Beta-receptor stimulation by adrenaline elevates plasma noradrenaline and enhances the pressor responses to cold exposure and isometric exercise.
Isoprenaline 3.5-35 ng/kg/min, salbutamol 17.5-175 ng/kg/min and prenalterol 1-32 micrograms/kg were given intravenously (i.v.) to 10, 12 and nine subjects with borderline hypertension respectively. For a given chronotropic effect the effects on plasma noradrenaline were in the order: salbutamol greater than isoprenaline greater than prenalterol, indicating that the increase in noradrenaline was a beta 2-receptor-mediated response. This was supported by the antagonistic effects of atenolol and propranolol on this response. Adrenaline 30 ng/kg/min i.v. raised plasma adrenaline by a factor of 10 in 17 subjects with borderline hypertension. Plasma noradrenaline rose from 218 +/- 29 to 264 +/- 35 pg/ml (mean +/- s.e.m., P less than 0.05). The increments in blood pressure and plasma noradrenaline in response to cold exposure and isometric exercise were greater during the adrenaline infusion than during saline. This effect of adrenaline was antagonized by propranolol 0.5 mg i.v. These in vivo results lend support to the view that adrenaline may act as a physiological modulator of sympathetic neurotransmission by facilitating the release of noradrenaline through activation of presynaptic beta 2-type receptors.


Efficacy of antifungal therapy in a nonneutropenic murine model of zygomycosis.
Three isolates of zygomycetes belonging to three different genera (Rhizopus microsporus, Absidia corymbifera, and Apophysomyces elegans) were used to produce a disseminated infection in nonimmunocompromised mice. The therapeutic efficacy of amphotericin B, given intraperitoneally at doses ranging from 0.5 to 4.5 mg/kg of body weight/day, oral itraconazole at 100 mg/kg/day, and oral terbinafine at 150 mg/kg/day was evaluated in this model. The markers of antifungal efficacy were the median survival time, the mortality rate, and the percentage of infected organs. Organ culture was performed along with microscopic direct examinations of tissues to assess the presence of an active infection. An acute and lethal infection was obtained in untreated mice challenged with each of the three strains. The data obtained for direct examinations and qualitative cultures indicate that, due to the nonseptate nature of the hyphae, each technique gives different information and should be used together with the others. Against all three strains, amphotericin B yielded a 90 to 100% survival rate. Itraconazole was inactive against R. microsporus but significantly reduced mortality in mice infected with A. corymbifera or A. elegans. Terbinafine had no beneficial effects against R. microsporus and A. corymbifera despite documented absorption of the drug. Overall, only limited correlations were observed between MICs determined in vitro and in vivo efficacy of the drugs. The efficacy of itraconazole in these models of zygomycosis suggests that this drug, as well as the new azole compounds presently under development, warrants close evaluation.


Porous and Intercrossed PbI2-CsI Nanorod Scaffold for Inverted Planar FA-Cs Mixed-Cation Perovskite Solar Cells.
Depth-dependent growth of perovskite crystals remains challenging for high-performance perovskite solar cells made by a two-step spin-coating method. Effective morphology engineering approaches that enable depth-independent perovskite crystals growth and facile characterization technique to monitor subtle yet influential accompanying changes are urgently required. Here, a porous and intercrossed PbI2-(CsI)0.15 nanorods scaffold is prepared by integrating CsI incorporation with toluene dripping in ambient air, and the underlying mechanism is uncovered. With this porous scaffold and moisture-assisted thermal annealing, depth-independent growth of FA0.85Cs0.15PbI3 is achieved, as evidenced in the photoluminescent (PL) spectra acquired by exciting the perovskite film from the top and bottom individually. It is of broad interest that PL spectroscopy is demonstrated as a sensitive technique to monitor the depth-dependent growth of perovskite. Moreover, the resulting inverted planar FA0.85Cs0.15PbI3 perovskite solar cells deliver an efficiency of 16.85%, along with superior thermal and photostability. By incorporating 2% large-sized diammonium cation, propane-1,3-diammonium, the efficiency is further increased to 17.74%. Our work not only proposes a unique porous PbI2-(CsI)0.15 nanorods scaffold to achieve high-quality perovskite films in a two-step method but also highlights the distinctive advantage of PL spectroscopy in monitoring the depth-dependent quality of perovskite films.


Three-dimensional co-culture of human spermatogonial stem cells with Sertoli cells in soft agar culture system supplemented by growth factors and Laminin.
Application of a three-dimensional (3D) culture system for in vitro proliferation and differentiation of human spermatogonial stem cells (SSCs) is a useful tool for the investigation of the spermatogenesis process and the management of male infertility particularly in prepubertal cancer patients. The main purpose of this study was to investigate the proliferation of human SSCs co-cultured with Sertoli cells in soft agar culture system (SACS) supplemented by Laminin and growth factors. Testicular cells were isolated from testes of brain-dead patients and cultured in two-dimensional (2D) culture system for 3 weeks. After 3 weeks, functional SSCs were evaluated by xenotransplantation and also identification of cells was assessed by immunocytochemistry, flow cytometry, and RT-PCR. Then, SSCs and Sertoli cells were transferred to the upper layer of SACS for 3 weeks. After 3 weeks, the number of colonies and the expression of specific SSCs and Sertoli cell markers, as well as apoptotic genes were evaluated. Our results showed that transplanted SSCs, migrated into the basement membrane of seminiferous tubules of recipient mice. The expression of PLZF, α6-Integrin, and Vimentin proteins in SSCs and Sertoli cells were observed in 2D and 3D culture systems. The expression rate of PLZF, α6-Integrin, Bcl2, and colony number in SACS supplemented by Laminin and growth factors group were significantly higher than non-supplemented groups (P ≤ 0.01), but the expression rate of c-kit and Bax in supplemented group were significantly lower than non-supplemented groups (P ≤ 0.05). This 3D co-culture system decreased apoptosis and increased propagation of human SSCs. Therefore, this designed system can be utilized to increase the proliferation of human SSCs in prepubertal male cancer and azoospermic men to obtain an adequate SSCs number to outotransplant success and in vitro spermatogenesis.


Designing Deferoxamine-Loaded Flaxseed Gum and Carrageenan-Based Controlled Release Biocomposite Hydrogel Films for Wound Healing.
In this study, biocomposite hydrogel films made from flaxseed gum (FSG)/kappa carrageenan (CGN) were fabricated, using potassium chloride as a crosslinker and glycerol as a plasticizer. The composite films were loaded with deferoxamine (DFX), an iron chelator that promotes neovascularization and angiogenesis for the healing of wounds. The properties of the biocomposite hydrogel films, including swelling, solubility, water vapor transmission rate, tensile strength, elongation at break, and Young's modulus studies, were tested. The films were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). In addition, drug release studies in PBS at pH 7.2 were investigated. In vivo analysis was performed by assessing the wound contraction in a full-thickness excisional wound rat model. Hematoxylin & eosin (H & E) and Masson's trichome staining were performed to evaluate the effect of the films on wound healing progress. The visual and micro-morphological analysis revealed the homogenous structure of the films; however, the elongation at break property decreased within the crosslinked film but increased for the drug-loaded film. The FTIR analysis confirmed the crosslinking due to potassium chloride. A superior resistance towards thermal degradation was confirmed by TGA for the crosslinked and drug-loaded films. Drug release from the optimum film was sustained for up to 24 h. In vivo testing demonstrated 100% wound contraction for the drug-loaded film group compared to 72% for the pure drug solution group. In light of the obtained results, the higher potential of the optimized biocomposite hydrogel film for wound healing applications was corroborated.


Changes in the Health Professions: A Commentary.
Increased life expectancy in the United States has been accompanied by a concomitant increase in the prevalence of chronic conditions in persons of all ages, especially older Americans. This necessitates new ways of organizing and conducting medical practice, and this affects the roles and interactions of health professionals. Physicians and other health professionals require appropriate training and more efficient workplaces to enhance their functioning and reduce burnout. Additional factors influencing the success of health professionals in further advancing the health and well-being of Americans are health information technology and ensuring that all have access to care.


The Genomic and Proteomic Profiles of NTRK Genes and Trk Receptors in Liver Hepatocellular Carcinoma.
The neurotrophic tyrosine kinase (NTRK) gene family includes NTRK1, NTRK2, and NTRK3, which encode tropomyosin receptor kinases TrkA, TrkB, and TrkC, respectively. This study aimed to initially assess the genomic and proteomic profiles of NTRK genes and Trk receptors in liver hepatocellular carcinoma (LIHC). The ONCOMINE, UALCAN, GEPIA, cBioPortal, FusionGDB, SurvivalMeth, and the Human Protein Atlas databases were searched for NTRK gene expression and protein data in LIHC. Immunohistochemistry was used to detect pan-Trk expression across a commercial microarray containing 96 hepatocellular carcinoma (HCC) and 94 para-cancerous tissue spots. A modified histological score (H-score) with a maximum score of 300 was used to quantify immunohistochemical staining for pan-Trk. Student's t- and chi-square tests were the main statistical analyses used. The transcriptional levels of NTRK genes in LIHC were not significantly different from healthy controls. Using UALCAN and GEPIA, only high expression of NTRK2 was significantly associated with longer disease-free survival (P = 0.004). The alteration frequencies were low (7% in NTRK1, 1.7% in NTRK2, and 2% in NTRK3). The methylation levels of NTRK genes were all significantly different as analyzed by UALCAN; the high-risk group displayed an unfavorable prognosis compared with the low-risk group for NTRK1 (P = 0.033) and NTRK3 (P = 0.005). The median H-score of pan-Trk in HCC and para-cancerous tissues was not statistically different (186.31 ± 23.86 and 192.38 ± 21.06, P = 0.065). No differences were observed in clinicopathological features of HCC with the median H-score for pan-Trk expression (p > 0.05). The survival rate of patients with pan-Trk expression was also not significantly different. The alteration frequency was low in NTRK genes, including gene fusion and methylation levels. Therefore, pan-Trk expression in HCC tissue has limited value in clinicopathological features and prognosis.


[In vitro effects of 1,25-dihydroxycholecalciferol on alkaline phosphatase and gamma-glutamyltransferase activity in hypophysectomized rats].
Effects in vitro of 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) on alkaline phosphatase (PAL), gamma-glutamyltransferase (gamma-GT) and acid phosphatase (PAC) activities were investigated on renal cortex from hypophysectomized rats. In these animals the biosynthesis of 1,25-(OH)2D3 and the specific activities of kidney PAL and gamma-GT were decreased. The course of these effects was determined from 45 min to 8 h. In the presence of 1,25-(OH)2D3 (2 x 10(-6) M) a delayed (5h) but simultaneous stimulation of the three enzymes was observed. It reached a maximum at 6h and disappeared at 8h. The dose-response relation was studied at 6h. In the presence of 1,25-(OH)2D3 (5 x 10(-7) M), the three enzymes were activated. The effect was maximal at 10(-6) M; it was +22% for PAL, +17% and +15% respectively for gamma-GT and PAC compared with controls. Cycloheximide suppressed the induction of PAL but not of gamma-GT activity. The effects of the secosteroid on renal enzymes seems to be a pharmacological more than a physiological one.


Indications for obtaining surveillance thoracic and lumbar spine radiographs.
The purpose of this study was to identify risk factors for thoracic/lumbar spine fractures in patients with blunt injuries and subsequently establish indications for obtaining surveillance thoracolumbar radiographs. Retrospective review of all patients with blunt injuries (n = 1485) admitted in 1992 to a level I trauma center with a discharge diagnosis of thoracolumbar spine fracture established entrance criteria for a 4-month prospective study. Relative risk of fracture (RR) was calculated. Retrospective. Seventy-six percent (176 of 233) had radiographs; 21% had fractures; one diagnosed late. Prospective. One hundred percent (167 of 167) had radiographs; 9% (15 of 167) had fractures; none diagnosed late or missed. Forty percent (26 of 65) of patients with fractures had no pain or tenderness; 35% (9) required surgical spinal fixation. Our data define these indications for obtaining thoracolumbar radiographs in patients with blunt injuries: back pain (RR1), fall > or = 10 feet, ejection from motorcycle/motor vehicle crash > or = 50 mph, GCS score < or = 8, (all RR2), and neurologic deficit (RR10). The sensitivity of our surveillance radiography protocol has increased to 100%. The absence of back pain does not exclude significant thoracolumbar trauma.


Arthroscopic treatment for symptomatic bilateral cam-type femoroacetabular impingement.
Arthroscopic femoral osteochondroplasty improves clinical outcome in patients with unilateral cam-type femoroacetabular impingement. The goal of this study was to evaluate the clinical outcome and pathological similarities in patients who have had bilateral arthroscopic femoral osteochondroplasy for cam-type femoroacetabular impingement. The study group included 82 patients who had sequential bilateral hip arthroscopies for symptomatic cam-type femoroacetabular impingement with a minimum of 12 months follow-up. All patients had bilateral restricted hips at presentation. We differentiated between patients who had bilateral painful hips and those with unilateral pain at presentation. Scores and surgical findings were compared between the 2 study groups and between bilateral surgeries in each group. Pre- and postoperative Modified Harris Hip Scores and Non-Arthritic Hip Scores were undertaken prospectively by an independent observer. Mean patient age at the first surgery was 29 years (range, 14-63 years). The average time difference between arthroscopies was 5 months (range, 0.3-30 months). Postoperative scores improved significantly in both study groups in the first and second (contralateral) surgeries. Intra-articular pathologies between sides were linearly correlated for both groups. The time interval between surgeries had a linear correlation to age, reverse correlation to chondral damage, and reverse correlation to postoperative scores at the first surgery. Our results suggest that symptomatic patients with cam-type femoroacetabular impingement have similar accompanied pathologies on both sides and can benefit from sequential arthroscopic osteochondroplasty.


Electrophysiologic effects of SD-3212, a new class I antiarrhythmic drug, on canine atrial flutter and atrial action-potential characteristics.
SD-3212 (levo-semotiadil fumarate) is a newly developed compound that exhibits potent antiarrhythmic activity because of its inhibitory action on sodium and calcium channels. In animal models, SD-3212 suppressed ventricular tachyarrhythmias, but the effects of this drug on atrial tachyarrhythmias have not been reported. We investigated the electrophysiologic effects of SD-3212 on canine atrial flutter induced after placement of the intercaval obstacle and on atrial action-potential characteristics. In all seven dogs, SD-3212 (1.9 +/- 0.3 mg/kg) terminated atrial flutter after significant increase in atrial flutter cycle length from 126 +/- 5 to 166 +/- 14 ms (increase, 31 +/- 8%; p < 0.005). SD-3212 increased right atrial effective refractory period (RAERP) significantly from 126 +/- 7 to 149 +/- 11 ms at a basic cycle length of 300 ms. The increases in RAERP after SD-3212 at basic cycle lengths of 300, 200, and 150 ms did not differ (increase, 18 +/- 4%, 17 +/- 3%, and 19 +/- 3%, respectively). Interatrial conduction time (IACT) was prolonged after SD-3212 from 63 +/- 4 to 81 +/- 6 ms (increase, 31 +/- 6%) at a basic cycle length of 150 ms. Prolongation of IACT was frequency dependent. The plasma concentration of SD-3212 after the termination of atrial flutter was 187 +/- 56 ng/ml in four dogs tested. In vitro study by using standard microelectrode techniques showed SD-3212 at concentrations of 1-3 microM significantly prolonged action-potential duration at 90% repolarization. Vmax was decreased by SD-3212 in a concentration-dependent manner (0.3-3 microM), and the inhibitory effect on Vmax was greatest at the highest stimulation frequency of 3.3 Hz. These results indicate that a new antiarrhythmic drug, SD-3212, is effective in interrupting canine atrial flutter, possibly by suppressing atrial conduction, and might be effective for the treatment of clinical atrial tachyarrhythmias.


Flavonoid components and flower color change in transgenic tobacco plants by suppression of chalcone isomerase gene.
A cDNA encoding chalcone isomerase (CHI) was isolated from the petals of Nicotiana tabacum and the effect of its suppression on flavonoid biosynthesis was analyzed in transgenic tobacco plants. CHI-suppression by RNA interference (RNAi) showed reduced pigmentation and change of flavonoid components in flower petals. The plants also accumulated high levels of chalcone in pollen, showing a yellow coloration. Our results first demonstrated that suppression of CHI by genetic transformation is possible in higher plants. This suggests that CHI plays a major part in the cyclization reaction from chalcone to flavanone, and that spontaneous reactions are few, if any, in tobacco plants.


The study of nafion/xanthine oxidase/au colloid chemically modified biosensor and its application in the determination of hypoxanthine in myocardial cells in vivo.
A novel hypoxanthine (Hx) microsensor was constructed. In this work, Nafion xanthine oxidase (XOD) and Au colloid were immobilized onto the surface of a Pt microelectrode. The enzyme biosensor displayed a quick and sensitive response to Hx. Under physiological conditions, a low detection limit, with high selectivity and sensitivity for Hx determination were obtained. The oxidation current [investigated using current-time (I-t) plots] was linear with Hx concentration ranging from 2.0 x 10(-7) to 2.0 x 10(-5) mol L(-1) with a calculated detection limit of 1.0 x 10(-7) mol L(-1) (S/N of 3). The biosensor should be promising for in vivo measurement of Hx without interferences and fouling. The change of Hx concentration in cardiac myocytes stimulated by L-arginine (L-Arg) and acetylcholine (Ach) was also studied.


Adjunctive anakinra in patients with active rheumatoid arthritis despite methotrexate, or leflunomide, or cyclosporin-A monotherapy: a 48-week, comparative, prospective study.
To assess the efficacy and safety of anakinra (ANK) as an add-on therapy in RA patients with inadequate response to monotherapy with non-biological DMARDs. A 48-week comparative, prospective study of patients with active RA [mean 28-joint disease activity score (DAS28): 6.81], despite MTX (n = 48), or LEF (n = 42), or CSA (n = 38) treatment, in whom ANK (100 mg/daily SC) was given with corticosteroid cream topical application. At 24 and 48 weeks the patient percentages meeting the ACR20 response criteria were 57 and 73%, respectively, 33 and 41% met ACR50, while 15 and 23% met ACR70. Significant improvements in number of swollen and tender joints, HAQ, pain, global disease assessment, CRP and haemoglobin from baseline to 24 and 48 weeks were evident. DAS28 decreased at 24 weeks (- 1.68; 95% CI - 1.46, - 1.90; P < 0.0001), as well as at study end (- 2.24; 95% CI - 2.01, - 2.47; P < 0.0001). Subgroup analysis revealed a significantly weaker response in terms of pain and DAS28 in patients treated with concomitant CSA. The most common ANK-related adverse event was injection-site reaction (29%), being less frequent in male patients, as well as in patients treated with CSA. There were 17 withdrawals, 6 of them due to inefficacy. No opportunistic infections or new safety signals were observed. Considering the limitations of an open-label study, addition of ANK appears to be an effective and well-tolerated treatment option for many RA patients with inadequate responses to non-biologic DMARDs in clinical practice.


Psychometric Analysis of the Modified Differential Emotions Scale and the Six-Item Life Orientation Test-Revised in a Cohort of Older Women from the Women's Health Initiative.
Background: Positive affect and emotional resources, such as optimism, may play a major role in women's health and promote healthy well-being later in life. However, positive affect and optimism measures have not been psychometrically assessed in older women, despite relations to health. Therefore, the objective of this study was to psychometrically assess measures of positive affect and optimism and test their association with other measures of well-being. Methods: In a Women's Health Initiative subcohort of 58,810 women (mean age [standard deviation] 79.0 [6.1]; 89% White), positive affect and optimism were measured using the modified Differential Emotions Scale (mDES) and Life Orientation Test-Revised (LOT-R), respectively. Reliability was tested using Cronbach's alpha and McDonald's omega. Performance was assessed using item response theory. Factor analysis was used to explore the construct validity of the LOT-R. Convergent and divergent validity with other well-being measures was tested. Results: Results suggest good reliability (mDES: Cronbach's alpha = 0.90 and omega total = 0.92; LOT-R: Cronbach's alpha = 0.79, omega hierarchical = 0.61, and omega total = 0.83). Item response analyses indicate mDES's ability to discriminate across positive affect; LOT-R was skewed toward lower optimism levels. Exploratory factor analyses suggest a two-factor solution for the LOT-R. Significant, but small correlations in expected directions to well-being measures confirmed validity hypotheses. Conclusions: The mDES and LOT-R measured positive affect and optimism with good reliability, item performance, and validity in a large sample of older postmenopausal women, supporting use of these measures to quantify effects of positive affect and optimism-promoting interventions.


Dietary inflammatory index and memory function: population-based national sample of elderly Americans.
The objective of this study was to examine the association between dietary inflammatory potential and memory and cognitive functioning among a representative sample of the US older adult population. Cross-sectional data from the 2011-2012 and 2013-2014 National Health and Nutrition Examination Survey were utilised to identify an aggregate sample of adults 60-85 years of age (n 1723). Dietary inflammatory index (DII®) scores were calculated using 24-h dietary recall interviews. Three memory-related assessments were employed, including the Consortium to Establish a Registry for Alzheimer's disease (CERAD) Word Learning subset, the Animal Fluency test and the Digit Symbol Substitution Test (DSST). Inverse associations were observed between DII scores and the different memory parameters. Episodic memory (CERAD) (b adjusted=-0·39; 95 % CI -0·79, 0·00), semantic-based memory (Animal Fluency Test) (b adjusted=-1·18; 95 % CI -2·17, -0·20) and executive function and working-memory (DSST) (b adjusted=-2·80; 95 % CI -5·58, -0·02) performances were lowest among those with the highest mean DII score. Though inverse relationships were observed between DII scores and memory and cognitive functioning, future work is needed to further explore the neurobiological mechanisms underlying the complex relationship between inflammation-related dietary behaviour and memory and cognition.


[Experience, prevalence and severity of dental caries and its association with nutritional status in Mexican infants 17-47 months].
To determine the experience, prevalence and severity of dental caries and its relationship with nutritional status in nursery infants 17 to 47 months of age. A cross-sectional study in 152 infants 17 to 47 months of age attending one of five day care centers of the city of Pachuca, Hidalgo was performed. Clinical examinations were performed using the methods recommended by the World Health Organization for epidemiologic studies on dental caries. We calculated the caries index (dmft), the significant caries index (SiC) as well as the treatment needs index (TNI) and the care index (CI). Nutritional status was determined using the weight and height for age, in Federico Gomez's scale. In the statistical analysis nonparametric tests were used. Mean age was 2.52 ± 0.76 years; 51.3% were boys. With regard to nutritional status, 19.1% were classified as malnourished and 19.1% were overweight/obese. The dmft index was 1.53 ± 2.52. The SiC index was 4.14, the TNI 86.3% and the CI 13.7%. Caries prevalence was 48.0%. It was observed that 33.5% of children had 1 to 3 teeth with caries experience and 14.5% had 4 or more teeth affected. Statistically significant differences for tooth decay were identified (p < 0.05) by age, height and weight but not (p> 0.05) by sex and nutritional status. This study shows that nearly half of children examined had caries experience. High treatment needs for dental caries were observed. A correlation was found between dmft index and age, weight and height. No association was identified between experience, prevalence and severity of dental caries and nutritional status of infants. It appears necessary to improve oral health preventive measures in these infants.


Where is the limit of highly fluorinated high-oxidation-state osmium species?
The structures and stabilities of various osmium fluorides and oxyfluorides in high oxidation states have been studied by quantum-chemical calculations at DFT (B3LYP), MP2, CCSD, and CCSD(T) levels. The calculations indicate that the homoleptic fluorides all the way up to OsF8 may exist, even though OsF8 will be difficult to prepare. The last missing osmium oxyfluoride, OsOF6, is computed to be thermochemically stable against mononuclear gas-phase elimination reactions. The problem with the nonexistence of such highly fluorinated complexes appears thus to be mainly in difficult synthetic access under typical condensed-phase conditions. Matrix-isolation techniques might provide a means to characterize the highly fluorinated OsVIII and OsVII species.


Insights from UKCTOCS for design, conduct and analyses of large randomised controlled trials.
Randomised controlled trials are challenging to deliver. There is a constant need to review and refine recruitment and implementation strategies if they are to be completed on time and within budget. We present the strategies adopted in the United Kingdom Collaborative Trial of Ovarian Cancer Screening, one of the largest individually randomised controlled trials in the world. The trial recruited over 202,000 women (2001-5) and delivered over 670,000 annual screens (2001-11) and over 3 million women-years of follow-up (2001-20). Key to the successful completion were the involvement of senior investigators in the day-to-day running of the trial, proactive trial management and willingness to innovate and use technology. Our underlying ethos was that trial participants should always be at the centre of all our processes. We ensured that they were able to contact either the site or the coordinating centre teams for clarifications about their results, for follow-up and for rescheduling of appointments. To facilitate this, we shared personal identifiers (with consent) with both teams and had dedicated reception staff at both site and coordinating centre. Key aspects were a comprehensive online trial management system which included an electronic data capture system (resulting in an almost paperless trial), biobanking, monitoring and project management modules. The automation of algorithms (to ascertain eligibility and classify results and ensuing actions) and processes (scheduling of appointments, printing of letters, etc.) ensured the protocol was closely followed and timelines were met. Significant engagement with participants ensured retention and low rates of complaints. Our solutions to the design, conduct and analyses issues we faced are highly relevant, given the renewed focus on trials for early detection of cancer. There is a pressing need to increase the evidence base to support decision making about all aspects of trial methodology. ISRCTN-22488978; ClinicalTrials.gov-NCT00058032. This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/46/01. The long-term follow-up UKCTOCS (2015 20) was supported by National Institute for Health and Care Research (NIHR HTA grant 16/46/01), Cancer Research UK, and The Eve Appeal. UKCTOCS (2001-14) was funded by the MRC (G9901012 and G0801228), Cancer Research UK (C1479/A2884), and the UK Department of Health, with additional support from The Eve Appeal. Researchers at UCL were supported by the NIHR UCL Hospitals Biomedical Research Centre and by the MRC Clinical Trials Unit at UCL core funding (MC_UU_00004/09, MC_UU_00004/08, MC_UU_00004/07). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the UK Department of Health and Social Care.


Deep transfer learning for clinical decision-making based on high-throughput data: comprehensive survey with benchmark results.
The rapid growth of omics-based data has revolutionized biomedical research and precision medicine, allowing machine learning models to be developed for cutting-edge performance. However, despite the wealth of high-throughput data available, the performance of these models is hindered by the lack of sufficient training data, particularly in clinical research (in vivo experiments). As a result, translating this knowledge into clinical practice, such as predicting drug responses, remains a challenging task. Transfer learning is a promising tool that bridges the gap between data domains by transferring knowledge from the source to the target domain. Researchers have proposed transfer learning to predict clinical outcomes by leveraging pre-clinical data (mouse, zebrafish), highlighting its vast potential. In this work, we present a comprehensive literature review of deep transfer learning methods for health informatics and clinical decision-making, focusing on high-throughput molecular data. Previous reviews mostly covered image-based transfer learning works, while we present a more detailed analysis of transfer learning papers. Furthermore, we evaluated original studies based on different evaluation settings across cross-validations, data splits and model architectures. The result shows that those transfer learning methods have great potential; high-throughput sequencing data and state-of-the-art deep learning models lead to significant insights and conclusions. Additionally, we explored various datasets in transfer learning papers with statistics and visualization.


Strong Inhibition of Secretory Sphingomyelinase by Catechins, Particularly by (-)-Epicatechin 3-O-Gallate and (-)-3'-O-Methylepigallocatechin 3-O-Gallate.
Sphingomyelinases (SMases) are key enzymes involved in many diseases which are caused by oxidative stress, such as atherosclerosis, diabetes mellitus, nonalcoholic fatty liver disease, and Alzheimer's disease. SMases hydrolyze sphingomyelin to generate ceramide, a well-known pro-apoptotic lipid. SMases are classified into five types based on pH optimum, subcellular localization, and cation dependence. Previously, we demonstrated that elevation of secretory sphingomyelinase (sSMase) activity increased the plasma ceramide concentration under oxidative stress induced by diabetes and atherosclerosis in murine models. These results suggest that sSMase inhibitors can prevent the progress of these diseases. The present study demonstrated that sSMase activity was activated by oxidation and inhibited by reduction. Furthermore, we examined whether catechins inhibited the sSMase activity in a physiological plasma concentration. Among catechins, (-)-epicatechin 3-O-gallate (ECg) exhibited strong inhibitory effect on sSMase (IC50=25.7 μM). This effect was attenuated by methylation at the 3″- or 4″-position. On the other hand, (-)-epigallocatechin 3-O-gallate (EGCg) and (-)-catechin 3-O-gallate (Cg) exhibited weaker inhibitory activity than ECg, and (-)-epicatechin and (-)-epigallocatechin did not affect sSMase activity. Additionally, one synthetic catechin, (-)-3'-O-methylepigallocatechin 3-O-gallate (EGCg-3'-O-Me), showed the strongest inhibitory effect (IC50=1.7 μM) on sSMase. This phenomenon was not observed for (-)-4'-O-methylepigallocatechin 3-O-gallate. These results suggest that the reduction potential, the presence of the galloyl residue at the C-3 position, and the steric requirement to interact with sSMase protein are important for effective inhibition of sSMase.


Preceding infection and risk of stroke: An old concept revived by the COVID-19 pandemic.
Anecdotal reports and clinical observations have recently emerged suggesting a relationship between COVID-19 disease and stroke, highlighting the possibility that infected individuals may be more susceptible to cerebrovascular events. In this review we draw on emerging studies of the current pandemic and data from earlier, viral epidemics, to describe possible mechanisms by which SARS-CoV-2 may influence the prevalence of stroke, with a focus on the thromboinflammatory pathways, which may be perturbed. Some of these potential mechanisms are not novel but are, in fact, long-standing hypotheses linking stroke with preceding infection that are yet to be confirmed. The current pandemic may present a renewed opportunity to better understand the relationship between infection and stroke and possible underlying mechanisms.


Frontofacionasal Dysplasia in a Newborn with a De Novo Duplication of 7p15.2-p15.1.
We report a new case of frontofacionasal dysplasia or dysostosis (FFND) with a 1.5 Mb duplication in the region of 7p15.2-p15.1, and provide a review of the literature to understand the underlying pathogenesis better.


Treatment of relapse after autologous blood stem cell transplantation for severe rheumatoid arthritis.
There is little information about the clinical course of patients with rheumatoid arthritis (RA) who relapse after autologous blood stem cell transplantation (ASCT). We describe 6 patients with severe RA who received ASCT in 3 US centers. Duration of followup was between 24 and 42 months posttransplant. Five patients achieved major responses but relapsed 3-22 months posttransplant. Two patients with relapse improved remarkably after restarting disease modifying antirheumatic drugs (DMARD). Two patients developed a mild RA flare at 3 and 5 months posttransplant and improved spontaneously. All 4 patients who improved after an initial disease flare remained highly functional at 14-22 months posttransplant. All patients in this study were anti-tumor necrosis factor (TNF) drug naive; all received a TNF blocker as a second line posttransplant salvage therapy, but only 3 responded. Future ASCT strategies need to focus on improving the durability of the early posttransplant responses.


Intra-oscillator high harmonic generation in a thin-disk laser operating in the 100-fs regime.
We demonstrate that Kerr lens modelocking is well-suited for operating an ultrafast thin-disk laser with intra-oscillator high harmonic generation (HHG) in the 100-fs pulse duration regime. Exploiting nearly the full emission bandwidth of the gain material Yb:YAG, we generate 105-fs pulses with an intracavity peak power of 365 MW and an intracavity average power of 470 W. We drive HHG in argon with a peak intensity of ∼7⋅1013 W/cm2 at a repetition rate of 11 MHz. Extreme-ultraviolet (XUV) light is generated up to the 31st harmonic order (H31) at 37 eV, with an average power of ∼0.4 µW in H25 at 30 eV. This work presents a considerable increase in performance of XUV sources based on intra-oscillator HHG and confirms that this approach is a promising technology for simple and portable XUV sources at MHz repetition rates.


Left Atrial 4-Dimensional Flow Magnetic Resonance Imaging: Stasis and Velocity Mapping in Patients With Atrial Fibrillation.
Left atrial (LA) 4-dimensional flow magnetic resonance imaging (MRI) was used to derive anatomic maps of LA stasis, peak velocity, and time-to-peak (TTP) velocity in patients with atrial fibrillation (AF) and to identify relationships between LA flow with LA volume and patient characteristics. Four-dimensional flow MRI for the in vivo assessment of time-resolved 3-dimensional LA blood flow velocities was performed in 111 subjects: 42 patients with a history of AF and in sinus rhythm (AF-sinus), 39 patients with persistent AF (AF-afib), 10 young healthy volunteers (HVs), and 20 age-appropriate controls (CTRL). Data analysis included the 3-dimensional segmentation of the LA and the calculation of LA stasis, peak velocity, and TTP maps. Regional LA flow dynamics were quantified by calculating mean stasis, peak velocity, and TTP in the LA center region and the region adjacent to the LA wall. A sensitivity analysis identified thresholds for global LA stasis (<0.1 m/s) and peak velocity (top 5% LA velocities), which detected significant differences between AF patients and controls for global LA stasis (HV, 25% ± 5%; CTRL, 29% ± 10%; AF-sinus, 41% ± 13%; AF-afib, 52% ± 17%) and peak velocity (HV, 0.43 ± 0.02 m/s; CTRL, 0.37 ± 0.04 m/s; AF-sinus, 0.33 ± 0.05 m/s; AF-afib, 0.30 ± 0.05 m/s). Regional analysis revealed significantly increased stasis at both LA center and wall for AF patients compared with age-appropriate controls (29%-84% difference, P < 0.006) and for AF-afib versus AF-sinus patients (22%-30% difference, P < 0.004). In addition, stasis close to the LA wall was significantly elevated (P < 0.001) compared with the LA center for all subject groups. Multiple regressions revealed significant (RAdj = 0.45-0.50, P < 0.001) relationships between impaired global LA flow (reduced velocity and increased stasis) with age (|β| = 0.27-0.50, P < 0.002) and LA volume (|β| = 0.26-0.50, P < 0.003). Atrial 4-dimensional flow MRI detected changes in global and regional LA flow dynamics associated with AF, age, and LA volume. Longitudinal studies are needed to test the diagnostic value of LA flow metrics as potential risk factors for thromboembolic events.


Histological investigation of diagnostically challenging tubule profiles in advanced chronic progressive nephropathy (CPN) in the fischer 344 RaT.
Recently, guidelines were suggested for discriminating proliferative-appearing tubule profiles encountered in advanced spontaneous chronic progressive nephropathy (CPN) of rats, from hyperplastic precursors of renal tubule tumors (Hard and Seely, 2005). These recommendations were based on histological evaluation of a large number of cases of severe to end-stage CPN in male F344 rats from 8 separate 2-year carcinogenicity studies held in the Archives of the National Toxicology Program, NIEHS. This work has now been extended to characterize the various lesions further, mainly by serial sectioning to track their origin and fate within the adjacent renal tissue, but also by applying special staining procedures such as immunohistochemical assessment of proliferative activity, as well as fluorescence microscopy, to seek further differences from atypical tubule hyperplasia. The results obtained from these additional investigations support the contention that certain tubule profiles with a misleading proliferative appearance, sometimes found in advanced CPN, should be distinguished from preneoplastic tubule foci, and regarded as components of the nephropathy process.


Stress decreases pollen foraging performance in honeybees.
Foraging in honeybees is energetically demanding. Here, we examined whether stressors, which generally increase metabolic demands, can impair foraging performance. A controlled non-pathogenic stressor (immune challenge) resulted in a change in the foraging preferences of bees. It reduced pollen foraging and increased the duration of trips in pollen foragers. Stress also reduced the amount of octopamine in the brain of pollen foragers (a biogenic amine involved in the regulation of foraging and flight behaviour in insects). According to the literature, flight metabolic rate is higher during pollen foraging than during nectar foraging, and nectar gives a higher energetic return relative to the foraging effort when compared with pollen. We thus propose that stress might be particularly detrimental to the performance of pollen foragers, and stressed bees prefer the energy-rich resource of nectar. In conclusion, stress, even at low levels, could have consequences for bee foraging behaviour and thereby the nutritional balance of the colony.


Astrocytoma of the ciliary body.
To report the occurrence of an astrocytoma of the ciliary body. The patient was evaluated by ophthalmoscopic examination (including color ultrasonography and ultrasound biomicroscopy) as well as operating therapy. Histopathology and immunocytochemical analysis were performed. A 29-year-old woman was found to have a left ciliary body tumor. Color ultrasonography revealed a 12 x 10 mm size, a low-level echo boundary, and a bright echogenic band. Ultrasound biomicroscopy showed that the lesion was located in the superior temporal quadrant of the ciliary body and extended backward for 6 mm from the limbus. The tumor was carefully dissected free and completely removed via episcleral incision. Histopathology revealed a fibrillary astrocytoma. Staining for glial fibrillary acidic protein yielded positive results and neuron-specific enolase yielded negative results. We describe an astrocytoma of the ciliary body in a patient, which is an extremely rare ocular tumor. Histopathology and immunocytochemical analysis were required to establish the diagnosis.


Preparation of Terpenoid-Invasomes with Selective Activity against S. aureus and Characterization by Cryo Transmission Electron Microscopy.
Terpenoids are natural plant-derived products that are applied to treat a broad range of human diseases, such as airway infections and inflammation. However, pharmaceutical applications of terpenoids against bacterial infection remain challenging due to their poor water solubility. Here, we produce invasomes encapsulating thymol, menthol, camphor and 1,8-cineol, characterize them via cryo transmission electron microscopy and assess their bactericidal properties. While control- and cineol-invasomes are similarly distributed between unilamellar and bilamellar vesicles, a shift towards unilamellar invasomes is observable after encapsulation of thymol, menthol or camphor. Thymol- and camphor-invasomes show a size reduction, whereas menthol-invasomes are enlarged and cineol-invasomes remain unchanged compared to control. While thymol-invasomes lead to the strongest growth inhibition of S. aureus, camphor- or cineol-invasomes mediate cell death and S. aureus growth is not affected by menthol-invasomes. Flow cytometric analysis validate that invasomes comprising thymol are highly bactericidal to S. aureus. Notably, treatment with thymol-invasomes does not affect survival of Gram-negative E. coli. In summary, we successfully produce terpenoid-invasomes and demonstrate that particularly thymol-invasomes show a strong selective activity against Gram-positive bacteria. Our findings provide a promising approach to increase the bioavailability of terpenoid-based drugs and may be directly applicable for treating severe bacterial infections such as methicillin-resistant S. aureus.


Linear and nonlinear components of human electroretinogram.
We compared electroretinographic (ERG) responses to uniform-field and a variety of pattern stimuli using both transient and steady-state analyses. Evidence is provided that for all of these stimuli, the peak at high temporal frequencies in the steady-state response corresponds to the fast wave of the transient response and that the peak at low temporal frequencies corresponds to the slow wave of the step response. A variety of contrast-modulated grating stimuli were used to demonstrate that the fast, high-frequency response can be regarded as the sum of two components, an "odd-symmetric" component, which behaves linearly and is independent of spatial frequency, and an "even-symmetric" component, which behaves nonlinearly and has a band-pass spatial-frequency dependence. The prevailing distinction that is made between pattern and uniform-field ERGs is a consequence of the fact that the uniform-field ERG is dominated by the odd-symmetric (linear) component, whereas the so-called pattern (contrast reversal) ERG reveals the even-symmetric (nonlinear) component in isolation. Since a uniform field can also drive the nonlinear component, the present dichotomy ("luminance" versus "pattern") can be better understood in terms of the linear and nonlinear components of the response rather than in terms of the stimuli that produce them.


Experiences of interpersonal victimization and abuse among autistic people.
What do we already know?Autistic people are more likely to have negative life experiences than non-autistic people, from bullying and ostracization, to being victims of crime, to unemployment and homelessness. This includes being victims of intimate partner violence, sexual assault and domestic abuse. Quantitative work has suggested that as many as 90% of autistic people experience these forms of abuse in some form during their lives, but there is little work asking them to talk about harmful relationships in their own words.What does this article add?This article reports on interviews with 24 autistic adults about their experiences of being victims of intimate partner violence, sexual assault and/or domestic abuse. Some of the themes which came from these interviews are shared with non-autistic victims, but others appeared unique to autistic people. One of these was evidence for unique autism-related vulnerabilities, as well as the impact the abuse had on their relationships long term. Participants also talked about how the sex and relationship education they had received had inadequately prepared them for adult relationships, and how this had contributed to their struggle to recognize and react to abusive behaviour.Implications for practice, research and policyPolicies around intimate partner violence and sexual assault need to be updated to account for the different ways in which neurodivergent people (people whose brains process information differently from the majority) may discuss their experiences, rather than looking for 'standard narratives' as an indicator of a need for support. Relationship and sex education should be tailored for autistic young people to help them recognize abusive behaviours, and include how to respond to these safely. We recommend that future research tries to focus specifically on the abuse experiences of autistic men, non-binary and trans people, who have been under-represented in studies to date. In addition, much less is known about the abuse experiences of autistic people of colour or autistic people with intellectual disabilities, who also need to be actively included in these discussions.


Predictors of Engagement in an Urban Geriatric Psychiatry Clinic.
The authors performed a chart review of 174 patients age 50 and over (mean age, 69 years) to test a model of social and clinical characteristics that predict engagement in outpatient treatment. "Engaged" patients were defined as those who had three or more clinic visits. Logistic regression analysis, using a 14-variable model, was highly significant (P = 0.0003) and able to correctly classify 70% of cases. There were four predictors of clinical engagement: being a Medicaid recipient (P < 0.01), shorter length of current symptoms (P < 0.05), younger age (P = 0.06), and having a diagnosis of schizophrenia (P = 0.06); and these variables accounted for all the explained variance. These findings indicated that predictors of engagement do not invariably follow the patterns reported for younger patients.


Aldosterone augments adrenomedullin production without stimulating pro-adrenomedullin N-terminal 20 peptide secretion in vascular smooth muscle cells.
Both adrenomedullin (AM) and pro-adrenomedullin N-terminal 20 peptide (PAMP), processed from the same precursor of prepro-adrenomedullin (preproAM), have differential biological properties; AM dilates blood vessels and presumably affects the vascular remodeling, while PAMP inhibits catecholamine secretion. Since aldosterone has been shown to be involved in vascular remodeling, we examined the effects of aldosterone on AM and PAMP secretion and preproAM gene expression in human aortic vascular smooth muscle cells (VSMC). AM and PAMP secreted from human VSMC incubated with aldosterone were measured by radioimmunoassay, and preproAM gene expression was evaluated by quantitative polymerase chain reaction. Cultured human VSMC secreted both AM and PAMP into the media, while the secretion rate of AM was much higher than that of PAMP. Aldosterone increased preproAM gene expression in the cultured VSMC in a dose-dependent fashion following incubation for 48 h, with a concomitant increase in AM secretion from the cells, but PAMP secretion remained unchanged. Aldosterone-stimulated AM secretion was significantly reduced by spironolactone. Reverse-phase high-performance liquid chromatography analyses showed that immunoreactive AM secreted from the VSMC untreated or treated with aldosterone emerged at the point of human AM(1-52)-NH2. AM production was stimulated by aldosterone in cultured human VSMC without an increase in PAMP secretion, suggesting a possible role of AM in modulating vascular remodeling by aldosterone.


Further delineation of the Kapur-Toriello syndrome.
The Kapur-Toriello syndrome (KTS) is a rare multiple congenital anomaly syndrome, with presumed autosomal recessive inheritance based on the initial report of affected siblings. Here we report on a female with multiple anomalies, including cleft lip and palate, coloboma, mental retardation with cerebral atrophy, and imperforate anus who, upon re-evaluation at 30 months, was recognized to have a columella that extended below the nares. This distinctive finding prompted the diagnosis of KTS. This is the 5th report of KTS, and the second female. Interestingly, both female cases also manifest an ano/rectal malformation, suggesting that this should be considered a component manifestation of this rare syndrome.


[Structure and function of the 22nd subfamily in Arabidopsis R2R3-MYB family].
R2R3-MYB transcription factors of Arabidopsis play important roles in regulatory networks controlling development, metabolism and responses to biotic and abiotic stresses. R2R3-MYB transcription factors can be divided into 25 subfamilies based on the conserved amino acid sequences. In these subfamilies, the 22nd subfamily that responses to biotic and abiotic stresses includ AtMYB44, AtMYB77, AtMYB73 and AtMYB70. In this review, we summarize these 4 genes of the 22nd subfamily from three aspects, including the similarity of gene function, consistency of gene expression and conservation of the genetic structure. Then we discuss the redundancy and diversity about gene structure and function of these 4 genes.


Structural comparison between oxidized and reduced Escherichia coli thioredoxin. Proton NMR and CD studies.
Escherichia coli thioredoxin (Mr 11,700) usually functions as a hydrogen carrier protein that undergoes reversible oxidation/reduction reactions of its active-site disulfide linkage. By use of a number of assigned and identified resonances in one- and two-dimensional 1H NMR spectra, the two forms of the protein have been compared. Only groups that are relatively close to the active-site Cys-32, Cys-35 linkage such as Trp-28, Trp-31, Phe-27, Ala-29, and Val-25 undergo substantial changes in their 1H NMR chemical shift upon reduction. Various residues that are further removed from the active site, like Tyr-49, Tyr-70, His-6, Phe-12, Phe-81, and Phe-102, appear to be little affected (less than 0.02 ppm) by the reduction, suggesting that the rest of the protein structure is not much affected. Thus, the structural changes that occur upon reduction appear to be localized to the disulfide-containing turn and the central strand of the twisted beta-sheet that directly leads to this turn. Notwithstanding the apparent similarity in the secondary and tertiary structures of the oxidized and reduced forms of the protein, the thermal stability of the protein decreases by 10 degrees C upon the reduction of the single disulfide. This was found by both 1H NMR and near- and far-ultraviolet circular dichroism studies. Oxidized thioredoxin was also more resistant to alkaline denaturation. Furthermore, the exchange rate of the relatively stable slow-exchanging backbone amide protons that are part of the core of the twisted five-stranded beta-sheet of thioredoxin increases substantially after reduction.(ABSTRACT TRUNCATED AT 250 WORDS)


[Diseases in the metaphor of Persius].
Medical metaphora is quite widespread in ancient literature; the description of a sick body is often used by Greek and Roman philosophers and writers to define a critical condition of the State, in which just one corrupt part can ruin the entire system. Especially Persius, in his Satire, uses this way of expression to flog Roman people's corrupt habits. Reading Persius' poems and studying his satiric metaphora, in comparing it to Ippocrates' description of a considerabe number of diseases, we can reconstruct the degree of diffusion of the Greek ancient medicine in Rome in the I century A.D., before Galen's arrival.


An inflammatory gene signature distinguishes neurofibroma Schwann cells and macrophages from cells in the normal peripheral nervous system.
Neurofibromas are benign peripheral nerve tumors driven by NF1 loss in Schwann cells (SCs). Macrophages are abundant in neurofibromas, and macrophage targeted interventions may have therapeutic potential in these tumors. We generated gene expression data from fluorescence-activated cell sorted (FACS) SCs and macrophages from wild-type and mutant nerve and neurofibroma to identify candidate pathways involved in SC-macrophage cross-talk. While in 1-month-old Nf1 mutant nerve neither SCs nor macrophages significantly differed from their normal counterparts, both macrophages and SCs showed significantly altered cytokine gene expression in neurofibromas. Computationally reconstructed SC-macrophage molecular networks were enriched for inflammation-associated pathways. We verified that neurofibroma SC conditioned medium contains macrophage chemo-attractants including colony stimulation factor 1 (CSF1). Network analysis confirmed previously implicated pathways and predict novel paracrine and autocrine loops involving cytokines, chemokines, and growth factors. Network analysis also predicted a central role for decreased type-I interferon signaling. We validated type-I interferon expression in neurofibroma by protein profiling, and show that treatment of neurofibroma-bearing mice with polyethylene glycolyated (PEGylated) type-I interferon-α2b reduces the expression of many cytokines overexpressed in neurofibroma. These studies reveal numerous potential targetable interactions between Nf1 mutant SCs and macrophages for further analyses.


The effect of dietary L-carnitine on semen traits of White Leghorns.
A previous study conducted in our laboratory showed that feeding 500 ppm of dietary L-carnitine to young and aging White Leghorns for 5 wk improved sperm concentration and reduced sperm lipid peroxidation during the last half of supplementation. The current study examined the effect of feeding dosimetric as well as lower levels of L-carnitine for longer durations on semen traits of White Leghorns. In experiments 1 and 2, White Leghorns consumed diets supplemented with 0, 125, 250, or 500 mg of L-carnitine/kg of feed. For experiment 1, an 8-wk trial was conducted with 48 White Leghorns from 46 to 54 wk of age. For experiment 2, a 17-wk trial was conducted with 96 White Leghorn roosters from 46 to 63 wk of age. For experiment 3, 84 roosters were provided for ad libitum consumption a diet formulated to contain 0 or 125 ppm of L-carnitine beginning at hatch until 37 wk of age. Long-term consumption of 125 ppm of L-carnitine beginning at hatch was the only dietary treatment that sustained a persistent increase in sperm concentration. These results suggest that L-carnitine's antioxidant influence on sperm production begins before the onset of sexual maturity.


Growth-associated protein 43 is up-regulated in the ganglion cells of the ischemic rat retina.
We investigated the expression and cellular localization of growth-associated protein (GAP)-43 in the rat retina following ischemia induced by transiently increased intraocular pressure. In the normal retina, GAP-43 immunoreactivity was restricted to profiles in the inner plexiform layer. Following ischemia and reperfusion, immunoreactivity appeared in ganglion cells. The cell density of labeled ganglion cells peaked three days post-lesion and then decreased at seven days. Quantitative evaluation by immunoblotting confirmed that GAP-43 expression increased at three days (to 190% of control levels) and then slightly decreased at seven days. Our findings suggest that some ganglion cells have the potential to regenerate through the up-regulation of GAP-43 in the ischemic rat retina.


Stability of New Erythrocyte and Reticulocyte Parameters in Testing for Anemia on the Sysmex XN 9000.
New erythrocyte and reticulocyte parameters provide improved classification of anemia and monitoring of erythropoeitic activity. Parameters available on the Sysmex XN analyzers include the percentage of microcytic red blood cells (%Micro-R), percentage of macrocytic red blood cells (%Macro-R), percentage of hypochromic red blood cells (%Hypo-He), percentage of hyperchromic red blood cells (%Hyper-He), reticulocyte hemoglobin content (Ret-He), and immature reticulocyte fraction (IRF). However, use of these parameters is limited by specimen stability. To verify the stability of the new erythrocyte and reticulocyte parameters during prolonged storage, 20 blood specimens were analyzed on the Sysmex XN-9000 hematology analyzer. The specimens included healthy patients (60%) and patients with anemia (40%). The specimens were stored at room temperature (RT) and at 4° to 8°C. Analysis was performed after 12, 24, 48, and 72 hours of storage. Reticulocyte parameters IRF and Ret-He were precise and stable for at least 72 hours after collection when stored at RT and 4° to 8°C. The volume-dependent parameters, %Macro-R and %Micro-R, were stable for less than 12 hours after collection at RT (mean [SD%], 6.55 [3.19%] and -20.70 [10.37%], respectively). Storage at 4° to 8°C showed a reduction in osmotic swelling. However, %Macro-R and %Micro-R were stable for less than 12 hours after collection (mean [SD%], 4.89 [2.02%] and -17.17 [8.38%], respectively). Similarly, %Hypo-He showed a mean (SD%) increase of 0.73 (4.05%) and %Hyper-He showed a decrease of -0.70 (9.72%) at less than 12 hours after storage at 4° to 8°C. New reticulocyte parameters stored at RT and 4° to 8°C are suitable for testing on the Sysmex XN analyzer.


One-pot synthesis of amino acid precursors with insoluble organic matter in planetesimals with aqueous activity.
The exogenous delivery of organic molecules could have played an important role in the emergence of life on the early Earth. Carbonaceous chondrites are known to contain indigenous amino acids as well as various organic compounds and complex macromolecular materials, such as the so-called insoluble organic matter (IOM), but the origins of the organic matter are still subject to debate. We report that the water-soluble amino acid precursors are synthesized from formaldehyde, glycolaldehyde, and ammonia with the presence of liquid water, simultaneously with macromolecular organic solids similar to the chondritic IOM. Amino acid products from hydrothermal experiments after acid hydrolysis include α-, β-, and γ-amino acids up to five carbons, for which relative abundances are similar to those extracted from carbonaceous chondrites. One-pot aqueous processing from simple ubiquitous molecules can thus produce a wide variety of meteoritic organic matter from amino acid precursors to macromolecular IOM in chondrite parent bodies.


Evaluation of the modified broth-disk method for determining antibiotic susceptibilities of anaerobic bacteria.
A total of 110 strains of anaerobic bacteria including 9 different genera was tested for antibiotic susceptibility by the modified broth-disk method of Wilkins and Thiel (1973), using prereduced media and the VPI anaerobic culture system. Results were compared with those obtained with an agar dilution technique with incubation in a GasPak jar. There was greater than 95% agreement between the two methods with ampicillin, cephalothin, chloramphenicol, and clindamycin, and 90% or greater agreement with erythromycin, penicillin, and tetracycline.


Strategies to Improve Bedside Clinical Skills Teaching.
The bedside encounter between a patient and physician remains the cornerstone of the practice of medicine. However, physicians and trainees spend less time in direct contact with patients and families in the modern health care system. The current pandemic has further threatened time spent with patients. This lack of time has led to a decline in clinical skills and a decrease in the number of faculty members who are confident in teaching at the bedside. We offer several strategies to get physicians and trainees back to the bedside to engage in clinical skills teaching and assessment. We recommend that providers pause before bedside encounters to be present with patients and learners and to develop clear goals for a bedside teaching session. We suggest that clinical teachers practice an evidence-based approach, which includes an hypothesis-driven physical examination. We encourage the use of point-of-care technology to assist in diagnosis and to allow learners to calibrate traditional physical examination skills with real-time visualization of disease. Tools like point-of-care ultrasound can be powerful levers to get learners excited about bedside teaching and to engage patients in their clinical care. We value telemedicine visits as unique opportunities to engage with patients in their home environment and to participate in patient-directed physical examination maneuvers. Finally, we recommend that educators provide feedback to learners on specific clinical examination skills, whether in the clinic, the wards, or during dedicated clinical skills assessments.


Type 2 diabetes in children: oxymoron or medical metamorphosis?
The full public health effects of the new epidemic of obesity and diabetes in children and adolescents may not be known for many years but are certain to be substantial. Diagnosed diabetes, which is present in only 4.2% of the US population, along with its consequences, already represents approximately 19% of the total personal healthcare expenditures in this country. Between 1997 and 2002, the estimated direct medical cost of diabetes increased from 44 billion dollars to 92 billion dollars, a staggering increase of 8 billion dollars a year. In 2002, diabetes annual costs per capita rose by more than 30% to 13,243 dollars per person, compared with the average annual health care costs for persons without diabetes of 2560.92 dollars. An estimate from the CDC indicates that approximately one-third of children born in 2000 will develop diabetes at some time in their life, and nearly one-half of all Hispanic children born in 2000 will develop diabetes. As type 2 diabetes is being diagnosed at an earlier age, more young people can expect to live many more years with diabetes and its complications, adding even further to this already enormous health burden. An appropriate starting place is recognition of the magnitude of the problem by physicians, politicians, public health policy makers, and other healthcare workers. An aggressive approach to management of diabetes must begin well before the appearance of cardiovascular, eye, renal, and other complications of diabetes appear, and even before obesity leads to diabetes. Currently, physicians and other healthcare workers are poorly reimbursed for management of obesity, for diabetes education, and for ongoing telephone contact with diabetic patients and families, essential for optimal diabetes management. National policies and priorities must be readjusted to emphasize prevention, rather than crisis management, if we are to avoid a catastrophic public health crisis within the next several decades.


Rat mammary gland differentiation in vitro in the absence of steroids.
Mammary glands from several strains of immature female rats will form small lobules of alveoli when cultured in chemically defined media lacking steroid hormones but containing insulin and prolactin. The degree of lobulo-alveolar differentiation is increased if estradiol, progesterone, and aldosterone are also included in the culture media.


Pituitary diseases and sleep disorders.
Patients with pituitary diseases have decreased quality of life. Sleep disorders are prevalent among patients with pituitary diseases and contribute to decreased quality of life. Patients previously treated for compression of the optic chiasm by surgery, and in some cases postoperative radiotherapy, suffer from sleep disorders. These are characterized by decreased sleep quality, delayed onset of sleep, and daytime sleepiness. Circumstantial evidence suggests that this may be caused by hypothalamic dysfunction. A challenging speculation is that previous compression of the optic chiasm compromised the function of the retinohypothalamic tract. Through this tract the eyes convey information on day-night cycles to the hypothalamic nuclei. Patients with acromegaly, even despite biochemical control, suffer frequently from obstructive sleep apnea. Patients with Cushing's disease suffer from fragmented sleep, sleep apnea, and snoring. Prolactinomas do not seem to affect sleep characteristics. The association between appropriately substituted pituitary insufficiency and sleep disorders is less clear. The effects of recombinant human growth hormone on sleep characteristics in adults are inconsistent. Pituitary disorders are associated with different sleep disorders. Different studies point to irreversible changes in sleep-wake rhythmicity in patients treated previously for pituitary tumors with chiasm compression. VIDEO ABSTRACT.


Relationship of open acute mania treatment to blinded maintenance outcome in bipolar I disorder.
Most bipolar treatment guidelines recommend that acutely effective therapy be continued as maintenance treatment, unless contraindicated. No published studies have statistically evaluated the relationship between the outcomes in maintenance treatment and the principal acute agent. Post-hoc analysis of prophylactic results obtained during a 12-month maintenance study in recently manic patients assessed the relationship between open treatment and randomized maintenance treatment. Patients were grouped according to mood stabilizer (if any) received on the last day of the open-label, stabilization phase (divalproex, lithium, or no mood stabilizer), and the mood stabilizer to which they were randomly assigned in the double-blind, maintenance phase (divalproex, lithium, or placebo). Patients treated with open-phase divalproex and randomized to divalproex maintenance therapy had a significantly longer period before development of a mood episode compared to those randomized to either placebo (Log-rank, p=0.05) or lithium (Log-rank, p=0.04), and better tolerability than those randomized to lithium. Patients treated with open-phase lithium showed no treatment-related differences in time to a mood episode after being randomized to lithium, divalproex, or placebo and tolerability was comparable in all groups. Open treatment was selected by treating physicians, contributing to possible selection bias. More patients were randomized to divalproex than to lithium or placebo. The study was therefore better powered to detect divalproex effects. Acute response to divalproex predicted both superior prophylactic response and tolerability to divalproex, than to placebo (efficacy) and to lithium (efficacy and tolerability). Results could have implications for both clinical practice and clinical trial design.


Solid lipid nanoparticles of Annona muricata fruit extract: formulation, optimization and in vitro cytotoxicity studies.
The present study was aimed to develop Annona muricata fruit extract loaded solid lipid nanoparticles (SLNs) and explore its cytotoxic potential in vitro model of breast cancers. Extract loaded SLNs were successfully prepared by high-pressure homogenization followed by ultrasonication method and optimized using 23 full factorial design. The extract loaded SLNs were characterized using different parameters such as particle size (PS), % entrapment efficiency (EE), zeta potential (ZP) and % cumulative drug release (CDR). The SLNs formulation was optimized on the basis of software analysis with an overall desirability factor. The PS and %EE of the optimized formulation were found to be 134.8 nm and 83.26%, respectively. The optimized formulation showed a CDR of 79.83% up to 48 h. In vitro cytotoxicity efficacy of extract loaded SLNs was determined using MTT and Apoptosis assay and compared to that of a free extract. The SLNs showed a notable apoptotic effect and better efficacy to kill MCF7 cancer cells as compared to free extract. Thus, extract loaded SLNs could be an alternative dosage form which possibly controls therapeutic action with reducing side effect.


Improved configuration space sampling: Langevin dynamics with alternative mobility.
We present a new and efficient method for determining optimal configurations of a large number (N) of interacting particles. We use a coarse-grained stochastic Langevin equation in the overdamped limit to describe the dynamics of this system and replace the standard mobility by an effective space dependent inverse Hessian correlation matrix. Due to the analogy of the drift term in the Langevin equation and the update scheme in Newton's method, we expect accelerated dynamics or improved convergence in the convex part of the potential energy surface Phi. The stochastic noise term, however, is not only essential for proper thermodynamic sampling but also allows the system to access transition states in the concave parts of Phi. We employ a Broyden-Fletcher-Goldfarb-Shannon method for updating the local mobility matrix. Quantitative analysis for one and two dimensional systems shows that the new method is indeed more efficient than standard methods with constant effective friction. Due to the construction, our effective mobility adapts high values/low friction in configurations which are less optimal and low values/high friction in configurations that are more optimal.


Molecular hairpin: a possible model for inhibition of tau aggregation by tannic acid.
Inhibition of anomalous aggregation of tau protein would be an attractive therapeutic target for Alzheimer's disease (AD). In this study, tannic acid (TA), a polymeric plant polyphenol, and its monomer, gallic acid (GA), were introduced as the references to afford a molecular framework that integrates tau binding properties and inhibitory effects. Using a thioflavin S fluorescence assay and electron microscopy, we demonstrated that TA could competently inhibit the in vitro aggregation of tau peptide R3, corresponding to the third repeat unit of the microtubule-binding domain, with an IC50 of 3.5 μM, while GA's inhibition was comparatively piddling (with an IC50 of 92 μM). In the isothermal titration calorimetry experiment, we found that TA could strongly bind to R3 with a large amount of heat released. Circular dichroism spectra showed TA dose-dependently suppressed the conformational transition of R3 from a random coil structure to a β-sheet structure during the aggregation process. Finally, a structural model was built using molecular docking simulation to elucidate the possible binding sites for TA on the tau peptide surface. Our results suggest that TA recognizably interacts with tau peptide by forming a hairpin binding motif, a key framework required for inhibiting tau polymerization, in addition to hydrogen bonding, hydrophilic-hydrophobic interactions, and static electrical interactions, as reported previously. The inhibitory effect of TA on human full-length tau protein (tau441) was also verified by electron microscopy. This finding hints at the possibility of TA as a leading compound of anti-AD drugs and offers a new stratagem for the rational molecular design of a tau aggregation inhibitor.


Molecular profiling of endometrial carcinoma precursor, primary and metastatic lesions suggests different targets for treatment in obese compared to non-obese patients.
Obesity is linked to increased incidence of endometrioid endometrial cancer (EEC) and complex atypical hyperplasia (CAH). We here explore pattern and sequence of molecular alterations characterizing endometrial carcinogenesis in general and related to body mass index (BMI), to improve diagnostic stratification and treatment strategies. We performed molecular characterization of 729 prospectively collected EEC and CAH. Candidate biomarkers were identified in frozen samples by whole-exome and Sanger sequencing, oligonucleotide gene expression and Reverse Phase Protein Arrays (investigation cohort) and further explored in formalin fixed tissues by immunohistochemistry and Fluorescent in Situ Hybridization (validation cohort). We here demonstrate that PIK3CA mutations, PTEN loss, PI3K and KRAS activation are early events in endometrial carcinogenesis. Molecular changes related to KRAS activation and inflammation are more common in obese CAH patients, suggesting different prevention and systemic treatment strategies in obese and non-obese patients. We also found that oncoprotein Stathmin might improve preoperative diagnostic distinction between premalignant and malignant endometrial lesions.


Opportunities and Benefits for Powerchair Users Through Power Soccer.
Power soccer (or powerchair football), the first competitive team sport for users of motorized wheelchairs, is receiving increased attention among people with disabilities, healthcare professionals, and academics. The present study provides a qualitative analysis of the experiences of 34 American power soccer athletes. Participant observation and in-depth interviews with 11 female and 23 male athletes were conducted between 2007 and 2013. Results indicate that involvement in power soccer provides participants with an increased sense of empowerment, acquisition of social capital, and psychosocial benefits, including a deep satisfaction of the desire to participate in competitive sports and an opportunity to be independent. Implications of these findings for improving the quality of life of people with physical disabilities and for future research are discussed.


The elements of pain care that the guidelines don't address.
I have managed many patients with chronic pain who were already on hefty doses of narcotics when they became my patients. Rather than refuse to care for them, we should seek to understand their story, continuously try other medications and therapies, repeatedly attempt to reduce dosages, and frequently check substance databases.


Revolutionizing the effect of Azadirachta indica extracts on edema induced changes in C-reactive protein and interleukin-6 in albino rats: in silico and in vivo approach.
The aim of the present study is to determine the in vivo and in silico anti-inflammatory effect of Azadirachta indica (A. indica) in carrageenan-induced rats and its blood biomarkers. A. indica (Neem) is a widely used medicinal plant across the world, especially in Pakistan. Neem leaves have been traditionally used for the synthesis of drugs and treatment of a wide variety of diseases. In this study, sixty albino rats (160-200 g) were divided into 4 groups: control (group I), standard (group II), ethanolic and aqueous (group III and IV) at doses of 50, 100, 200 and 400 mg/kg. Ethanolic and aqueous extracts showed maximum inhibition in paw size at the 5th hour (400 mg/kg). Similarly, biomarkers measured, including Interleukin-6 and C-reactive protein, exhibited significant anti-inflammatory activity at the highest dose of 400 mg/kg in both experimental groups but were more distinct in the group treated with ethanolic extracts. Correlation between C-reactive protein (CRP) and inter-leukin-6 (IL-6) showed positive correlation in group III, while negative in group IV. Similarly, positive and negative correlations were observed between CRP biomarkers and paw size in group III and IV, and the same results were also shown in the case of IL-6 and paw size. In molecular docking, the binding energy value of protein CRP and IL-1β with the identified ligands quercetin and nimbosterol showed (-8.2 kcal/mol and -7.7 kcal/mol) the best binding affinity as compared to standard drug diclofenac with -7.0 kcal/mol binding energy respectively. In conclusion, in silico and in vivo analysis revealed that the extracts of A. indica leaves can be used as an effective drug to manage inflammation.


Oxidative stress in benign prostatic hyperplasia: a systematic review.
Several parameters including inflammatory mediators, hormones, dietary factors, inflammatory genes, and oxidative stress (OS) have been considered to play a role in the development of benign prostatic hyperplasia (BPH). Prostate tissue damage and OS may lead to compensatory cellular proliferation with resulting hyperplastic growth. We searched MEDLINE for articles in English published up to March 2014 using the key words 'oxidative stress', 'antioxidants' and 'benign prostatic hyperplasia'. Prostatic inflammation can cause the generation of free radicals. The extent of oxidative damage can be exacerbated by a decreased efficiency of antioxidant defense mechanisms. The balance between OS and the antioxidant component also has a role in developing prostate disease. Several works show the role of oxidant products and of depletion of antioxidant substances in BPH patients. It is accepted that free radicals play a role in carcinogenesis and that BPH should be considered a premalignant condition which may evolve into prostate cancer. High OS parameters and low antioxidant activity are more prominent in prostate cancer patients compared with BPH and controls. Further studies are needed to clarify the potential role of antioxidants in BPH also in view of preventing the progression to prostate cancer.


Stroke Subtype Among Individuals With Chronic Kidney Disease.
It is widely accepted that there is a stepwise increase in the risk of acute ischemic stroke with chronic kidney disease (CKD). However, whether the risk of specific ischemic stroke subtypes varies with CKD remains unclear. To assess the association between ischemic stroke subtypes (cardioembolic, arterial, lacunar, and other) classified using the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) and CKD stage. retrospective cohort study. Ontario, Canada. A total of 17 434 adults with an acute ischemic stroke in Ontario, Canada between April 1, 2002 and March 31, 2013, with an estimated glomerular filtration rate (eGFR) measurement or receipt of maintenance dialysis captured in a stroke registry were included. Kidney function categorized as an eGFR of ≥60, 30-59, <30 mL/min/1.73 m2, or maintenance dialysis. Ischemic stroke classified by TOAST included arterial, cardioembolic, lacunar, and other (dissection, prothrombotic state, cortical vein/sinus thrombosis, and vasculitis) types of strokes. Adjusted regression models. In our cohort, 58.9% had an eGFR of ≥60, 34.7% an eGFR of 30-59, 6.0% an eGFR of <30 and 0.5% were on maintenance dialysis (mean age of 73 years; 48% women). Cardioembolic stroke was more common in patients with non-dialysis-dependant CKD (eGFR 30-59: 50.4%, adjusted odds ratio [OR] 1.20, 95% confidence interval [CI]: 1.02, 1.44; eGFR<30: 50.6%, OR 1.21, 95% CI: 1.02, 1.44), whereas lacunar stroke was less common (eGFR 30-59: 22.7% OR 0.85, 95% CI: 0.77, 0.93; eGFR <30: 0.73, 95% CI: 0.61, 0.88) compared with those with an eGFR ≥60. In stratified analyses by age and CKD, lacunar strokes were more frequent in those aged less than 65 years, whereas cardioembolic was higher in those aged 65 years and above. TOAST classification was not captured for all patients. Non-dialysis CKD was associated with a higher risk of cardioembolic stroke, whereas an eGFR ≥60 mL/min/1.73 m2 was associated with a higher risk of lacunar stroke. Detailed stroke subtyping in CKD may therefore provide mechanistic insights and refocus treatment strategies in this high-risk population.


A comparison of surveillance methods for small incidence rates.
A number of methods have been proposed for detecting an increase in the incidence rate of a rare health event, such as a congenital malformation. Among these are the sets method, two modifications of the sets method, and the CUSUM method based on the Poisson distribution. We consider the situation where data are observed as a sequence of Bernoulli trials and propose the Bernoulli CUSUM chart as a desirable method for the surveillance of rare health events. We compared the performance of the sets method and its modifications with that of the Bernoulli CUSUM chart under a wide variety of circumstances. Chart design parameters were chosen to satisfy a minimax criteria. We used the steady-state average run length to measure chart performance instead of the average run length (ARL), which was used in nearly all previous comparisons involving the sets method or its modifications. Except in a very few instances, we found that the Bernoulli CUSUM chart has better steady-state ARL performance than the sets method and its modifications for the extensive number of cases considered. Thus, we recommend the use of the Bernoulli CUSUM chart to monitor small incidence rates and provide practical advice for its implementation.


Pattern of fibronectin in hepatocellular carcinoma and its significance.
Fibronectin is a multifunctional large molecular weight glycoprotein that can bind extra-cellular and cellular components. The aim of the present study was to evaluate expression of fibronectin and its significance in cases of hepatocellular carcinoma (HCC). A few previous studies have shown abnormal over- expression of fibronectin in cases of HCC. Expression of the fibronectin protein was studied in eleven cases of HCC by immunohistochemical method. Fibronectin was seen to localize predominantly in perisinusoidal region and strong positivity was noted in other fibrotic areas. Positivity around nests of cells and tumor nodules was noted in 8/11 cases of HCC and faint cytoplasmic positivity in tumor cells was seen in 5/11 cases. Staining pattern of fibronectin in HCC was definitely abnormal but decreased in the present study. The controversial results as seen in few previous studies also have been partially explained in the present article and further studies using larger sample size is suggested to clarify the issue.


Cardiovascular diseases in the developing countries: dimensions, determinants, dynamics and directions for public health action.
The global burden of disease due to cardiovascular diseases (CVDs) is escalating, principally due to a sharp rise in the developing countries which are experiencing rapid health transition. Contributory causes include: demographic shifts with altered population age profiles; lifestyle changes due to recent urbanisation, delayed industrialisation and overpowering globalisation; probable effects of foetal undernutrition on adult susceptibility to vascular disease and possible gene-environment interactions influencing ethnic diversity. Altered diets and diminished physical activity are critical factors contributing to the acceleration of CVD epidemics, along with tobacco use. The pace of health transition, however, varies across developing regions with consequent variations in the relative burdens of the dominant CVDs. A comprehensive public health response must integrate policies and programmes that effectively impact on the multiple determinants of these diseases and provide protection over the life span through primordial, primary and secondary prevention. Populations as well as individuals at risk must be protected through initiatives that espouse and enable nutrition-based preventive strategies to protect and promote cardiovascular health. An empowered community, an enlightened policy and an energetic coalition of health professionals must ensure that development is not accompanied by distorted nutrition and disordered health.


Superior Quality Low-Temperature Growth of Three-Dimensional Semiconductors Using Intermediate Two-Dimensional Layers.
The low-temperature growth of materials that support high-performance devices is crucial for advanced semiconductor technologies such as integrated circuits built using monolithic three-dimensional (3D) integration and flexible electronics. However, low growth temperature prohibits sufficient atomic diffusion and directly leads to poor material quality, imposing severe challenges that limit device performance. Here, we demonstrate superior quality growth of 3D semiconductors at growth temperatures reduced by >200 °C by using two-dimensional (2D) materials as intermediate layers to optimize the potential energy barrier for adatom diffusion. We reveal the benefits of maintaining, but reducing, the potential field through the 2D layer, which coupled with the inert surface of the 2D material lowers the kinetic barriers, enabling long-distance atomic diffusion and enhanced material quality at lower growth temperatures. As model systems, GaN and ZnSe, grown using WSe2 and graphene intermediate layers, exhibit larger grains, preferred orientation, reduced strain, and improved carrier mobility, all at temperatures lower by >200 °C compared to direct growth as characterized by diffraction, X-ray photoelectron spectroscopy, Raman, and Hall measurements. The realization of high-performance materials using 2D intermediate layers can enable transformative technologies under thermal budget restrictions, and the 2D/3D heterostructures could enable promising heterostructures for future device designs.


Protein Encapsulation Using Complex Coacervates: What Nature Has to Teach Us.
Protein encapsulation is a growing area of interest, particularly in the fields of food science and medicine. The sequestration of protein cargoes is achieved using a variety of methods, each with benefits and drawbacks. One of the most significant challenges associated with protein encapsulation is achieving high loading while maintaining protein viability. This difficulty is exacerbated because many encapsulant systems require the use of organic solvents. By contrast, nature has optimized strategies to compartmentalize and protect proteins inside the cell-a purely aqueous environment. Although the mechanisms whereby aspects of the cytosol is able to stabilize proteins are unknown, the crowded nature of many newly discovered, liquid phase separated "membraneless organelles" that achieve protein compartmentalization suggests that the material environment surrounding the protein may be critical in determining stability. Here, encapsulation strategies based on liquid-liquid phase separation, and complex coacervation in particular, which has many of the key features of the cytoplasm as a material, are reviewed. The literature on protein encapsulation via coacervation is also reviewed and the parameters relevant to creating protein-containing coacervate formulations are discussed. Additionally, potential opportunities associated with the creation of tailored materials to better facilitate protein encapsulation and stabilization are highlighted.


An update on emerging therapies for urinary tract infections.
Urinary tract infections (UTIs) are the most common healthcare-acquired infections, and are associated with high morbidity and mortality. Worldwide use of antibiotics has led to a significant rise in resistant uropathogens emanating from both hospitals and communities. The huge concern of multidrug resistance (MDR) has led the Food and Drug Administration (FDA) to encourage drug companies to invest in the development of new antibiotics. Area covered: In this review we summarized data on already approved antibiotics, and selected emerging therapies that are currently in phase II and III trials with emphasis on complicated urinary tract infections (cUTIs). We performed our search using PubMed, ClinicalTrials.gov, Google Scholar and Pharmaprojects. Expert opinion: Efficacious antimicrobials are needed to overcome MDR organisms. There are several dugs in initial and later stages of development, but most of them lack full spectrum of activity against some Gram-negative organisms, particularly against MDR Pseudomonas aeruginosa. Better understanding of the pathogenesis of UTI and genetic engineering of pathogens can provide new drugs to combat resistance in the future.


An improved approach to histofluorescence using the SPG method for tissue monoamines.
A modification of the SPG histofluorescence method for the visualization of monoamines in tissues using cryostat sections is described. This modification has let to consistent standardization of the fluorescent intensity from one tissue section to another while also eliminating a cumbersome step in the procedure. The present procedure results in highly rapid and sensitive visualization of dopamine-, noradrenaline- and serotonin-containing neurons and their axonal varicosities. Processing time from fresh tissue to microscopic examination requires less than 15 min.


A novel inhibitor of Mycobacterium tuberculosis pantothenate synthetase.
Pantothenate synthetase (PS; EC 18.104.22.168), encoded by the panC gene, catalyzes the essential adenosine triphosphate (ATP)-dependent condensation of D-pantoate and beta-alanine to form pantothenate in bacteria, yeast, and plants; pantothenate is a key precursor for the biosynthesis of coenzyme A (CoA) and acyl carrier protein (ACP). Because the enzyme is absent in mammals and both CoA and ACP are essential cofactors for bacterial growth, PS is an attractive chemotherapeutic target. An automated high-throughput screen was developed to identify drugs that inhibit Mycobacterium tuberculosis PS. The activity of PS was measured spectrophotometrically through an enzymatic cascade involving myokinase, pyruvate kinase, and lactate dehydrogenase. The rate of PS ATP utilization was quantitated by the reduction of absorbance due to the oxidation of NADH to NAD+ by lactate dehydrogenase, which allowed for an internal control to detect interference from compounds that absorb at 340 nm. This coupled enzymatic reaction was used to screen 4080 compounds in a 96-well format. This discussion describes a novel inhibitor of PS that exhibits potential as an antimicrobial agent.


Computer modeling studies of the structural role of NADPH binding to active site mutants of human dihydrofolate reductase in complex with piritrexim.
Dihydrofolate reductase (DHFR, EC 220.127.116.11) is one of the enzymes active in the folate cycle which plays an important role in DNA synthesis. Inhibition of DHFR is a key element in the treatment of many diseases, including cancer and AIDS related infections. A search for new selective inhibitors is motivated by the resistance to common drugs observed in the course of treatment. In this paper, results of a detailed computer analysis of human DHFR interactions with the lipophilic inhibitor piritrexim (PTX) are presented. It was found that the NADPH cofactor contributes 30% of the total PTX-enzyme interaction energy. Substitution of the highly conserved Glu30 with alanine does not lead to the release of the inhibitor from the hDHFR pocket. The important L22F point mutation does affect PTX orientation but does not changethe binding energy. Simulations of the dynamics of binary hDHFR-PTX complexes were performed with the use of Extensible Systematic Force Field (ESFF) and the results indicate structural changes in the enzyme induced by NADPH binding.


Human illnesses caused by Opisthorchis felineus flukes, Italy.
We report 2 outbreaks of Opisthorchis felineus infection caused by the consumption of tench filets (Tinca tinca) from a lake in Italy. Of the 22 infected persons, 10 (45.4%) were asymptomatic. When present, symptoms (fever, nausea, abdominal pain, and myalgias) were mild. Eosinophilia occurred in all infected persons.


Amorphous drug delivery systems: molecular aspects, design, and performance.
The biopharmaceutical properties-especially the solubility and permeability-of a molecule contribute to its overall therapeutic efficacy. The newer tools of drug discovery have caused a shift in the properties of drug-like compounds, resulting in drugs with poor aqueous solubility and permeability, which offer delivery challenges, thus requiring considerable pharmaceutical manning. The modulation of solubility is a more viable option for enhancing bioavailability than permeability, because of the lack of "safe" approaches to enhance the latter. Solid-state manipulation in general, and amorphization in particular, are preferred ways of enhancing solubility and optimizing delivery of poorly soluble drugs. This review attempts to address the diverse issues pertaining to amorphous drug delivery systems. We discuss the various thermodynamic phenomenon such as glass transition, fragility, molecular mobility, devitrification kinetics, and molecular-level chemical interactions that contribute to the ease of formation, the solubility advantage, and the stability of amorphous drugs. The engineering of pharmaceutical alloys by solubilizing and stabilizing carriers, commonly termed solid dispersions, provide avenues for exploiting the benefits of amorphous systems. Carrier properties, mechanisms of drug release, and study of release kinetics help to improve the predictability of performance. The review also addresses the various barriers in the design of amorphous delivery systems, use of amorphous form in controlled release delivery systems, and their in vivo performance.


Photodynamic therapy for treatment of recurrent hemoptysis secondary to pulmonary endometriosis: a case report.
Pulmonary endometriosis (PEM) is rare, and drug therapy remains the primary treatment. However, patients with PEM frequently experience recurrent hemoptysis that is refractory to pharmacological intervention. We herein describe a patient with PEM who developed recurrent hemoptysis and was successfully treated with photodynamic therapy (PDT) after drug withdrawal. The patient was admitted to our hospital because of recurrent hemoptysis despite repeated drug treatments for more than 1 year. Given that PDT targets specific tissues and destroys vascular endothelial cells through the cytotoxic effect produced by the photodynamic reaction of the photosensitizer, we considered that it may effectively control hemoptysis secondary to vascular morphological changes in PEM. Therefore, we performed PDT in this case, and the patient's recurrent hemoptysis regressed. Approximately 2 years following PDT, the patient had recovered well and reported no discomfort. We recommend consideration of PDT as a treatment option for patients with PEM who develop recurrent hemoptysis after drug withdrawal. Notably, the patient's lung lesions should be superficial and limited, and no contraindications should be present.


An In-vivo Comparison of Vertical and Horizontal Distance between Incisive Papilla and Incisal Edge of Maxillary Central Incisors in Dentates with Different Arch Forms.
The incisive papilla is one of the most stable landmarks for assessing the original position of certain key teeth. To place anterior artificial teeth back in its original position such as in denture construction and full mouth rehabilitation cases vertical and horizontal distance from incisive papilla in different arch forms, imparts a significant role. The average distance will be helpful for arrangement of teeth in its original position which not only provides a pleasing appearance and normal function but also will save the dentists' chair side effort. To determine the average vertical and horizontal distance of the maxillary central incisors from the incisive papilla in dentate individuals with different arch forms. Primary impressions and casts were made for 72 dentate patients, sorted into different arch forms and mid point of the incisive papilla was established. The vertical and horizontal distances were measured with the digital vernier caliper. The mean and standard deviation were subjected to Students t-test. The range of horizontal distance was 4-7 mm, 6-8 mm, 5-8 mm and vertical distance was 4-6 mm in ovoid, square and tapered arch forms respectively. Horizontal distance of the maxillary central incisors from the incisive papilla varies in different arch forms whereas, vertical distance is almost same in all the arch forms.