Cerebral amino acid levels and uptake in rats after portocaval anastomosis: II. Regional studies in vivo.
Amino acid levels have been determined in plasma and in four cerebral regions of rats one month after portocaval shunt. Many plasma amino acids are significantly lowered (asparagine, glutamine, theonine, serine, alanine, valine, leucine, isoleucine, cystine, lysine), while others remain unchanged (taurine, glycine, proline, tryptophan, ornithine, histidine, arginine). Asparagine and glutamine levels are significantly higher than in normal rats, and a net increase of tyrosine (100%), phenylalanine (50%) and citrulline (50%) is evident. In the shunted rat brain the most prominent feature is a very large rise (up to fivefold) of tyrosine, phenylalanine, histidine, citrulline, tryptophan, and glutamine uniformly in the tested regions. Other neutral amino acids are slightly increased. Lysine and arginine are decreased in cerebellum and pons-medulla; taurine, in forebrain and cerebellum. Cerebral permeability to L-amino acids was studied in vivo. Neutral amino acid permeability is greatly increased, whereas basic amino acids show a net decrease in their rate of passage from blood to the brain. No changes are observed for GABA and glutamic acid. These data suggest an altered permeability of the cerebral capillary membranes, which seems to be selective for the different amino acid transport classes. Competitive inhibition experiments demonstrated that the increased brain permeability to neutral amino acids after portocaval shunt is due to an enhancement of the saturable transport. The sharp rise in the brain of some essential neutral amino acids (phenylalanine, tyrosine, trytophan, histidine), largely exceeding their changes in plasma, and the slight cerebral increase of other neutral amino acids despite their lowered level and the rise of competing amino acids in the plasma, is consistent with our observation of enhanced transport for the neutral class. In hepatic encephalopathy, correction of the altered plasma amino acid levels has been reported to improve the clinical status. If this result is connected to the concomitant correction of the brain amino acid levels, carefully selected competitive inhibition among various plasma amino acids could be a useful therapeutic tool in this pathologic condition. However, the increased activity of the neutral amino acid transport system adds a new factor to the problem, since it probably implies that the competing amino acids will accumulate to unphysiological levels in the brain.


Ellisras Longitudinal Study 2017: association of hypertension with increasing levels of adiposity in 10- to 14-year-old boys and girls in the Eastern Cape (ELS 31).
Previous studies suggest a strong relationship between obesity and hypertension. This study aimed at evaluating the prevalence of hypertension and pre-hypertension in 10- to 14-year-old boys and girls in the Eastern Cape Province of South Africa and to determine the association between blood pressure parameters and selected measures of adiposity. A cross-sectional, school-based study of 540 10- to14-year-old children from seven schools in the Eastern Cape Province was carried out. Anthropometry and blood pressure parameters were determined. All measures of adiposity and blood pressure were significantly higher in the girls (p < 0.05). The prevalence of hypertension and pre-hypertension was over 20 and 12%, respectively. Systolic blood pressure and pulse pressure were associated (r > 0.27; p < 0.05) with increasing levels of adiposity. This study highlights the importance of weight-control strategies for the prevention of hypertension in these adolescents and later on in life.


Are anti-glutamic acid decarboxylase 65-kDa isoform antibodies related to diabetes or brain tumor?
Antibodies against the 65-kDa isoform of glutamic acid decarboxylase (GAD65) are biomarkers of autoimmune disorders and are more common in non-neurological autoimmune diseases than in neurological disorders. As for the central nervous system (CNS), it is well known that GAD65 is primarily associated with stiff-person syndrome, cerebellar ataxia, epilepsy, and paraneoplastic neurological syndrome. However, GAD65 antibodies have not been reported in patients with brain tumors. This study presents the case of a 62-year-old man who manifested rapidly progressive dizziness with gradually worsening physical disturbance and unstable gait in the 2 months prior to consultation. Antibodies against GAD65 were detected in his serum. Brain magnetic resonance imaging (MRI) showed abnormal signals in the corpus callosum, the semi-oval center in both hemispheres, and the area below the frontal cortex, along with enhanced intracranial lesions in the same regions. Positron emission tomography-computed tomography (PET-CT) showed high metabolism in the corpus callosum, which protruded into both ventricles. Due to signs of malignancy, the patient was diagnosed with a malignant glioma. This case raises awareness on the fact that anti-GAD65 antibodies may be associated with CNS neoplastic lesions. Early recognition of anti-GAD antibodies could be of great importance for the early diagnosis and targeted treatment of neoplastic lesions, and could lead to better prognosis.


Amlodipine potentiates metalloproteinase activity and accelerates elastin degradation in a model of aneurysmal disease.
Abdominal aortic aneurysms are characterised by changes in the extracellular matrix of the arterial media, in particular a reduction in elastin concentration. These changes are mediated by increased levels of endogenous matrix metalloproteinases (MMPs). Recently, calcium channel blockers have been shown to increase the proteolytic activity of MMP-2 secreted by vascular smooth muscle cells. It may therefore by hypothesised that calcium antagonists may potentiate the activity of MMPs in aneurysmal disease and thus accelerate AAA expansion. In this study, the ability of amlodipine--a calcium antagonist--to influence elastin degradation, was assessed in a previously described model of aneurysmal disease. Porcine aortic segments (n = 8) were pre-incubated in exogenous pancreatic elastase for 24 h prior to culture in standard conditions for 6 days with 10 and 100 micrograms/l amlodipine. Control segments were cultured both with and without amlodipine and without elastase. At the termination of culture MMPs were extracted from the tissue and quantified by a combination of substrate gel enzymography and immunoblotting. The volume fractions of elastin and collagen were determined by stereological analysis of EVG stained sections. Gel enzymography demonstrated significantly increased MMP-9 activity in the amlodipine treated segments, median 4.218 vs. 2.809 arbitrary units (p < 0.01) and this elevated activity was reflected in a significant destruction of medial elastin 27.0 vs. 40.5% (p < 0.05). Therapeutic ranges of amlodipine significantly enhanced elastin degradation and potentiated MMP-9 activity within the aortic organ cultures.


Significance of septa in first trimester increased nuchal translucency thickness.
The objective of this study was to investigate perinatal outcome in cases of increased nuchal translucency (NT) with or without cystic hygroma (CH), and to determine whether first-trimester CH engenders a greater risk than simple increased NT. In this retrospective study, data from singleton pregnancies in which fetal NT was found to be 3 mm or more at the 11 + 0 to 13 + 6 weeks scan were reviewed. Cases were classified into two groups, namely 'CH' and 'increased NT'. Of the 76 cases with increased NT, 30 (39.4 %) presented with CH. NT measurement was significantly higher in the CH group (7.25 vs. 3.5 mm, p < 0.001). Abnormal fetal karyotype, major chromosomal anomalies in chromosomally normal fetuses, and adverse outcome were significantly more frequent in the CH group as compared with the increased NT group (p = 0.019, p = 0.021, and p = 0.001, respectively). Regression analysis revealed that NT thickness was the only significant variable in the prediction of chromosomal defect and/or major congenital anomaly (OR 2.05, 95 % CI 1.23-3.42, p = 0.005). Cystic hygroma results in poorer outcome due to higher NT measurement, and the thickness of NT rather than the presence of septa should be the mainstay of prenatal counseling in cases of increased NT in the first trimester.


From Dental to Mental Institutions: Elmer McKesson's Secondary Saturation with Nitrous Oxide.
As popularized by Elmer McKesson, MD, "secondary saturation" with nitrous oxide could expose patients to a second burst of 100% laughing gas to relax their muscles to assist surgeons. On rare occasions, this technique could provide a second opportunity for hypoxic brain damage and possible admission postoperatively to insane asylums.


Complete genome sequence of Rickettsia slovaca, the agent of tick-borne lymphadenitis.
The present study reports the complete and annotated genome sequence of the human pathogen Rickettsia slovaca strain 13-B, which was isolated from a Dermacentor tick in Slovakia in 1968. The 1.27-Mb genome provides further insights into the acquisition of virulence related to genome reduction in Rickettsia species.


Quantitative imaging of chromatin inheritance using a dual-color histone in Drosophila germinal stem cells.
We detail a stepwise protocol for the investigation and quantification of chromatin features during asymmetric cell division (ACD) of Drosophila germline stem cells (GSCs). We describe the use of a dual-color histone to study the inheritance of new and old histones. We detail steps for imaging and analysis of sister chromatid condensation dynamics and nucleosome density changes. In addition, this protocol could be applied to identify stem cells, which can be challenging to identify in intact tissues. For complete details on the use and execution of this protocol, please refer to Tran et al. (2012), Ranjan et al. (2019), and Ranjan et al. (2022).


Experimental arthrosis from intra-articular vitamin A injection in the rabbit. Morphological and biochemical study: considerations on the pathogenesis of human arthrosis in relation to the experimental model.
The key to the pathogenesis of arthrosis lies in the mechanism responsible for the initial lesions. In this experimental work the possibility of producing arthrosic changes is demonstrated by activating lysosomal chondrocytic enzymes by the intra-articular injection of Vitamin A in rabbits. On the basis of the experimental results the authors discuss the possible role that activation of the lysosomal hydrolytic enzymes might play in producing primary and secondary arthrosis in humans. They advance the hypothesis that this mechanism may be the common final step in the degradation of the articular cartilage, whatever the aetiological factor.


T-cell hybridoma-produced lymphokine that activates macrophages to suppress intracellular growth of Histoplasma capsulatum.
Supernatants from concanavalin A-stimulated T-cell hybridomas activated macrophages to suppress the intracellular growth of Histoplasma capsulatum and to kill tumor cells. The supernatants had high interferon activity and were pH 2 sensitive and heat resistant. Gamma interferon is suggested to be among the active substances in the supernatants. Neither alpha interferon nor beta interferon activated macrophages for the Histoplasma growth inhibitory activity.


Development and validation of a specialized system for self-tapping medical bone screw testing.
A specialized system for accurate self-tapping medical bone screw testing is developed, fully meeting the requirements of ASTM F543-A4 (YY/T 1505-2016). The onset of self-tap is identified automatically according to a change in the slope of the torque curve. Precise load control is applied to determine the self-tapping force accurately. A simple mechanical platform is embedded to ensure the automatic axial alignment of a tested screw with the pilot hole in a test block. In addition, comparative experiments are conducted on different self-tapping screws to verify the system's effectiveness. By the automatic identification and alignment method, both torque curves and axial force curves for each screw exhibit significant consistency. The self-tapping time point derived from the torque curve agrees well with the turning point of the axial displacement curve. The determined self-tapping forces' mean values and standard deviations are both small, which are proved to be effective and accurate in the insertion tests. This work contributes to improving the standard test method for accurate determination of the self-tapping performance of medical bone screws.


[Surgical treatment of acute suppurative cholangitis. Our experience].
The results obtained in 13 cases of acute suppurative cholangitis are reported, stress being laid on the seriousness of the pathology and the need for emergency surgical treatment.


Disinfectant dodecyl dimethyl benzyl ammonium chloride (DDBAC) disrupts gut microbiota, phospholipids, and calcium signaling in honeybees (Apis mellifera) at an environmentally relevant level.
One of the impacts of the Coronavirus disease 2019 (COVID-19) pandemic has been a profound increase in the application amounts of disinfectants. Dodecyl dimethyl benzyl ammonium chloride (DDBAC) is a widely used disinfectant, yet its hazards to non-target species remain largely unknown. We are unaware of any studies assessing DDBAC's impacts on honeybee, a pollinator species that is a useful indicator of environmental pollution essential for many forms of agricultural production. Here, we assessed the potentially negative effects of DDBAC on honeybees. After conducting a formal toxicity evaluation of DDBAC on honeybee mortality, we detected an accumulation of DDBAC in the honeybee midgut. We subsequently studied the midgut tissues of honeybees exposed to sub-lethal concentrations of DDBAC: histopathological examination revealed damage to midgut tissue upon DDBAC exposure, microbiome analysis showed a decreased abundance of beneficial midgut microbiota, lipidomics analysis revealed a significant reduction in cell membrane phospholipids with known functions in signal transduction, and a transcriptome analysis detected altered expression of genes involved in calcium signaling pathways (that variously function in calcium absorption, muscle contraction, and neurotransmission). Thus, our study establishes that DDBAC impacts honeybee midgut functions at multiple levels. Our study represents an early warning about the hazards of DDBAC and appeals for the proper stewardship of DDBAC to ensure the protection of our ecological environment.


The effects of antipsychotics on behavioral abnormalities of the Gunn rat (unconjugated hyperbilirubinemia rat), a rat model of schizophrenia.
There have been reports of a positive relationship between schizophrenia and hyperbilirubinemia. Patients with schizophrenia show a significantly higher frequency of hyperbilirubinemia than patients suffering from other psychiatric disorders and when compared to the general population. Previously we observed that patients suffering from schizophrenia frequently present an elevated unconjugated bilirubin plasma concentration, when admitted to the hospital. In addition it was recently reported that unconjugated bilirubin exhibited neurotoxicity in the developing nervous system. We also reported that Gunn rats, which tend to show a high frequency of hyperbilirubinemia, may be used as an animal model of schizophrenia. In the present study, we assessed the effects of antipsychotics on Gunn rat behavioral abnormalities. We examined the behavior of Gunn rats after treatment with risperidone (0.1mg/kg), haloperidol (0.2mg/kg), or aripiprazole (0.4mg/kg) using an open-field test, social interaction test and a prepulse inhibition (PPI) test. The administration of antipsychotics alleviated behavioral abnormalities, mimicking some positive and negative symptoms and cognitive defects of schizophrenia. The pharmacological reaction of Gunn rats to antipsychotics echoes the pharmacological response of humans to such antipsychotics. Our study suggested that the Gunn rat may be useful as a preclinical model of schizophrenia with which to evaluate the pharmacological properties of antipsychotics. The results obtained to date have been encouraging and warrant further research.


Supramolecular cage encapsulation as a versatile tool for the experimental quantification of aromatic stacking interactions.
The widespread presence of aromatic stacking interactions in chemical and biological systems, combined with their relatively small energetic contribution, have led to a plethora of theoretical and experimental studies for their quantification and rationalization. Typically, π-π aromatic interactions are studied as a function of substituents to gather information about the interaction mechanism. While experiments suggest that aromatic interactions are dominated by local electrostatic contacts between π-electron density and CH groups, theoretical work has raised the possibility that direct electrostatic interactions between local dipoles of the substituents may play a role. We describe a supramolecular cage that binds two aromatic carboxylates in a stacked geometry such that the aromatic substituents are remote in space. Chemical Double Mutant Cycles (DMCs) were used to measure fifteen different aromatic stacking interactions as a function of substituent (NMe2, OMe, Me, Cl and NO2). When both aromatic rings have electron-withdrawing nitro substituents, the interaction is attractive (-2.8 kJ mol-1) due to reduced π-electron repulsion. When both aromatic rings have electron-donating di-methylamino substituents, the interaction is repulsive (+2.0 kJ mol-1) due to increased π-electron repulsion. The results show that aromatic stacking interactions are dominated by short range electrostatic contacts rather than substituent dipole interactions.


Improved clonal and nonclonal growth of human, rat and bovine adrenocortical cells in culture.
This report describes the development of a culture system for long-term growth and cloning of human fetal adrenocortical cells. Optimal conditions for stimulating clonal growth were determined by testing the efficacy of horse serum (HS), fetal bovine serum (FBS), fibroblast growth factor (FGF), epidermal growth factor (EGF), fibronectin, and a combination of growth factors, UltroSer G, in stimulating growth from low density. Optimal conditions for clonal growth were achieved using fibronectin-coated dishes and DME/F12 medium with 10% FBS, 10% HS, 2% UltroSer G, and 100 ng/ml FGF or 100 pM EGF. Conditions for growth at clonal density were found to be optimal for growth of early passage, nonclonal cultures at higher densities. The improved growth conditions used for cloning were shown to allow continued long-term growth of nonclonal human adrenocortical cells without fibroblast overgrowth. All cells in cultures grown in HS, FBS, and UltroSer G had morphologic characteristics of adrenocortical cells, whereas cells grown in FBS only rapidly became overgrown with fibroblasts. Clonal and nonclonal early passage human adrenocortical cells had similar mitogenic responses to FGF and EGF. Whereas FGF, EGF, and UltroSer G showed similar stimulation of DNA synthesis and clonal growth in human adrenocortical cells and human adrenal gland fibroblasts, the tumor promoter 12-O-tetradecanoylphorbol-13-acetate stimulated growth only in adrenocortical cells and was strongly inhibitory to growth in fibroblasts. In both cell types, forskolin inhibited DNA synthesis. Human adrenocortical cell cultures were functional and synthesized cortisol, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. The improved growth conditions for clonal growth of human adrenocortical cells also provided optimal conditions for long-term growth of cultured rat adrenocortical cells and increased the cloning efficiency of cultured bovine adrenocortical cells.


Ten kilohertz SCS for Treatment of Chronic Upper Extremity Pain (UEP): Results from Prospective Observational Study.
Chronic upper extremity pain (UEP) has complex etiologies and is often disabling. It has been shown that 10 kHz SCS can provide paresthesia-free and durable pain relief in multiple pain types and improve the quality of life of patients. To gain additional evidence on the safety and effectiveness of 10 kHz SCS for the treatment of chronic UEP. It was a prospective, multicenter, and observational study. The study was registered on ClinicalTrials.gov prospectively (clinical trial identifier: NCT02703818). Multicenter. A total of 43 subjects with chronic UEP of ≥5 cm (on a 0-10 cm visual analog scale; VAS) underwent a trial of 10 kHz SCS, and subjects with ≥40% pain relief received a permanent implant. All subjects had upper limb pain at baseline, while some had concomitant shoulder or neck pain. Subject outcomes were assessed for 12 months, and the primary outcome was the responder rate (percentage of subjects experiencing ≥50% pain relief from baseline) at three months. Thirty-eight subjects successfully completed the trial (88.3% success rate), 33 received permanent implants (five withdrew consent), and 32 had device activation (per protocol population). There were no paresthesias or uncomfortable changes in stimulation related to changes in posture during the study and there were no neurological deficits. Responder rates at 12 months for upper limb, shoulder, and neck pain in per protocol population (N=32) were 78.1%, 85.2%, and 75.0%, respectively. At 12 months, 84.4% of subjects were satisfied or very satisfied with 10 kHz SCS, and 38.7% either reduced or eliminated opioid usage. This study further supports the effectiveness of 10 kHz SCS for chronic UEP treatment and documents the safety profile of the therapy. NCT02703818.


[Keratoconus lenses: the small correction miracle].
Keratoconus is a non-inflammatory corneal disease associated with a cone-shaped protrusion and progressive corneal thinning. Apart from progression control and stabilizing interventions, correcting the optical error induced by a mostly highly irregular corneal surface is of paramount importance with respect to quality of life and ability to work. This goal can be achieved efficiently by contact lenses with only rare adverse conditions. This article provides a current overview on contact lens fitting in keratoconus and presents own associated results.


A novel interferon-alpha-regulated, DNA-binding protein participates in the regulation of the IFP53/tryptophanyl-tRNA synthetase gene.
We have investigated the transcriptional response of the IFP53/tryptophanyl-tRNA synthetase gene to interferon-alpha (IFN-alpha). A single gamma-interferon activation site (GAS) in proximity to the transcription start sites was found to mediate the response of the IFP53 gene to IFN-alpha. This DNA element bound two distinct protein factors, alpha-interferon activation factor 1 (AAF1) and AAF2, which were rapidly activated in the cytoplasm of IFN-alpha-treated HeLa cells. AAF1, like the gamma-interferon activation factor, bound to the GAS from different IFN-responsive promoters and contained the 91-kDa ISGF3 protein (p91). However, in complexes with the IFP53 or Ly6A/E GAS, p91 was the only ISGF3 protein, whereas in the case of the GBP GAS, the 48-kDa protein (p48) was also present. AAF2 was found to preferentially bind to the IFP53 GAS, but not at all to the GBP GAS, and contained no ISGF3 protein. Therefore, GAS-binding regulatory factors in the IFN-alpha response can either consist of proteins found in ISGF3 or be formed by distinct proteins that are similarly linked to IFN-alpha-induced signal transduction.


Purification and separation of enveloped and unenveloped herpes simplex virus particles.
Enveloped and unenveloped forms of herpes simplex virus (HSV) occurring in infected rabbit lung (ZP line) cells were purified by differential and discontinuous Ficoll density gradient centrifugation. Then the viral particles were separated in a sucrose-D2O density gradient. In the course of the procedures, both virus preparations were freed of Mg2+-dependent Na+ plus K+-stimulated adenosine triphosphatase (ATPase), 5'-nucleotidase, and glucose-6-phosphatase activities. However, Mg2+ -activated ATPase was shown to be firmly associated with purified virions. The recovery of infectious virus was 50-60 percent. The specific infectivities (TCID50/mg protein) of the purified enveloped and unenveloped viral particles were 1-2 times 10(10) and 2-5 times 10(6), respectively. The infectivity of the unenveloped viral particles was discussed.


Photo-protection and photo-inhibition during light induction in Barbula indica and Conocephalum conicum under different light gradients.
The objectives of this study were to measure the chlorophyll fluorescence (ChlF) parameters of Barbula indica (Hook.) Spreng and Conocephalum conicum (L.) Dumort subjected to various light intensities (LI) as a reflection of their adaptability to their habitats. The electron transport rate (ETR) of all plants under 500 μmol m-2 s-1 photosynthetic photon flux density (PPFD) was significantly higher than other LI treatments, implying that these plants could be grown under a specific and optimal light intensity adapted to 500 PPFD conditions. As LI increased from 50 to 2,000 PPFD, we observed in all plants increased non-photochemical quenching (NPQ) and photo-inhibitory quenching (qI) and decreased photosystem II efficiency (ΦPSII), potential quantum efficiency of PSII (Fv/Fm), actual PSII efficiency (ΔF/Fm'%), and Fv/Fm%. In addition, energy-dependent quenching (qE), the light protection system (qE + qZ + qT), and qI increased as ΦPSII decreased and photo-inhibition% increased under 1000, 1500, and 2000 PPFD conditions, suggesting that these plants had higher photo-protective ability under high LI treatments to maintain higher photosynthetic system performance. B. indica plants remained photochemically active and maintained higher qE under 300, 500, and 1000 PPFD, whereas C. conicum qZ + qT exhibited higher photo-protection under 500, 1000, and 1500 PPFD conditions. These ChlF indices can be used for predicting photosynthetic responses to light induction in different bryophytes and provide a theoretical basis for ecological monitoring.


Efficacy of therapeutic drug monitoring in prevention of hypoglycemia caused by cibenzoline.
The purpose of this study was to evaluate the efficacy of our therapeutic drug monitoring (TDM) services in cibenzoline therapy using the risk of hypoglycemia as an end point. The TDM services of cibenzoline were introduced in March 1998. If the serum concentrations of cibenzoline deviated from the therapeutic range, adjustment of dosage was recommended. In addition, the physicians were recommended to pay attention to the hypoglycemia induced by cibenzoline. A series of case-control studies were performed before and after introduction of TDM services. After introduction of TDM services of cibenzoline, four case-control studies were performed every 6 months between March 1998 and February 2000 (stage 2 between March 1998 and August 1998; stage 3 between September 1998 and February 1999; stage 4 between March 1999 and August 1999; stage 5 between September 1999 and February 2000) using the same method as in the previous study which had been performed between September 1997 and February 1998 (stage 1). The TDM data of inpatients and outpatients between March 1998 and February 2000 were reviewed. A significantly increased risk of hypoglycemia was observed for users of cibenzoline during stage 1 [crude odds ratio (OR) 10.4; 95% confidence interval (CI) 2.7-40.3], stage 2 (crude OR 3.1; 95% CI 1.0-9.0), and stage 3 (crude OR 3.8; 95% CI 1.2-12.7). However, during stage 4 and stage 5, no significantly increased risk of hypoglycemia was observed. There was no significant difference between the mean doses during stage 1 and stage 5. However, there was a significant difference in the distributions of the trough levels among the four stages. During stage 4 and stage 5, the percentage of samples with a trough level of 200-400 ng/ml was higher than during stage 2 and stage 3. During stage 2, the percentage of samples with a trough level over 400 ng/ml was 42.9%. Furthermore, the risk of hypoglycemia associated with cibenzoline use decreased together with the increase in the percentage of outpatients whose serum concentrations of cibenzoline had been measured in the past. The risk of hypoglycemia associated with cibenzoline use decreased after introduction of TDM of cibenzoline. Dose adjustment based on TDM and the physicians' increased recognition of hypoglycemia associated with cibenzoline use were beneficial for those patients treated with cibenzoline in order to prevent hypoglycemia.


A comparative biomechanical evaluation of different osteosynthesis techniques used for intracapsular condylar head fractures.
The aim of the present experimental study was to evaluate the biomechanical behavior in different types of osteosynthesis (titanium screws, bioresorbable pins and miniplates) used in management of intracapsular condylar head fractures. Experimental models of the condylar head fractures were simulated on 15 dry human cadaveric mandibles. Osteotomized mandibles were randomly divided into three groups with different fixation systems used: 1) 15 mm long titanium screws, 2) 15 mm long bioresorbable pins Sonic Pins Rx, 3) T-shaped titanium miniplate and 7 mm long titanium screws. Mandibles were loaded in TIRAtest testing machine (Germany). The main types of deformations, including torsion, bending and shearing, were simulated to study the biomechanical characteristics of the fixation systems. Titanium bicortical screws demonstrated the highest stiffness in standard loading conditions. The fixation with bioresorbable pins showed lower stiffness in both frontal and sagittal loads. This is indicative of the fact that resorbable pins, which have numerous advantages for clinical usage, cannot provide adequately stable fixation in maximal masticatory loads. The mandibles fixed with T-shaped plate had the lowest stiffness. Screw or pin fixation, regardless of the material used, was not resistant to rotational loads. On the contrary, the stiffness of T-shaped plates was quite significant. In real clinical conditions, if rotational displacements are not effectively compensated by irregularities in the fracture surface and precise repositioning of the bone fragments, combined use of miniplates and bicortical titanium screws or two screws can be beneficial.


Invisible woman?
The number of invited women speakers at scientific meetings is much less than their proportion in a field. This means that women have fewer venues to present their research, less opportunity to increase their professional network, and smaller chances of promotion and financial support. The paucity of women speakers also sends a message to aspiring young female researchers that there is no room for them at the top. So how can we help?


Parenteral nutrition-associated cholestasis: an American Pediatric Surgical Association Outcomes and Clinical Trials Committee systematic review.
The aim of this study was to review evidence-based data addressing key clinical questions regarding parenteral nutrition-associated cholestasis (PNAC) and parenteral nutrition-associated liver disease (PNALD) in children. Data were obtained from PubMed, Medicine databases of the English literature (up to October 2010), and the Cochrane Database of Systematic Reviews. The review of PNAC/PNALD has been divided into 4 areas to simplify one's understanding of the current knowledge regarding the pathogenesis and treatment of this disease: (1) nonnutrient risk factors associated with PNAC, (2) PNAC and lipid emulsions, (3) nutritional (nonlipid) considerations in the prevention of PNAC, and (4) supplemental medications in the prevention and treatment of PNAC. The data for each topic area relevant to the clinical practice of pediatric surgery were reviewed, evaluated, graded, and summarized. Although the conditions of PNAC and PNALD have been well recognized for more than 30 years, only a few concrete associations and treatment protocols have been established.


"It is like a pet in a way": The self-management experiences of people with cystic fibrosis diabetes.
Cystic fibrosis diabetes (CFD) is a very common co-morbidity affecting the lives of people with cystic fibrosis. Surprisingly, minimal research has been undertaken to understand the experiences of people with CFD and how they self-mange this condition. Using interpretative phenomenological analysis, the present study examined the self-management experiences of people with CFD. In-depth semi-structure interviews were conducted with eight people who had CFD. The following three superordinate themes were identified: forming a relationship with CFD, balancing the CFD self-management triad, and the unmet need for information and support. The findings suggest that the management of CFD is challenging and, although people with CFD experience many adaptation and management processes similar to people with type 1 diabetes, they struggle with the additional complexity of balancing CF and CFD. The provision of appropriate education, support and person-centred care needs to be addressed.


Association between statin treatment and LDL-cholesterol levels on the rate of ST-elevation myocardial infarction among patients with acute coronary syndromes: ACS Israeli Survey (ACSIS) 2002-2010.
STEMI is thought to occur as a result of a vulnerable coronary plaque rupture. Statins possess hypolipidemic and pleotropic effects that stabilize coronary plaque. We sought to determine the association between LDL-C levels, statin use prior to the index event on the type of acute coronary syndrome (ACS) presentation: STEMI vs. non-STEMI/unstable angina. Data was drawn from the ACS Israeli Survey (ACSIS), a biennial prospective survey of ACS patients hospitalized in all CCU/Cardiology departments during 2002-2010. Among 6790 patients, 2760 (41%) reported statin use prior to the index ACS event. The proportion of STEMI was significantly lower among statin treated vs. statin naive patients (36% vs. 57%, p<0.0001). At each LDL-C level, the proportion of STEMI was significantly lower only among statin treated patients (p<0.0001). LDL-C<70 mg/dL was associated with a lower proportion of STEMI only among statin treated but not among statin naive patients (33% vs. 57%, p<0.0001). Multivariate analysis revealed that statin use was independently associated with a lower probability of presenting with STEMI (ORadj=0.73, p=0.007), but not LDL-C<70 mg/dL (ORadj=1.13, p=0.32). Patients on high-intensity statin therapy (HIST) were less likely to present with STEMI as compared with low-intensity statin therapy (LIST) or statin naive patients (27%, 38%, 56%, respectively, p for trend <0.0001; HIST ORadj=0.28, p=0.01; LIST ORadj=0.48, p=0.026). Among patients admitted with ACS, statin use but not LDL-C level, was associated with a lower probability of presenting with STEMI. Patients on HIST had the lowest likelihood of presenting with STEMI.


Vesicular (liposomal and nanoparticulated) delivery of curcumin: a comparative study on carbon tetrachloride-mediated oxidative hepatocellular damage in rat model.
The liver plays a vital role in biotransforming and extricating xenobiotics and is thus prone to their toxicities. Short-term administration of carbon tetrachloride (CCl4) causes hepatic inflammation by enhancing cellular reactive oxygen species (ROS) level, promoting mitochondrial dysfunction, and inducing cellular apoptosis. Curcumin is well accepted for its antioxidative and anti-inflammatory properties and can be considered as an effective therapeutic agent against hepatotoxicity. However, its therapeutic efficacy is compromised due to its insolubility in water. Vesicular delivery of curcumin can address this limitation and thereby enhance its effectiveness. In this study, it was observed that both liposomal and nanoparticulated formulations of curcumin could increase its efficacy significantly against hepatotoxicity by preventing cellular oxidative stress. However, the best protection could be obtained through the polymeric nanoparticle-mediated delivery of curcumin. Mitochondria have a pivotal role in ROS homeostasis and cell survivability. Along with the maintenance of cellular ROS levels, nanoparticulated curcumin also significantly (P<0.0001) increased cellular antioxidant enzymes, averted excessive mitochondrial destruction, and prevented total liver damage in CCl4-treated rats. The therapy not only prevented cells from oxidative damage but also arrested the intrinsic apoptotic pathway. In addition, it also decreased the fatty changes in hepatocytes, centrizonal necrosis, and portal inflammation evident from the histopathological analysis. To conclude, curcumin-loaded polymeric nanoparticles are more effective in comparison to liposomal curcumin in preventing CCl4-induced oxidative stress-mediated hepatocellular damage and thereby can be considered as an effective therapeutic strategy.


[Use of an in vitro model in bovine to evidence a functional and molecular dialogue between preimplantation embryo and oviduct epithelial cells].
Beyond being a pipe between ovary and uterus, the oviduct is an active player in different aspects of early reproductive processes, in particular in the transport of embryos to the site of implantation and the regulation of its early development. Different studies evidenced a communication between oviduct and early embryo at the molecular and functional levels. Since the study of these interactions is difficult in vivo, different in vitro systems have been developed to mimic the maternal milieu during early development. These systems allowed to confirm the action of the cells on the quality of early development (blastocyst rate and viability). In turn, the embryos are producing signals that are able to modify and adapt the activity of maternal cells.


Statistical optimization of medium components for the production of Antrodia cinnamomea AC0623 in submerged cultures.
The nutritional medium requirement for biomass and triterpenoid production by Antrodia cinnamomea AC0623 strain was optimized. Box-Behnken was applied to optimize biomass and triterpenoid production. According to response surface methodology (RSM), the optimum concentrations of N-source were determined. The results indicate that when a submerged culture in shake flasks was operated at 28 degrees C, initial pH 5.5, and rotation speed 105 rpm, the biomass and triterpenoid content in dry basis could be increased to 3.20% (w/w) and 31.8 mg/g, respectively. The experiments were further scaled up to 100- and 700-l fermentors. Higher content of triterpenoids (63.0 mg/g) was obtained in 700-l fermentations by means of the control of cultural conditions and the modification of medium composition based on the RSM.


Assessment of reactive oxygen species production and genotoxicity of rare earth mining dust: Implications for public health and mining management.
Mining rare earth elements (REEs) can release large amounts of metal(loid)-rich dust, which can pose significant health risks to local residents. However, compared to other types of particulates, toxicity of mining dust has been largely overlooked. To provide experimental evidence on toxicity of REE mine dust, the study assessed the oxidative stress potential and genotoxicity of inhalable particles collected in a REE mining area, and associated toxicological response with source compositions. Both source types (i.e., mine and tailing area) and distances from source (i.e., industrial and residential areas) were considered when selecting the 44 sampling sites. The particle samples contained 2.3-3.5 folds higher concentrations of tested metal(loid)s than background concentrations in soil. Specially, elevated Fe, REEs, Cd, Pb were found. In spite of low cytotoxicity in lung epithelial A549 cells, there was increased cellular ROS production by of particle exposure. Samples with higher mining-originated source contributions (Provenance Index <0.3) had higher cellular ROS production (1.72 fold, 95%CI: 1.66-1.79 fold) than samples with lower mining contributions (1.58 fold, 95%CI: 1.52-1.65 fold). The factors soil (~46%), mine (~22%), and heavy metal (~20%) sources were recognized by source apportionment analysis as the main contributors to cellular ROS production; importantly, mine and heavy metal sources counted more in industrial samples. While samples generated genotoxicity, there were no differences in DNA damage between the location groups of sampling. Collectively, the results indicate that particles in mining areas may cause ROS production and DNA damage in lung cells depending on mine dust. Coupled with the long-range transportation potential of mine dust, safety measures on open pit and dust disposal sites should be adopted.


Underpinning mechanistic understanding of the segregation phenomena of pharmaceutical blends using a near-infrared (NIR) spectrometer embedded segregation tester.
The segregation of an active pharmaceutical ingredient (API) within a powder blend is one of the major manufacturing obstacles in achieving content uniformity. Segregation can be due to differences in physicochemical properties of formulation components and/or perturbations experienced during secondary processing steps, such as granulation, fluidization, die-filling and compression. A near-infrared (NIR) spectrometer embedded segregation tester, which could mimic the external stimulations (vibration and fluidization) experienced by a blend in a manufacturing facility, was used to evaluate and predict blend segregation. Two different GlaxoSmithKline (GSK) product blends with variations in the API particle size and concentration were tested. Drug content was further measured at different locations along the powder bed by NIR to sketch the segregation profile and calculate the overall segregation intensity of each blend. The study indicated that the segregation potential was dependent on the particle sizes of API and excipients, as well as the type of stimulus applied (vibration vs fluidization). Drug concentration profiles obtained from this mode of analysis decoded the underlying segregation mechanisms (sieving, trajectory and air elutriation) easily. The employed NIR-based segregation tester proved to be a useful small-scale predictive tool to evaluate and rank the segregation risk of the studied pharmaceutical blends.


PD-L1 expression predicts efficacy in the phase II SPiReL trial with MVP-S, pembrolizumab, and low-dose CPA in R/R DLBCL.
Patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) have limited treatment options. R/R DLBCL patients, who were mostly ineligible for ASCT due to age or comorbidities, were treated with maveropepimut-S (MVP-S, previously DPX-Survivac) a survivin directed T cell educating therapy, pembrolizumab, and intermittent low-dose cyclophosphamide. We identified, using univariate analysis, a subset of patients with enhanced ORR, PFS and DOR. Patients with baseline CD20+/PD-L1 expression had an ORR of 46% (6/13) and the disease control rate was 10/13 (77%). The PFS and OS of the positive CD20+/PD-L1 patients were 7.1 months and 17.4 months, whereas in the intent-to-treat (ITT) population of 25 enrolled patients, the ORR was 28% (7/25), median PFS and OS were 4.2 months and 10.1 months respectively. A total of 6/7 clinical responders occurred in CD20+/PD-L1 patients. The regimen was well-tolerated, requiring only minor dose modifications and one discontinuation. Grade 1 or 2 injection site reactions occurred in 14/25, (56%). Statistically significant associations were also seen between PFS and; injection site reactions; and ELISpot response to survivin peptides, both identifying the mechanistic importance of specific immune responses to survivin. This immunotherapy combination was found to be active and safe in this clinically challenging patient population.


Correlation between 6q25.3 deletion status and survival in pediatric intracranial ependymomas.
Losses and rearrangements of genetic material on chromosome 6q are frequently found in several human malignancies, including primary central nervous system tumors. We previously used microsatellite analysis of ependymomas to identify frequent deletions in regions 6q15 approximately q16, 6q21 approximately q22.1, and 6q24.3 approximately q25.3. To refine our preliminary analysis of potential prognostic regions, we used a panel of 25 microsatellite markers located between 6q15 and 6qter in 49 pairs of matched normal and tumor specimens from 28 children and 21 adults with ependymoma. Allelic deletions were detected in 34 of 49 patients (69%), and two common regions of deletions (6q24.3 and 6q25.2 approximately q25.3) were identified. A short segment of approximately 0.4 Mb between D6S1612 and D6S363 on 6q25.3, containing the SNX9 and SYNJ2 genes, exhibited the highest number of aberrations (n = 38). Pediatric tumors showed slightly fewer aberrations (64%) than adult tumors (76%) and also predominantly exhibited small interstitial deletions, in contrast to the extensive losses of genetic material in adults. Pediatric anaplastic intracranial (supra- and infratentorial) ependymomas harboring the 6q25.3 deletion (n = 9) showed significantly longer overall survival than did patients of the same group without the aberration (n = 6), independent of the extent of resection (P = 0.013). This supports the identified deletion on 6q25.3 as a candidate favorable prognostic parameter and warrants further investigation.


Virus isolation and genotype identification of human respiratory syncytial virus in Guizhou Province, China.
To investigate the genetic variation and molecular epidemiology characteristics of Human Respiratory Syncytial Virus (HRSV) in Guizhou Province, nasopharyngeal aspirates were collected from patients with acute respiratory infection (ARI) in Guizhou Provincial People's Hospital, from December 2017 to March 2018, and inoculated to Hep-2 cells to isolate HRSV. Cells that showed cytopathic effect (CPE) were then confirmed by indirect immunofluorescence assay and reverse transcription. The sequence of the PCR products was determined for HRSV isolates, and the genetic variation was analyzed. Out of 196 nasopharyngeal aspirate samples, HRSV were isolated in 39. The second hypervariable region at the 3' terminal of glycoprotein gene (HVR2) sequence analysis showed that subgroup A was dominant. Seventy-nine percent of the isolates belonged to subgroup A, ON1 genotype, and 21 % belonged to subgroup B, BA9 genotype, which indicates that the dominant HRSV circulating in Guizhou Province was subgroup A, genotype ON1, co-circulating with a less prevalent subgroup B, genotype BA9.


Thermoresponsive polymeric gel as an on-demand transdermal drug delivery system for pain management.
The main aim of this work is to design a heat triggered transdermal drug delivery system (TDDS) using a thermoresponsive polymer, poly (N-vinyl caprolactam) [PNVCL] based gel, where in patients can themselves administer a pulse of drug on mere application of heat pad over the TDDS, whenever pain is experienced. The phase transition temperature of PNVCL was tuned to 35 °C by grafting it onto a pH sensitive biopolymer, Chitosan, to synthesize Chitosan-g-PNVCL (CP) co-polymer which render the gel both thermo- and pH-responsive property. The application of triggered delivery was explored by loading acetamidophenol (a model hydrophilic drug) and etoricoxib (a model hydrophobic drug). In vitro drug release experiments were performed at three different temperatures (25, 32 and 39 °C) at two different pH (5.5 and 7) to study its drug release with response to temperature and pH. Drug release profiles obtained were found to have enhanced release for both the drugs respectively at 39 °C (above LCST) and pH5.5 when compared to other release conditions. In vitro skin permeation of both the drugs performed in rat abdominal skin using Franz diffusion cell showed enhanced drug release when the skin was subjected to higher temperature (39 °C). Moreover, it was also found that skin permeation for hydrophobic drug was better than that of hydrophilic drug. The in vivo biocompatibility studies of the CP gel in rat skin proved that the gel is biocompatible. The results obtained demonstrated the potential use of the thermoresponsive CP gel as an on-demand localized drug delivery system.


Insights of Extracellular Vesicles of Mesenchymal Stem Cells: a Prospective Cell-Free Regenerative Medicine for Neurodegenerative Disorders.
Mesenchymal stem cells (MSCs) are multipotent, adult stem cells which are found in numerous tissues like the umbilical cord, Wharton's jelly, bone marrow, and adipose tissue. They possess the capacity of self-renewal by dividing and differentiating into various cellular lineages. Their characteristic therapeutic potential exploited so far has made them a desirable candidate in regenerative medicine. Neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and ischemic stroke have been treated with MSCs and MSC-derived products. Over the past few decades, we have witnessed significant contributions in discovering the etiology of various NDs and their possible therapeutic solutions. One of the MSC-based therapeutics is extracellular vesicles (EVs), which contain multiple biologically active molecules like nucleic acids and proteins. The contents of EVs are ferried between cells for intercellular communication which then leads to regulation of the homeostasis of recipient cells. EVs serve as a considerable means of cell-free therapies like for tissue repair or regeneration as EVs can maintain therapeutically effective cargo of parent cells and are free of various ethical issues in cell-based therapies. Due to paucity of standard protocols in extraction procedures of EVs and their pharmacological properties and mechanisms, the development of new EV dependent therapies is challenging. With this review, an attempt has been made to annotate these mechanisms, which can help advance the novel therapeutic approaches towards the treat and define a more narrowed down approach for each ND to devise effective MSC-based therapies to cure and avert these diseases.


Effector T Cell Egress via Afferent Lymph Modulates Local Tissue Inflammation.
Memory/effector T cells recirculate through extralymphoid tissues by entering from blood and egressing via afferent lymph. Although T cell entry into effector sites is key to inflammation, the relevance of T cell egress to this process is unknown. In this study, we found that Ag recognition at the effector site reduced the tissue egress of proinflammatory Th1 cells in a mouse model of delayed hypersensitivity. Transgenic expression of "tissue exit receptor" CCR7 enhanced lymphatic egress of Ag-sequestered Th1 cells from the inflamed site and alleviated inflammation. In contrast, lack of CCR7 on Th1 cells diminished their tissue egress while enhancing inflammation. Lymph-borne Th1 and Th17 cells draining the inflamed skin of sheep migrated toward the CCR7 ligand CCL21, suggesting the CCR7-CCL21 axis as a physiological target in regulating inflammation. In conclusion, exit receptors can be targeted to modulate T cell dwell time and inflammation at effector sites, revealing T cell tissue egress as a novel control point of inflammation.


Lymphatic microvessel density combined with CT used in the diagnosis of mediastinal and hilar lymph node metastasis of non-small cell lung cancer.
Lymphatic microvessel density (LMVD) has been demonstrated to correlate with tumor metastasis. The purpose of this study is to determine whether the criteria combining LMVD with computed tomography (CT) could improve the diagnostic accuracy of lymph node (LN) metastasis in non-small cell lung cancer (NSCLC). Ninety four patients with NSCLC who had chest CT scans preoperatively and LMVD tested by immunohistochemistry postoperatively were randomized into two groups: the training set (n = 66) and the test set (n = 28). Cut-off point of LMVD was selected to separate the LN metastasis-predictive positive and negative groups. On the basis of LMVD levels, chest CTs of the training set were re-analyzed and hypothetical criteria for LN metastasis diagnosis were established. Diagnostic characteristics for LN metastasis were tested by using the combined criteria in the test set as compared to those of CT alone. There was a significantly positive correlation between LMVD and LN metastasis (p <0.01). For sensitivity, specificity, positive predictive value (PPV) and negative predictive values (NPV), accuracy was 67, 81, 75, 81 and 79% for the combined criteria, respectively. Diagnostic efficacy of the combined criteria was significantly higher than that of CT only (p <0.05). Diagnosis of LN metastasis using a combination of LMVD and CT is superior to the CT-only diagnosis. In future clinical trials, it is necessary to evaluate the efficacy of adjuvant therapy for the selection of patients according to the combined criteria.


Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses.
Myelofibrosis (MF) is associated with a variety of burdensome symptoms and reduced survival compared with age-/sex-matched controls. This analysis evaluated the long-term survival benefit with ruxolitinib, a Janus kinase (JAK)1/JAK2 inhibitor, in patients with intermediate-2 (int-2) or high-risk MF. This was an exploratory analysis of 5-year data pooled from the phase 3 COMFORT-I and -II trials. In both trials, patients could cross over to ruxolitinib from the control group (COMFORT-I, placebo; COMFORT-II, best available therapy). All continuing patients in the control groups crossed over to ruxolitinib by the 3-year follow-up. Overall survival (OS; a secondary endpoint in both trials) was evaluated using pooled intent-to-treat data from patients randomized to ruxolitinib or the control groups. OS was also evaluated in subgroups stratified by baseline anemia and transfusion status at week 24. A total of 528 patients were included in this analysis; 301 were originally randomized to ruxolitinib (COMFORT-I, n = 155; COMFORT-II, n = 146) and 227 to control (n = 154 and n = 73, respectively). The risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control group (median OS, 5.3 vs 3.8 years, respectively; hazard ratio [HR], 0.70 [95% CI, 0.54-0.91]; P = 0.0065). After correcting for crossover using a rank-preserving structural failure time (RPSFT) method, the OS advantage was more pronounced for patients who were originally randomized to ruxolitinib compared with patients who crossed over from control to ruxolitinib (median OS, 5.3 vs 2.3 years; HR [ruxolitinib vs RPSFT], 0.35 [95% CI, 0.23-0.59]). An analysis of OS censoring patients at the time of crossover also demonstrated that ruxolitinib prolonged OS compared with control (median OS, 5.3 vs 2.4 years; HR [ruxolitinib vs censored at crossover], 0.53 [95% CI, 0.36-0.78]; P = 0.0013). The survival benefit with ruxolitinib was observed irrespective of baseline anemia status or transfusion requirements at week 24. These findings support ruxolitinib treatment for patients with int-2 or high-risk MF, regardless of anemia or transfusion status. Further analyses will be important for exploring ruxolitinib earlier in the disease course to assess the effect on the natural history of MF. ClinicalTrials.gov identifiers, NCT00952289 and NCT00934544 .


Effect of cross polarization radiofrequency phases on signal phase.
Utilizing phases of radio frequency (RF) pulses to manipulate spin dynamics is routine in NMR and MRI, leading to spectacular techniques like phase cycling. In a very different area, cross polarization (CP) also has a long history as part of a vast number of solid-state NMR pulse sequences. However, a detailed study devoted to the effect of CP RF phases on NMR signal, seems not to be readily available. From first principles, we arrive at a simple dependence of NMR signal on arbitrary CP RF phases, for static and MAS conditions, accompanied by experimental verification. In the process, the CP propagator emerges as a product of RF "pulses" and a period of "free precession", conforming to coherence transfer pathway theory. The theoretical expressions may lend confidence for dealing with CP blocks with tunable phases in pulse sequences.


Intravital Two-Photon Imaging of Lymphocytes Crossing High Endothelial Venules and Cortical Lymphatics in the Inguinal Lymph Node.
Lymphocyte recirculation through lymph nodes (LNs) requires their crossing of endothelial barriers present in blood vessels and lymphatics by means of chemoattractant-triggered cell migration. The chemoattractant-chemoattractant receptor axes that predominately govern the trafficking of lymphocytes into, and out of, LNs are CCL19/CCR7 and sphingosine 1-phosphate (S1P)/S1P receptor 1 (S1PR1), respectively. Blood-borne lymphocytes downregulate S1PR1 and use CCR7 signaling to adhere to high endothelial venules (HEVs) for transmigration. During their LN residency, recirculating lymphocytes reacquire S1PR1 and attenuate their sensitivity to chemokines. Eventually lymphocytes exit the LN by entering the cortical or medullary lymphatics, a process that depends upon S1PR1 signaling. Upon entering into the lymph, lymphocytes lose their polarity, downregulate their sensitivity to S1P due to the high concentration of S1P, and upregulate their sensitivity to chemokines. However, many of the details of lymphocyte transmigration across endothelial barriers remain poorly understood. Intravital two-photon imaging with advanced microscope technologies not only allows the real-time observation of immune cells in intact LN of a live mouse, but also provides a means to monitor the interactions between circulating lymphocytes and stromal barriers. Here, we describe procedures to visualize lymphocytes engaging and crossing HEVs, and approaching and crossing the cortical lymphatic endothelium to enter the efferent lymph in live mice.


Fetectomy alters maternal endocrine and uterine activity rhythms in rhesus macaques during late gestation.
The current study was designed to test the hypothesis that fetectomy will eliminate or substantially alter rhythms in maternal estradiol concentrations and subsequently reduce or eliminate uterine activity rhythms. Six rhesus macaques underwent surgery for catheter implantation between days 117 and 122 of gestation (term = 167 days). At surgery the fetuses were removed and the membranes and placenta remained intact. Thirteen additional catheterized pregnant animals served as controls. Maternal arterial blood samples were collected for hormone analysis at 3-hour intervals for 24 hours, starting at 9 AM. This sampling protocol was performed four times at weekly intervals until 151 to 157 days' gestation. A significant rhythm (p < 0.01) in estradiol was determined in the control animals with peak concentrations observed in the morning hours whereas the progesterone peak was observed at night. In the fetectomy group mean plasma estradiol concentrations decreased significantly from 312 +/- 34 to 110 +/- 8 pg/ml throughout the study (p < 0.01). Despite a trend toward elevated morning levels, the estradiol rhythm was ablated. The uterine contractile rhythm observed in the control animals with peak activity between 10 PM and midnight (p < 0.01) was also ablated after fetectomy. Basal concentrations of progesterone were significantly lower than control values. (1) Fetectomy resulted in the elimination of the maternal estradiol rhythm. (2) The uterine activity rhythm was lost after fetectomy. These data suggest that the fetus, by supplying precursors of estrogen, may play an indirect role in the regulation of maternal estradiol rhythms, which in turn appear to play a key role in regulating uterine activity rhythms.


The role of neoadjuvant hormonal manipulation in localized prostatic cancer.
Although hormonal manipulation is standard therapy for patients with metastatic prostatic cancer, its use in localized disease in combination with surgical extirpation of the gland has not been investigated thoroughly and systematically. The authors report their initial pilot studies using preoperative neoadjuvant endocrine therapy. Although marked reduction in serum prostate-specific antigen (PSA) levels occurred in all patients, the PSA level after endocrine manipulation did not predict the pathologic stage. In addition, immunohistochemical staining of the radical prostatectomy specimen for PSA, in several patients with a zero serum PSA level, after endocrine therapy revealed intense PSA staining in the cancer cells but not in benign epithelium. The effects on tumor downstaging were inconclusive. Overall, only 33% of patients had organ-confined disease, but in some patients, complete tumor regression (PO) occurred. Neoadjuvant hormonal therapy in prostatic cancer, although definitely not standard therapy, bears investigation. In addition to the effect on the "index" cancer, it also provides an opportunity to evaluate the effect of hormonal agents on microfocal ("early") cancer and known precursors of malignant change. Therefore, it may provide a means of assessing agents of potential use in the development of chemopreventive strategies.


Are liver transplant recipients protected against hepatitis A and B?
Liver transplant recipients are at an increased risk for liver failure when infected with hepatitis A virus (HAV) and hepatitis B virus (HBV). Therefore, it is important to vaccinate these individuals. The aim of the study was to evaluate how well liver transplanted patients in our unit were protected against HAV and HBV infection. Furthermore we investigated the vaccination rate and the antibody response to vaccination in these liver transplanted patients. Patients liver transplanted from January 2007 until August 2010 with a posttransplant check-up during the period March-November 2010 were included (n = 51). Information considering diagnose, date of transplantation, Child-Pugh score, and vaccination were collected from the patient records. Anti-HAV IgG and anti-HBs titers in serum samples were analyzed and protective levels were registered. Of the patients 45% were protected against hepatitis A infection and 29% against hepatitis B infection after transplantation. Only 26% were vaccinated according to a complete vaccination schedule and these patients had a vaccine response for HAV and HBV of 50% and 31%, respectively. An additional 31% received ≥ 1 doses of vaccine, but not a complete vaccination and the vaccine response was much lower among these patients, stressing the importance of completing the vaccination schedule. Even when patients were fully vaccinated, they did not respond to the same degree as healthy individuals. Patients seemed to be more likely to respond to a vaccination if they had a lower Child-Pugh score, suggesting that patients should be vaccinated as early as possible in the course of their liver disease.


Isolation of bacterial strains from compost teas and screening of their PGPR properties on potato plants.
The beneficial effect of compost and compost tea on plant growth and protection is mainly associated with the microbial diversity and the presence of bacteria with plant growth-promoting effect. PGPR are considered as eco-friendly bio-fertilizers that may reduce the use of chemical pesticides and fertilizers. Three composts (AT, A10, and A30) were previously prepared from industrial wastes (olive mill wastewater, olive pomace, coffee ground, and phosphogypsum). In the present study, we isolated three bacterial strains from the compost teas. The phylogenetic identification of these bacterial strains (B.AT, B.A10, and B.A30) showed that they correspond to Serratia liquefaciens (B.AT and B.A10) and Achromobacter spanius (B.A30) species. A further characterization of the PGPR traits of these bacteria showed that they produce siderophore, exopolysaccharides, and IAA. Their effect on potato plant growth, yields, and tuber quality was performed under field culture conditions. Results showed that these strains can be characterized as PGPR, the best effect on potato plant growth was observed with Serratia liquefaciens (B.AT), the best yield and tuber quality was observed with Serratia liquefaciens (B.A10) while bacterial treatment with Achromobacter spanius (B.A30) is a Cd-tolerant PGPR.


Human placental acetylcholine content and release at parturition.
1. Measurements were made of human placental acetylcholine (ACh) content and release into maternal and fetal circulations from placenta obtained before, during and after labours of both spontaneous and induced onsets. ACh content was determined in ex vivo placental biopsies using a radio-enzymatic assay. ACh release was determined by bioassay of the effluent from placental lobules perfused with amniotic fluid-like Kreb's containing physostigmine (2.4 mumol/l). 2. ACh content of placentae obtained after labour (spontaneous onset of labour, normal vaginal delivery) and during labour (spontaneous onset of labour, Caesarean section delivery) was significantly less than before labour (no labour onset, Caesarean section delivery). 3. Mean ACh output into maternal vessels 1.5-4.0 h after commencement of perfusion of placentae obtained after labour (spontaneous onset of labour, normal vaginal delivery) was significantly less than from those obtained before labour (no labour onset, Caesarean section delivery). No differences were found in ACh output into fetal vessels of placentae obtained before, during or after labour. 4. These results suggest a role for placental ACh in the events of human labour. The decrease in ACh content and maternal vascular release in placenta obtained after labour is consistent with a depletion of placental ACh during labour which may indicate ACh release at this time. The lack of any significant change in fetal vascular release of ACh in placenta obtained before, during or after labour, raises the possibility of different roles for ACh released into fetal and maternal vasculature.


Increased degradation of low density lipoproteins by mononuclear leukocytes associated with coronary artery disease.
Low density lipoprotein (LDL) and peripheral blood mononuclear leukocytes (MNL) were isolated from patients with (n = 11) and without (n = 11) angiographically documented coronary artery disease (CAD). LDL degradation rates in MNL were determined in vitro using both autologous and homologous LDL. The mean rate of LDL degradation was 1.7-fold higher in CAD-MNL than in control-MNL (P less than 0.05), independent of the LDL source. The increased LDL degradation rate in CAD-MNL appeared to be due to an increased receptor-mediated LDL degradation rate in CAD-MNL and not to an increased CAD-LDL interaction with the receptor since LDL isolated from patients with and without CAD had similar in vitro degradation rates in HL-60 cells and 1.25-dihydroxyvitamin D3-induced HL-60 macrophages. An increased ratio of apo B to cholesterol, specifically apo B to cholesteryl ester, was observed in LDL isolated from patients with CAD. LDL particles isolated from CAD patients contained 14.8% less cholesteryl ester than LDL from control subjects (P less than 0.01). The data suggest that CAD patients have an increased plasma LDL particle number even though they have similar plasma LDL-cholesterol levels as compared to control subjects. These data indicate that CAD patients with normal plasma LDL cholesterol levels have two metabolic abnormalities: an altered LDL composition resulting in particles with reduced cholesteryl ester content and an increased LDL catabolism resulting in an increased influx of LDL cholesterol into MNL; both of which may play a role in the development of coronary heart disease.


Home Sweet Home: The Impact of Lifestyle on a Cat's Approach to Impossible Tasks in the Home Environment.
Cat welfare is a topic of growing interest in the scientific literature. Although previous studies have focused on the effects of living style (i.e., indoor/outdoor) on cat welfare, there has been a noticeable dearth of analysis regarding the impact of lifestyle on cats' inclination and mode of communication with humans. Our research aimed to analyze the possible effect of lifestyle (e.g., living indoors only or indoor/outdoor) on cat-human communication. The cats were tested using the impossible task paradigm test, which consists of some solvable trials in which the subject learns to obtain a reward from an apparatus, followed by an impossible trial through blocking the apparatus. This procedure triggers a violation of expectations and is considered a useful tool for assessing both the decision-making process and the tendency to engage in social behaviors towards humans. A specific ethogram was followed to record the behavioral responses of the cats during the unsolvable trial. Our results show the effects of lifestyle and age on domestic cats, providing valuable insights into the factors that influence their social behaviors. Cats that can roam freely outdoors spent less time interacting with the apparatus compared to indoor-only cats. Additionally, roaming cats showed stress behaviors sooner following the expectancy of violation compared to indoor cats. The lifestyle of cats can influence their problem-solving approach while not affecting their willingness to interact with humans or their overall welfare. Future studies on this topic can be useful for improving the welfare of domestic cats.


Clinical pharmacokinetics of candesartan.
Candesartan cilexetil is the prodrug of candesartan, an angiotensin II type 1 (AT1) receptor antagonist. Absorbed candesartan cilexetil is completely metabolised to candesartan. Oral bioavailability is low (about 40%) because of incomplete absorption. Plasma protein binding in humans is more than 99%. The volume of distribution in healthy individuals is 0.13 L/kg. CV-15959 is the inactive metabolite of candesartan. Candesartan that reaches the systemic circulation is mainly cleared by the kidneys, and to a smaller extent by the biliary or intestinal route. The apparent oral clearance of candesartan is 0.25 L/h/kg after a single dose in healthy individuals. Oral clearance (3.4 to 28.4 L/h) is highly variable among patients. No relevant pharmacokinetic drug-food or drug-drug interactions are known. The terminal elimination half-life remains unclear, but appears to be longer than the currently used range of 4 to 9 hours. Non-compartmental models do not appear to be appropriate for the analysis of candesartan pharmacokinetic data. A 2-compartment analysis revealed a much longer half-life of 29 hours using data from patients with hypertension. However, a further indepth analysis has never been performed. The concentration-effect relationship is unaffected by age. No gender or race differences have been shown in the effect or pharmacokinetics of candesartan. Renal function affects the pharmacokinetic profile of candesartan. For patients with creatinine clearances of >60 ml/min x 1.73m(2), 30 to 60 ml/min x 1.73m(2) and 15 to 30 ml/min x 1.73m(2), the elimination half-life is 7.1, 10.0 and 15.7 hours, respectively, at a dose of 8 mg/day. However, at 12 mg/day an accumulation factor of 1.71 was found. Thus, a maximum daily dose of up to 8mg appears suitable in patients with severe renal dysfunction. No significant elimination of candesartan occurs with haemodialysis. In patients with mild to moderate hepatic impairment, no relevant pharmacokinetic alterations have been observed. Dosages of up to 12 mg/day do not require precautions in patients with mild to moderate liver disease. Clinically effective dosages range between 8 and 32 mg/day. The response rate of monotherapy with candesartan in patients with hypertension increases with dosage, but never exceeds 60% at a daily dosage of 16mg of candesartan. Dosages up to 32 mg/day do not increase this response rate.


Muramyl dipeptide (MDP) synergizes with interleukin 2 and interleukin 4 to stimulate, respectively, the differentiation and proliferation of B cells.
The synthetic immunomodulator muramyldipeptide (MDP) can stimulate B cells. MDP, when used alone, was apparently unable to induce the differentiation or proliferation of resting B cells. In contrast, MDP appeared to synergize with a single recombinant interleukin (IL) to stimulate either their differentiation or proliferation. We used single interleukins to avoid synergistic and antagonistic effects inherent in the use of several factors. IL-2 was found to be sufficient to restore the specific immune response of resting B cells to sheep erythrocytes; MDP greatly increased the number of plaque-forming cells of such IL-2-stimulated B cells. In contrast, IL-4 and interferon-gamma (IFN-gamma), either alone or in the presence of MDP, had no effect in this differentiation assay. MDP was also able to stimulate polyclonally activated B cells. IL-4 increased the proliferation of anti-IgM-stimulated B cells, leading to enlargement and driving more cells into the cell cycle; these effects were further enhanced by MDP, more cells being induced to proliferate, to enlarge, and to progress into the cycle with a higher frequency of cells in the G1B, S, and G2/M compartments. Intracellular free calcium levels were not increased by IL-4 and/or MDP, and the two compounds did not modify the anti-IgM-induced calcium mobilization. Therefore, MDP appears to amplify cytokine effects in B cell activation, by a mechanism which does not appear to involve free calcium mobilization.


Evaluation of epigallocatechin-3-gallate (EGCG) cross-linked collagen membranes and concerns on osteoblasts.
Collagen membranes have ideal biological and mechanical properties for supporting infiltration and proliferation of osteoblasts and play a vital role in guided bone regeneration (GBR). However, pure collagen can lead to inflammation, resulting in progressive bone resorption. Therefore, a method for regulating the level of inflammatory cytokines at surgical sites is paramount for the healing process. Epigallocatechin-3-gallate (EGCG) is a component extracted from green tea with numerous biological activities including an anti-inflammatory effect. Herein, we present a novel cross-linked collagen membrane containing different concentrations of EGCG (0.0064%, 0.064%, and 0.64%) to regulate the level of inflammatory factors secreted by pre-osteoblast cells; improve cell proliferation; and increase the tensile strength, wettability, and thermal stability of collagen membranes. Scanning electron microscope images show that the surfaces of collagen membranes became smoother and the collagen fiber diameters became larger with EGCG treatment. Measurement of the water contact angle demonstrated that introducing EGCG improved membrane wettability. Fourier transform infrared spectroscopy analyses indicated that the backbone of collagen was intact, and the thermal stability was significant improved in differential scanning calorimetry. The mechanical properties of 0.064% and 0.64% EGCG-treated collagen membranes were 1.5-fold greater than those of the control. The extent of cross-linking was significantly increased, as determined by a 2,4,6-trinitrobenzenesulfonic acid solution assay. The Cell Counting Kit-8 (CCK-8) and live/dead assays revealed that collagen membrane cross-linked by 0.0064% EGCG induced greater cell proliferation than pure collagen membranes. Additionally, real-time polymerase chain reaction and enzyme-linked immunosorbent assay results showed that EGCG significantly affected the production of inflammatory factors secreted by MC3T3-E1 cells. Taken together, our results indicate that treatment of collagen membranes with appropriate concentrations of EGCG has an anti-inflammatory effect and shows promise for GBR applications.


Prognostic implication of lymphatic vessel invasion in stage IB (pT2aN0M0) non-small cell lung cancer.
To clarify the prognostic factors for recently revised stage IB non-small cell lung cancer. Twenty-six specimens of completely resected stage IB (pT2aN0M0) non-small cell lung cancer were studied. Clinicopathological profiles of the 26 patients, including age, sex, smoking status, tumor size, histology, pleural invasion, and lymphatic and blood vessel invasion, were assessed. Correlation between tumor recurrence and these factors was assessed by statistical analysis. Lymphatic vessel invasion was the only statistically significant factor for postoperative tumor recurrence as assessed by multivariate analysis. Kaplan-Meier survival curves showed a 5-year recurrence-free rate of 77.8% in 26 patients with no lymphatic vessel invasion compared with 28.6% in those with lymphatic vessel invasion. Lymphatic vessel invasion of cancer cells was indicated as an independent prognostic factor in revised stage IB non-small cell lung cancer.


Acquired coccygeal nodule due to repeated stimulation by a bicycle saddle.
Four Japanese male students, aged 14, 16, 18 and 19, were found to have a nodule in their coccygeal regions. The typical lesion was a rugby-ball-shaped, normal-colored or slightly erythematous nodule measuring 5 to 6 cm in its long axis. Histopathologically, it showed hyperplasia of collagen fibers and slight acanthosis. All four students rode to school by bicycle over long distances and long periods; three of them developed the nodule after they started bicycle riding to school. We found that the nodule shape corresponded to the saddle of the bicycle. X-ray abnormalities included bending or anterior dislocation of the coccyx in all cases and spina bifida in two cases. These nodules may have developed as a result of irritation of this region by the saddle of the bicycle.


Protective effect of leaves of Raphinus sativus Linn on experimentally induced gastric ulcers in rats.
Raphinus sativus Linn (Cruciferae) commonly known as 'Radish' is a multipurpose herb cultivated in different parts of the world for its edible roots and leaves. The present study was aimed to evaluate the antiulcer activity of leaf extracts of R. sativus Linn on acetic acid induced chronic gastric ulcer and pylorus ligation induced gastric ulcer in rats. The acute oral toxicity study revealed that all the extracts were safe up to 2000 mg/kg per oral dose; hence one-tenth of this dose was selected for evaluation of antiulcer activity. In acetic acid induced gastric ulcer models, the ERS, CRS, EARS and AQRS have offered significant protection against acetic acid induced ulcers when compared to control group. While in pylorus ligation induced ulcer model the ERS, EARS and AQRS showed significant protection by decreasing the ulcer index, total acidity and free acidity. In conclusion the leaf extracts of R. sativus Linn are found to possess antiulcer property in the experimental animal models of gastric ulcers, which is consistent with the literature report in the folk medicine.


Social task switching: On the automatic social engagement of executive functions.
Humans are quintessentially social, yet much of cognitive psychology has focused on the individual, in individual settings. The literature on joint action is one of the most prominent exceptions. Joint-action research studies the sociality of our mental representations by examining how the tasks of other people around us affect our own task performance. In this paper we go beyond examining whether we represent others and their tasks, by asking whether we also automatically do their tasks with them, even if they require effortful executive functions. To this end we examine one of the core executive functions, shifting, in a new paradigm that allows us to investigate task-switching in a joint-action setup.


'Shooting at the sun god Apollo': the Apollonian-Dionysian balance of the TimeSlips Storytelling Project.
In The Birth of Tragedy, Friedrich Nietzsche celebrated the dueling forces of reason and emotion as personified by the ancient Greek gods Apollo and Dionysus. A subtle Apollonian-Dionysian balance can be observed in TimeSlips, a group-based creative storytelling activity developed in the 1990s and increasingly used in dementia care settings worldwide. This article explains how the Apollonion-Dionysian aspects of TimeSlips are beneficial not only for persons with dementia, but also for their carers. Narrative data from medical students at Penn State College of Medicine who participated in TimeSlips at a local retirement community are shared.


An audit of skeletal surveys for suspected non-accidental injury following publication of the British Society of Paediatric Radiology guidelines.
To audit change in the content and standard of skeletal surveys in the UK following the publication of the British Society of Paediatric Radiology (BSPR) guidelines for skeletal surveys in suspected non-accidental injury. One hundred skeletal surveys, which were performed throughout England and Wales between February 2004 and September 2006 and received for a second opinion at a single children's hospital, were reviewed. The views obtained were compared with the defined reference standard 20 views as recommended by the BSPR. Additionally, each view was assessed for technical quality out of a maximum score of 11. The results were compared with an earlier study published prior to the definitive guideline. Additional information included whether images were film or digital and whether a computed tomography examination of the head was documented. A mean of 16.5 (range 5-20) of the 20 recommended views were covered per survey and 15% of surveys included all 20 recommended views (previously 0%). The mean technical score per film was 9.7/11 (88%). Sixty-two percent of the skeletal surveys were digitally acquired and 59% included a CT examination of the head. There is still considerable variation in skeletal surveys performed in the UK, but progress has been observed in all areas in the light of the BSPR guidelines. There remains room for improvement, and further publicity of the guidelines is recommended.


Kinetic analysis of secretory protein traffic and characterization of golgi to plasma membrane transport intermediates in living cells.
Quantitative time-lapse imaging data of single cells expressing the transmembrane protein, vesicular stomatitis virus ts045 G protein fused to green fluorescent protein (VSVG-GFP), were used for kinetic modeling of protein traffic through the various compartments of the secretory pathway. A series of first order rate laws was sufficient to accurately describe VSVG-GFP transport, and provided compartment residence times and rate constants for transport into and out of the Golgi complex and delivery to the plasma membrane. For ER to Golgi transport the mean rate constant (i.e., the fraction of VSVG-GFP moved per unit of time) was 2.8% per min, for Golgi to plasma membrane transport it was 3.0% per min, and for transport from the plasma membrane to a degradative site it was 0.25% per min. Because these rate constants did not change as the concentration of VSVG-GFP in different compartments went from high (early in the experiment) to low (late in the experiment), secretory transport machinery was never saturated during the experiments. The processes of budding, translocation, and fusion of post-Golgi transport intermediates carrying VSVG- GFP to the plasma membrane were also analyzed using quantitative imaging techniques. Large pleiomorphic tubular structures, rather than small vesicles, were found to be the primary vehicles for Golgi to plasma membrane transport of VSVG-GFP. These structures budded as entire domains from the Golgi complex and underwent dynamic shape changes as they moved along microtubule tracks to the cell periphery. They carried up to 10,000 VSVG-GFP molecules and had a mean life time in COS cells of 3.8 min. In addition, they fused with the plasma membrane without intersecting other membrane transport pathways in the cell. These properties suggest that the post-Golgi intermediates represent a unique transport organelle for conveying large quantities of protein cargo from the Golgi complex directly to the plasma membrane.


Enhanced potentiation of cisplatin cytotoxicity in human ovarian carcinoma cells by prolonged glutathione depletion.
We have determined the effect of extended glutathione (GSH) depletion on cis-diamminedichloroplatinum(II) (DDP) cytotoxicity in parent and DDP-resistant human ovarian carcinoma cells. Cells were exposed to 50 microM buthionine sulfoximine (BSO) for 48 h and exposed to DDP for the last 24 h of this time. This treatment protocol sensitized 2008 cells to DDP. The dose modification factor (DMF) defined as IC50 control cells/IC50 GSH depleted cells was 1.6 +/- 0.5 (N = 9). DDP-resistant cells selected by acute, high dose DDP exposure were also sensitized by this treatment; the DMF in the 3-6-fold resistant 2008/DDP cells was 2.4 +/- 1.2 (N = 9). The sensitization was not significantly greater in the resistant cells than in the parent cells (P greater than 0.05). When the rebound of GSH following BSO exposure was reexamined, the GSH levels were found to rise rapidly following trypsinizing and plating. BSO treatment following DDP exposure had no effect on DDP cytotoxicity in 2008 and 2008/DDP cells. These results indicate that simply depleting GSH prior to DDP exposure is not sufficient for sensitizing these cells to DDP. In contrast to the potentiation of nitrogen mustard cytotoxicity, exposure to GSH depletion must be maintained during DDP treatment for enhancement of DDP cytotoxicity to occur.


Triad pattern algorithm for predicting strong promoter candidates in bacterial genomes.
Bacterial promoters, which increase the efficiency of gene expression, differ from other promoters by several characteristics. This difference, not yet widely exploited in bioinformatics, looks promising for the development of relevant computational tools to search for strong promoters in bacterial genomes. We describe a new triad pattern algorithm that predicts strong promoter candidates in annotated bacterial genomes by matching specific patterns for the group I sigma70 factors of Escherichia coli RNA polymerase. It detects promoter-specific motifs by consecutively matching three patterns, consisting of an UP-element, required for interaction with the alpha subunit, and then optimally-separated patterns of -35 and -10 boxes, required for interaction with the sigma70 subunit of RNA polymerase. Analysis of 43 bacterial genomes revealed that the frequency of candidate sequences depends on the A+T content of the DNA under examination. The accuracy of in silico prediction was experimentally validated for the genome of a hyperthermophilic bacterium, Thermotoga maritima, by applying a cell-free expression assay using the predicted strong promoters. In this organism, the strong promoters govern genes for translation, energy metabolism, transport, cell movement, and other as-yet unidentified functions. The triad pattern algorithm developed for predicting strong bacterial promoters is well suited for analyzing bacterial genomes with an A+T content of less than 62%. This computational tool opens new prospects for investigating global gene expression, and individual strong promoters in bacteria of medical and/or economic significance.


Effects of progesterone on gender affirmation outcomes as part of feminizing hormone therapy.
The use of progesterone as a component of feminizing gender-affirming hormone therapy (GAHT) is controversial; however, use in transgender women continues owing to anecdotal reports of benefit. This study aimed to provide quantifiable outcomes data regarding the use of progesterone in transgender women by comparing groups from this population who use feminizing GAHT with and without progesterone. This retrospective cohort study captured data from transgender female patients seen at the Summa PRIDE Clinic between September 2019 and December 2021. Data were extracted from chart documentation for patients who were prescribed feminizing GAHT, with and without progesterone, for at least 6 months during the study window. Outcomes included satisfaction with breast development, satisfaction with libido, mental health trends, and weight change at 0, 6, and 9 months from initiation of GAHT. A total of 88 charts were reviewed (59 in the standard group, 29 in the progesterone group). The progesterone group had statistically significant improvements in satisfaction with breast development at 6 months (53.8% vs. 19.6%; P = 0.004) and 9 months (71.4% vs. 20.8%; P = 0.003). The progesterone group had more patients at goal testosterone levels < 55 ng/dL at 6 months (47.6% vs. 33%) and 9 months (50% vs. 24.4%), but these were not statistically different. The progesterone group was also more likely to show improved provider-documented mental health at 6 months (70.6% vs. 28.2%; P = 0.009); however, the difference was not statistically significant at 9 months. There were no differences between groups for weight change and patient satisfaction with libido. The addition of progesterone to standard feminizing GAHT was associated with greater satisfaction with breast development and improved patient mental health within 6 months compared with standard GAHT regimens alone in this patient population. Progesterone's impact on libido, testosterone suppression, and weight were nonsignificant.


Development and regression of intimal thickening of arterially transplanted autologous vein grafts in dogs.
To investigate the influence of hemodynamic conditions on intimal thickening of arterially transplanted autologous vein grafts, two experimental models of canine femoral arteries were prepared. In group I, in which an autologous vein graft was transplanted under abnormal flow conditions (distal poor runoff), intimal thickening gradually developed and reached 358 +/- 33 microns at 8 months, whereas no thickening was observed under normal flow conditions at any time throughout the observation period. In group II the thickened intima, which developed under abnormal flow conditions for 1 month, was reimplanted into the contralateral leg under normal flow conditions. The thickness of the intima markedly regressed to about 66% at 1 month, 50% at 3 months, and 25% at 8 months, respectively, whereas no regression of the thickened intima was observed under continued abnormal flow conditions. Electron microscopic studies revealed that the thickened intima in group I was composed of proliferation of transformed smooth muscle cells with a marked increase in the mitochondria, the rough endoplasmic reticulum, and an abundant fibrous matrix, whereas with the regressed thickness of the intima of group II, the smooth muscle cells were spindle-shaped with distinct myofibrillae. These results provide pertinent data on the process involved in the intimal thickening in cases of graft placement.


Combining genetic risk score with artificial neural network to predict the efficacy of folic acid therapy to hyperhomocysteinemia.
Artificial neural network (ANN) is the main tool to dig data and was inspired by the human brain and nervous system. Several studies clarified its application in medicine. However, none has applied ANN to predict the efficacy of folic acid treatment to Hyperhomocysteinemia (HHcy). The efficacy has been proved to associate with both genetic and environmental factors while previous studies just focused on the latter one. The explained variance genetic risk score (EV-GRS) had better power and could represent the effect of genetic architectures. Our aim was to add EV-GRS into environmental factors to establish ANN to predict the efficacy of folic acid therapy to HHcy. We performed the prospective cohort research enrolling 638 HHcy patients. The multilayer perception algorithm was applied to construct ANN. To evaluate the effect of ANN, we also established logistic regression (LR) model to compare with ANN. According to our results, EV-GRS was statistically associated with the efficacy no matter analyzed as a continuous variable (OR = 3.301, 95%CI 1.954-5.576, P < 0.001) or category variable (OR = 3.870, 95%CI 2.092-7.159, P < 0.001). In our ANN model, the accuracy was 84.78%, the Youden's index was 0.7073 and the AUC was 0.938. These indexes above indicated higher power. When compared with LR, the AUC, accuracy, and Youden's index of the ANN model (84.78%, 0.938, 0.7073) were all slightly higher than the LR model (83.33% 0.910, 0.6687). Therefore, clinical application of the ANN model may be able to better predict the folic acid efficacy to HHcy than the traditional LR model. When testing two models in the validation set, we got the same conclusion. This study appears to be the first one to establish the ANN model which added EV-GRS into environmental factors to predict the efficacy of folic acid to HHcy. This model would be able to offer clinicians a new method to make decisions and individual therapeutic plans.


Outcome of war-injured patients treated at first aid posts of the International Committee of the Red Cross.
This study describes the effects of 'echelons' on the outcome of victims of the Afghan internal armed conflict in terms of mortality and drain of surgical resources. A group of 1127 victims of war treated at ICRC first aid posts (FAPs) and subsequently referred to a surgical hospital of the International Committee of the Red Cross (group A), and a group of 596 victims who were transported directly from the area where the injury occurred to the hospital (group B) were analysed retrospectively. Mortality in patients treated initially at a FAP and admitted within 6-24 h after injury was slightly lower than in patients admitted directly. The number of surgical interventions was higher in patients initially treated at the FAP. Notably, patients belonging to group A with gunshot injuries underwent operation more often than those belonging to group B. No differences were found in relation to the incidence of fever, number of units of blood transfused and average stay in hospital. The study shows that initial treatment at a FAP had no significant influence on the prognosis of the injured. Presumably the best ways to improve the prognosis of the victims of war are to train local people in first aid, to support locally existing medical facilities and to establish an evacuation system in order to support these first aiders and medical facilities.


Gut Microbiota and Its Role in the Brain-Gut-Kidney Axis in Hypertension.
The role of the gut microbiota in modulating blood pressure is increasingly being recognized, currently. The purpose of this review is to summarize recent findings about the mechanisms involved in hypertension with regard to the phenomenon of "gut dysbiosis." Gut dysbiosis, i.e., the imbalance between the gut microbiota and the host, is characterized by a disruption of the tight junction proteins, such as occludins, claudins, and JAMs (junctional adhesion molecules), resulting in increased gut permeability or the so called "leaky gut." Due to the influence of genetic as well as environmental factors, various metabolites produced by the gut microbiota, such as indole and p-cresol, are increased. Thereby, uremic toxins, such as indoxyl sulfates and p-cresol sulfates, accumulate in the blood and the urine, causing damage in the podocytes and the tubular cells. In addition, immunological mechanisms are implicated as well. In particular, a switch from M2 macrophages to M1 macrophages, which produce pro-inflammatory cytokines, occurs. Moreover, a higher level of Th17 cells, releasing large amounts of interleukin-17 (IL-17), has been reported, when a diet rich in salt is consumed. Therefore, apart from the aggravation of uremic toxins, which may account for direct harmful effects on the kidney, there is inflammation not only in the gut, but in the kidneys as well. This crosstalk between the gut and the kidney is suggested to play a crucial role in hypertension. Notably, the brain is also implicated, with an increasing sympathetic output. The brain-gut-kidney axis seems to be deeply involved in the development of hypertension and chronic kidney disease (CKD). The notion that, by modulating the gut microbiota, we could regulate blood pressure is strongly supported by the current evidence. A healthy diet, low in animal protein and fat, and low in salt, together with the utilization of probiotics, prebiotics, synbiotics, or postbiotics, may contribute to our fight against hypertension.


High FOXA1 protein expression might predict late recurrence in patients with estrogen-positive and HER2-negative breast cancer.
Multi-gene expression assays have been developed with the aim of predicting late recurrence in patients with estrogen receptor (ER)-positive breast cancer. However, establishment of alternative markers based on immunohistochemistry is also important for achieving practical use. Based on our previous study, forkhead box A1 (FOXA1) protein was tested as a potentially useful predictive marker for late recurrence. 117 patients with ER-positive HER2-negative invasive breast cancer who developed distant metastasis following curative surgery were retrospectively investigated. We also evaluated responsiveness to endocrine therapy according to FOXA1 expression. Furthermore, publicly available mRNA microarray data were analyzed to examine patterns of metastasis according to FOXA1 mRNA expression, employing the Kaplan-Meier plotter. High expression of FOXA1 was an independent factor predicting long disease-free survival (DFS), along with small tumor size (p = 0.010 and 0.016, respectively). Discrimination of DFS was improved by combining these two factors, i.e., patients with FOXA1-high small tumors had the longest DFS while those with FOXA1-low large tumors had the shortest DFS. Moreover, we revealed that risk of distant metastasis started to increase after the completion of adjuvant endocrine therapy in patients with FOXA1-high tumors. Among patients who developed distant metastasis, those with FOXA1-high tumors had significantly longer DFS. We believe our data to raise the possibility of FOXA1 being a useful predictive marker for late recurrence and to provide new insights into the biology of FOXA1-high breast cancers.