Perry syndrome: Novel DCTN1 mutation in a large kindred and first observation of prodromal disease.
Perry syndrome (PS) is a hereditary neurodegenerative disorder caused by mutations in the DCTN1 gene and characterized by TDP-43 pathology. As the diagnosis is usually made at the advanced stages of the disease, there are no studies on the asymptomatic mutation carriers and their conversion to overt disease. We personally examined 27 members of the large kindred of 104 individuals with familial parkinsonism. We evaluated each case with clinical (neurological examination; motor and non-motor scales), genetic testing (whole-exome or Sanger sequencing), and laboratory (neurofilament light, NFL; glial fibrillary acidic protein, GFAP) measures. Autopsy study was done on two individuals. The mean age at evaluation was 49 years. Comorbidities were present in 20 cases, including sleep problems (n = 15 total, sleep apnea in 7), dysautonomia (n = 10), weight loss (n = 8), and anxiety/depression (n = 8). Neurological abnormalities were present in 18, including parkinsonism (n = 7), isolated tremor (n = 2), and varied isolated signs in individual cases. Cognition and smell were preserved. Genetic testing revealed a novel c.200G > T (Gly67Val) mutation in the DCTN1 gene in 10 individuals. The mutation, segregated with the PS phenotype (n = 4), was absent in gnomAD, and in silico predictions indicated it was pathogenic. Three young mutation carriers were monosymptomatic (prodromal), and three were asymptomatic. Plasma NFL and GFAP values were similar among the cases. Autopsy studies showed typical PS neuropathological findings. We identified a novel pathogenic Gly67Val DCTN1 mutation. We report prodromal disease of PS in some mutation carriers; however, more investigation is necessary to confirm this observation.


Risk of ectopic pregnancy following day-5 embryo transfer compared with day-3 transfer.
The incidence of ectopic pregnancy after IVF is increased approximately 2.5-5-fold compared with natural conceptions; however, the aetiology for this increased risk remains unclear. One proposed practice change to decrease the incidence of ectopic pregnancy is blastocyst embryo transfer on day 5 rather than cleavage-stage embryo transfer on day 3. A retrospective cohort study was conducted to compare the risk of ectopic pregnancy following fresh day-5 embryo transfer with day-3 embryo transfer among women who underwent IVF and achieved pregnancy from 1998 to 2011. There were 13,654 eligible pregnancies; 277 were ectopic. The incidence of ectopic pregnancy was 2.1% among day-3 pregnancies and 1.6% among day-5 pregnancies. The adjusted risk ratio for ectopic pregnancy from day-5 compared with day-3 transfer was 0.71 (95% confidence interval 0.46-1.10). Although this analysis included 13,654 cycles, with a two-sided significance level of 0.05, it had only 21.9% power to detect a difference between the low incidence of ectopic pregnancy among both day-3 and day-5 transfers. In conclusion, this study was not able to demonstrate a difference in the risk of ectopic pregnancy among day-3 compared with day-5 transfers.


Comparison of sleep disorders in chronic hepatitis C patients treated with interferon-based therapy and direct acting antivirals using actigraphy.
This study aimed to compare the severity of sleep problems between chronic hepatitis C (CHC) patients treated with interferon (IFN)-based triple therapy (pegylated [Peg]-IFN plus ribavirin [RBV] plus simeprevir [SMV]) and those who received IFN-free direct-acting antiviral (DAA) therapy. Our study included 31 patients in group A (Peg-IFN/RBV/SMV combination therapy) and 41 patients in the group B (IFN-free DAA therapy). We prospectively compared the effect of each antiviral treatment regimen on sleep conditions between the two groups adding actigraphy data. Five parameters detected by actigraphy (objective assessment) and scores of the Pittsburgh Sleep Quality Index (subjective assessment, n = 30 [group A] and 35 [group B]) were estimated. The causal effect of each therapy on sleep disturbances was evaluated at baseline and at 4 weeks after commencement of therapy. In terms of baseline characteristics, no significant differences between groups were found, except for hepatitis C virus genotype. In group A, sustained virological response 12 rate was 83.9% (26/31), whereas in group B it was 95.1% (39/41). In group A, each score of waking after sleep onset, activity index, wake episodes, and Pittsburgh Sleep Quality Index at 4 weeks significantly increased compared to those evaluated at baseline. In group B, scores of all variables except for sleep episodes at 4 weeks did not significantly change compared to those at baseline. Interferon-based triple therapy in patients with CHC may cause significant sleep disturbances. Interferon-free DAA therapy is less likely to deteriorate sleep conditions in patients with CHC.


Imaging cerebral palsy.
Neuroimaging in children with (suspected) cerebral palsy is useful for contributing to or corroborating the diagnosis, clarifying the etiology and the "timing" of the underlying brain lesion, establishing a prognosis and, in some cases, as a basis for genetic counseling. Therefore, each child with cerebral palsy should undergo at least one neuroimaging procedure. While cranial ultrasound is often the first and least invasive technique applied in newborns and infants, and computed tomography is beneficial especially in emergency situations, the "gold standard" technique for imaging children with cerebral palsy is magnetic resonance imaging, ideally performed after the age of 2 years. Underlying brain lesions can be subdivided into brain malformations (including disorders of neuronal proliferation and cellular lineage, disorders of neuroblast migration, and disorders of neocortical organization) and defective lesions. Defective lesions, which typically occur only during the 3rd trimester of pregnancy or peri-/postnatally, are subdivided into lesions affecting primarily the periventricular white matter ("early 3rd trimester lesions") and those affecting primarily structures of cortical/deep gray matter ("late 3rd trimester lesions"). The understanding of the functional consequences of such lesions can be enhanced by diffusion tensor tractography; cortical (re-)organization can be visualized using functional magnetic resonance imaging (fMRI).


Neutrophil to Lymphocyte Ratio and Serum Biomarkers : A Potential Tool for Prediction of Clinically Relevant Cerebral Vasospasm after Aneurysmal Subarachnoid Hemorrhage.
Subarachnoid hemorrhage (SAH) is a condition characterized by bleeding in the subarachnoid space, often resulting from the rupture of a cerebral aneurysm. Delayed cerebral ischemia caused by vasospasm is a significant cause of mortality and morbidity in SAH patients, and inflammatory markers such as systemic inflammatory response index (SIRI), systemic inflammatory index (SII), neutrophil-to-lymphocyte ratio (NLR), and derived NLR (dNLR) have shown potential in predicting clinical vasospasm and outcomes in SAH patients. This article aims to investigate the relationship between inflammatory markers and cerebral vasospasm after aneurysmatic SAH (aSAH) and evaluate the predictive value of various indices, including SIRI, SII, NLR, and dNLR, in predicting clinical vasospasm. A retrospective analysis was performed on a cohort of 96 patients who met the inclusion criteria out of a total of 139 patients admitted Trakya University Hospital with a confirmed diagnosis of aSAH between January 2013 and December 2021. Diagnostic procedures, neurological examinations, and laboratory tests were performed to assess the patients' condition. The Student's t-test compared age variables, while the chi-square test compared categorical variables between the non-vasospasm (NVS) and vasospasm (VS) groups. Receiver operating characteristic (ROC) curve analyses were used to evaluate the diagnostic accuracy of laboratory parameters, calculating the area under the ROC curve, cut-off values, sensitivity, and specificity. A significance level of p<0.05 was considered statistically significant. The study included 96 patients divided into two groups : NVS and VS. Various laboratory parameters, such as NLR, SII, and dNLR, were measured daily for 15 days, and statistically significant differences were found in NLR on 7 days, with specific cut-off values identified for each day. SII showed a significant difference on day 9, while dNLR had significant differences on days 2, 4, and 9. Graphs depicting the values of these markers for each day are provided. Neuroinflammatory biomarkers, when used alongside radiology and scoring scales, can aid in predicting prognosis, determining severity and treatment decisions for aSAH, and further studies with larger patient groups are needed to gain more insights.


Cell type-aware analysis of RNA-seq data.
Most tissue samples are composed of different cell types. Differential expression analysis without accounting for cell type composition cannot separate the changes due to cell type composition or cell type-specific expression. We propose a computational framework to address these limitations: Cell Type Aware analysis of RNA-seq (CARseq). CARseq employs a negative binomial distribution that appropriately models the count data from RNA-seq experiments. Simulation studies show that CARseq has substantially higher power than a linear model-based approach and it also provides more accurate estimate of the rankings of differentially expressed genes. We have applied CARseq to compare gene expression of schizophrenia/autism subjects versus controls, and identified the cell types underlying the difference and similarities of these two neuron-developmental diseases. Our results are consistent with the results from differential expression analysis using single cell RNA-seq data.


Regulation of opticin on bioactivity of retinal vascular endothelial cells cultured in collagen.
To investigate the effects of collagen and opticin on the bioactivity of human retinal vascular endothelial cells (hRVECs), and explore its regulations by integrins and RhoA/ROCK1 signal pathway. hRVECs were cultured in collagen and treated by opticin, and cell-based bioactivity assays of cell proliferation, migration, and adhesion were performed. The expression of integrin α2, integrin β1, RhoA and ROCK1 were examined with real-time PCR and Western blotting. Collagen could promote cell viability of proliferation and migration (all P<0.05), and enhance the mRNA expression of integrin α2, integrin β1, RhoA and ROCK1 (all P<0.05). Opticin could inhibit proliferation and migration ability of hRVECs cultured in collagen, and reduce the mRNA expression of integrin α2, integrin β1, RhoA and ROCK1 (all P<0.05). Collagen and opticin can affect bioactivity of hRVECs, which may be regulated by α2-, β1-integrins and RhoA/ROCK1 signal pathway.


Iron loading into ferritin can be stimulated or inhibited by the presence of cations and anions: a specific role for phosphate.
Phosphate and other oxo-anions have been shown to stimulate the rate of iron loading into ferritin (J. Polanams, A.D. Ray, R.K. Watt, Inorg. Chem. 44 (2005) 3203-3209). This study was undertaken to determine if accelerated iron loading was a specific effect for phosphate and closely associated oxo-anions or if it was a general anion effect. Controls were also performed with mono-valent cations to determine the effect of these cations on iron loading into ferritin. Cations were shown to slow the rate of iron loading into ferritin. Fluoride and iodide were shown to slow the iron loading process of ferritin. Sulfate was also shown to slow iron loading into ferritin to a more significant extent than the cations or halides tested. The trigonal planar oxo-anions, carbonate and nitrate, did not inhibit or stimulate iron loading. We conclude that the increased rate of iron loading into ferritin is specific to phosphate and other closely associated tetrahedral oxo-anion analogs, that the effect is driven by the insolubility of the iron and anion complex, and that in general, cations and anions slow the rate of iron loading into ferritin.


Temporospatial pattern of flavonoid metabolites and potential regulatory pathway of PbMYB211-coordinated kaempferol-3-O-rhamnoside biosynthesis in Phoebe bournei.
Phoebe is a well-known timber tree species that contains abundant metabolites characterized by flavonoids that are widely used in the pharmaceutical industry. Nevertheless, temporospatial flavonoid metabolism variations substantially impact the Phoebe industry. Thus, a metabolomics analysis was carried out and identified 465 metabolites (102 flavonoids) in P. bournei, revealing distinct distribution patterns among five studied organs, and most of the flavonoids were dominant in the leaves. Furthermore, three kaempferol glycoside derivatives were significantly accumulated in the leaves and showed higher contents in young leaves than in mature leaves and differences between spring and autumn. For instance, greater accumulation of kaempferol-7-O-rhamnoside was detected in spring, whereas higher contents of kaempferol-3-O-arabinofuranoside and kaempferol-3-O-rhamnoside were found in autumn. Integrated metabolomics and transcriptomics identified 20 transcription factors (TFs) and 12 structural genes that participate in kaempferol derivative synthesis and elucidated a potential regulatory mechanism in P. bournei. Of the identified genes, PbMYB211 might contribute significantly to the kaempferol-3-O-rhamnoside content by regulating the target structural gene PbUGT139, as revealed by transient overexpression analysis. Overall, this study illuminated the temporospatial accumulation of flavonoids among different organs, seasons, and developmental stages in P. bournei and elucidated a potential regulatory pathway of kaempferol-3-O-rhamnoside. The results provide important insights into harvest techniques and a theoretical basis for the comprehensive utilization of P. bournei.


Tetracaine lollipops for the suppression of extreme gag reflex in dental patients.
An extreme gag reflex renders prophylactic dental care and undergoing operative dental procedures impossible for many people. Commercially available oral spray and lozenge anesthetics have an unpleasant taste and provide an insufficient duration of anesthesia. Compounded flavored tetracaine lollipops are an excellent alternative to other oral anesthetics and have enabled the treatment of many patients who have a strong aversion to dental care. In this report, we describe the use of the preparation in such patients. A formulation for tetracaine lollipops 0.5% is included.


Excess thermodynamic properties of thin water films confined between hydrophobized gold surfaces.
Surface forces between gold surfaces were measured in pure water at temperatures in the range of 10-40 °C using an atomic force microscope (AFM). The surfaces were hydrophobized by self-assembly of alkanethiols (C(n)SH) with n=2 and 16 in ethanol solutions. The data were used to determine the changes in excess free energies (ΔG(f)) of the thin water films per unit area by using the Derjaguin approximation [1]. The free energy data were then used to determine the changes in excess film entropy (ΔS(f)) and the excess film enthalpy (ΔH(f)) per unit area. The results show that both ΔS(f) and ΔH(f) decrease with decreasing film thickness, suggesting that the macroscopic hydrophobic interaction involves building some kind of structures in the intervening thin films of water. It was found that |ΔH(f)|>|TΔS(f)|, which is a necessary condition for an attractive force to appear when the enthalpy and entropy changes are both negative. That macroscopic hydrophobic interaction is enthalpically driven is contrary to the hydrophobic interactions at molecular scale. The results obtained in the present work are used to discuss possible origins for the long-range attractions observed between hydrophobic surfaces.


A wavelet-based reduction of heart sound noise from lung sounds.
Heart sounds produce an incessant noise during lung sounds recordings. This noise severely contaminates the breath sounds signal and interferes in the analysis of lung sounds. In this paper, the use of a wavelet transform domain filtering technique as an adaptive de-noising tool, implemented in lung sounds analysis, is presented. The multiresolution representations of the signal, produced by wavelet transform, are used for signal structure extraction. In addition, the use of hard thresholding in the wavelet transform domain results in a separation of the nonstationary part of the input signal (heart sounds) from the stationary one (lung sounds). Thus, the location of the heart sound noise (1st and 2nd heart sound peaks) is automatically detected, without requiring any noise reference signal. Experimental results have shown that the implementation of this wavelet-based filter in lung sound analysis results in an efficient reduction of the superimposed heart sound noise, producing an almost noise-free output signal. Due to its simplicity and its fast implementation the method can easily be used in clinical medicine.


Examining the Colonization and Survival of E. coli from Varying Host Sources in Drainage Basin Sediments and Stormwater.
It is widely understood that stormwater drainage has a significant impact on the health of tidal creek systems via regular inputs of runoff from the surrounding watershed. Due to this hydrologic connection, contamination of the upstream drainage basin will have a direct effect on estuaries and tidal creeks that often act as receiving waters. This study focuses on the importance of drainage basin sediments as they enhance the persistence and transport of the fecal indicator bacteria E. coli within a watershed. Experiments presented use microcosm environments with drainage basin sediments and stormwater to investigate E. coli colonization of stagnant waters and to examine the importance of host sources to bacterial survival. A novel method for establishing microcosms using environmental sediments with in situ bacterial populations and sterile overlying waters is used to examine E. coli colonization of the water column in the absence of flow. Colonization of sterile sediment environments also is examined using two common host sources (human and avian). Each experiment uses sediments of varying grain size and organic content to examine the influence of physical characteristics on bacterial prevalence. Results suggest host source of bacteria may be more important to initial bacterial colonization while physical characteristics of drainage basin sediments better explains extended E. coli persistence. Findings also suggest an indirect control of water column bacterial concentration by sediment type and erodibility.


Association between muscle trigger points, ongoing pain, function, and sleep quality in elderly women with bilateral painful knee osteoarthritis.
The objectives of this study were to investigate if referred pain elicited by active trigger points (TrPs) reproduced the symptoms in individuals with painful knee osteoarthritis (OA) and to determine the relationship between the presence of active TrPs, intensity of ongoing pain, function, quality of life, and sleep quality in individuals with painful knee OA. Eighteen women with bilateral painful knee OA, aged 79 to 90 years, and 18 matched controls participated. Muscle TrPs were bilaterally explored in several muscles of the lower extremity. Trigger points were considered active if the elicited referred pain reproduced knee symptoms, and TrPs were considered latent if the elicited pain did not reproduce symptoms. Pain was collected with a numerical pain rate scale (0-10), function was assessed with Western Ontario and McMaster Universities, quality of life was assessed with the Medical Outcomes Study Short Form 36 questionnaire, and sleep quality was determined with the Pittsburgh Sleep Quality Index. Women with knee OA exhibited a greater number of active TrPs (mean, 1 ± 1; P < .001) but similar number of latent TrPs (mean, 4 ± 2) than healthy women (mean, 4 ± 3; P = .613). A greater number of active TrPs were associated with higher intensity of ongoing pain (r = 0.605; P = .007). Higher intensity of ongoing knee pain was associated with lower physical function (P < .05). The referred pain elicited by active TrPs in the lower extremity muscles contributed to pain symptoms in painful knee OA. A higher number of active TrPs was associated with higher intensity of ongoing knee pain.


Procedural performance between two cryoballoon systems for ablation of atrial fibrillation depends on pulmonary vein anatomy.
Cryoballoon ablation is a first-line therapy for atrial fibrillation. We compared the efficacy and safety of two ablation systems and addressed the influence of pulmonary vein (PV) anatomy on performance and outcome. We consecutively enrolled 122 patients who were planned for first-time cryoballoon ablation. Patients were assigned 1:1 for ablation with the POLARx or the Arctic Front Advance Pro (AFAP) system and followed-up for 12 months. Procedural parameters were recorded during the ablation. Before the procedure, a magnetic resonance angiography (MRA) of the PVs was generated and diameter, area, and shape of each PV ostium were assessed. We applied an evaluated PV anatomical scoring system on our MRA measurement data ranging from 0 (best anatomical combination) to 5. Procedures performed with POLARx were associated with shorter time to balloon temperature -30°C (p < .001), lower balloon nadir temperature (p < .001), and longer thawing time till 0°C (p < .001) in all PVs, however, time to isolation was similar. We observed a decreasing performance with each increase in the score for the AFAP, whereas the POLARx performed constant regardless of the score. At 1 year, AF recurred in 14 of 44 patients treated with AFAP (31.8%) and in 10 of 45 patients treated with POLARx (22.2%) (hazard ratio, 0.61; 95% CI 0.28 to 1.37; p = .225). There was no significant correlation between PV anatomy and clinical outcome. We found significant differences in cooling kinetics, especially when anatomical conditions are difficult. However, both systems have a comparable outcome and safety profile.


Isolation and identification of chondroitin sulfates from the mud snail.
Chondroitin sulfates were isolated from the mud snail. For the quantitative analysis of enzymatic digestion products of isolated chondroitin sulfates, strong anion exchange-high performance liquid chromatography (SAX-HPLC) was performed. By the action of chondroitinase ABC, three unsaturated disaccharides 2-acetamide-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-D-galactose (delta Di-OS), 2-acetamide-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-6-O-sulfo-D-galactose (delta Di-6S) and 2-acetamide-2-deoxy-3-O-(beta-D-gluco-4-enepyranosyluronic acid)-4-O-sulfo-D-galactose (delta Di-4S) were produced from the mud snail chondroitin sulfates. The analysis showed that relative proportion of delta Di-OS/delta Di-6S/delta Di-4S was 58.7/3.1/38.2. The immunomodulating activity of chondroitin sulfate was examined by cell proliferation assay and these results suggest that it might be a immunosuppressant.


Metal(loid) speciation in dermal bioaccessibility extracts from contaminated soils and permeation through synthetic skin.
Dermal exposure to metal(loid)s from contaminated soils can contribute to health risk. Metal(loid) speciation will influence their bioaccessibility in sweat and subsequent permeation across the skin. Therefore, the speciation of the bioaccessible fraction of metal(loid)s in two synthetic sweat formulations (sweat A (pH 6.5) and B (pH 4.7)) was assessed using chemical equilibrium modelling (Visual MINTEQ). Permeation through synthetic skin and the influence of sebum in the permeation of As, Cr, Cu, Ni, Pb, and Zn were also investigated using Franz cells. Following dermal bioaccessibility tests for five Chromated Copper Arsenate (CCA)-contaminated soils and one certified soil (SQC001), mean metal(loid) bioaccessibility (%) was higher in sweat B (2.33-18.8) compared to sweat A (0.12-7.53). Arsenic was almost entirely found as As(V) in both sweats. In sweat A, comparable concentrations of Cr(III) and Cr(VI) were found whereas in sweat B, Cr was primarily present as Cr(III). Copper was primarily found as Cu2+. Bioaccessible Cr extracted from nearly all soils permeated through the Strat-M membrane when it was coated with sebum. The Cr permeation coefficient (Kp) ranged between 0.004 and 0.13 cm/h and the Kp for Cu was higher (0.024-0.52 cm/h). As, Ni, Pb, and Zn did not permeate the synthetic skin.


Spontaneous coronary artery dissection.
Spontaneous coronary artery dissection is a rare coronary pathology whose precise incidence, etiology, pathogenesis, treatment and evolution have not been clearly established. Sudden death accounts for the majority of presentations. It occurs most commonly in young women in the left anterior descending coronary artery. We report the case of a 48-year-old male with asymptomatic spontaneous dissection in the anterior descending coronary artery.


Prevalence of diabetic comorbidities and knowledge and practices of foot care among diabetic patients: a cross-sectional study.
Diabetes mellitus with comorbid complications constitute a major public health problem worldwide. The aim of this study was to evaluate the risk of comorbid complications with glycosylated hemoglobin levels and diabetes duration. Also assessed were patients' diabetic foot-care knowledge and practices. This was a quasiexperimental study. A total of 360 type 2 diabetes mellitus patients were interviewed at a government health care center in Riyadh, Saudi Arabia. Diabetic complications and HbA1c-level data were collected from hospital records. A standard questionnaire was used to assess their diabetic foot-care knowledge and practice. Of the type 2 diabetes mellitus patients, 32.5% had highly uncontrolled glycosylated hemoglobin (HbA1c) levels (≥8.6%) and 62.8% had had diabetes >10 years. The patients had comorbid complications, such as hypertension (61.4%), dyslipidemia (58.6%), retinopathy (23.3%), heart disease (14.4%), and severe foot complications (3.9%). The majority of highly uncontrolled HbA1c-level patients had retinopathy (OR 8.90, P=0.0001), foot complications (OR 8.09, P=0.0001), dyslipidemia (OR 2.81, P=0.010), and hypertension (OR 2.0, P=0.028) compared to the controlled HbA1c-level (<7%) group. Patients with diabetes >10 years also had higher prevalence of foot complications (OR 2.92, P=0.0001), retinopathy (OR 2.17, P=0.011), and hypertension (OR 1.67, P=0.033). From patient responses, physicians examined only 34.2% of patient feet and 36.7% of patients received physicians advice for foot care. About 70% of patients had knowledge of diabetic foot care; however, only 41.7% of patients always examined their feet, 41.4% washed feet with warm water, 31.4% carefully dried between the toes, and 33.1% were using foot-moisturizing substances. The prevalence of comorbid complications was higher in the Saudi population compared to other international studies. Also, foot-care practice was not satisfactory. Therefore, there is need of improvement and increased awareness among physicians and patients to check regularly for proper care of the diabetic foot to avoid diabetic foot-related complications.


Structure and rheology of oleogels made from rice bran wax and rice bran oil.
Structural and rheological properties of oleogels consisting of 0.5-25 wt% rice bran wax (RBX) in rice bran oil (RBO) were explored. RBX was an efficient, thermoreversible oleogelator capable of structuring RBO at concentrations as low as 0.5 wt% RBX. A qualitative temperature-composition phase diagram showed that oleogels containing higher concentrations of RBX were expectedly the most resistant to melting. In oleogels at higher RBX concentrations, polarized light microscopy revealed the presence of a network of interlinked, long aspect ratio wax crystal needles up to 50 μm long. Upon heating, RBX crystals did not undergo any structural transition, based on the constant short spacings at ~ 4.16 and ~ 3.73 Å, indicative of an orthorhombic subcell, and d001 long spacing at 74-76 Å that persisted until RBX fusion. This long spacing was ascribed to the presence of wax esters consisting of long-chain saturated fatty acids (C24 and C22) esterified to C28 - C34 saturated fatty alcohols. During cooling from 90 to 20 °C, the increase in oleogel viscosity resulting from the RBX liquid-solid phase transition was corroborated by DSC-based crystallization onset and enthalpy data. Similarly, elastic moduli and hardness both rose with increasing RBX concentration. This study, which demonstrated that RBX can structure RBO with distinct concentration-dependent properties, serves as the foundation for the development of oleogel-based approaches to saturated and trans fats replacement in processed foods.


Effect of Modified Pharyngeal Electrical Stimulation on Patients with Severe Chronic Neurogenic Dysphagia: A Single-Arm Prospective Study.
Current treatments for severe chronic neurogenic dysphagia (SCND) are limited. Modified pharyngeal electrical stimulation (mPES) was modified from pharyngeal electrical stimulation (PES). This prospective study aimed to explore the efficacy and safety of mPES on SCND. 30 patients with severe chronic neurogenic dysphagia were recruited. mPES was administered to patients once daily until the functional oral intake scale score (FOIS) reach 3. Videofluoroscopic swallow study (VFSS), flexible endoscopic evaluation of swallowing (FEES), and high-resolution manometry (HRM) were utilized for evaluating the swallowing function. After mPES, 24 of 30 patients (80%) reached the endpoint (FOIS = 3) (P < 0.001). 3 of 6 tracheotomized patients (50%) removed the tracheal tube. The median number of mPES sessions for the 24 patients who met the criteria was 28 (17, 38) and the median period was 43 (29, 63) days. Moreover, a significant increase was observed in hypopharyngeal peak pressure (P = 0.015), hypopharyngeal contraction duration (P = 0.023), velopharyngeal peak pressure (P = 0.044), and velopharyngeal contraction duration (P = 0.031). A reduction was observed in PAS (P < 0.001), secretion (P = 0.001), vallecular residue (P < 0.001), left (P = 0.001), and right (P < 0.001) pyriform sinus residue. The median FOIS of 30 patients at 3-month follow-up was 5 (3, 6). No serious side effects were reported. mPES is a promising effective and safe therapeutic approach that is simple to use in patients with SCND.


Targeting drug delivery in the vascular system: Focus on endothelium.
The bloodstream is the main transporting pathway for drug delivery systems (DDS) from the site of administration to the intended site of action. In many cases, components of the vascular system represent therapeutic targets. Endothelial cells, which line the luminal surface of the vasculature, play a tripartite role of the key target, barrier, or victim of nanomedicines in the bloodstream. Circulating DDS may accumulate in the vascular areas of interest and in off-target areas via mechanisms bypassing specific molecular recognition, but using ligands of specific vascular determinant molecules enables a degree of precision, efficacy, and specificity of delivery unattainable by non-affinity DDS. Three decades of research efforts have focused on specific vascular targeting, which have yielded a multitude of DDS, many of which are currently undergoing a translational phase of development for biomedical applications, including interventions in the cardiovascular, pulmonary, and central nervous systems, regulation of endothelial functions, host defense, and permeation of vascular barriers. We discuss the design of endothelial-targeted nanocarriers, factors underlying their interactions with cells and tissues, and describe examples of their investigational use in models of acute vascular inflammation with an eye on translational challenges.


Women had favourable reverse left ventricle remodelling after TAVR.
Being woman is associated with higher survival rates after transcatheter aortic valve replacement (TAVR) despite the increase in periprocedural complications. The left ventricle (LV) remodelling process that follows TAVR is considered to play an important role. We aim to investigate whether gender difference affects the process of LV remodelling after TAVR. A total of 100 patients (50 men and 50 women) after TAVR were enrolled. Echocardiography was performed at baseline before the TAVR procedure and repeated upon discharge, and at three, nine and 12 months post-TAVR. Women exhibited an early regression of LV mass and the LV mass index (LVMi) decreased 12.0% from 148.3 ± 48.0 to 130.5 ± 43.7 g/m2 at just a median of 17 days after the procedure (P < .001). Almost one-half of the LVMi regression occurred by 17 days post-TAVR and the LVMi regressed 22.0% by 12 months post-TAVR. In contrast, the regression of LVMi in men seemed to be more gradual and the significant regression of LVMi from baseline began to be observed since three months later after TAVR. The LVMi reduction at nine months was 11.5% and achieved 15.4% over one year. Multivariable logistic regression analysis showed only the female sex, better LVEF and greater baseline LVMi were independently associated with greater LVMi regression after TAVR, indicating female gender is an independent predictor for favourable LV remodelling after TAVR. In conclusion, female patients with AS had favourable reverse remodelling with greater and earlier LV mass regression post-TAVR compared with the male patients.


Granulomatous and xanthogranulomatous prostatitis: A case report.
Granulomatous prostatitis is a rare condition that is diagnosed only by histopathological examination. Though rare, the condition was reported to have different presentations (mimicking prostate cancer or prostatitis and prostatic abscess) and to have different etiologies which classified it into three main entities; nonspecific (idiopathic), post-surgery, and specific. Specific granulomatous prostatitis is further sub-classified to infective, xanthogranulomatous, Malacoplakia and associated with systemic granulomatous disease and allergy. We hereby report a rare case of xanthogranulomatous prostatitis that presented with persistent urinary tract infection.


Mechanism of insulin sensitization by BMOV (bis maltolato oxo vanadium); unliganded vanadium (VO4) as the active component.
Organovanadium compounds have been shown to be insulin sensitizers in vitro and in vivo. One potential biochemical mechanism for insulin sensitization by these compounds is that they inhibit protein tyrosine phosphatases (PTPs) that negatively regulate insulin receptor activation and signaling. In this study, bismaltolato oxovanadium (BMOV), a potent insulin sensitizer, was shown to be a reversible, competitive phosphatase inhibitor that inhibited phosphatase activity in cultured cells and enhanced insulin receptor activation in vivo. NMR and X-ray crystallographic studies of the interaction of BMOV with two different phosphatases, HCPTPA (human low molecular weight cytoplasmic protein tyrosine phosphatase) and PTP1B (protein tyrosine phosphatase 1B), demonstrated uncomplexed vanadium (VO(4)) in the active site. Taken together, these findings support phosphatase inhibition as a mechanism for insulin sensitization by BMOV and other organovanadium compounds and strongly suggest that uncomplexed vanadium is the active component of these compounds.


Effects of habitat fragmentation and isolation on species richness: evidence from biogeographic patterns.
Habitat subdivision by geography or human activity may be an important determinant of regional species richness. Cumulative species-area relationships for vertebrates, land plants, and insects on island archipelagoes show that collections of small islands generally harbor more species than comparable areas composed of one or a few large islands. The effect of the degree of habitat subdivision in increasing species richness appears to increase with the distance from potential sources of colonists. Mountaintop biotas show no clear differences between species richness on large alpine areas and collections of smaller peaks. National park faunas generally have more species in collections of small parks than in the larger parks. In all cases where a consistent effect of subdivision is observed, the more subdivided collection of islands or isolates contains more species. To the degree that these data provide guidance for establishing nature reserves, they suggest that increasing the numbers of reserves may be an important component of conservation strategies.


An in vitro system to characterize prostate cancer progression identified signaling required for self-renewal.
Mutations in RB and PTEN are linked to castration resistance and poor prognosis in prostate cancer. Identification of genes that are regulated by these tumor suppressors in a context that recapitulates cancer progression may be beneficial for discovering novel therapeutic targets. Although various genetically engineered mice thus far provided tumor models with various pathological stages, they are not ideal for detecting dynamic changes in gene transcription. Additionally, it is difficult to achieve an effect specific to tumor progression via gain of functions of these genes. In this study, we developed an in vitro model to help identify RB- and PTEN-loss signatures during the malignant progression of prostate cancers. Trp53-/- ; Rbf/f , Trp53-/- ; Ptenf/f , and Trp53-/- ; Rbf/f ; Ptenf/f prostate epithelial cells were infected with AD-LacZ or AD-Cre. We found that deletion of Rb, Pten or both stimulated prostasphere formation and tumor development in immune-compromised mice. The GO analysis of genes affected by the deletion of Rb or Pten in Trp53-/- prostate epithelial cells identified a number of genes encoding cytokines, chemokines and extracellular matrix remodeling factors, but only few genes related to cell cycle progression. Two genes (Il-6 and Lox) were further analyzed. Blockade of Il-6 signaling and depletion of Lox significantly attenuated prostasphere formation in 3D culture, and in the case of IL-6, strongly suppressed tumor growth in vivo. These findings suggest that our in vitro model may be instrumental in identifying novel therapeutic targets of prostate cancer progression, and further underscore IL-6 and LOX as promising therapeutic targets. © 2015 Wiley Periodicals, Inc.


Effect of standard and Aircast tennis elbow bands on integrated electromyography of forearm extensor musculature proximal to the bands.
Classic tennis elbow, or lateral epicondylitis, has been described as an overuse or misuse injury resulting in a tendinitis. The extensor carpi radialis brevis (ECRB) and extensor digitorum communis (EDC) have been implicated as primary culprits in this pathology. Tennis elbow has been treated using a constrictive band placed several centimeters distal to the origin of these two muscles. Aircast (Aircast Inc., Summit, NJ) has developed a new style of band that employs an air-filled bladder as the counterpressure element. This study tested the effect of both standard and Aircast bands on EMG activity of the EDC and ECRB proximal to the band compared to control values. Ten normal subjects, ranging in age from 20 to 43 years, were tested. Right upper extremities were tested in all cases. The subjects' forearms were stabilized in the CYBEX II forearm stabilization V-pad. The ECRB and EDC were then impaled with monopolar EMG needle electrodes. The CYBEX data were recorded using the HUMAC system and the EMG data were recorded and analyzed using the Cadwell 7400. EMG data were recorded at 80% of maximum voluntary isometric contraction (MVIC) with no band, the standard band, and the Aircast band. An analysis of variance (ANOVA) with repeated measures of integrated EMG (IEMG) and Duncan's multiple comparison tests revealed that the Aircast caused a significant reduction in IEMG of the ECRB and EDC when compared with control values and the standard band. The decrease in IEMG with the standard band was not statistically significant.(ABSTRACT TRUNCATED AT 250 WORDS)


Development of PCR assays targeting the genes involved in synthesis and assembly of the new Escherichia coli O 174 and O 177 O antigens.
Escherichia coli O 174 and O 177 are newly described O serogroups which were reported as human pathogens. Identification of these strains by serotyping has been restricted, as the required sera are not commercially available. In this study, a collection of 13 E. coli O 174 strains and 12 E. coli O 177 strains was studied on the O:H serotypes and virulence markers. The O-antigen gene clusters of E. coli O 174 and O 177 were sequenced, and associated genes were assigned functions on the basis of homology. Two genes, each specific for E. coli O 174 and O 177, were identified. PCR assays based on the O-antigen-specific genes were developed and tested on 25 clinical and environmental isolates of those two serogroups as well as 26 isolates of other O serogroups. As little as 1 pg per mul of chromosomal DNA and as few as 0.1 CFU per g of pork and water samples were detected for either strain. The PCR assays established in this study were shown to be highly sensitive and reliable and could be the method of choice for detection of these two human pathogens from clinical, food, and other environmental samples.


Anti-inflammatory effects of Perillae Herba ethanolic extract against TNF-α/IFN-γ-stimulated human keratinocyte HaCaT cells.
Perillae Herba is a perennial plant that is widely distributed throughout Asia. The leaves of Perillae Herba have been widely used to treat various diseases, such as cold due to wind-cold, headache, cough, abdominal fullness, distention, and fish and crab poisoning. To assess the anti-inflammatory activity of Perillae Herba leaf ethanolic extract (PHE) in human keratinocytes, we measured the tumor necrosis factor (TNF)-α/interferon (IFN)-γ-induced mRNA expression and production of proinflammatory chemokines such as thymus and activation-regulated chemokines; regulated on activation, normal T cell expressed and secreted; interleukin (IL)-6; and IL-8 in HaCaT cells. We evaluated the ability of PHE to decrease the expression of proinflammatory marker proteins, such as mitogen-activated protein kinase (MAPK), STAT-1, and NK-κB, using western blot analysis and immunocytochemistry. PHE inhibited activation of p38, ERK, and JNK and suppressed the phosphorylation of STAT-1 and NK-κB in TNF-α/IFN-γ-stimulated HaCaT cells. PHE also suppressed chemokine mRNA and protein levels in TNF-α/IFN-γ-stimulated HaCaT cells. PHE appears to regulate chemokine formation by inhibiting activation of MAPK, as well as the STAT-1 and NK-κB pathways. PHE suppresses the expression and production of TNF-α/IFN-γ-stimulated proinflammatory chemokines by blocking NF-κB, STAT-1, and MAPK activation.


Effect of prenalterol on contractility, relaxation, and filling phase in coronary artery disease patients with previous myocardial infarction.
Twelve postmyocardial infarction patients, with angiographically proven asynergic areas, but without overt cardiac failure, were treated with prenalterol intravenously, (a new cardioselective inotropic agent) at a dose of 30 micrograms/kg. The aim of this study was to test the usefulness and safety of this new drug in postmyocardial infarction patients, monitoring systolic and diastolic acute hemodynamic changes. Significant improvement in cardiac contractility was demonstrated by the increase of ejection fraction (+23%), stroke volume index (+22%), cardiac output (+41%), positive dp/dt (+82%), and Vmaxd (+39%). Left ventricular systolic, mean aortic, and mean right atrial pressure remained unchanged; a slight decrease in end-diastolic volume index (-2%) occurred. A significant increase in heart rate (from 66 +/- 7 to 85 +/- 14 beats/min), without electrocardiographic changes or subjective complaints of angina pectoris, was observed. Segmental wall motion analysis showed an improved systolic shortening in normal (from 34 to 44%) and in asynergic areas (from 10 to 18%), whereas no changes were observed in dyskinetic areas. The relaxation and filling phase also improved, as tested by negative dp/dt (+39%), time constant of relaxation (-36%), and by indices of ventricular compliance. Side effects consisted of a slight feeling of tension in two patients and a short episode of ventricular tachycardia (5 beats) in another patients. No episode of angina pectoris was observed. These results, with special emphasis on lack of exacerbation of pre-existing ischemia (although obtained in patients without evident heart failure), suggest the potential usefulness of prenalterol in acute cardiac failure, as well as postmyocardial infarction low-output syndrome.


Diagnosis and Initial Emergency Department Management of Subarachnoid Hemorrhage.
Atraumatic subarachnoid hemorrhage represents a small proportion of strokes, but is a true medical emergency that results in significant morbidity and mortality. Making the diagnosis can be challenging and misdiagnosis can result in devastating consequences. There are several time-dependent diagnostic and management considerations for emergency physicians and other frontline providers. This article reviews the most up-to-date literature on the diagnostic workup of subarachnoid hemorrhage, avoiding misdiagnosis, and initial emergency department management recommendations.


Propranolol for the treatment of hypertension in pregnancy.
Twenty-five women were treated with propranolol during 26 pregnancies complicated by hypertension. The fetal wastage, which had been 48 per cent before treatment with propranolol was reduced to 15.4 per cent, with one missed abortion and three stillbirths. Of the 22 liveborn infants 2 were small-for-dates but all 22 had Apgar scores of 9 or 10 at five minutes. There were no congenital anomalies in 25 viable infants and none of the 22 liveborn infants had clinical or laboratory evidence of hypoglycaemia. The blood pressure was controlled in 17 of 19 patients taking propranolol alone (40 to 160 mg/day) and in 6 of 7 taking propranolol with diuretics.


Translocation t(2;7)(p11;q21) associated with the CDK6/IGK rearrangement is a rare but recurrent abnormality in B-cell lymphoproliferative malignancies.
Structural abnormalities of chromosome 7q have been regularly reported in chronic B-cell lymphoproliferative disorders. They include chromosomal translocations involving 7q21, leading to overexpression of the CDK6 gene. Three different translocations, t(7;14)(q21;q32), t(7;22)(q21;q11), and t(2;7)(p11;q21), leading to the juxtaposition of the CDK6 gene with a immunoglobulin gene enhancer during B-cell differentiation, have been described. In the past 2 years, we identified three patients with lymphoproliferative malignancy associated with a t(2;7)(p11;q21). Fluorescent in situ hybridization using an IGK probe and a library of bacterial artificial chromosome (BAC) clones located in bands 7q21.2 and 7q21.3, containing CDK6, revealed that the telomeric part of the IGK probe was translocated on the der(7) within a 51-kb region upstream of the transcriptional start site of CDK6. A total of 23 patients with indolent B-cell lymphoproliferative disorders and juxtaposition of the IG and CDK6 genes, including 20 with IGK and CDK6 juxtaposition, have been reported thus far. This rearrangement leads to the overexpression of CDK6, which encodes a cyclin-dependent protein kinase involved in cell cycle G1 phase progression and G1/S transition.


Safety and efficacy of low-dose esterified estrogens and methyltestosterone, alone or combined, for the treatment of hot flashes in menopausal women: a randomized, double-blind, placebo-controlled study.
This study evaluated safety and efficacy of esterified estrogens and methyltestosterone administered alone or in combination for the treatment of hot flashes in menopausal women. The 0.30-mg esterified estrogens and 0.30-mg methyltestosterone combination was the lowest effective dose, and our results are consistent with the known safety profile of estrogen and androgen combination products.


Women: Diet, Cardiometabolic Health, and Functional Medicine.
Cardiovascular disease was previously considered a problem for men, despite more women dying annually from cardiovascular causes. As a result of flawed assumptions, clinical research relied on men, leading to biased guidelines and treatment protocols. Emerging evidence demonstrates that women have unique sex and gender differences that must be considered, particularly their cardiometabolic health, in a systems biology framework that can be organized into a functional medicine model of care. Our aim is to help clinicians recognize the value added by functional medicine in the assessment of women vis-à-vis cardiometabolic pathways, phenotypes, and differences in risk compared with men.


Increased risk of incident HIV during pregnancy in Rakai, Uganda: a prospective study.
HIV acquisition is significantly higher during pregnancy than in the postpartum period. We did a prospective study to estimate HIV incidence rates during pregnancy and lactation. We assessed 2188 HIV-negative sexually active women with 2625 exposure intervals during pregnancy and 2887 intervals during breastfeeding, and 8473 non-pregnant and non-lactating women with 24,258 exposure intervals. Outcomes were HIV incidence rates per 100 person years and incidence rate ratios estimated by Poisson multivariate regression, with the non-pregnant or non-lactating women as the reference group. We also assessed the husbands of the married women to study male risk behaviours. HIV incidence rates were 2.3 per 100 person years during pregnancy, 1.3 per 100 person years during breastfeeding, and 1.1 per 100 person years in the non-pregnant and non-lactating women. The adjusted incidence rate ratios were 2.16 (95% CI 1.39-3.37) during pregnancy and 1.16 (0.82-1.63) during breastfeeding. Pregnant women and their male partners reported significantly fewer external sexual partners than did the other groups. In married pregnant women who had a sexual relationship with their male spouses, the HIV incidence rate ratio was 1.36 (0.63-2.93). In married pregnant women in HIV-discordant relationships (ie, with HIV-positive men) the incidence rate ratio was 1.76 (0.62-4.03). The risk of HIV acquisition rises during pregnancy. This change is unlikely to be due to sexual risk behaviours, but might be attributable to hormonal changes affecting the genital tract mucosa or immune responses. HIV prevention efforts are needed during pregnancy to protect mothers and their infants.


Exploration of more effective neurorrhaphy in facial nerve reconstruction: A comparison focusing on the difference of neural window size and condition of the neurorrhaphy site.
Various techniques have been introduced for reconstruction of the facial nerve. An improved method of neurorrhaphy to achieve satisfactory mimetic muscle function is required. We made and compared three different neurorrhaphy models to elucidate the effect of neural window size and condition of the neurorrhaphy site on axonal regeneration. Rats were divided into four groups: group A, untreated incomplete palsy; group B, treatment by end-to-side neurorrhaphy through a small perineural window; group C, treatment by side-to-side neurorrhaphy through a large perineural window; and group D, treatment by side-to-side neurorrhaphy through a small perineural window. After surgery, mimetic muscle movement was evaluated. Retrograde-labeled neurons through the facial nuclei were counted, and mimetic muscle specimens were examined. The axon number was counted in nerve specimens. The facial palsy scores of groups B and C were significantly greater than those of groups A and D. With regard to the number of neurons at the facial nuclei, groups B and C had more neurons than groups A and D. Group D had significantly more neurons than group A. With respect to the number of axons, groups B, C, and D had significantly greater numbers than group A, but there were no significant differences between the reconstructed groups. Window size and condition of the neurorrhaphy site, which affected mainly the number of axons, influenced axonal regeneration in nerve reconstruction. This result indicates the possibility of obtaining a better result for facial nerve or other peripheral nerve reconstruction with a tidbit of operative artifice.


Molecular characterization of reticuloendotheliosis virus insertions in the genome of field and vaccine strains of fowl poxvirus.
Evidence of the widespread occurrence of reticuloendotheliosis virus (REV) sequence insertions in fowl poxvirus (FPV) genome of field isolates and vaccine strains has increased in recent years. However, only those strains carrying a near intact REV provirus are more likely to cause problems in the field. Detection of the intact provirus or REV protein expression from FPV stocks has proven to be technically difficult. The objective of the present study was to evaluate current and newly developed REV and FPV polymerase chain reaction (PCR) assays to detect the presence of REV provirus in FPV samples. The second objective was to characterize REV insertions among recent "variant" FPV field isolates and vaccine strains. With REV, FPV, and heterologous REV-FPV primers, five FPV field isolates and four commercial vaccines were analyzed by PCR and nucleotide sequence analysis. Intact and truncated REV 5' long terminal repeat (LTR) sequences were detected in all FPV field isolates and vaccine strains, indicating heterogeneous REV genome populations. However only truncated 3' LTR and envelope sequences were detected among field isolates and in one vaccine strain. Amplifications of the REV envelope and 3' LTR provided strong evidence to indicate that these isolates carry a near intact REV genome. Three of the four FPV vaccine strains analyzed carried a solo complete or truncated 5' LTR sequence, indicating that intact REV provirus was not present. Comparison of PCR assays indicated that assays amplifying REV envelope and REV 3' LTR sequences provided a more accurate assessment of REV provirus than PCR assays that amplify the REV 5' LTR region. Therefore, to differentiate FPV strains that carry intact REV provirus from those that carry solo 5' LTR sequences, positive PCR results with primers that amplify the 5' LTR should be confirmed with more specific PCR assays, such as the envelope, or the REV 3' LTR PCR.


Developmental consequences of short apneas and periodic breathing in preterm infants.
We investigated the relationship between respiratory events experienced before and after hospital discharge and developmental outcomes at 6 months corrected age (CA). Preterm infants born between 28-32 weeks gestational age (GA) were studied at 32-36 weeks postmenstrual age (PMA), 36-40 weeks PMA, 3- and 6-months CA. Percentage total sleep time (%TST) with respiratory events (isolated apneas, sequential apneas and periodic breathing (PB)) at each study was calculated. Stepwise multiple linear regressions determined significant predictors of developmental outcomes at 6 months. %TST with respiratory events at term were significant predictors of language (R2 = 0.165, β = -0.416) and motor (R2 = 0.180, β = -0.485) composite scores of the Bayley Scales of Infant Development at 6 months, independent of GA, birth weight and sex. In clinically stable very preterm infants at term equivalent age, time spent having respiratory events, was related to a reduction in language and motor outcomes at 6 months.


Guinea pig very low density lipoproteins are a good substrate for lipoprotein lipase.
In contrast to plasma from most other animals, guinea pig plasma causes little or no stimulation of lipoprotein lipase activity. Very low density lipoproteins (VLDL) isolated by ultracentrifugation of guinea pig serum caused a definite stimulation of lipase activity, whereas the infranatant inhibited the activity. Gel filtration in 5 M guanidinium hydrochloride of delipidated VLDL demonstrated that the activation was caused by a low molecular weight protein. The VLDL themselves were hydrolized at similar rates as human VLDL both by guinea pig and by bovine lipoprotein lipases. Thus, guinea pig VLDL contain an activator for lipoprotein lipase analogous to that in other animals and there is enough of the activator to support rapid hydrolysis of the VLDL lipids by the lipase.


Structure-property studies on the antioxidant activity of flavonoids present in diet.
The screening of natural flavonoids for their bioactivity as antioxidants is usually carried out by determinination of their profile as chain-breaking antioxidants, by the evaluation of their direct free radical-scavenging activity as hydrogen- or electron-donating compounds. Since this may not be the only mechanism underlying the antioxidant activity it is important to check the ability of these compounds to act as chelators of transition metal ions. Accordingly, in the present study the acidity constants of catechin and taxifolin, as well as the formation constants of the corresponding copper (II) complexes, were investigated by potentiometry and/or spectrophotometry. Moreover, a detailed quantitative examination of the coordination species formed is presented. In addition, the partition coefficients of both catechin and taxifolin in a biomimetic system (micelles) were determined, since these properties may also contribute to the antioxidant behavior of this type of compound. The log P values determined depend on the electrostatic interactions of the compounds with the differently charged micelles (the highest values were obtained for zwitterionic and cationic micelles). The prooxidant behavior of the compounds was assessed through the oxidation of 2'-deoxyguanosine, induced by a Fenton reaction, catalyzed by copper. The data obtained reveal that the flavonoids under study did not present prooxidant activity, in this particular system. The results obtained are evidence of a clear difference among the pKa, the complexation properties, and the lipophilicity of the flavonoids studied, which can partially explain their distinct antioxidant activity. The most stable geometries of the free compounds were determined by theoretical (ab initio) methods, in order to properly account for the electron correlation effects which occur in these systems, thus allowing a better interpretation of the experimental data.


The rewarding recovery study: a randomized controlled trial of incentives for alcohol and drug abstinence with a rural American Indian community.
To test if contingency management (CM) interventions for alcohol and drug abstinence were associated with increased alcohol and drug abstinence among American Indian adults with alcohol dependence who also use drugs. In this 2 × 2 factorial randomized controlled trial, American Indian adults with alcohol dependence who also used drugs were randomized to four conditions: (1) incentives for submission of urine samples only (control condition), (2) CM incentives for alcohol abstinence, (3) CM incentives for drug abstinence or (4) CM incentives for abstinence from both alcohol and drugs. A Northern Plains Reservation in the United States. A total of 114 American Indian adults aged 35.8 years (standard deviation = 10.4); 49.1% were male. Participants received incentives if they demonstrated abstinence from alcohol (CM for alcohol, n = 30), abstinence from their most frequently used drug (CM for drugs, n = 27) or abstinence from both alcohol and their most frequently used drug (CM for alcohol and drugs, n = 32) as assessed by urine tests. Controls (n = 25) received incentives for submitting urine samples only. Primary outcomes were urine ethyl glucuronide (alcohol) and drug tests conducted three times per week during the 12-week intervention period. Data analyses included listwise deletion and multiple imputation to account for missing data. The three CM groups were significantly (P < 0.05) more likely to submit alcohol-abstinent urine samples compared with the control condition, with odds ratios ranging from 2.4 to 4.8. The CM for drugs (OR = 3.2) and CM for alcohol and drugs (OR = 2.5) were significantly more likely to submit urine samples that indicated drug abstinence, relative to the control condition (P < 0.05). However, these differences were not significant in multiple imputation analyses (P > 0.05). Contingency management (CM) incentives for abstinence were associated with increased alcohol abstinence in American Indian adults diagnosed with alcohol dependence who also used drugs, living on a rural reservation. The effect of CM incentives on drug abstinence was inconclusive.


Direct immunofluorescence testing in vasculitis-A single institution experience with Henoch-Schönlein purpura.
Direct immunofluorescence (DIF) panels (IgG, IgA, IgM, C3 and fibrinogen) are ordered for clinically suspected vasculitis, with frequently negative results. Cases submitted for DIF and histology (2010-2014) with "vasculitis" in the clinical data were examined, and the electronic medical record reviewed for clinical suspicion of Henoch-Schönlein purpura (HSP). Peri/intravascular IgA was considered positive, other reactants non-specific and no immunoreactivity negative. Vasculitis was the given indication for 20% (258/1318) of DIF studies. HSP was clinically suspected in 36% (95/258). In this setting, leukocytoclastic vasculitis (LCV) was common (66%, 63/95) and DIF was positive in 43% (27/63). One hundred percentage of DIF+ had LCV+. In cases without HSP suspicion, 26% (42/163) were LCV+ and <1% DIF+. Of the 258 cases, LCV+ greatly enriched for DIF+ (105/258 LCV+ with 28/105 [27%] DIF+), captured 100% of HSP and included cases with non-specific DIF/etiologic findings. In LCV cases, DIF positivity was not seen, HSP was not diagnosed and non-specific DIF findings were common. LCV is an H&E-based histopathologic diagnosis that can have positive, negative and non-specific DIF results that are rarely contributory except in the setting of HSP, where DIF is best utilized with IgA as the sole immunoreactant. H&E-based triage of DIF orders is recommended.


A longitudinal assessment of racial and ethnic inequities in food environment exposure and retail market concentration.
This paper assesses trends in food environment and market concentration and racial and ethnic inequities in food environment exposure and food retail market concentration at the US census tract level from 2000 to 2019. Establishment-level data from the National Establishment Time Series were used to measure food environment exposure and food retail market concentration. We linked that dataset to race, ethnicity and social vulnerability information from the American Community Survey and the Agency for Toxic Substances and Disease Registry. A geospatial hot-spot analysis was conducted to identify relatively low and high healthy food access clusters based on the modified Retail Food Environment Index (mRFEI). The associations were assessed using two-way fixed effects regression models. Census tracts spanning all US states. 69 904 US census tracts. The geospatial analysis revealed clear patterns of areas with high and low mRFEI values. Our empirical findings point to disparities in food environment exposure and market concentration by race. The analysis shows that Asian Americans are likelier to live in neighbourhoods with a low food environment exposure and low retail market concentration. These adverse effects are more pronounced in metro areas. The robustness analysis for the social vulnerability index confirms these results. US food policies must address disparities in neighbourhood food environments and foster a healthy, profitable, equitable and sustainable food system. Our findings may inform equity-oriented neighbourhood, land use and food systems planning. Identifying priority areas for investment and policy interventions is essential for equity-oriented neighbourhood planning.


The antitumour activity of alkylating agents is not correlated with the levels of glutathione, glutathione transferase and O6-alkylguanine-DNA-alkyltransferase of human tumour xenografts. EORTC SPG and PAMM Groups.
Twenty-three human xenografts, including five colon, five gastric, nine lung (three small cell lung cancer) and four breast carcinomas, were investigated for their sensitivity to nitrosoureas, dacarbazine (DTIC), cyclophosphamide (CTX) and cisplatin (DDP). In 12 cases, at least one of the drugs produced complete or partial remission, in 2, a minor regression was observed and in the other 9, treatment was ineffective. The level of sensitivity to each drug, using a score from 1 to 5, was correlated to three biochemical parameters reported to be involved in resistance to alkylating agents: glutathione (GSH), glutathione transferase (GST) and O6-alkylguanine-DNA-alkyltransferase (AGT). A wide variability was found in these parameters in the xenografts investigated. No correlation was found between any of the three parameters and sensitivity to the drugs used or between sensitivity to one drug and to any of the other drugs tested. These results illustrate the complexity of the question of resistance to alkylating agents and indicate that, at least in xenografts, the biochemical parameters examined are not predictive of response to alkylating agents.


Identification in human erythrocytes of mono(ADP-ribosyl) protein hydrolase that cleaves a mono(ADP-ribosyl) Gi linkage.
A novel enzymatic activity, the hydrolysis of linkages between mono(ADP-ribose) and cysteine residues in Gi prepared by eukaryotic ADP-ribosyltransferase C [(1988) J. Biol. Chem. 263, 5485-5489] was found in the cytosol of human erythrocytes. The mono(ADP-ribosyl) Gi hydrolase, tentatively named ADP-ribosyl protein hydrolase C was partially purified by sequential chromatographies on DEAE-cellulose and Blue Sepharose. This enzyme catalyzes the release of ADP-ribose from mono(ADP-ribosyl) Gi. Its activity was enhanced by Ca2+ and inhibited by ADP-ribose. The presence of this enzyme in eukaryotic cells suggests that endogenous mono(ADP-ribosyl)ation of Gi is a reversible post-translational modification.


Diagonal band projection towards the hypothalamic supraoptic nucleus: light and electron microscopic observations in the rat.
Supraoptic nucleus (SON) neurons receive a prominent gamma-amino-butyric acid (GABA) input. This study evaluated the hypothesis, partly on the basis of recent electrophysiological data, that this innervation might arise from GABAergic neurons located in the ventral diagonal band of Broca area. For retrograde transport studies, pentobarbital-anesthetized male Long-Evans rats received 0.03-0.20-microliter injections of a suspension of rhodamine tagged latex microspheres into the SON. In two cases where such injections were confined to the SON, less than 60 retrogradely labeled neurons were detected in the ipsilateral diagonal band. In three animals where injections extended into the perinuclear zone around the SON, more than 2,000 retrogradely labeled cells were counted in the ipsilateral diagonal band. For anterograde transport studies, another group of animals received either 30% horseradish peroxidase (HRP) in 0.5% poly-L-ornithine (0.05-0.10 microliter injections) or Phaseolus vulgarus (iontophoresed from a 2% solution) into the diagonal band. After survivals of 18-24 hours (HRP) or 5 days (PHAL-L) labeled axon terminals invested the perinuclear zone above the SON. The presence of just a single fiber within the nucleus indicated a minor projection to the SON itself. The HRP-injected material was processed for ultrastructural examination and revealed dense HRP-labeled axon terminals in this perinuclear zone, most often (98%) forming axodendritic appositions. A postembedding colloidal gold technique to visualize GABA-synthesizing terminals revealed that fewer than 5% of these perinuclear HRP-labeled terminals also exhibited GABA-like immunoreactivity. Within the SON, where GABAergic axon terminals are abundant, few (less than 5%) GABAergic terminals contained HRP.(ABSTRACT TRUNCATED AT 250 WORDS)


Transcriptomic analysis identifies novel candidates in cardiorenal pathology mediated by chronic peritoneal dialysis.
Peritoneal dialysis (PD) is associated with increased cardiovascular (CV) risk. Studies of PD-related CV pathology in animal models are lacking despite the clinical importance. Here we introduce the phenotypic evaluation of a rat model of cardiorenal syndrome in response to chronic PD, complemented by a rich transcriptomic dataset detailing chronic PD-induced changes in left ventricle (LV) and kidney tissues. This study aims to determine how PD alters CV parameters and risk factors while identifying pathways for potential therapeutic targets. Sprague Dawley rats underwent Sham or 5/6 nephrectomy (5/6Nx) at 10 weeks of age. Six weeks later an abdominal dialysis catheter was placed in all rats before random assignment to Control or PD (3 daily 1-h exchanges) groups for 8 days. Renal and LV pathology and transcriptomic analysis was performed. The PD regimen reduced circulating levels of BUN in 5/6Nx, indicating dialysis efficacy. PD did not alter blood pressure or cardiovascular function in Sham or 5/6Nx rats, though it attenuated cardiac hypertrophy. Importantly PD increased serum triglycerides in 5/6Nx rats. Furthermore, transcriptomic analysis revealed that PD induced numerous changed transcripts involved with inflammatory pathways, including neutrophil activation and atherosclerosis signaling. We have adapted a uremic rat model of chronic PD. Chronic PD induced transcriptomic changes related to inflammatory signaling that occur independent of 5/6Nx and augmented circulating triglycerides and predicted atherosclerosis signaling in 5/6Nx LV tissues. The changes are indicative of increased CV risk due to PD and highlight several pathways for potential therapeutic targets.


Diagnostic and prognostic significance of electroencephalography with intravenous diazepam in epilepsy.
Thirty cases of intractable epilepsy in children were investigated to observe the correlation between the suppression of seizure discharges to intravenous diazepam and the type of seizure or effects of subsequent therapy. Suppression of seizure discharges were bilaterally poor in 75% of the cases with infantile spasms and 89% of cases with Lennox syndrome and other generalized seizures while it was unilaterally poor in 80% of the cases with focal or unilateral seizures. ACTH or steroid therapy was clinically and electroencephalographically effective in 80% of the cases with good suppression responses and in none of cases with good suppression that was resistant to the therapy. On the other hand, clinical seizures were not controlled in 73% of the cases showing poor suppression and EEG did not reveal improvement in 82% of the cases with poor suppression. EEG with intravenous diazepam is valuable for understanding the pharmacophysiological mechanism of epilepsy and it may be possible to select cases as candidates for ACTH or steroid therapy using this technique.


Small bowel MRI: comparison of a polyethylene glycol preparation and water as oral contrast media.
To compare water and a polyethylene glycol (PEG) preparation as potential oral contrast media for magnetic resonance imaging (MRI) of the small bowel. Twenty-two healthy volunteers underwent separate MRI examinations after drinking up to two liters of water or PEG preparation. Small bowel images were obtained every 10 minutes for at least two hours using breath-hold single shot half-Fourier imaging, including both thick section projection and thin section images. Examinations were evaluated by two radiologists in consensus, blinded to the volunteer and contrast details, for arrival at the terminal ileum, transit time, and demonstration of small bowel segments. The PEG preparation was significantly better than water at reaching the terminal ileum (PEG 21/22 volunteers [95.45%], water 14/22 volunteers [63.6%], P = 0.04). There was no significant difference in the mean transit time (water 51 +/- 48 minutes, PEG 37.7 +/- 22 minutes) or in the demonstration of the stomach, duodenum, and jejunum, but the PEG preparation was significantly better at demonstrating the ileum (P = 0.005) and terminal ileum (P = 0.002). A PEG preparation is significantly better than water as an oral contrast medium for demonstrating the distal small bowel during breath-hold T2-weighted MRI.


Development and characterization of bZIP transcription factor based SSRs in wheat.
Assessment of existing diversity is the key for germplasm conservation and crop improvement. Wheat (Triticum aestivum L.) is among the most important cereal crop and consumed by two billion world's populations. DNA-based markers are predominantly used for diversity characterization because they are easy to develop and not influenced by environment. Among them microsatellites (simple sequence repeats, SSRs) are most suitable due to their genome-wide distribution, hypervariability and reproducibility for their applications in diversity, genetic improvement, and molecular breeding. bZIP transcription factors play major roles in plants in light and stress signalling, seed development, and defence. A total of 846 SSRs were identified from 370 wheat cDNA sequences and a sub-set of 35 polymorphic TabZIPMS (TriticumaestivumbZIP MicroSatellites) was used for diversity and genetic structure analysis of 92 Indian wheat varieties and related species. 114 SSR variants ranging from 2 to 5 per SSR locus were detected for 35 SSRs in the varieties. Average polymorphic information content (PIC) and observed heterozygosity was found to be 0.135 and 0.838, respectively. Thirty-four SSRs showed cross-transferability into different related species. Combined Bayesian model and Jaccard's similarity based genetic clustering analysis revealed two clusters of 80 bread wheat varieties and one separate cluster of related species. In this study, a total 35 novel bZIP-derived SSRs were identified in a set 370 bZIP genes and shown high polymorphism and cross-species transferability in wheat. The findings provide resources for future utilization in genetic resource conservation, trait introgression, breeding and varietal development.


Successful treatment of a cohort of infants with neonatal diabetes using insulin pumps including data on genetics and estimated incidence.
Neonatal diabetes is rare, and treatment is challenging. We present aspects on treatment, genetics and incidence. This was a prospective cohort study including all cases in our study area in Sweden. We compared with data from the National Diabetes Registry, the Neonatal Quality Register and the National Patient Register. In the 19-year study period January 1, 1998 to December 31, 2016, we treated seven infants, five of them boys. Six patients used a subcutaneous insulin pump, and the smallest patient started at a weight of 938 g. Most important was for the pump to deliver minute doses of insulin and the design of cannulas and tubing. All patients could stop insulin treatment at 17-145 days of age. One patient relapsed at age 4.5 years. Four patients used the insulin pump after discharge. A mutation was identified in five patients, and this included all patients born after 30 weeks of gestation. The incidence of neonatal diabetes was 2/1 00 000, higher than previously estimated for Europe. Similar but lower incidences were reported in the registries. Insulin pumps were safe in neonatal diabetes. All seven cases were transient. Neonatal diabetes was more common in our area than reported from Europe.


Melatonin-and serotonin-stimulated release of vasopressin from rat neurohypophysis in vitro.
In order to study the control of vasopressin-release, the effect of a series of potential agents was studied in an in vitro perifusion system of rat neurohypophysis after in vivo treatment with nialamide, a monoamine oxidase inhibitor. In this system, metlatonin stimulated vasopressin-release in a dose-dependent manner (1 x 10-8 to 1 x 10-3 M). Serotonin (1 x 10-3 M) also led to a significant increase of vasopressin-release whereas quipazine (1 x 10-3 M), a putative serotonin agonist and monoamine oxidase inhibitor, caused a 3-fold stimulation of the release of the neurohormone. The stimulatory effects of melatonin and serotonin were prevented by omission of Ca2+ combined to an excess of Mg2+ (12mM) in the perifusion medium. 1 x 10-6 M somatostatin did not affect basal or melatonin-stimulated vasopressin-release. These results show that melatonin and serotonin can have a direct stimulatory effect on vasopressin release at the neurohypophyseal level.


A beam hardening and dispersion correction for x-ray dark-field radiography.
X-ray dark-field imaging promises information on the small angle scattering properties even of large samples. However, the dark-field image is correlated with the object's attenuation and phase-shift if a polychromatic x-ray spectrum is used. A method to remove part of these correlations is proposed. The experimental setup for image acquisition was modeled in a wave-field simulation to quantify the dark-field signals originating solely from a material's attenuation and phase-shift. A calibration matrix was simulated for ICRU46 breast tissue. Using the simulated data, a dark-field image of a human mastectomy sample was corrected for the finger print of attenuation- and phase-image. Comparing the simulated, attenuation-based dark-field values to a phantom measurement, a good agreement was found. Applying the proposed method to mammographic dark-field data, a reduction of the dark-field background and anatomical noise was achieved. The contrast between microcalcifications and their surrounding background was increased. The authors show that the influence of and dispersion can be quantified by simulation and, thus, measured image data can be corrected. The simulation allows to determine the corresponding dark-field artifacts for a wide range of setup parameters, like tube-voltage and filtration. The application of the proposed method to mammographic dark-field data shows an increase in contrast compared to the original image, which might simplify a further image-based diagnosis.


The impact of Hfq-mediated sRNA-mRNA interactome on the virulence of enteropathogenic Escherichia coli.
Small RNAs (sRNAs) exert their regulation posttranscriptionally by base pairing with their target mRNAs, often in association with the RNA chaperone protein Hfq. Here, integrating RNA-seq–based technologies and bioinformatics, we deciphered the Hfq-mediated sRNA-target interactome of enteropathogenic Escherichia coli (EPEC). The emerging network comprises hundreds of sRNA-mRNA pairs, including mRNAs of virulence-associated genes interacting with known sRNAs encoded within the core genome, as well as with newly found sRNAs encoded within pathogenicity islands. Some of the sRNAs affect multiple virulence genes, suggesting they function as hubs of virulence control. We further analyzed one such sRNA hub, MgrR, and one of its targets identified here, the major virulence-associated chaperon, cesT. We show that MgrR adjusts the level of EPEC cytotoxicity via regulation of CesT expression. Our results reveal an elaborate sRNA-mRNA interactome controlling the pathogenicity of EPEC and reinforce a role for sRNAs in the control of pathogen-host interaction.


Implications of short and long term (30 days) sorption on the desorption kinetic of trace metals (Cd, Zn, Co, Mn, Fe, Ag, Cs) associated with river suspended matter.
The desorption kinetic of trace elements (Cd, Zn, Co, Mn, Fe, Ag, and Cs) associated with Loire river natural suspended particulate matter (SPM; 0.4-63 microm) was followed up on times varying from 0.5 h to 30 days, from SPM previously contaminated during 1 h, 24 h and 30 days. Long term sorption kinetics indicated that the difference between sorption occurring during the period 0-30 days (time investigated in this study) and the period 0-48 h (time often used for sorption experiments) ranges from few to 25% according to the element. Desorption kinetics show that, whatever the age of the complex formed during the sorption step, the release tends to equilibrium between complexed and dissolved elements equivalent to the equilibrium obtained for sorption after a given time. However, the time to get this equilibrium depends on the aging of the complex and on the element. All the above features indicate different types of complexes formation and strength of the binding according to the age of the complex and according to the element. Using a multi-compartmental model, simulating the transfer of metals between water and different types of particulate sites, the relationships between the parameters describing slow and rapid processes helped in explaining the "aging" effect observed.


Prophylactic effects of pirenzepine (M1-blocker) on intraoperative stress ulcer: comparison with an H2-blocker.
Patients under general anesthesia were treated with either an H2-blocker, ranitidine 50 mg, or an M1-blocker, pirenzepine 10 mg, and the effects of the two drugs on the gastric mucosa were compared by the measurement of the gastric juice pH and viscosity. The results showed that pirenzepine increased the gastric juice pH sufficiently while maintaining the gastric juice viscosity, and that ranitidine maintained the gastric juice pH higher than pirenzepine while decreasing the gastric juice viscosity. These results suggest that treatment with pirenzepine may have advantages in the prevention of stress ulcers.


Stochastic rotational catalysis of proton pumping F-ATPase.
F-ATPases synthesize ATP from ADP and phosphate coupled with an electrochemical proton gradient in bacterial or mitochondrial membranes and can hydrolyse ATP to form the gradient. F-ATPases consist of a catalytic F1 and proton channel F0 formed from the alpha3beta3gammadelta and ab2c10 subunit complexes, respectively. The rotation of gammaepsilonc10 couples catalyses and proton transport. Consistent with the threefold symmetry of the alpha3beta3 catalytic hexamer, 120 degrees stepped revolution has been observed, each step being divided into two substeps. The ATP-dependent revolution exhibited stochastic fluctuation and was driven by conformation transmission of the beta subunit (phosphate-binding P-loop/alpha-helix B/loop/beta-sheet4). Recent results regarding mechanically driven ATP synthesis finally proved the role of rotation in energy coupling.


Optimal wavelengths for vein-selective photothermolysis.
Oxyhemoglobin (HbO(2)) has been regarded as the primary target chromophore for selective photothermolysis of vascular malformations. In theory, venous lesions might be better treated with wavelengths preferentially absorbed by deoxyhemoglobin (Hb). Wavelength-dependent fluence thresholds for photocoagulation of whole human blood were determined in glass capillary samples with measured oxygen saturation levels. Pulsed dye lasers at 585, 590, 595, 600, 633 nm, a 694 nm ruby laser, a 755 nm alexandrite laser, and a 1,064 nm Nd:Yag laser were used, all with 1.5-3 milliseconds pulse width and similar exposure spot size. Selectivity (a lower fluence threshold) for venous blood was maximal at 694 nm, and significant at 595, 600, 633, and 755 nm. At 633 nm, a wavelength with strong relative absorption by metHb, selectivity for venous blood was much less than expected. The Nd:YAG laser at 1,064 nm showed significant selectivity for arterial blood. Preferential photocoagulation of venous blood is possible at wavelengths with a high Hb/HbO(2) absorption coefficient ratio. Laser-induced metHb may also affect wavelength-dependent selective photothermolysis. Venular malformations such as port wine stains could potentially be treated more selectively with ~630-780 nm sources. Nd:YAG laser pulses at 1,064 nm tend to affect arterial more than venous blood.


[Natural feeding and its importance in forming local immunological protection in the gastrointestinal tract during the neonatal period].
The immune proteins content in the breast milk at the 1st week of lactation as contrasted to the data obtained by investigating immunoglobulins in feces of newborns breast-fed was studied. Both in the breast milk and in feces the A-class immunoglobulins being of great importance in the immunological protection of the mucosae prevail. A high level of immune proteins resistant to proteolytic enzymes ensures the state of local passive immunity in neonates receiving breast milk.


Carotid flow as a surrogate of the left ventricular stroke volume.
Transthoracic echocardiography (TTE) is a fundamental tool for hemodynamic monitoring in critical patients. It allows evaluating the left ventricle's stroke volume based on the measurement of the velocity-time integral (VTI) of the left ventricle outflow tract (LVOT). However, in the intensive care unit obtaining adequate echocardiographic views may present a challenge. We propose to measure, as a surrogate of the stroke volume, the carotid flow with a novel technique. This is an observational, prospective, and simple blind study, conducted in the intensive care unit of Sanatorio de los Arcos and Hospital Aleman, in Buenos Aires, Argentina. We measured the carotid systodiastolic flow (CSD) VTI and the carotid systolic flow (CS) VTI at the level of the left supraclavicular fossa and we compared it with the LVOT VTI obtained by TTE. We evaluated 43 subjects. Spearman's correlation coefficient between LVOT VTI and CS VTI was 0.81 (95% CI 0.67-0.89) and between LVOT VTI and CSD VTI was 0.89 (95% CI 0.81-0.94). The Bland-Altman method analysis of the 5-chamber apical window LVOT VTI compared to the CSD VTI showed a bias of - 0.2 (95% CI - 0.82 to 0.43), with a concordance interval between - 4.2 (95% CI - 5.2 to - 3.1) and 3.8 cm (95% CI 2.7 to 4.9). The percentage error was 37.9%. Almost 100% of the values fell within the concordance limits, and no trend was observed in bias across the spectrum of mean variables. Although the CSD VTI could not be interchangeable with the LVOT VTI, it could be considered as its surrogate.


Anticalins small engineered binding proteins based on the lipocalin scaffold.
Anticalins are a novel class of small, robust proteins with designed ligand-binding properties derived from the natural lipocalin scaffold. Due to their compact molecular architecture, comprising a single polypeptide chain, they provide several benefits as protein therapeutics, such as high target specificity, good tissue penetration, low immunogenicity, tunable plasma half-life, efficient Escherichia coli expression, and suitability for furnishing with additional effector functions via genetic fusion or chemical conjugation. The lipocalins are a widespread family of proteins that naturally serve in many organisms, including humans, for the transport, storage, or sequestration of small biological compounds like vitamins and hormones. Their fold is dominated by an eight-stranded antiparallel β-barrel, which is open to the solvent at one end. There, four loops connect the β-strands in a pairwise manner and, altogether, they form the entry to a ligand-binding site. This loop region can be engineered via site-directed random mutagenesis in combination with genetic library selection techniques to yield "Anticalins" with exquisite specificities-and down to picomolar affinities-for prescribed molecular targets of either hapten or antigen type. Several Anticalins directed against medically relevant disease targets have been successfully engineered and can be applied, for example, for the blocking of soluble signaling factors or cell surface receptors or for tissue-specific drug targeting. While natural lipocalins were already subject to clinical studies in the past, a first Anticalin has completed Phase I trials in 2011, thus paving the way for the broad application of Anticalins as a promising novel class of biopharmaceuticals.


The 'mauve factor' of schizophrenia and porphyria, 5-hydroxyhaemopyrrole lactam, has low pharmacological potency on guinea-pig ileum.
5-Hydroxyhaemopyrrole lactam, the 'mauve factor' reported in the urine of schizophrenics and porphyrics was found to inhibit electrically-stimulated contractions of guinea-pig ileum only at high concentrations (ID50 = 8.5 mM). This low potency makes it unlikely that the compound can account for neurotoxic effects in human porphyria.


[The TRALI syndrome--a life-threatening transfusion reaction].
Transfusion related acute lung injury (TRALI) is a serious complication of blood transfusion, characterized by non-cardiogenic lung oedema. We describe a case of TRALI due to granulocyte-specific antibodies. The 58-year-old patient received 2 units of fresh frozen plasma following colon surgery and within 30 min the patient developed an acute respiratory distress syndrome. Granulocyte-specific antibodies were found in one of the transfused plasma of a female blood donor who most likely became immunized against granulocyte alloantigens during her three pregnancies.


Calcium channel blockers as first line treatment for broad complex tachycardia with right bundle branch block: ingenuity or folly?
To study the response of regular broad-complex tachycardia (BCT) demonstrating right bundle branch block (RBBB) to treatment in the Emergency department (ED). Retrospective chart review of management of patients with BCT, RBBB without a history of ischaemic heart disease. A diagnosis of ventricular tachycardia (VT) was made if the ECG showed features such as atrioventricular dissociation, capture or fusion beats or if VT was demonstrated during electrophysiological studies (EPS). A total of 25 patients were eligible. Nineteen patients were given intravenous (IV) calcium channel blockers (either verapamil or diltiazem), as first line treatment. Of these, 18 converted to sinus rhythm and the other one patient subsequently converted with amiodarone. The remaining six patients were given IV adenosine (n=3), lignocaine (n=2) or amiodarone (n=1) as first line treatment but none of them were converted. Of these, four of them converted with IV calcium channel blockers eventually. Of the other two patients, who were both given lignocaine initially, one deteriorated haemodynamically with the use of verapamil and required synchronised cardioversion to convert. The other patient did not respond to amiodarone and synchronised cardioversion but was subsequently converted with verapamil. The difference between the success rate of calcium channel blockers and other anti-arrhythmics is statistically significant (P<0.01 by Fischer's exact method). Fourteen cases had diagnoses of VT, including the two patients given lignocaine. Five cases were found to have supraventricular tachycardia with aberrant conduction. Six cases did not have confirmed diagnoses. In patients presenting with BCT and RBBB but without underlying ischaemic heart disease, there is evidence to suggest that calcium channel blockers could effectively be used as the treatment of choice.


Transient troponin elevations in the blood of healthy young children.
Whilst cardiac troponin is considered to be indicative of cardiac necrosis, the advent of new high sensitivity assays for troponin suggests that troponin may be present in the blood of healthy persons. We have examined a cohort of healthy children and measured TnT in their blood. In this community-based prospective study, we collected blood samples from a large cohort of healthy children at ages 8, 10 and 12 years and measured hs-TnT on these samples. 727 children had at least one blood sample collected and of these 28.6% had at least one sample in which troponin was detected. The number of samples with a positive troponin at each period of blood collection varied between 14.0% and 20.3%. Statistical analysis showed that the prevalence of positive TnT varied between schools and the between school pattern was different in different years. Low concentrations of troponin may be seen transiently in healthy children with no evidence of cardiac injury. This between-school by year variation is highly significant and is suggestive of a transient infective agent.


Thioredoxins regulate the metabolic fluxes throughout the tricarboxylic acid cycle and associated pathways in a light-independent manner.
The metabolic fluxes throughout the tricarboxylic acid cycle (TCAC) are inhibited in the light by the mitochondrial thioredoxin (TRX) system. However, it is unclear how this system orchestrates the fluxes throughout the TCAC and associated pathways in the dark. Here we carried out a13C-HCO3 labelling experiment in Arabidopsis leaves from wild type (WT) and mutants lacking TRX o1 (trxo1), TRX h2 (trxh2), or both NADPH-dependent TRX reductase A and B (ntra ntrb) exposed to 0, 30 and 60 min of dark or light conditions. No 13C-enrichment in TCAC metabolites in illuminated WT leaves was observed. However, increased succinate content was found in parallel to reductions in Ala in the light, suggesting the latter operates as an alternative carbon source for succinate synthesis. By contrast to WT, all mutants showed substantial changes in the content and 13C-enrichment in TCAC metabolites under both dark and light conditions. Increased 13C-enrichment in glutamine in illuminated trxo1 leaves was also observed, strengthening the idea that TRX o1 restricts in vivo carbon fluxes from glycolysis and the TCAC to glutamine. We further demonstrated that both photosynthetic and gluconeogenic fluxes toward glucose are increased in trxo1 and that the phosphoenolpyruvate carboxylase (PEPc)-mediated 13C-incorporation into malate is higher in trxh2 mutants, as compared to WT. Our results collectively provide evidence that TRX h2 and the mitochondrial NTR/TRX system regulate the metabolic fluxes throughout the TCAC and associated pathways, including glycolysis, gluconeogenesis and the synthesis of glutamine in a light-independent manner.


Chemotherapy in the management of intraocular lymphoma.
Six patients with intraocular (vitreous) lymphomas were treated with high-dose intravenous cytosine arabinoside (Ara-C). Four patients were previously untreated, one patient had previously received ocular and central nervous system radiation therapy and relapsed, and one patient had previously received chemotherapy for systemic lymphoma. Five responses were observed: one complete and four partial. High-dose Ara-C is active in intraocular (vitreous) lymphoma, but complete response is uncommon. Adjunctive use of Ara-C in combination with ocular irradiation may be a useful form of therapy in this uncommon lymphoma.


Phosphorylation site mutated RB exerts contrasting effects on apoptotic response to different stimuli.
The retinoblastoma tumor-suppressor protein (RB) is an important regulator of cell cycle and apoptosis. RB is phosphorylated by cyclin-dependent protein kinase during cell cycle progression. A phosphorylation site mutated (PSM)-RB has previously been shown to cause G1 arrest and to interfere with S phase progression. In this study, we examined the effect of inducible PSM-RB expression on the apoptotic response to three different death stimuli: doxorubicin (DOXO), staurosporine (STS) and tumor necrosis factor (TNF) in Rat-16 cells. Induced expression of PSM-RB attenuated caspase activation by DOXO as a result of cell cycle arrest. STS has been shown to cause RB-dependent G1 arrest or apoptosis; however, expression of PSM-RB did not prevent caspase activation by STS. Surprisingly, induced expression of PSM-RB stimulated the apoptotic response to TNF in Rat-16 cells, which mostly undergo necrosis in the absence of PSM-RB. These results show that PSM-RB exerts disparate effects on apoptotic response to different stimuli, and that cell cycle arrest does not always associate with resistance to apoptosis.


Interaction between ether glycerophospholipid vesicles and serum proteins in vitro.
The effect of blood serum on the stability of small unilamellar vesicles consisting of 1-O-(1'-alkenyl)-2-acyl-sn-glycerophosphocholine (choline plasmalogen) or of the alkylacyl-, dialkyl- and diacyl analogs was evaluated by measuring either release of entrapped calcein or transfer of phospholipids from vesicles to serum high-density lipoproteins. The following order of stability was found: alkenyloleoylGPC greater than dioleoylGPC greater than di-O-octadecenylGPC greater than acyloleoylGPC = egg phosphatidylcholine = alkyloleoylGPC. AlkyloleoylGPC and acyloleoylGPC had aliphatic chain compositions similar to that of alkenyloleoylGPC. From the results obtained it is concluded that stability of vesicles in the presence of serum depends on vesicle size (larger vesicles are more stable) and on the type of bond (ether or ester) in position 2 of glycerol. Dioctadecenyl vesicles are about the same size as alkylacylGPC vesicles, but are significantly more stable in the presence of serum. Thus, it appears that an ester bond in position 2 of glycerol (which is replaced by an ether bond in dioctadecenylglycerol) favors the interaction of phospholipids with serum high-density lipoproteins or lipid-exchange proteins. The addition of cholesterol greatly enhances vesicle stability; among the vesicles used in this study those composed of alkenylacylGPC plus 30 mol% cholesterol were most resistant to disruption by serum. Experiments with sn-1 and sn-3 enantiomers of alkylacylGPC and diacylGPC have shown that interaction of vesicle membranes with serum components is independent of the steric configuration of vesicle phospholipids.