortices. During the gambling task, controls showed significant activation in the ventral and dorsal PFC; this was attenuated in BD patients where increased activation was seen in lateral temporal and polar regions. Our findings suggest that there are trait abnormalities in dorsal and ventral PFC function in BD that may be more pronounced during tasks that rely on ventral-dorsal PFC interaction.


[Calculation of prognoses of lung cancer in males from technogenic contamination of atmosphere in the Kemerovo region].
In this paper there are described the variants of the models of the regression analysis (linear exponential, exponential and hyperbolic) for the detection of relationships between the lung cancer rate in the male population and anthropogenic emissions in the Kemerovo region. After analyzing of the each model there was chosen the one seemed to be the most adequate to describe the dependence of cancer incidence from pollutant emissions into the atmosphere. At a later stage this model has served for the calculation of the medium-term forecasting of lung cancer rate in males in the dependence on the actual number of man-made emissions in previous years.


[Characteristics of the metastatic spread of transplanted tumors under high-altitude conditions].
The data on nature of metastatic spreading of transplantable animal tumours of the Tien-Shan mountains at an altitude of 3200 m above sea level are reviewed. It is shown that the adaptation of mice with Ehrlich adenocarcinoma is followed by the primary tumour growth inhibition and a two-fold decrease of frequency of metastatic spreading into regional lymph nodes as compared with the control animals at sea level. In mountains the activity of metastatic spreading into lungs of Lewis lung carcinoma and Walker carcinosarcoma decreases. In experiments with (CBA x C57Bl)F1 mice-hybrids with Lewis lung carcinoma the enhancement of antitumour and antimetastatic effect of the cyclophosphamide is revealed under high-altitude hypoxia influence.


A probabilistic threshold model: analyzing semantic categorization data with the Rasch model.
According to the Threshold Theory (Hampton, 1995, 2007) semantic categorization decisions come about through the placement of a threshold criterion along a dimension that represents items' similarity to the category representation. The adequacy of this theory is assessed by applying a formalization of the theory, known as the Rasch model (Rasch, 1960; Thissen & Steinberg, 1986), to categorization data for eight natural language categories and subjecting it to a formal test. In validating the model special care is given to its ability to account for inter- and intra-individual differences in categorization and their relationship with item typicality. Extensions of the Rasch model that can be used to uncover the nature of category representations and the sources of categorization differences are discussed.


Expression of the psbDII gene in Synechococcus sp. strain PCC 7942 requires sequences downstream of the transcription start site.
The psbDI and psbDII genes in Synechococcus sp. strain PCC 7942 encode the D2 polypeptide, an essential component of the photosystem II reaction center. Previous studies have demonstrated that transcripts from psbDII, but not psbDI, increase in response to high light intensity. Soluble proteins from Synechococcus cells shifted to high light were found to have affinity for DNA sequences upstream from the psbDII coding region. DNA mobility-shift and copper-phenanthroline footprinting assays of a 258-bp fragment revealed three distinct DNA-protein complexes that mapped to the untranslated leader region between +11 and +84. Deletion of the upstream flanking region to -42 had no effect on the expression of a psbDII-lacZ reporter gene or its induction by light, whereas a promoterless construct supported only minimal background levels of beta-galactosidase. A 4-bp deletion within the first protected region of the footprint decreased the beta-galactosidase activity to approximately 2% of that of the undeleted control, but gene expression remained responsive to light. Deletion of the three protected regions completely abolished both gene expression and light induction. These results suggest that the psbDII gene requires elements within the untranslated leader region for efficient gene expression, one of which may be involved in regulation by light.


Potentiation of paclitaxel activity by curcumin in human breast cancer cell by modulating apoptosis and inhibiting EGFR signaling.
It has been suggested that combined effect of natural products may improve the treatment effectiveness in combating proliferation of cancer cells. Here, we examined the combined anticancer activities of compounds of three natural origin including baicalein, curcumin, and resveratrol with chemotherapy drug paclitaxel respectively, which showed that combination of paclitaxel with curcumin exhibited synergistic growth inhibition and induced significant apoptosis in MCF-7 cell lines. Treatment of MCF-7 cell lines with paclitaxel and curcumin induced the apoptosis of regulatory protein Bcl-2 but decreased Bax expression. In addition, simultaneous treatment with paclitaxel and curcumin strongly inhibited paclitaxel-induced activities of EGFR signaling. Furthermore, the combination of paclitaxel and curcumin exerted increased anti-tumor efficacy on mouse models. Overall, our data described the promising therapeutic potential and underlying mechanisms of combining paclitaxel with curcumin in treating breast cancer.


Three new species of Demidospermus (Monogenea: Dactylogyridae) parasitic on Brachyplatystoma filamentosum (Siluriformes: Pimelodidae) from the Araguaia River, Brazil.
Three new species of dactylogyrids (Monogenea) from the Araguaia River in Brazil are described herein. Specimens of Demidospermus ceccarellii n. sp., Demidospermus brachyplatystomae n. sp., and Demidospermus araguaiaensis n. sp. were collected from the gills of the siluriform fish, Brachyplatystoma filamentosum (Lichtenstein, 1819). The 3 new species can be easily distinguished from their congeners by the shape of the male copulatory organ (MCO) and accessory piece. Demidospermus ceccarellii n. sp. presents a J-shaped and robust MCO, a base with a short sclerotized margin, and a slightly curved and robust accessory piece with the base slightly dilated. In contrast, D. brachyplatystomae n. sp. has a thin MCO forming an incomplete ring, a base with an irregular sclerotized margin, and a long and curved accessory piece with a wider distal portion. Demidospermus araguaiaensis n. sp. has a thin MCO with a base directly coupled to the accessory piece and an articulated accessory piece that is sinuous in shape in the distal portion. In addition, the 3 species present haptoral hooks similar in shape and size and, thus, were compared in detail with the other Demidospermus species with this particular characteristic. This is the first record of monogeneans that are parasitic on B. filamentosum.


A safety radiation marker in the cardiac catheterization lab.
Nowadays, in order to deal with cardiovascular disease, coronary angiography (CRA) is the best tool and gold standard for diagnosis and assessment. CRA inevitably exposes both patient and operator to radiation. The purpose of this study was to calculate the radiation exposure in association with the radiation absorbed by interventional cardiologists, in order to estimate a safety radiation marker in the catheterization laboratory. In 794 successive patients undergoing CRA and in three interventional cardiologists the following parameters were examined: radioscopy duration, radiation exposure during fluoroscopy, total radiation exposure and the number of stents per procedure. Every interventional cardiologist was exposed to 562,936 μGym2 of total radiation during CRA procedures, to 833,371 μGym2 during elective CRA + percutaneous coronary intervention (PCI) procedures and to 328,250 μGym2 during primary CRA + PCI. Hence, the total amount of radiation that every angiographer was exposed to amounted to 1,724,557.5 μGym2 (median values). During the same period, the average radiation that every angiographer absorbed was 15,253 while the average dose of radiation absorbed during one procedure was 0.06 mSv for each operator. Therefore, the ratio between radiation exposure and the radiation finally absorbed by every operator was 113:1 μGym2/mSv. The present study, indicating the ratio above, offers a safety marker in order to realistically estimate the dose absorbed by interventional cardiologists, suggesting a specified number of permitted procedures and an effective level of radiation use protection tools.


Fast analysis of malachite green, leucomalachite green, crystal violet and leucocrystal violet in fish tissue based on a modified QuEChERS procedure.
Triphenylmethane dyes malachite green (MG) and crystal violet (CV) have been used as antimicrobial, antiparasitic and antiseptic agents in aquaculture. However, MG and CV, as well as their metabolites leucomalachite green (LMG) and leucocrystal violet (LCV) are potential mutagens and carcinogens. Thus, the efficient determination of dye residues is of great concern. Considering the complexity of the aquatic products, the sample pretreatment is significant for decreasing matrix interference and improving detection sensitivity. In this study, a simple and rapid QuEChERS procedure was developed and combined with HPLC analysis for the simultaneous determination of the four dyes in fish tissue. An XCharge C18 column was applied in HPLC analysis to achieve good peak shape and selectivity. The pretreatment method involved the extraction of dyes from fish tissue and further clean-up with dispersive solid phase extraction (d-SPE) material. The extraction volume, extraction time as well as d-SPE materials were systematically optimized. The results indicated that reversed-phase/strong anion exchange (C18SAX) adsorbent in the d-SPE procedure could effectively improve the recovery compared with conventional C18 or C18 incorporated with primary secondary amine (PSA) material. Under optimized conditions, good linearity was achieved in the concentration range of 0.5-100 mg/L with R2 greater than 0. 998. The recoveries were 73%-91% and the precisions were 0.66%-5.41%. The results demonstrated the feasibility and efficiency of QuEChERS procedure incorporated with HPLC for dye monitoring.


Acetoxycycloheximide enhances audiogenic seizures in DBA-2J mice.
Inborn errors of metabolism often cause epilepsy, as with certain strains of mice. Aggravating the metabolic defect with a protein synthesis inhibitor increases the symptoms. Mature animals that have "outgrown" their genetic susceptibility to audiogenic seizures are made susceptible again by acetoxycycloheximide. After a single small dose the incidence and severity of audiogenic seizures increases at 16 hours, reaches a maximum of 40 hours, and then declines gradually.


Stereotactic core needle biopsy of nonpalpable breast lesions using a conventional mammography unit with an add-on device.
The purpose of this prospective study was to assess the accuracy of an add-on stereotactic unit for core needle biopsy of mammographic lesions. SUBJECTS AND METHODS. Between September 1994 and February 2001, 506 stereotactic core needle biopsies of mammographic lesions in 492 patients were performed in our center on a mammography unit with add-on stereotactic equipment. Of the initial 92 patients, 80 underwent stereotactic core needle biopsy and surgical excision simultaneously. In subsequent cases, surgical biopsy was performed after core biopsy in patients who had malignant or atypical histologic results or discordance between mammographic and pathologic findings. Follow-up mammography was advised for all patients whose core biopsy results were diagnosed as benign lesions. Histologic results for 506 lesions undergoing stereotactic core needle biopsy were as follows: 113 (22.3%) were malignant; 369 (72.9%), benign; and 24 (4.7%), atypical. Of 113 malignant lesions identified at stereotactic core needle biopsy, 111 were confirmed as malignant, whereas two showed no evidence of malignancy at surgical excision. Of 369 lesions diagnosed as benign at stereotactic core needle biopsy, 172 (46.6%) showed no change on follow-up mammography, 114 (30.9%) were lost to follow-up, and 83 (22%) underwent surgical excision. Of 24 lesions with atypical histology, 23 had surgical follow-up, six were malignant, nine were benign, and eight were confirmed as showing atypical histology. Stereotactic core needle biopsy of the 506 lesions was complicated by five (1.0%) cases of vasovagal attack and four (0.8%) cases of bleeding. The resulting sensitivity, specificity, and positive and negative predictive values were 98.3%, 93.0%, 86.0%, and 99.2% respectively. Biopsy with an add-on unit is safe, reliable, accurate, and cost-effective with results comparable to those reported for dedicated prone biopsy devices.


The role of video-assisted feedback sessions in resident teaching: A pre-post intervention.
This article was migrated. The article was marked as recommended. Purpose: Despite providing a large component of teaching to trainees, internal medicine residents receive little feedback on their teaching ability. Methods: This was a single-center, mixed methods study of 19 senior internal medicine residents in Canada. Classroom-based teaching sessions delivered by the participants were individually video recorded. The individual recording was then watched by the participant and by two feedback facilitators, who then met for face-to-face feedback. Participants completed a self-reflective exercise after this intervention. Audience members of the recorded session and a post-feedback teaching session completed an evaluation form. Scores from the evaluation forms from each phase were analyzed with the Wilcoxon Signed-Rank Test. Inductive coding was performed for qualitative data from the feedback sessions and reflective exercises. Results: 19 residents participated. There was no statistical difference in the evaluation form scores between the pre-intervention and post-intervention teaching sessions. Mean scores varied from 4.6 to 5.0 out of 5.0 on combined pre-and post-intervention evaluations. 89% of participants found viewing their recorded session useful. 94% of residents stated the intervention was worth continuing. Common themes of feedback and self-evaluation included "time-management," "organization," "communication," and "environment." Conclusion: Video-assisted feedback of teaching improved self-perception of a resident's teaching ability.


Banding studies on chromosomes in diffuse "histiocytic" lymphomas: correlation of 14q+ marker chromosome with cytology.
Chromosomes were studied in cells from tissues primarily involved by diffuse "histiocytic" lymphoma in nine patients. Two of the patients had stage II disease; their tumors were fibrotic and had no mitotic cells. One patient was in stage III, and the remaining six patients had stage IV disease. The modal chromosome number of abnormal cells from these last seven patients was hypodiploid in two, hyperdiploid in four, and near-triploid in one. Complete banding studies of six cases and partial analysis of the seventh indicate that (1) every patient had a distinct cell line with common markers, with a few cells showing minor variants; (2) although certain chromosomes (Nos. 1, 2, 3, 9, 12, and 14) were structurally affected more often than others, no markers with the same banding pattern were noted among them; and (3) the cytologic type of lymphoma could be correlated with the karyotype in all seven patients. When the Lukes and Collins classification was used, three patients whose tumors were composed predominantly of large noncleaved cells showed a 14q translocation leading to the formation of a 14q+ marker chromosome. This marker was not observed in four patients whose tumors had a majority of large cleaved cells. These preliminary results, if confirmed in a larger series of patients, will provide additional evidence that there are consistent chromosome changes associated with specific subtypes of lymphoproliferative disorders analogous to the Ph1 chromosome in chronic myelogenous leukemia.


[New evidence for mass reproduction of midges (Diptera, Simuliidae) in the Voronezh Region].
In the forest-steppe zones, the bloodsucking dipterans--midges (Diptera, Simuliidae)--tend to drastically increase in size, which poses medical and veterinary problems (the toxic saliva administered into the victim's body on blood sucking causes diseases in man, disability, and even animals' death). According to our data, the role of dominating bloodsuckers varies in different districts of the Voronezh Region, depending on their Iocal conditions (the types of water systems and landscapes).


Diagnostic Performance of the Measurement of Skinfold Thickness for Abdominal and Overall Obesity in the Peruvian Population: A 5-Year Cohort Analysis.
The escalating prevalence of overall and abdominal obesity, particularly affecting Latin America, underscores the urgent need for accessible and cost-effective predictive methods to address the growing disease burden. This study assessed skinfold thicknesses' predictive capacity for overall and abdominal obesity in Peruvian adults aged 30 or older over 5 years. Data from the PERU MIGRANT 5-year cohort study were analyzed, defining obesity using BMI and waist circumference. Receiver operating characteristic curves and area under the curve (AUC) with 95% confidence intervals (CI) were calculated. Adults aged ≥ 30 (n = 988) completed the study at baseline, with 47% male. A total of 682 participants were included for overall and abdominal obesity analysis. The 5-year prevalence values for overall and abdominal obesity were 26.7% and 26.6%, respectively. Subscapular skinfold (SS) best predicted overall obesity in men (AUC = 0.81, 95% CI: 0.75-0.88) and women (AUC = 0.77, 95% CI: 0.67-0.88). Regarding abdominal obesity, SS exhibited the highest AUC in men (AUC = 0.83, 95% CI: 0.77-0.89), while SS and the sum of trunk skinfolds showed the highest AUC in women. In secondary analysis excluding participants with type-2 diabetes mellitus (DM2) at baseline, SS significantly predicted DM2 development in men (AUC = 0.70, 95% CI: 0.58-0.83) and bicipital skinfold (BS) did in women (AUC = 0.73, 95% CI: 0.62-0.84). The findings highlight SS significance as an indicator of overall and abdominal obesity in both sexes among Peruvian adults. Additionally, SS, and BS offer robust predictive indicators for DM2.


[In vivo development of Trichinella spiralis in rats].
The causative agent is Trichinella spiralis which lives in the intestines in adult form or in skeletal muscles in larval form. After ingestion of raw or undercooked infected meat that contains larvae of trichinella, these larvae enter the blood and the lymphatic circulation. They usually settle in the skeletal muscles and develop further. This study was conducted in the Department of Parasitology of the Dokuz Eylul University, School of Medicine. The aim of this experimental study was to develop Trichinella spiralis in vivo experimentally using Wistar albino rats. It was also found that Trichinella spiralis can be experimentally developed in the Rattus norvegicus species of rodents, and it is possible to use the obtained Trichinella spiralis larva's for numerous purposes, in particular for supplying the antigens required for serological diagnosis of the disease. In addition, we investigated the range of the the skeletal muscles in which the causative agent, Trichinella spiralis, lives in larval form.


Use of Hounsfield units of S1 body to diagnose osteoporosis in patients with lumbar degenerative diseases.
OBJECTIVEThe aim of this study was to evaluate the use of Hounsfield unit (HU) values of the S1 body to diagnose osteoporosis in patients with lumbar degenerative diseases.METHODSThe records of 316 patients of ages ≥ 50 years and requiring surgery for lumbar degenerative diseases were reviewed. The bone mineral density (BMD) of the S1 body and L1 was measured in HU with preoperative lumbar CT. Circular regions of interest (ROIs) were placed on midaxial and midsagittal images of the S1 body. Dual-energy x-ray absorptiometry (DXA) and the criterion of L1 HU ≤ 110 HU were used to diagnose osteoporosis. The area under the receiver operating characteristic curve (AUC) was calculated to assess the use of HUs of the S1 body to diagnose osteoporosis.RESULTSThe interobserver and intraobserver reliability of measuring HU of the S1 body was excellent with intraclass correlation coefficients over 0.8 (p < 0.001). The correlation between HUs of the S1 body and average T-score of L1-4 was significant with Pearson correlation coefficients ≥ 0.60 (p < 0.001). The AUCs for using HUs of the S1 body to diagnose osteoporosis were 0.86 and 0.88 for axial HU and sagittal HU, respectively (p < 0.001). The HU thresholds with balanced sensitivity and specificity for diagnosing osteoporosis were 202 HU for axial HU (sensitivity: 76%; specificity: 76%) and 185 HU for sagittal HU (sensitivity: 80%; specificity: 80%).CONCLUSIONSBoth sagittal and axial HUs of the S1 body are useful tools for assessing BMD and diagnosing osteoporosis. Measuring HUs of the S1 body preoperatively from lumbar CT may help with surgical planning for patients with lumbar degenerative diseases.


Histidine Triad Nucleotide-Binding Protein 1 Improves Critical Limb Ischemia by Regulating Mitochondrial Homeostasis.
Critical limb ischemia (CLI) is a common complication of diabetes mellitus that typically occurs in the later stages of the disease. Vascularization is indeed an important physiological process involving the formation of new blood vessels from existing ones. It occurs in response to various normal and pathophysiological conditions, and one of its critical roles is to compensate for inadequate oxygen supply, which is often seen in situations like chronic limb ischemia (CLI). Histidine triad nucleotide-binding protein 1 (Hint1) is a member of the Hint family that has been shown to attenuate cardiac hypertrophy, but its role in vascularization still needs to be clarified. In this study, we investigated the role of Hint1 in CLI. We found that Hint1 is significantly reduced in the muscle tissue of STZ-induced diabetic mice and high-glucose (HG)-treated endothelial cells (ECs). Hint1 deletion impaired blood flow recovery and vascularization, whereas Hint1 overexpression promoted these processes. In addition, our in vitro study showed that Hint1 deficiency aggravated mitochondrial dysfunction in ECs, as evidenced by impaired mitochondrial respiration, decreased mitochondrial membrane potential, and increased reactive oxygen species. Our findings suggest that Hint1 deficiency impairs blood perfusion by damaging mitochondrial function and that Hint1 may represent a potential therapeutic target for treating CLI.


Lunar topography: first radar-interferometer measurements of the alphonsus-ptolemaeus-arzachel region.
Radar interferometry is a new technique for accurately measuring the topography of the lunar surface from the earth. Measurements have been made with this technique of an area including the craters Ptolemaeus, Alphonsus, and Arzachel and a portion of Mare Nubium. There is evidence for a late episode of volcanism that partially filled two of the craters through a crustal fault of Imbrian origin. Several other features of the topography, particularly those coinciding with local gravitational anomalies, can be correlated with flow events.


Altered functional connectivity in asymptomatic MAPT subjects: a comparison to bvFTD.
To determine whether functional connectivity is altered in subjects with mutations in the microtubule associated protein tau (MAPT) gene who were asymptomatic but were destined to develop dementia, and to compare these findings to those in subjects with behavioral variant frontotemporal dementia (bvFTD). In this case-control study, we identified 8 asymptomatic subjects with mutations in MAPT and 8 controls who screened negative for mutations in MAPT. Twenty-one subjects with a clinical diagnosis of bvFTD were also identified and matched to 21 controls. All subjects had resting-state fMRI. In-phase functional connectivity was assessed between a precuneus seed in the default mode network (DMN) and a fronto-insular cortex seed in the salience network, and the rest of the brain. Atlas-based parcellation was used to assess functional connectivity and gray matter volume across specific regions of interest. The asymptomatic MAPT subjects and subjects with bvFTD showed altered functional connectivity in the DMN, with reduced in-phase connectivity in lateral temporal lobes and medial prefrontal cortex, compared to controls. Increased in-phase connectivity was also observed in both groups in the medial parietal lobe. Only the bvFTD group showed altered functional connectivity in the salience network, with reduced connectivity in the fronto-insular cortex and anterior cingulate. Gray matter loss was observed across temporal, frontal, and parietal regions in bvFTD, but not in the asymptomatic MAPT subjects. Functional connectivity in the DMN is altered in MAPT subjects before the occurrence of both atrophy and clinical symptoms, suggesting that changes in functional connectivity are early features of the disease.


FOXO1-dependent DNA damage repair is regulated by JNK in lung cancer cells.
DNA damage or mutation in cells contributes to tumorigenesis. The transcription factor FOXO1 modulates the expression of genes involved in DNA damage repair, cell cycle arrest and apoptosis. The transcriptional activity of FOXO1 is fundamentally regulated by post-translational modification and subcellular localization. H1299 lung cancer cells were treated with the alkylating agent MNNG, and the cell viability and DNA damage were separately determined by MTT and comet assay. Using immunofluorescence and western blotting, we observed the subcellular localization of FOXO1 and measured the relevant protein expression levels, respectively. To examine cell cycle arrest and apoptosis, flow cytometry analysis was preformed. The interaction between FOXO1 and JNK was analyzed through immunoprecipitation. Our results showed that cell viability was reduced at 24 h after MNNG treatment, and appeared to recover to some degree at 48 h. The increased expression and nuclear export of FOXO1 emerged at 4 h after the treatment. Nuclear FOXO1 played a pivotal role in cell cycle arrest, apoptosis and DNA damage repair by upregulating p27(Kip1), Bim and GADD45 gene expression, respectively. AKT-dependent S256 phosphorylation of FOXO1 and the S473 phosphorylation of AKT were both enhanced following DNA damage. Moreover, our studies revealed that FOXO1 directly interacted with JNK, and the inhibition of the JNK activity led to decreased expression of FOXO1 target genes. These findings suggest for the first time that FOXO1 is a promising candidate substrate for JNK, and the FOXO1-dependent DNA damage repair may be regulated positively by the JNK pathway in H1299 lung cancer cells.


Timing and competence of neural crest formation.
Neural crest cells can be induced by an interaction between neural plate and ectoderm. To clarify the timing and nature of these inductive interactions, we have examined the time of competence of the neural plate to become neural crest as well as the time of neural fold specification. The neural plate is competent to respond to inductive interactions with the nonneural ectoderm for a limited period, rapidly losing its responsive ability after stage 10. In contrast, nonneural ectoderm from numerous stages retains the ability to induce neural crest cells from competent neural plate. When neural folds are explanted to test their ability to produce neural crest without further tissue interactions, we find that folds derived from all rostrocaudal levels of the open neural plate are already specified to express the neural crest marker Slug. However, additional signals may be required for maintenance of Slug expression, since the transcript is later down-regulated in vitro in the absence of tissue interactions. Taken together, these results suggest that there are multiple stages of neural crest induction. The earliest induction must have occurred by the end of gastrulation, since the newly formed neural fold population is already specified to form neural crest. However, isolated neural folds eventually down-regulate Slug, suggesting a second phase that maintains neural crest formation. Thus, induction of the neural crest may involve multiple and sustained tissue interactions.


Phonological decisions require both the left and right supramarginal gyri.
Recent functional imaging studies demonstrated that both the left and right supramarginal gyri (SMG) are activated when healthy right-handed subjects make phonological word decisions. However, lesion studies typically report difficulties with phonological processing after left rather than right hemisphere damage. Here, we used a unique dual-site transcranial magnetic stimulation (TMS) approach to test whether the SMG in the right hemisphere contributes to modality-independent (i.e., auditory and visual) phonological decisions. To test task-specificity, we compared the effect of real or sham TMS during phonological, semantic, and perceptual decisions. To test laterality and anatomical specificity, we compared the effect of TMS over the left, right, or bilateral SMG and angular gyri. The accuracy and reaction times of phonological decisions were selectively disrupted relative to semantic and perceptual decisions when real TMS was applied over the left, right, or bilateral SMG. These effects were not observed for TMS over the angular gyri. A follow-up experiment indicated that the threshold-intensity for inducing a disruptive effect on phonological decisions was identical for unilateral TMS over the right or left SMG. Taken together, these findings provide converging evidence that the right SMG contributes to accurate and efficient phonological decisions in the healthy brain, with no evidence that the left and right SMG can compensate for one another during TMS. Our findings motivate detailed studies of phonological processing in patients with acute or long-term damage of the right SMG.


Dietary manipulation and exercise in the heat: thermoregulatory and metabolic effects in rats.
To determine the effects of dietary manipulation on the metabolic, physical, and physiological responses to exercise in the heat, adult male rats (n 5 16/group) were food deprived for 72 h followed by ad lib consumption of a high protein (HIPROT) or high carbohydrate (HICARB) diet for 96 h. Each dietary regimen was followed immediately by exercise (9.14 m . min-1) in the heat (35.58C) to hyperthermic exhaustion (TCO approximately 43 8C). Animals consuming the HICARB or HIPROT diet had an increased mean TCO prior to the acute heat/exercise protocol when compared with a control (CONT) group with uninterrupted access to a normal rodent diet; the HICARB rats also manifested a decreased endurance when compared with the CONT group. Plasma levels of urea nitrogen, lactate, and potassium were increased following exercise in the heat in all groups, but greatly exacerbated increments in urea nitrogen occurred in the HIPROT group. Following exercise, significant increments occurred in circulating levels of glucose and insulin in the HIPROT and HICARB groups. Plasma triglycerides were decreased by the exercise/heat regimen but increased by both diets. Thus, these dietary manipulations elicited a variety of metabolic responses which did not markedly alter the physiological and physical effects of work in the heat.


Characterization of cancer-induced bone pain: an exploratory study.
Cancer-induced bone pain (CIBP) is the commonest cause of pain in patients with cancer. Its association with increased morbidity combined with limitations of currently available therapies makes it a clinical challenge. Clinical characterization of this complex pain syndrome is essential in underpinning clinical management and informing future research. The aim of this exploratory study was to characterise CIBP using self-rating scales. A cross-sectional survey of patients with CIBP was carried out in a regional oncology centre. Patients described their pain over the preceding 24 h using the McGill Pain Questionnaire, Brief Pain Inventory (BPI), and a breakthrough pain questionnaire. Multiple linear regression analyses were conducted. Fifty-five patients were recruited. Annoying, gnawing, aching, and nagging were the most commonly used words to describe CIBP. From the BPI, median average pain was 4/10 and worst pain was 7/10 on a 0-10 Numerical Rating Scale. The worst pain score correlated more strongly with BPI interference score (p=0.001). Forty-one patients had breakthrough pain. Patients with breakthrough pain had higher total BPI interference scores than those with no breakthrough pain; median (IQR); 35.0 (2.5-44.7) vs. 18.5 (5.5-26.7), p<0.01. Of the patients, 20/41 (48%) had breakthrough pain of rapid onset (less than 5 min) and short duration (less than 15 min). In CIBP, worst pain most accurately reflects the characteristics of pain flares and functional impairment. Breakthrough pain is often unpredictable, sudden onset and short duration. Further characterization studies of CIBP in the broader cancer population are needed.


Recent Developments in the Practical Application of Novel Carboxylic Acid Bioisosteres.
The carboxylic acid moiety is an important functional group which features in the pharmacophore of some 450 drugs. Unfortunately, some carboxylic acid-containing drugs have been withdrawn from market due to unforeseen toxicity issues. Other issues associated with the carboxylate moiety include reduced metabolic stability or limited passive diffusion across biological membranes. Medicinal chemists often turn to bioisosteres to circumvent such obstacles. The aim of this review is to provide a summary of the various applications of novel carboxylic acid bioisosteres which have appeared in the literature since 2013. We have summarised the most recent developments in carboxylic acid bioisosterism. In particular, we focus on the changes in bioactivity, selectivity or physicochemical properties brought about by these substitutions, as well as the advantages and disadvantages of each isostere. The topics discussed herein highlight the continued interest in carboxylate bioisosteres. The development of novel carboxylic acid substitutes which display improved pharmacological profiles is a testament to the innovation and creativity required to overcome the challenges faced in modern drug design.


Spreading-induced dewetting for monolayer colloidosomes with responsive permeability.
Herein, we present a spreading-induced dewetting approach of Pickering emulsion droplets for fabricating monolayer colloidosomes. The dewetting of the water-in-oil-in-water (W/O/W) double emulsion droplets is triggered by the quick spreading and wetting of the fluorinated oil phase on the water/air surface. By combining this colloidosome formation mechanism with thermo-responsive copolymer that adsorbs or desorbs at the surface of the colloidosome shell, we fabricated smart monolayer colloidosomes using a microfluidic-templated approach. These colloidosomes are highly monodisperse and possess a well-defined shell microstructure, tunable permeability, biocompatibility, mechanical stability, and high encapsulation efficiency. These attributes will pave the way for effective encapsulation, transport, and release of a range of active ingredients, especially the biologically active materials.


Structural and biological properties of thermosensitive chitosan-graphene hybrid hydrogels for sustained drug delivery applications.
Chitosan has the ability to make injectable thermosensitive hydrogels which has been highly investigated for drug delivery applications. The addition of nanoparticles is one way to increase the mechanical strength of thermosensitive chitosan hydrogel and subsequently and control the burst release of drug. Graphene nanoparticles have shown unique mechanical, optical and electrical properties which can be exploited for biomedical applications, especially in drug delivery. This study, have focused on the mechanical properties of a thermosensitive and injectable hybrid chitosan hydrogel incorporated with graphene nanoparticles. Scanning electron microscope (SEM), Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, and X-ray diffraction (XRD) have been used for morphological and chemical characterization of graphene infused chitosan hydrogels. The cell viability and cytotoxicity of graphene-contained hydrogels were analyzed using the alamarBlue® technique. In-vitro methotrexate (MTX) release was investigated from MTX-loaded hybrid hydrogels as well. As a last step, to evaluate their efficiency as a cancer treatment delivery system, an in vitro anti-tumor test was also carried out using MCF-7 breast cancer cell lines. Results confirmed that a thermosensitive chitosan-graphene hybrid hydrogel can be used as a potential breast cancer therapy system for controlled delivery of methotrexate. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2381-2390, 2017.


Survival of oral bacteria.
The global distribution of individual species of oral bacteria demonstrates their ability to survive among their human hosts. Such an ubiquitous existence is the result of efficient transmission of strains and their persistence in the oral environment. Genetic analysis has identified specific clones of pathogenic bacteria causing infection. Presumably, these express virulence-associated characteristics enhancing colonization and survival in their hosts. A similar situation may occur with the oral resident flora, where genetic variants may express specific phenotypic characteristics related to survival. Survival in the mouth is enhanced by dental plaque formation, where persistence is associated with the bacteria's capacity not only to adhere and grow, but also to withstand oxygen, wide fluctuations in pH and carbohydrate concentration, and a diverse array of microbial interactions. Streptococcus mutans has been discussed as a 'model' organism possessing the biochemical flexibility that permits it to persist and dominate the indigenous microflora under conditions of stress.


Infected femorodistal bypass: is graft removal mandatory?
Infected lower extremity bypass grafts have been associated with high rates of limb loss. Traditionally treatment has included graft excision. To compare aggressive local treatment, without graft removal, with more conventional graft excision, we reviewed 38 consecutive patients with 39 infected lower extremity bypasses treated during the last 10 years. The grafts used were prosthetic in 33 cases, vein in 4, and composite in 2. Median follow-up was 2.7 years. Twenty-eight infected grafts were treated with either complete (14) or partial (14) graft removal. Nine new grafts were placed. Recurrent infection developed in five cases, and two patients died of complications of graft infection. Ten of 20 limbs at risk were lost. Eleven patients with patent bypasses (4 vein, 2 composite, 5 prosthetic) were treated without graft excision. Treatment of five patients in this group included muscle transposition. Five patients were treated with incision and drainage of abscesses, and one had excision of a persistent sinus tract. One patient underwent major amputation 6.3 years after treatment of graft infection. Limb salvage was significantly higher (p = 0.012, log-rank test) than in patients treated with graft excision. One patient died, and no recurrent infections developed; these were not significant differences compared with those having graft excision. We conclude that aggressive local treatment of infected lower extremity bypass grafts, including drainage, debridement, and muscle transposition may treat infection in selected patients without the need for graft removal and with rates of limb salvage superior to those obtained with excisional therapy.


Correlation between quality and geographical origins of Leonuri Herba revealed by the qualitative fingerprint profiling and quantitative determination of chemical components.
Leonuri Herba (Yimucao) is a very common Chinese herbs for treating menstrual and maternal diseases for thousands of years in China. However, the herb collected in different origins was easily found in the markets which induce the unstable quality for clinic use. In this study, a comprehensive strategy of using multiple chromatographic analysis and chemometric analysis was firstly investigated for chemical discrimination of Leonuri Herba from different geographical origins. UHPLC-QTOF-MS/MS was applied to identify the peaks of Leonuri Herba and chemical fingerprints were established in 30 batches from different geographical origins. Meanwhile, dissimilarities of chemical compositions among different origins were further investigated by principal component analysis and cluster analysis. And a quantitative UHPLC-QTOF-MS/MS approach were established to investigate the potential marker for quality control of Leonuri Herba. A total of 49 chromatographic peaks of Leonuri Herba were identified by UHPLC-QTOF-MS/MS. Leonuri Herba were classified into four categories, and eight major compounds detected could be used as chemical markers for discrimination. Also, the eight components, including leonurine, 4',5-dihydroxy-7-methoxyflavone, rutin, hyperoside, apigenin, quercetin, kaempferol and salicylic acid, were simultaneously quantified using the extracting ion mode of UHPLC-QTOF-MS/MS. The current strategy not only clearly expounded the correlation between quality and geographical origins of Leonuri Herba, but also provided a fast, accurate and comprehensive qualitative and quantitative method for assessing the quality of Leonuri Herba.


Host-range restriction of vaccinia virus E3L deletion mutant can be overcome in vitro, but not in vivo, by expression of the influenza virus NS1 protein.
During the last decades, research focused on vaccinia virus (VACV) pathogenesis has been intensified prompted by its potential beneficial application as a vector for vaccine development and anti-cancer therapies, but also due to the fear of its potential use as a bio-terrorism threat. Recombinant viruses lacking a type I interferon (IFN) antagonist are attenuated and hence good vaccine candidates. However, vaccine virus growth requires production in IFN-deficient systems, and thus viral IFN antagonists that are active in vitro, yet not in vivo, are of great value. The VACV E3 and influenza virus NS1 proteins are distinct double-stranded RNA-binding proteins that play an important role in pathogenesis by inhibiting the mammalian IFN-regulated innate antiviral response. Based on the functional similarities between E3 and NS1, we investigated the ability of NS1 to replace the biological functions of E3 of VACV in both in vitro and in vivo systems. For this, we generated a VACV recombinant virus lacking the E3L gene, yet expressing NS1 (VVΔE3L/NS1). Our study revealed that NS1 can functionally replace E3 in cultured cells, rescuing the protein synthesis blockade, and preventing apoptosis and RNA breakdown. In contrast, in vivo the VVΔE3L/NS1 virus was highly attenuated after intranasal inoculation, as it was unable to spread to the lungs and other organs. These results indicate that there are commonalities but also functional differences in the roles of NS1 and E3 as inhibitors of the innate antiviral response, which could potentially be utilized for vaccine production purposes in the future.


IBS-like Symptoms in Patients with Ulcerative Colitis in Deep Remission Are Associated with Increased Levels of Serum Cytokines and Poor Psychological Well-being.
Gastrointestinal symptoms (GI) compatible with irritable bowel syndrome (IBS) are common in patients with ulcerative colitis (UC) in remission. The causes of these symptoms remain to be clarified. Our aim was to investigate prevalence and factors associated with IBS-like symptoms in patients with UC in deep remission. We included 298 patients with UC and used Mayo score, sigmoidoscopy, and fecal calprotectin to define deep remission versus active disease. Presence of IBS-like symptoms according to the Rome III criteria, severity of GI, extraintestinal and psychological symptoms, stress levels, and quality of life were measured with validated questionnaires. Serum cytokines and high-sensitive C-reactive peptide were determined. The criteria for deep remission was fulfilled by 132 patients (44%) and 24 of these fulfilled the Rome III criteria for IBS (18%). Patients with UC in deep remission with IBS-like symptoms had comparable levels of GI symptoms, non-GI somatic symptoms, and quality of life as patients with active UC. The patients with UC in deep remission with IBS-like symptoms had similar levels of fecal calprotectin as patients in deep remission without IBS-like symptoms (18 versus 31 μg/g, P = 0.11), but higher levels of serum cytokines (interleukin [IL]-1β, IL-6, IL-13, IL-10 and IL-8, P < 0.05) and higher levels of anxiety (P < 0.001), depression (P = 0.02) and perceived stress (P = 0.03). IBS-like symptoms in patients with UC in deep remission are common, but not as prevalent as previously reported. Poor psychological well-being and increased serum cytokine levels, but not colonic low-grade inflammation, were associated with IBS-like symptoms.


Challenging conventional wisdom: the etiologic role of dopamine oxidative stress in Parkinson's disease.
Oxidative stress is well documented in Parkinson's disease (PD) and has been attributed to dopamine oxidative metabolism. However, evidence of oxidative stress is found in a variety of neurodegenerative disorders, suggesting that more general factors are responsible or that cytodestructive processes secondarily generate oxyradical products. Increasing evidence points away from dopamine metabolism as an important contributor to PD neurodegeneration. Predictions from the dopamine oxidative stress hypothesis of PD reveal multiple inconsistencies. Although the clinical and therapeutic importance of the nigrostriatal dopaminergic system is undeniable, PD neuropathology is much more widespread.


Effectively changing the management methodology for tornado evacuation procedures.
This article discusses how action research was used to identify, diagnose, and involve focus group members in resolving problems associated with the safe evacuation of patients and employees during imminent tornado weather. Collaboration and joint action planning among group members, says the author, resulted in new evacuation procedures that increased dependable communications among staff, ensured the continuation of good patient care, and assured the expedient and safe evacuation of patients and employees.


Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics.
Alcohol dehydrogenase-2 (ADH2) and aldehyde dehydrogenase-2 (ALDH2) gene polymorphisms play roles in ethanol metabolism, drinking behavior and esophageal carcinogenesis in Japanese; however, the combined influence of ADH2 and ALDH2 genotypes on other aerodigestive tract cancers have not been investigated. ADH2/ALDH2 genotyping was performed on lymphocyte DNA samples from Japanese alcoholic men (526 cancer-free; 159 with solitary or multiple aerodigestive tract cancers, including 33 oropharyngolaryngeal, 112 esophageal, 38 stomach and 22 multiple primary cancers in two or three organs). After adjustment for age, drinking and smoking habits, and ADH2/ALDH2 genotypes, the presence of either ADH2*1/2*1 or ALDH2*1/2*2 significantly increased the risk for oropharyngolaryngeal cancer [odds ratios (ORs), 6.68 with ADH2*1/2*1 and 18.52 with ALDH2*1/2*2] and esophageal cancer (ORs, 2.64 and 13.50, respectively). For patients with both ADH2*1/2*1 and ALDH2*1/2*2, the risks for oropharyngolaryngeal and esophageal cancers were enhanced in a multiplicative fashion (OR = 121.77 and 40.40, respectively). A positive association with ALDH2*1/2*2 alone was observed for stomach cancer patients who also had oropharyngolaryngeal and/or esophageal cancer (OR = 110.58), but it was not observed for those with stomach cancer alone. Furthermore, in the presence of ALDH2*1/2*2, the risks for multiple intra-esophageal cancers (OR = 3.43) and for esophageal cancer with oropharyngolaryngeal and/or stomach cancer (OR = 3.95) were higher than the risks for solitary intra-esophageal cancer and for esophageal cancer alone, but these tendencies were not observed for ADH2*1/2*1 genotype. Alcoholics' population attributable risks due to ADH2/ALDH2 polymorphisms were estimated to be 82.0% for oropharyngolaryngeal cancer and 63.9% for esophageal cancer.


2-Phenethylimidazole derivatives. Synthesis and antimycotic properties.
Compounds of type (X = O, NH; Ar and Ar' = phenyl of substituted phenyl; ten examples) were prepared and assayed against miconazole (II,X = O; Ar = Ar' =2,4-Cl2C6H3) as potential antimycotic agents. Optimal activity was noted for I(X = O; Ar = Ar' = 2,4-Cl2C6H3), the direct analog of miconazole. It is about one-tenth as active.


Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1 Disease.
To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Multimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia. Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression. RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials. This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.


Microbacterium suaedae sp. nov., isolated from Suaeda aralocaspica.
Two bacterial strains, YZYP 306T and YZGP 509, were isolated from the halophyte Suaeda aralocaspica collected from the southern edge of the Gurbantunggut desert, north-west China. Cells were Gram-stain-positive, aerobic, non-motile, short rods. Strain YZYP 306T grew at 4-40 °C, while strain YZGP 509 grew at 4-42 °C, with optimum growth at 28 °C, and they both grew at pH 6.0-12.0 and 0-15 % (w/v) NaCl. Phylogenetic analyses of the 16S rRNA gene sequences placed the two strains within the genus Microbacterium with the highest similarities to Microbacterium indicum BBH6T (97.8 %) and Microbacterium sorbitolivorans SZDIS-1-1T (97.2 %). The average nucleotide identity value between YZYP 306T and M. indicum BBH6T was 78.3 %. The genomic DNA G+C contents of strains YZYP 306T and YZGP 509 were 68.49 and 68.53 mol%, respectively. The characteristic cell-wall amino acid was ornithine. Whole-cell sugars were galactose, mannose and ribose. The acyl type of the peptidoglycan was glycolyl. The major cellular fatty acids were anteiso-C15 : 0, anteiso-C17 : 0 and iso-C16 : 0. The major menaquinones were MK-10 and MK-11. The polar lipids were diphosphatidylglycerol, phosphatidylglycerol, an unidentified phospholipid and an unidentified glycolipid. These results are consistent with the classification of the two strains into the genus Microbacterium. On the basis of the evidence presented in this study, strains YZYP 306T and YZGP 509 are representatives of a novel species in the genus Microbacterium, for which the name Microbacterium suaedae sp. nov. is proposed. The type strain is YZYP 306T (=CGMCC 1.16261T=KCTC 49101T).


AuTom: A novel automatic platform for electron tomography reconstruction.
We have developed a software package towards automatic electron tomography (ET): Automatic Tomography (AuTom). The presented package has the following characteristics: accurate alignment modules for marker-free datasets containing substantial biological structures; fully automatic alignment modules for datasets with fiducial markers; wide coverage of reconstruction methods including a new iterative method based on the compressed-sensing theory that suppresses the "missing wedge" effect; and multi-platform acceleration solutions that support faster iterative algebraic reconstruction. AuTom aims to achieve fully automatic alignment and reconstruction for electron tomography and has already been successful for a variety of datasets. AuTom also offers user-friendly interface and auxiliary designs for file management and workflow management, in which fiducial marker-based datasets and marker-free datasets are addressed with totally different subprocesses. With all of these features, AuTom can serve as a convenient and effective tool for processing in electron tomography.


Agricultural chemistry and bioenergy.
Renewed interest in converting biomass to biofuels such as ethanol, other forms of bioenergy, and bioenergy byproducts or coproducts of commercial value opens opportunities for chemists, including agricultural chemists and related disciplines. Applications include feedstock characterization and quantification of structural changes resulting from genetic modification and of the intermediates formed during enzymatic and chemical processing; development of improved processes for utilizing chemical coproducts such as lactic acid and glycerol; development of alternative biofuels such as methanol, butanol, and hydrogen; and ways to reduce greenhouse gas emission and/or use carbon dioxide beneficially. Chemists will also be heavily involved in detailing the phytochemical composition of alternative energy crops and genetically improved crops. A resurgence of demand for agricultural chemistry and related disciplines argues for increasing output through targeted programs and on-the-job training.


Phase IIa study of the immunogenicity and safety of the novel Staphylococcus aureus vaccine V710 in adults with end-stage renal disease receiving hemodialysis.
Bacteremia is the second leading cause of death in patients with end-stage renal disease who are on hemodialysis. A vaccine eliciting long-term immune responses against Staphylococcus aureus in patients on chronic hemodialysis may reduce the incidence of bacteremia and its complications in these patients. V710 is a vaccine containing iron surface determinant B (IsdB), a highly conserved S. aureus surface protein, which has been shown to be immunogenic in healthy subjects. In this blinded phase II immunogenicity study, 206 chronic hemodialysis patients between the ages of 18 and 80 years old were randomized to receive 60 μg V710 (with or without adjuvant), 90 μg V710 (with adjuvant), or a placebo in various combinations on days 1, 28, and 180. All 201 vaccinated patients were to be followed through day 360. The primary hypothesis was that at least 1 of the 3 groups receiving 2 V710 doses on days 1 and 28 would have a ≥2.5 geometric mean fold rise (GMFR) in anti-IsdB IgG titers over the baseline 28 days after the second vaccination (day 56). At day 56, all three groups receiving 2 doses of V710 achieved a ≥2.5 GMFR in anti-IsdB antibodies compared to the baseline (P values of <0.001 for all 3 groups), satisfying the primary immunogenicity hypothesis. None of the 33 reported serious adverse experiences were considered vaccine related by the investigators. V710 induced sustained antibody responses for at least 1 year postvaccination in patients on chronic hemodialysis.


Establishing a baseline phase behavior in magnetic resonance imaging to determine normal vs. abnormal iron content in the brain.
To establish a baseline of phase differences between tissues in a number of regions of the human brain as a means of detecting iron abnormalities using magnetic resonance imaging (MRI). A fully flow-compensated, three-dimensional (3D), high-resolution, gradient-echo (GRE) susceptibility-weighted imaging (SWI) sequence was used to collect magnitude and phase data at 1.5 T. The phase images were high-pass-filtered and processed region by region with hand-drawn areas. The regions evaluated included the motor cortex (MC), putamen (PUT), globus pallidus (GP), caudate nucleus (CN), substantia nigra (SN), and red nucleus (RN). A total of 75 subjects, ranging in age from 55 to 89 years, were analyzed. The phase was found to have a Gaussian-like distribution with a standard deviation (SD) of 0.046 radians on a pixel-by-pixel basis. Most regions of interest (ROIs) contained at least 100 pixels, giving a standard error of the mean (SEM) of 0.0046 radians or less. In the MC, phase differences were found to be roughly 0.273 radians between CSF and gray matter (GM), and 0.083 radians between CSF and white matter (WM). The difference between CSF and the GP was 0.201 radians, and between CSF and the CN (head) it was 0.213 radians. For CSF and the PUT (the lower outer part) the difference was 0.449 radians, and between CSF and the RN (third slice vascularized region) it was 0.353 radians. Finally, the phase difference between CSF and SN was 0.345 radians. The Gaussian-like distributions in phase make it possible to predict deviations from normal phase behavior for tissues in the brain. Using phase as an iron marker may be useful for studying absorption of iron in diseases such as Parkinson's, Huntington's, neurodegeneration with brain iron accumulation (NBIA), Alzheimer's, and multiple sclerosis (MS), and other iron-related diseases. The phases quoted here will serve as a baseline for future studies that look for changes in iron content.


Adenovirus-mediated overexpression of p14(ARF) induces p53 and Bax-independent apoptosis.
The human INK4a gene locus encodes two structurally unrelated tumor suppressor proteins, p16(INK4a) and p14(ARF), which are frequently inactivated in human cancer. Whereas p16(INK4a) acts through engagement of the Rb-cdk4/6-cyclin D pathway, both the pro-apoptotic and cell cycle-regulatory functions of p14(ARF) were shown to be primarily dependent on the presence of functional p53. Recent reports have also implicated p14(ARF) in p53-independent mechanisms of cell cycle regulation and apoptosis induction, respectively. To further explore the pro-apoptotic function of p14(ARF) in relation to functional cellular p53, we constructed a replication-deficient adenoviral vector for overexpression of p14(ARF) (Ad-p14(ARF)). As expected, Ad-p14(ARF) efficiently induced apoptosis in p53/Rb wild-type U-2OS osteosarcoma cells at low multiplicities of infection. Interestingly, Ad-p14(ARF) also induced apoptosis in both p53-deleted SAOS-2 osteosarcoma cells and HCT116 colon cancer cells with a bi-allelic knock-out of p53 (HCT116-p53(-/-)). Similarly, adenovirus-mediated overexpression of p14(ARF) induced apoptosis in p53/Bax-mutated DU145 prostate cancer cells as well as in HCT116 cells devoid of functional Bax (HCT116-Bax(-/-)). Restoration of Bax expression by retroviral gene transfer in DU145 cells did not further enhance p14(ARF)-triggered cell death. Infection with Ad-p14(ARF) induced activation of mitochondrial permeability shift transition, caspase activation and apoptotic DNA fragmentation irrespective of the presence or absence of either Bax or functional cellular p53. Nevertheless, overexpression of the anti-apoptotic Bcl-2 homolog Bcl-x(L) markedly inhibited p14(ARF)-induced apoptosis. This may indicate that p14(ARF) triggers a so far unknown activator of mitochondrial apoptosis which can be inhibited by Bcl-2 but which acts either independently or downstream of Bax. Taken together, this report demonstrates the participation of signaling pathways apart from the p53/Mdm-2 rheostat and Bax in p14(ARF)-mediated apoptosis.


Synthesis of aberrant decay-accelerating factor proteins by affected paroxysmal nocturnal hemoglobinuria leukocytes.
Paroxysmal nocturnal hemoglobinuria (PNH) leukocytes fail to express decay-accelerating factor (DAF) but contain DAF mRNA transcripts resembling those in normal cells. To further investigate the nature of the DAF defect in affected cells, patients' polymorphonuclear and mononuclear leukocytes (PMN and MNC) were biosynthetically labeled and newly synthesized DAF proteins examined. Analyses of greater than 98% surface DAF-negative PMN and MNC from a patient with PNH III erythrocytes showed precursor DAF protein approximately 3 kD smaller in each cell type than in normal cells. The proportion of precursor to mature (O-glycosylated) DAF protein was increased and soluble DAF protein was detected in the medium. Studies of 70-80% surface DAF-negative PMN and MNC from four patients with type II erythrocytes showed mixtures of the 3 kD smaller and normal DAF precursors. Partitioning with Triton X-114 detergent and biosynthetic labeling with the anchor precursor [3H]ethanolamine indicated that the abnormal peptides lacked glycosyl-inositolphospholipid membrane-anchoring structures. Thus, in PNH cells nascent DAF polypeptides are synthesized. Some of the abnormal pro-DAF molecules are processed in the Golgi and some are released extracellularly.


[Phosphorescent analysis of lipid peroxidation products in liposomes].
It was found that lipid peroxidation products incorporated into liposomes prepared from oxidized preparations of bovine heart phosphatidylcholine and the total lipid fraction of human erythrocyte membranes are able to phosphoresce at room temperature was studied. The temperature dependences of kinetic and spectral parameters of phosphorescence were measured. It is shown that mechanism of phosphorescence quenching of lipid chromophores has a dynamic nature. It is proposed to use endogenic molecules of the lipid peroxidation products capable of phosphorescence as intrinsic phosphorescence probes for studying the slow molecular dynamics of lipids in artificial and biological membranes in a millisecond range.


A multi-suckling system combined with an enriched housing environment during the growing period promotes resilience to various challenges in pigs.
Little is known about the impact of social and environmental enrichment on improving livestock resilience, i.e. the ability to quickly recover from perturbations. We evaluated the effect of an alternative housing system (AHS) on resilience of pigs, as compared to conventional housing (CONV). The AHS consisted of multi-litter housing during lactation, delayed weaning, extra space allowance and environmental enrichment at all times. We assessed recovery to a 2 h-transport challenge, an LPS injection, 2 h-heat stress and a biopsy wound in 96 pigs. Additionally, indicators of long-term "wear and tear" on the body were determined. AHS pigs had better physiological recoveries with quicker returns to baseline in the transport and LPS challenges, showed lower cortisol accumulation in hairs and lower variance in weight gain over the experimental period compared to conventionally-housed (CONV) pigs. They also had higher levels of natural antibodies binding KLH than CONV pigs. Their response to heat stress revealed a different strategy compared to CONV pigs. Taken together, AHS pigs appear to be more resilient and experience less chronic stress. Enhancing welfare by provision of social and environmental enrichment that better meets the behavioural needs of pigs seems to be a promising approach to improve their resilience.


Keratoconjunctivitis associated with sialodacryoadenitis in rats.
A high incidence of keratoconjunctivitis was observed in a closed colony of inbred Lewis/Wistar rats. Clinical signs including blinking, ocular discharge, circumcorneal flush, corneal opacity, ulceration, pannus, hypopyon, and hyphema were observed at about three weeks of age. Acute disease subsided by six weeks of age, but some lesions progressed to low-grade chronic keratitis. Six per cent of affected rats developed megaloglobus, which usually appeared by three weeks of age. Lesions included focal or diffuse interstitial keratitis, corneal ulceration, anterior synechia, and inflammatory exudate in the anterior chamber. A high incidence of lenticular and retinal degeneration was associated with megaloglobus. Most affected rats also had harderian dacryoadenitis. Sialodacryoadenitis virus (SDA) was recovered from nasal washes, but not from affected eyes. Serological evidence indicated that SDA virus infection was widespread in the colony.


Verification of serum reference intervals for free light chains in a local South African population.
Monoclonal serum free light chain measurements are used to follow up and manage patients with monoclonal gammopathies, and abnormal serum free light chain ratios are associated with risk of progression in certain diseases. We aimed to validate the reference intervals in our population. Reference intervals for κ and λ free light chains were established on 120 healthy adults. Creatinine levels were measured to exclude renal dysfunction and serum protein electrophoresis was performed. All creatinine values were within normal limits. After exclusion of subjects with abnormal serum protein electrophoreses, 113 subjects were available for analysis. The 95% reference interval was 6.3-20.6 mg/L for κ free light chains, 8.7-25.9 mg/L for λ free light chains and 0.46-1.23 for free light chain ratio. Most of the values fell within the manufacturer's recommended limits and therefore could be used for our population.


Nucleolar protein B23 translocation after doxorubicin treatment in murine tumor cells.
Rats bearing Novikoff hepatoma ascites cells were given i.p. injections of actinomycin D, doxorubicin, or daunorubicin. Four hours after injection, tumor cells were removed from the ascites fluid and analyzed for protein B23 translocation using an immunofluorescence technique. Bright nucleolar fluorescence was observed in untreated cells. Treatment with actinomycin D (1.25 mg/kg), doxorubicin (25 mg/kg), or daunorubicin (12.5 mg/kg) produced a uniform nucleoplasmic fluorescence. This change in immunofluorescence distribution indicated that protein B23 translocated from the nucleolus to the nucleoplasm after drug treatment. These results are an extension of previous studies with HeLa cells (Yung et al., Cancer Res. 46: 922-925, 1986). Doxorubicin-resistant and -sensitive mouse leukemia cells (P388) were cultured in medium containing various doses of doxorubicin for 4 h, and the responsive levels of the cells to doxorubicin were compared. At 50 micrograms/ml doxorubicin, 86% of the doxorubicin-sensitive cells showed uniform nucleoplasmic fluorescence, and less than 2% of the cells retained nucleolar fluorescence. At this same dose, only 9% of the resistant cells showed nucleoplasmic fluorescence, and 75% of the cells retained nucleolar fluorescence. At 100 micrograms/ml, about 26% of the resistant cells showed translocation, in contrast to 100% of the sensitive cells that showed B23 translocation. About 57% of the resistant cells showed an intermediate effect, and about 17% of the resistant cells maintained bright nucleolar fluorescence at this dose. The resistant cells also showed less responsiveness to actinomycin D. These results suggest that identification of "B23 translocation" may be used to detect drug-resistant cells and to study the efficacy of certain antitumor agents.


alpha subunit partners to beta1 and beta2 integrins during IL-4-induced foreign body giant cell formation.
As beta1 and beta2 integrins were previously found to mediate adhesion during IL-4-induced foreign body giant cell (FBGC) formation, we pursued the identities of the alpha integrin partners of these adhesion receptors using our in vitro system of human monocyte-derived macrophage fusion. Immunoprecipitation with beta1 and immunoblotting reveal the presence of alpha5 and alphaV, as well as alpha2 and alpha3. alphaM and alphaX immunoprecipitate with beta2 but not with beta1. Immunocytochemistry coupled with confocal microscopy indicates that alpha5 and alphaX are poorly expressed on day 0. However, following the induction of fusion by IL-4 on day 3, they are each readily detectable in fusing macrophages/FBGC on day 7. In contrast, alphaM and alphaV are present throughout the culture period, with very strong alphaM expression on day 7. We also demonstrate expression and colocalization of alpha3, alpha5, or alphaV with beta1 on fusing macrophages/FBGC at this time point as well as strong colocalization of alphaM and alphaX with beta2 in FBGC and at fusion interfaces. Therefore, IL-4-induced FBGC are characterized by the expression of alphaMbeta2, alphaXbeta2, alpha5beta1, alphaVbeta1, alpha2beta1, and alpha3beta1, which indicates potential interactions with fragments of complement C3, fibrin(ogen), fibronectin, Factor X, and vitronectin, and possibly with certain collagens, laminin, and thrombospondin at sites of biomaterial implantation.


Justification of Biowaiver and Dissolution Rate Specifications for Piroxicam Immediate Release Products Based on Physiologically Based Pharmacokinetic Modeling: An In-Depth Analysis.
A quantitative prediction of human pharmacokinetic (PK) profiles has become an increasing demand for the reduction of the clinical failure of drug formulations. The existing in vitro and in vivo correlation (IVIVC) methodology could achieve this goal, but the development of IVIVC for immediate release (IR) products is challenging. Herein, we report that for certain weakly acidic biopharmaceutical classification system (BCS) class II molecules (piroxicam, PIRO), physiologically based PK (PBPK) modeling could be used as a tool to quantitatively predict PK in beagle dogs and to conduct an interspecies extrapolation to humans. First, robust PBPK models were constructed in beagle dogs under both fasted and fed states. Then, a Z-factor model was integrated to assess the effect of in vitro dissolution rates on the in vivo PK performance, and the results illustrated that PIRO IR products had a much wider dissolution space than was anticipated by bioequivalence. In addition, the parameter sensitivity analysis (PSA) assay showed that good oral absorption was achieved only when the particle size was below 150 μm. Finally, the combined PBPK models were extrapolated to humans to specify a quality control strategy; this extrapolation constituted an extension of a biowaiver for PIRO IR formulations. The results showed that the developed method can be utilized to quantitatively predict human PK, which would be meaningful for future scale-up or postapproval changes.


Foraging conditions for breeding penguins improve with distance from colony and progression of the breeding season at the South Orkney Islands.
According to central place foraging theory, animals will only increase the distance of their foraging trips if more distant prey patches offer better foraging opportunities. Thus, theory predicts that breeding seabirds in large colonies could create a zone of food depletion around the colony, known as "Ashmole's halo". However, seabirds' decisions to forage at a particular distance are likely also complicated by their breeding stage. After chicks hatch, parents must return frequently to feed their offspring, so may be less likely to visit distant foraging patches, even if their quality is higher. However, the interaction between prey availability, intra-specific competition, and breeding stage on the foraging decisions of seabirds is not well understood. The aim of this study was to address this question in chinstrap penguins Pygoscelis antarcticus breeding at a large colony. In particular, we aimed to investigate how breeding stage affects foraging strategy; whether birds foraging far from the colony visit higher quality patches than available locally; and whether there is evidence for intraspecific competition, indicated by prey depletions near the colony increasing over time, and longer foraging trips. We used GPS and temperature-depth recorders to track the foraging movements of 221 chinstrap penguins from 4 sites at the South Orkney Islands during incubation and brood. We identified foraging dives and calculated the index of patch quality based on time allocation during the dive to assess the quality of the foraging patch. We found that chinstrap penguin foraging distance varied between stages, and that trips became shorter as incubation progressed. Although patch quality was lower near the colony than at more distant foraging patches, patch quality near the colony improved over the breeding season. These results suggest chinstrap penguin foraging strategies are influenced by both breeding stage and prey distribution, and the low patch quality near the colony may be due to a combination of depletion by intraspecific competition but compensated by natural variation in prey. Reduced trip durations towards the end of the incubation period may be due to an increase in food availability, as seabirds time their reproduction so that the period of maximum energy demand in late chick-rearing coincides with maximum resource availability in the environment. This may also explain why patch quality around the colony improved over the breeding season. Overall, our study sheds light on drivers of foraging decisions in colonial seabirds, an important question in foraging ecology.


Role of moving average analysis for development of multi-target (Q)SAR models.
In modern drug discovery era, multi target- quantitative structure activity relationship [mt- (Q)SAR] approaches have emerged as novel and powerful alternatives in the field of in-silico drug design so as to facilitate the discovery of new chemical entities with multiple biological activities. Amongst various machine learning approaches, moving average analysis (MAA) has frequently exhibited high accuracy of prediction of diverse biological activities against different biological targets and experimental conditions. Role of MAA in developing (Q)SAR models for prediction of single/dual or multi target activity has been briefly reviewed in the present article. Subsequently, MAA was successfully utilized for developing mt-(Q)SAR models for simultaneous prediction of anti-Plasmodium falciparum and anti-Trypanosoma brucei rhodesiense activities of benzyl phenyl ether derivatives. The statistical significance of models was assessed through intercorrelation analysis, sensitivity, specificity and Matthew's correlation coefficient. Proposed MAA based models were also validated using test set. High predictability of the order of 80% to 95% amalgamated with safety (indicated by high value of selectivity index) of proposed mt-(Q)SAR models justifies use of MAA in developing models in order to obtain more realistic and accurate results for prediction of anti-protozal activity against multiple targets. Active ranges of the proposed models can play a significant role in the development of novel, potent, versatile and safe anti-protozoal drugs with improved profile in terms of both anti-Plasmodium falciparum and anti-Trypanosoma brucei rhodesiense activities.


Status of antimicrobial stewardship programmes in Nigerian tertiary healthcare facilities: Findings and implications.
The problem of antimicrobial resistance (AMR) is increasing worldwide, with health-related and economic consequences. This is a concern in Africa, including Nigeria, the most populous country in Africa, with its high rates of infectious diseases. Approaches to reducing AMR include instigating antimicrobial stewardship programmes (ASPs) in hospitals. Currently, no information is available regarding the extent of ASPs in Nigerian hospitals. Consequently, the objective was to address this starting in tertiary hospitals. This was a cross-sectional, questionnaire-based study among tertiary healthcare facilities. Tertiary hospitals were chosen initially since if there are concerns in these training hospitals, such concerns will likely to be exacerbated in other hospitals. Completed questionnaires were received from 17 of 25 tertiary healthcare facilities across five of the six geopolitical regions of Nigeria. Ten (59%), four (24%), two (12%) and one (6%) respondents were in internal medicine, infectious diseases, medical microbiology and clinical pharmacology, respectively. Only six healthcare facilities (35%) had a formal organisational structure and a team responsible for ASP. Facility-specific treatment recommendations, based on local AMR patterns, were available in only four facilities (24%). Policies on approval for prescribing specified antimicrobials and formal procedures for reviewing their appropriateness after 48h were present in only two facilities (12%). A cumulative antimicrobial susceptibility report for the previous year was available in only two facilities (12%), and only one facility routinely monitored antimicrobial use. Significant inadequacies in the availability of ASPs were observed. This needs to be urgently addressed to reduce AMR rates in Nigeria.


Will molecular biology contribute to refine prognosis and to select treatment? The Molecular Biology Committee. Italian Cooperative Study Group on Chronic Myeloid Leukemia.
The possible prognostic value of the position of the breakpoint within the M-BCR in patients with Ph1+ CML is still being debated. We analyzed the DNA rearrangements and the transcript types of 244 patients and tried to correlate the data obtained with prognostic features, defined according to Sokal's risk index, and with chronic phase and/or survival duration. The exact location of the breakpoint, either 5' or 3' to the Hind III restriction site within the M-BCR was identified. Moreover, the exact M-BCR subregion was also identified. As a whole, 150 pts were rearranged in the 5' part and 94 in the 3' part of the M-BCR. No correlation was observed between the site of rearrangement on the one hand and the Sokal's prognostic index and survival, on the other. Transcript analysis was performed in 130 patients; 59 carried an a2b2 and 69 an a2b3 pattern. Two patients carried both transcripts. Of the patients rearranged in the 5' area, according to Southern blotting, 29.2% showed an a2b3 transcript. Therefore, RT-PCR analysis allowed a better definition of the breakpoint. However, also the type of transcript did not show any correlation either with risk categories or survival. No difference in response to therapy, either chemotherapy or alpha interferon, was observed between 5' and 3' rearranged patients.


Physical examination of arteriovenous fistula: The influence of professional experience in the detection of complications.
Vascular access is one of the leading causes of mobilization of financial resources in health systems for people with chronic kidney disease on hemodialysis. Physical examination of the arteriovenous fistula (AVF) has demonstrated its effectiveness in identifying complications. We decided to evaluate the influence of nurses' professional experience in the detection of complications of the AVF (venous stenosis and steal syndrome). The study took place in eight hemodialysis centers between May and September of 2011 in the north of Portugal. Sample was constituted by registered nurses. The nurses involved in the experiment were divided in two groups: those who had more than 5 years of experience and those who had less than 5 years of experience. Ninety-two nurses participated in the study: 34 nurses had less than 5 years of professional experience and 58 had more than 5 years of professional experience. In the practices considered by nurses in the detection of venous stenosis, there were no differences observed between the groups (P > 0.05). In steal syndrome, there were no differences observed between the groups in the practices of the nurses in the detection of this complication of the AVF (P > 0.05). We concluded that professional experience does not influence the detection of venous stenosis and steal syndrome.


Zanamivir aqueous solution in severe influenza: A global Compassionate Use Program, 2009-2019.
Zanamivir is a neuraminidase inhibitor effective against influenza A and B viruses. In 2009, GlaxoSmithKline (GSK) began clinical development of intravenous (IV) zanamivir and initiated a global Compassionate Use Program (CUP) in response to the evolving H1N1 global pandemic. The goal of the CUP was to provide zanamivir to critically ill patients with limited treatment options. Zanamivir was administered to patients with suspected or confirmed influenza infection who were not suitable for other approved antiviral treatments. Reporting of serious adverse events (SAEs) was mandatory and recorded in the GSK safety database. A master summary tracking sheet captured requests and patient characteristics. A case report form was available for detailing medical conditions, dosing, treatment duration, and clinical outcomes. In total, 4,033 requests were made for zanamivir treatment of hospitalized patients from 38 countries between 2009 and 2019; ≥95% patients received zanamivir via the IV route. Europe had the highest number of requests (n = 3,051) followed by North America (n = 713). At least 20 patients were aged ≤6 months, of whom 12 were born prematurely. The GSK safety database included 466 patients with ≥1 SAE, of whom 374 (80%) had a fatal outcome. Drug-related SAEs were reported in 41 (11%) patients, including hepatic failure (n = 6 [2%]) and acute kidney injury (n = 5 [1%)]. The CUP facilitated global access to zanamivir prior to product approval. No new safety concerns were identified in the CUP compared with IV zanamivir clinical studies.


Mangosteen Pericarp Extract Supplementation Boosts Antioxidant Status via Rebuilding Gut Microbiota to Attenuate Motor Deficit in 6-OHDA-Induced Parkinson's Disease.
Oxidative stress and gut dysbiosis have been known to precede Parkinson's disease (PD). An antioxidant-rich product, mangosteen pericarp (MP), has the ability to counterbalance excessive free radicals and the imbalanced gut microbiota composition, suggesting the MP's capacity to delay PD progression. In this study, we explored the effects of two doses of MP extract in a unilateral 6-hydroxydopamine (6-OHDA)-induced PD rat model. We revealed that the 8-week supplementation of a low dose (LMP) and a high dose of the MP extract (HMP) improved motor function, as observed in decreased contralateral rotation, improved time spent on rod, and higher dopamine binding transporter (DAT) in the substantia nigra pars compacta (SNc). The MP extract, especially the HMP, also increased antioxidant-related gene expressions, restored muscle mitochondrial function, and remodeled fecal microbiota composition, which were followed by reduced reactive oxygen species levels in brain and inflammation in plasma. Importantly, bacterial genera Sutterella, Rothia, and Aggregatibacter, which were negatively correlated with antioxidant gene expressions, decreased in the HMP group. It is imperative to note that in addition to directly acting as an antioxidant to reduce excessive free radicals, MP extract might also increase antioxidant state by rebuilding gut microbiota, thereby enhanced anti-inflammatory capacity and restored mitochondrial function to attenuate motor deficit in 6-OHDA-induced PD-like condition. All in all, MP extract is a potential candidate for auxiliary therapy for PD.


Real-time three-sensitivity measurements based on three-color digital Fresnel holographic interferometry.
This Letter presents a method for real-time 3D measurements based on three-color digital holographic interferometry. The optical setup is considerably simplified, since the reference beams are combined into a unique beam. A convolution algorithm allows the three monochrome images to be superposed to provide simultaneous full-field 3D measurements. Experimental results confirm the suitability of the proposed method.


LC-ESI-MS characterisation of phytoalexins induced in chickpea and pea tissues in response to a biotic elicitor of Hypnea musciformis (red algae).
A simple extraction procedure and HPLC method was developed to analyse the major and minor components of induced phytoalexins of elicited tissues (seeds) of chickpeas (Cicer arietinum L.) and peas (Pisum sativum L.) treated with a biotic elicitor (k-carrageenan) of Hypnea musciformis (red algae) from the Karachi coast. The level and timing of the induced phytoalexin production were estimated on the basis of various elicitor dilutions and as a function of time; the results are presented and discussed. A LC-ESI-MS/MS technique has been employed for the detection and characterisation of the induced phytochemical components (flavonoids and their glyco-conjugates). Nine flavonoids were identified from chickpeas: naringin, naringin malonate, liquiritigenin, naringenin, biochanin A, daidzein, formononetin, maackiain and medicarpin, while five flavonoids were identified from peas: afrormosin, anhydropisatin, pisatin, pseudobaptigenin and maackiain. These compounds play a vital role as phytoalexins because of their antimicrobial activity.


Character displacement: in situ evolution of novel phenotypes or sorting of pre-existing variation?
Character displacement - the divergence of traits between species in response to competition for resources or mates - has long been viewed as a major cause of adaptive diversification and species coexistence. Yet, we lack answers to basic questions concerning the causes and consequences of character displacement, not the least of which is why some species are more prone than others to undergo character displacement. Here, we address these questions by describing how character displacement can proceed through two nonexclusive routes that differ in the source of phenotypic variation, and, hence, in the ease with which character displacement may unfold. During in situ evolution of novel phenotypes, new traits that are divergent from a heterospecific competitor are generated and spread in sympatry. During sorting of pre-existing variation, such traits are initially favoured in allopatry before the two species encounter one another. Later, when they come into contact, character displacement transpires when these pre-existing divergent phenotypes increase in frequency in sympatry relative to allopatry. Because such sorting of pre-existing variation should unfold relatively rapidly, we suggest that species that express resource or mating polymorphism prior to interactions with heterospecifics may be more prone to undergo character displacement. We discuss the key differences between these two routes, review possible examples of each, and describe how the distinction between them provides unique insights into the evolutionary consequences of species interactions, the origins of diversity, and the factors that govern species coexistence.