Association of HIV viral load and CD4 cell count with human papillomavirus detection and clearance in HIV-infected women initiating highly active antiretroviral therapy.
The extent to which highly active antiretroviral therapy (HAART) affects human papillomavirus (HPV) acquisition and clearance in HIV-infected women is not well understood. We sought to describe high-risk HPV detection and clearance rates over time since HAART initiation, based on time-varying HIV viral load (VL) and CD4 T-cell count, using novel statistical methods. We conducted a retrospective analysis of data from the completed AIDS Clinical Trials Group (ACTG) A5029 study using multi-state Markov models. Two sets of high-risk HPV types from 2003 and 2009 publications were considered. There was some evidence that VL>400 HIV-1 RNA copies/mL was marginally associated with a higher rate of HPV detection [P=0.068; hazard ratio (HR) =4.67], using the older set of high-risk HPV types. Such an association was not identified using the latest set of HPV types (P=0.343; HR=2.64). CD4 count >350 cells/μL was significantly associated with more rapid HPV clearance with both sets of HPV types (P=0.001, HR=3.93; P=0.018, HR=2.65). There was no evidence that HPV affects VL or CD4 cell count in any of the analyses. High-risk HPV types vary among studies and can affect the results of analyses. Use of HAART to improve CD4 cell count may have an impact on the control of HPV infection. The decrease in VL may also have an effect, although to a lesser degree.


Hepatitis E Virus Genotype 7 RNA and Antibody Kinetics in Naturally Infected Dromedary Calves, United Arab Emirates.
Orthohepevirus A genotype 7 is a novel zoonotic variant of hepatitis E virus. To clarify infection in the animal reservoir, we virologically monitored 11 dromedary dam-calf pairs. All calves became infected during the first 6 months of life and cleared the virus after an average of 2 months. Dams did not become infected.


Effect of sol-gel encapsulation on the unfolding of ferric horse heart cytochrome c.
Electronic absorption and resonance Raman spectra of ferric cytochrome c embedded in wet silica gels, in the presence of guanidine HCl as unfolding agent, between pH 0.35 and 7.0 are presented. The data clearly show that the ferric form of the protein encapsulated in sol-gel preserves its active site conformation. However, the spectra of the unfolded embedded protein are different from the corresponding spectra in solution suggesting that a strong interaction between the protein and the sol-gel takes place upon unfolding. The unfolding process mainly depends on the interaction between the exposed positive charges of the unfolded protein and the negatively charged functional groups of the silica surfaces. While this interaction partially stabilizes the protein in its native structure even at very acidic pH, in the presence of denaturants it has the opposite effect, causing mainly the weakening of both the heme-protein and the heme-ligand interactions.


The protein 4.1R downregulates VEGFA in M2 macrophages to inhibit colon cancer metastasis.
M2 macrophages are crucial components of the tumour microenvironment and have been shown to be closely related to tumour progression. Co-culture with 4.1R-/- M2 macrophages enhances the malignancy of colon cancer (CC), but the mechanism remains unclear. Here, we report that protein 4.1R knockout reduced the phagocytosis of M2 macrophages (M-CSF/IL-4-treated bone marrow cells) and promoted MC38 colon cancer cell proliferation, migration, invasion, tumour formation and epithelial-mesenchymal transition (EMT), which are regulated by M2 macrophages. Further mechanistic dissection revealed that the 4.1R knockout upregulated vascular endothelial growth factor A (VEGFA) secreted by M2 macrophages and promoted colon cancer progression by activating the PI3K/AKT signalling pathway. In summary, our present study identified that 4.1R downregulates VEGFA secretion in M2 macrophages and delays the malignant potential of colon cancer by inhibiting the PI3K/AKT signalling pathway.


Pain endurance in unilateral cerebral lesions.
The purpose of the present experiment was to study whether a unilateral cerebral lesion modifies pain parameters with respect to a control group. Electric stimuli were applied to brain damaged patients on the forearm ipsilateral to the lesion, and to both forearms of a control group. No significant difference was found between experimental groups for either pain or tolerance thresholds, whereas pain endurance--the difference between pain threshold and pain tolerance threshold--was significantly greater in right brain damaged patients, compared to both the control group and the left brain damaged group. In the latter group, pain endurance was not significantly different from controls, although there was a tendency towards its decrease. Result are discussed in relation to the problem of the hemispheric specialization for emotional processes.


Toward deep learning replacement of gadolinium in neuro-oncology: A review of contrast-enhanced synthetic MRI.
Gadolinium-based contrast agents (GBCAs) have become a crucial part of MRI acquisitions in neuro-oncology for the detection, characterization and monitoring of brain tumors. However, contrast-enhanced (CE) acquisitions not only raise safety concerns, but also lead to patient discomfort, the need of more skilled manpower and cost increase. Recently, several proposed deep learning works intend to reduce, or even eliminate, the need of GBCAs. This study reviews the published works related to the synthesis of CE images from low-dose and/or their native -non CE- counterparts. The data, type of neural network, and number of input modalities for each method are summarized as well as the evaluation methods. Based on this analysis, we discuss the main issues that these methods need to overcome in order to become suitable for their clinical usage. We also hypothesize some future trends that research on this topic may follow.


Immunogenetic factors in donors and patients that affect the outcome of hematopoietic stem cell transplantation.
We have correlated the clinical outcome with the level of HLA matching in 423 patients who received a transplant from a volunteer unrelated donor in the United Kingdom. HLA matching was performed at the allelic level (i.e. high-resolution) using reference strand mediated conformation analysis (RSCA) at HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1. The three-year probability of overall survival (OS) was 45% (median survival of 593 days; six-year overall survival probability was 40%). The mean follow-up was 1013 days (range 89-2697). Those matched for their HLA loci had a significantly better overall survival than the mismatched pairs (47% versus 40%, p=0.040). This result could be refined based on the number of alleles that were mismatched. In patients with a single HLA mismatch, the overall survival was 43%, compared to 30% in those with multiple mismatches; however, there was no statistically significant difference between matched pairs or those with one mismatch. Although there was no significant difference in the overall survival dependent on DPB1 matching in the group overall, in acute lymphocytic leukemia, DPB1-matched pairs had a significantly worse overall survival (log rank; p=0.025). Thus, a match for DPB1 is associated with a significantly increased risk of disease relapse, irrespective of the matching status for the other HLA molecules. In a multivariate analysis, a high pre-transplant levels of Tregs resulted in worse overall survival (relative risk (RR), 2.74; p=0.01), a trend to reduce disease-free survival (RR, 2.05; p=0.060) and to increase disease relapse (RR, 3.36; p=0.006). Residual patient CD4(+)CD25(hi) regulatory T cells may suppress graft-versus-tumour responses, decreasing the overall survival by increasing the rates of relapse. In acute leukemia, the presence of NOD2/CARD15 SNPs in the genotype of unrelated donor hematopoietic stem cell transplant pairs results in significant increases in disease relapse and consequently in death. These data show an important role for NOD2/CARD15 genotyping in transplantation and suggest a possible effect of the NOD2 protein in alloreactivity and tumour surveillance. Genotyping recipients and donors prior to transplant may present valuable information for planning and management of pre-transplant conditioning regimens, and for prognosis of the outcome.


[Health behavior from the gender perspective--The concept of "doing genders" and the perspective of intersectionality as an explanation].
Unfortunately, the wrong institution was specified, the correct one is: Karl-Franzens-University Graz, coordinator for Gender Studies,Women's Studies and Gender Equality. You can find the corrected post here:10.1055 / s-0035-1562984. Please excuse the mistake.


Successful resection of rectal cancer and perirectal abscess following systemic chemotherapy and chemoradiotherapy: A case report.
Perirectal abscesses are uncommon in colorectal cancer. Although abscess infection should be controlled before colorectal cancer treatment, abscess formation makes surgical resection and preoperative treatment difficult. There is currently no established treatment for colorectal cancer with perirectal abscesses. Here, we present a case of rectal cancer with a perirectal abscess that was resected after systemic chemotherapy followed by chemoradiotherapy. A 73-year-old man presented to the outpatient clinic with complaints of weight loss and general malaise. Colonoscopy revealed a circumferential tumor 3 cm from the anal verge, and examination of the endoscopic biopsy specimen indicated a well-differentiated tubular adenocarcinoma. Pelvic magnetic resonance imaging revealed a perirectal abscess on the ventral aspect of the rectum. After sigmoid colostomy was performed to control the infection, 4 cycles of panitumumab and modified fluorouracil, leucovorin, and oxaliplatin were administered. After the perirectal abscess disappeared, chemoradiotherapy to the whole pelvis (radiotherapy 45Gy/25 fractions plus tegafur-gimeracil-oteracil) was administered. Total pelvic exenteration with an ileal conduit was performed via open surgery. The pathological diagnosis was well-differentiated tubular adenocarcinoma with complete resection and negative resection margins. No recurrence of cancer has been observed 26 months after surgery. Treatment of colorectal cancer with perirectal abscess is difficult to define the extent of resection due to the spread of inflammation. We believe that treatment should address high risk of local recurrence. After sigmoid colostomy, complete resection of colorectal cancer with perirectal abscess could be achieved by systemic chemotherapy followed by chemoradiotherapy.


Pregnancy following incontinence surgery.
A two-page questionnaire was distributed to 304 members of the American Urogynecology Society. Ninety-nine of the 149 respondents reported that they had performed continence surgery on patients who specifically stated their desire for future childbearing. One hundred and eleven recommended the Burch colposuspension, 29 favored the sling procedure, and others advocated different procedures. Urologists as a subset more often recommended either a sling or needle suspension. Twenty-eight percent of respondents felt a trial of labor and vaginal delivery was indicated following incontinence surgery, but 40% stated that they would always perform cesarean section in these patients. A total of 40 vaginal deliveries and 47 cesarean sections were reported. When postpartum continence status was known, only 73% of women who had vaginal deliveries were continent, whereas 95% were continent following cesarean section. Fisher's exact test revealed this to be a statistically significant difference (P = 0.0344).


Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of apoe-/- mice.
Atherosclerotic plaques that are prone to disruption and acute thrombotic vascular events are characterized by large necrotic cores. Necrotic cores result from the combination of macrophage apoptosis and defective phagocytic clearance (efferocytosis) of these apoptotic cells. We previously showed that macrophages with tyrosine kinase-defective Mertk receptor (Mertk(KD)) have a defect in phagocytic clearance of apoptotic macrophages in vitro. Herein we test the hypothesis that the Mertk(KD) mutation would result in increased accumulation of apoptotic cells and promote necrotic core expansion in a mouse model of advanced atherosclerosis. Mertk(KD);Apoe(-/-) mice and control Apoe(-/-) mice were fed a Western-type diet for 10 or 16 weeks, and aortic root lesions were analyzed for apoptosis and plaque necrosis. We found that the plaques of the Mertk(KD);Apoe(-/-) mice had a significant increase in terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive apoptotic cells. Most importantly, there were more non-macrophage-associated apoptotic cells in the Mertk(KD) lesions, consistent with defective efferocytosis. The more advanced (16-week) Mertk(KD);Apoe(-/-) plaques were more necrotic, consistent with a progression from apoptotic cell accumulation to plaque necrosis in the setting of a defective efferocytosis receptor. In a mouse model of advanced atherosclerosis, mutation of the phagocytic Mertk receptor promotes the accumulation of apoptotic cells and the formation of necrotic plaques. These data are consistent with the notion that a defect in an efferocytosis receptor can accelerate the progression of atherosclerosis and suggest a novel therapeutic target to prevent advanced plaque progression and its clinical consequences.


Determination and pharmacokinetic study of indirubin in rat plasma by high-performance liquid chromatography.
A specific, simple and sensitive HPLC method with UV detection was developed and validated for the pharmacokinetic studies of indirubin in rat plasma for the first time. Indirubin, with osthole as the internal standard, was extracted from plasma samples by liquid-liquid extraction. Chromatographic separation was conducted on a reverse-phase ODS column (200 mm x 4.6 mm, i.d., 5 microm), using a mixture of methanol-water (75:25, v/v) as the mobile phase at a flow rate of 1.0 ml/min with UV detection at 289 nm. The calibration curve of indirubin was linear over the range of 6.5-1950 ng/ml in rat plasma. The lower limit of quantification (LLOQ) was found to be 6.5 ng/ml. The present method was successfully applied for estimating the pharmacokinetic parameters of indirubin following intravenous and intraperitoneal administration of indirubin to rats.


The cell engineering construction and function evaluation of multi-layer biochip dialyzer.
We report the fabrication and function evaluation of multi-layer biochip dialyzer. Such device may potentially be applied to the wearable hemodialysis systems. By merging the advantages of microfluidic chip technology with cell engineering, both functions of glomerular filtration and renal tubule physiological activity are integrated in the same device. This device is designed into a laminated structure, in which the chip number of the superimposed layer can be arbitrarily tailored in accordance with the requirements of dialysis capacity. We propose that such structure can overcome the obstacles of large size and detached structure of the traditional hollow fiber dialyzer. To construct this multilayer biochips dialyzer, two types of dialyzer device with two-layered and six-layered chips are assembled, respectively. Cell adhesion and proliferation on three different dialysis membrane materials under static and dynamic conditions are investigated and compared. The filtration capability, re-absorption function and excrete ammonia function of the resulting multi-layer biochip dialyzer are evaluated. The results reveal that the constructed device can perform higher filtration efficiency and also play a role of renal tubule. This methodology may be useful in developing "scaling down" artificial kidneys that can act as wearable or even implantable hemodialysis systems.


Prenatal famine, birthweight, reproductive performance and age at menopause: the Dutch hunger winter families study.
Is there an association between acute prenatal famine exposure or birthweight and subsequent reproductive performance and age at menopause? No association was found between intrauterine famine exposure and reproductive performance, but survival analysis showed that women exposed in utero were 24% more likely to experience menopause at any age. Associations between prenatal famine and subsequent reproductive performance have been examined previously with inconsistent results. Evidence for the effects of famine exposure on age at natural menopause is limited to one study of post-natal exposure. This cohort study included men and women born around the time of the Dutch famine of 1944-1945. The study participants (n = 1070) underwent standardized interviews on reproductive parameters at a mean age of 59 years. The participants were grouped as men and women with prenatal famine exposure (n = 407), their same-sex siblings (family controls, n = 319) or other men and women born before or after the famine period (time controls, n = 344). Associations of famine exposure with reproductive performance and menopause were analysed using logistic regression and survival analysis with competing risk, after controlling for family clustering. Gestational famine exposure was not associated with nulliparity, age at birth of first child, difficulties conceiving or pregnancy outcome (all P> 0.05) in men or women. At any given age, women were more likely to experience menopause after gestational exposure to famine (hazard ratio 1.24; 95% CI 1.03, 1.51). The association was not attenuated with an additional control for a woman's birthweight. In this study, there was no association between birthweight and age at menopause after adjustment for gestational famine exposure. Age at menopause was self-reported and assessed retrospectively. The study power to examine associations with specific gestational periods of famine exposure and reproductive function was limited. Our findings support previous results that prenatal famine exposure is not related to reproductive performance in adult life. However, natural menopause occurs earlier after prenatal famine exposure, suggesting that early life events can affect organ function even at the ovarian level. This study was funded by the NHLBI/NIH (R01 HL-067914). Not applicable.


The Association of Performance Status and Disease Severity in Patients With Chronic Graft-vs-Host Disease.
Determine the relationship between functional status and degree of specific organ involvement, physical performance, and subjective well-being chronic graft-vs-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation. Observational cohort. Outpatient clinic. Adult patients (N=121) with cGVHD with 634 assessments. Not applicable. Karnofsky Performance Status (KPS). Skin, fascia/joints, lungs, upper and lower extremity range of motion, liver, eye, mucosal, and gastrointestinal involvement were measured using the National Institutes of Health GVHD scale. Physical performance was assessed with the 2-minute walk test (2MWT) and hand grip strength. Subjective measures were the Patient Health Questionnaire 9 (PHQ-9) and Lee Symptom Burden (LSB) scale. Myofascial (P<.001) and lung (P=.001) involvement, 2MWT (P<.001), LSB (P<.001), and PHQ-9 (P=.03) had the largest associations with KPS with liver (P=.05) and hand grip strength (P<.001) more modest associations with KPS. Patients with cGVHD experience multifactorial impairment in function associated with potentially modifiable symptoms physiatrists have the expertise to address to enhance function. More research is needed to determine rehabilitation interventions to mitigate the impact of cGVHD on function.


Wild type p53 reactivation: from lab bench to clinic.
The p53 tumor suppressor is the most frequently inactivated gene in cancer. Several mouse models have demonstrated that the reconstitution of the p53 function suppresses the growth of established tumors. These facts, taken together, promote the idea of p53 reactivation as a strategy to combat cancer. This review will focus on recent advances in the development of small molecules which restore the function of wild type p53 by blocking its inhibitors Mdm2 and MdmX or their upstream regulators and discuss the impact of different p53 functions for tumor prevention and tumor eradication. Finally, the recent progress in p53 research will be analyzed concerning the role of p53 cofactors and cellular environment in the biological response upon p53 reactivation and how this can be applied in clinic.


Identification of a fetal hematopoietic precursor with B cell, T cell, and macrophage potential.
Despite years of investigation, precursor-progeny relationships within the developing lymphoid lineages of the hematopoietic system remain poorly defined. We have characterized the potential of precursors found within a subpopulation of fetal liver defined by AA4.1 and Fc gammaRII/III expression and predominantly restricted to lymphoid and macrophage development. When cultured in methylcellulose with appropriate cytokines, AA4.1+/Fc gammaR+ precursors generate colonies consisting of various lineages, including the combination of B cell, T cell, and macrophage. Retroviral marking studies showed that the lymphoid cells and macrophages within these colonies arise from a common precursor. These results demonstrate the presence of a common precursor with B cell-, T cell-, and macrophage-restricted potential and as such define an early restriction point within the fetal lymphoid system.


A validated fast difference spectrophotometric method for 5-hydroxymethyl-2-furfural (HMF) determination in corn syrups.
Corn syrups, important ingredients used in food and beverage industries, often contain high levels of 5-hydroxymethyl-2-furfural (HMF), a toxic contaminant. In this work, an in house validation of a difference spectrophotometric method for HMF analysis in corn syrups was developed using sophisticated statistical tools by the first time. The methodology showed excellent analytical performance with good selectivity, linearity (R2=99.9%, r>0.99), accuracy and low limits (LOD=0.10mgL-1 and LOQ=0.34mgL-1). An excellent precision was confirmed by repeatability (RSD (%)=0.30) and intermediate precision (RSD (%)=0.36) estimates and by Horrat value (0.07). A detailed study of method precision using a nested design demonstrated that variation sources such as instruments, operators and time did not interfere in the variability of results within laboratory and consequently in its intermediate precision. The developed method is environmentally friendly, fast, cheap and easy to implement resulting in an attractive alternative for corn syrups quality control in industries and official laboratories.


The relationship of clozapine and haloperidol treatment response to prefrontal, hippocampal, and caudate brain volumes.
The study was designed to assess the predictive relationship between brain structure volume and positive and negative symptom response to clozapine and haloperidol. Partially responsive outpatients with schizophrenia who participated in a 10-week, parallel-group, double-blind comparison of clozapine and haloperidol and who had an available magnetic resonance imaging scan were included in the current study. Prefrontal gray and white matter, hippocampal, and caudate volumes were manually measured. The Scale for the Assessment of Negative Symptoms (SANS) and the Brief Psychiatric Rating Scale (BPRS) were used to assess symptom changes. The Simpson-Angus Rating Scale was used to assess extrapyramidal symptoms. Twenty-two patients randomly assigned to clozapine and 23 patients assigned to haloperidol met study entry criteria. There were significant interactions between treatment and right prefrontal gray matter volume for BPRS total score and SANS total score. There were no significant treatment-by-brain structure interactions for BPRS positive symptom items. Right prefrontal gray matter volume was also related to differential treatment effects for the BPRS subscales of anxiety/depression and hostility and the Simpson-Angus Rating Scale akathisia item. These results suggest that there is a differential interaction among clozapine and haloperidol, brain structure, and treatment response. Partially responsive patients with larger brain volumes may be more likely to experience the benefits of clozapine treatment, but they may be more vulnerable to side effects and experience a subsequent worsening of their symptoms when treated with haloperidol.


Chemotactic peptides. Mechanisms, functions, and possible role in inflammatory bowel disease.
An important component of host defenses is the ability of inflammatory cells to detect and respond to minute concentrations of chemoattractant substances. Chemotactic peptides elaborated by both bacteria and leukocytes are the focus of this review. These peptides induce directed migration of inflammatory cells towards their targets, and stimulate biological functions including degranulation, release of oxygen radicals, phagocytosis, and eicosanoid production. Among the released eicosanoids, leukotriene B4 potentiates the leukocyte response. As with other chemotactic factors, these functions are regulated partially through differential coupling to high- and low-affinity receptors and via calcium as the second messenger. Some chemotactic peptides are elaborated by normal colonic luminal bacteria. Recent evidence demonstrates that these peptides can produce mucosal inflammation in vivo. A possible mechanism for this effect involves abnormal colonic permeability in susceptible individuals that allows bacterial chemotactic peptides access to the mucosa where they may induce inflammation. Remaining questions include the mechanism by which the mucosal barrier is breached and the role of leukotrienes in the potentiation of colonic inflammation.


Distinct functional effects of human 5-HT4 receptor isoforms on beta-amyloid secretion.
The serotonin 5-HT(4) receptor is of potential interest for the treatment of Alzheimer's disease because it increases memory and learning and influences amyloid precursor protein (APP) processing. Several 5-HT(4) receptor isoforms have been cloned in humans. They all belong to the G-protein-coupled receptor superfamily and differ in composition and length of their amino acid intracellular C-terminal sequence. At present, it is still unknown whether 5-HT(4) receptor isoforms may have distinct effects on APP processing. In this study, we investigated the effect of an ultrashort isoform of the human 5-HT(4) receptor (2 amino acids after the splicing site), the 5-HT(4(d)) receptor isoform (h5-HT(4(d))), on APP processing in Chinese hamster ovary cells (CHO cells). Non-amyloidogenic soluble sAPPalpha was determined by immunoblot and beta-amyloid peptides (Abeta(1-40) and Abeta(1-42)) were assayed by ELISA in CHO cells stably expressing h5-HT(4(d)) and transiently transfected with human APP(695). We show here that activation of h5-HT(4(d)) strongly stimulates the release of sAPPalpha and concomitantly decreases extracellular Abeta peptides. These data contrast with our previous findings showing that the h5-HT(4(e/g)) receptor isoform, which has 20 amino acids after the splicing site, did not influence Abeta secretion. We conclude that C-terminal tails of 5-HT(4) receptor isoforms may influence their functional effect on Abeta secretion and that the pathways regulating either beta- or gamma-secretase may be differentially controlled by 5-HT(4) receptor isoforms.


Open software for biologists: from famine to feast.
Developing and deploying specialized computing systems for specific research communities is achievable, cost effective and has wide-ranging benefits.


Long-term survivors among patients with cancer of unknown primary.
There is a general conception among oncologists that CUP patients behave poorly to treatment and carry a dismal survival. In this paper we are trying to elucidate the different groups of CUP patients and to describe in details the diagnostic and therapeutic management of the prognostically favorable patients. Clinicians should be aware that the favorable CUP cases must be treated according to recent guidelines with either specific locoregional and/or systemic therapy and that they commonly enjoy a long survival. Survival data of 219 CUP patients treated at Ioannina University Hospital from 1995 until 2011 are also presented.


Costs and effects of cardiovascular risk reclassification using the ankle-brachial index (ABI) in addition to the Framingham risk scoring in women.
Ankle brachial index (ABI) is a simple and cheap parameter to assess the presence of atherosclerosis. It could also help correctly reclassify the cardiovascular risk when added to the Framingham risk score (FRS). Recent evidence has demonstrated improvement in prediction performance of ABI when added to FRS, particularly in women. However, no studies have been published yet evaluating the cost-effectiveness of this approach. This study attempts to fill in this gap by assessing the cost-effectiveness of ABI measurements in primary prevention in women. We developed a Markov model to compare two different strategies for assessing the cardiovascular risk (low, intermediate and high) among women in the general population: 1) FRS strategy, and 2) FRS + ABI strategy; and the relative impact associated with interventions for preventing CV events in intermediate and high-risk categories. In the base-case analysis, FRS + ABI reported an additional cost of € 110 and a gain of 0.0039 QALYs per patient, resulting in an ICER of € 27.986/QALY, when compared to FRS alone. The ICER improved to €1.641/QALY when using a lifetime horizon. The effectiveness of preventive CV disease interventions reported also a significant impact. A 32% reduction of CV events was the minimum value estimated to maintain FRS + ABI as a cost-effective strategy. The addition of ABI to FRS is a cost-effective approach in women classified at low and intermediate risk with FRS only. This new approach gives the possibility to reclassify and allocate them into the appropriate risk group and treatment.


ABH isoantigens, histology and DNA ploidy in 36 consecutive patients with transitional cell bladder cancer. Status of tumor and biopsies taken from visually normal urothelium.
Tumors and biopsies from visibly normal urothelium in 36 consecutive patients with transitional cell bladder carcinoma were analysed for histological pathology, DNA ploidy and ABH isoantigens. Tumor isoantigen deletion correlated strongly with malignant histology (p = 0.016) and aneuploidy (p = 0.005). In 4/12 patients with ABH isoantigens present on the tumor, and in 6/8 with isoantigens absent, isoantigen changes were found in normal looking urothelium, usually with normal histology and ploidy. It was concluded that the ABH isoantigen change was an early event in bladder carcinoma.


Changes in Cajal cell density in ureteropelvic junction obstruction in children.
Congenital ureteropelvic junction obstruction is one the most common causes of neonatal hydronephrosis. The etiology of the ureteropelvic junction (UPJ) obstruction has not been clearly established. The presence of a hypoplastic, adynamic ureteral segment is thought to be the major cause of an UPJ obstruction. We evaluated the distribution of Cajal cells using immunohistologic methods coupled with light microscopy of the UPJ tissues in obstructed and normal UPJs. The study group consisted of 19 patients who underwent pyeloplasty for UPJ obstruction. Twelve patients who had been operated on for oncological indications constituted the control group. The sections were stained immunohistochemically using CD117 (c-kit) antibody; the numbers of CD117 (+) interstitial cells of Cajal were counted in 10 consecutive high-power fields under the light microscope and the cell density was determined for each case. The mean age of the cases who underwent dismembered pyeloplasty and the control group were 116 ± 116 months (14 male, 5 female; 6-420 months) and 279 ± 312 months (9 male, 3 female; 24-948 months) (p = 0.1), respectively. The mean interstitial Cajal cell number in the UPJ obstruction and the control groups were 2.37 ± 2.19 and 24.5 ± 9.73, respectively (p < 0.0001). Thirteen (68.4%) patients had very few, five (26.3%) patients had few, and one (5.3%) patient had many Cajal cells in the UPJ obstruction group. In the control group, all patients had more than seven cells per high-power field. We found that in cases of UPJ, obstruction the numbers of interstitial Cajal cells were decreased, being either absent or significantly reduced. Although data about the motility are currently not sufficient, the decrease in the number of Cajal cells in patients with UPJ highlights that they might be responsible for the initiation, coordination, and conduction of peristaltic activity along the pelvicalyceal system. Improvement and enhancement of contraction waves arising from the upper urinary system depend on interstitial cells of Cajal, which are the pacemaker cells in smooth muscles. We think that a decreased number of interstitial cells of Cajal have a close relationship with changing ureteral motility when we compare our UPJ obstruction cases with the limited data in the literature. Further investigations on these cells will probably give detailed information about the neurophysiology of the urinary system and the diseases that cause congenital hydronephrosis.


Monitoring of the heparinization in the rabbit animal model during endovascular interventions.
The purpose of this study was to monitor and to optimize heparinization during endovascular procedures in the New Zealand White Rabbit (NZWR) model. Right common carotid artery aneurysms were surgically created in 43 NZWR, with an average weight of 4,330 g (range 3,500-5,430 g). The activated partial thromboplastin time (aPTT) was measured during different stages of the interventional procedures. Blood samples were taken before and 10 min after administration of heparin and at the end of each endovascular procedure. We compared three different experimental groups: 100 U heparin, 500 U heparin and 100 U heparin plus pretreatment with aspirin and clopidogrel. The individual aPTT values were measured using a ball coagulometer. The average baseline aPTT in the rabbit is 75.2 ± 18.9 s compared to a mean of 33 s (range 26-40 s) in humans. The dosages of heparin used achieved anticoagulation in all cases. Five hundred units of heparin increased the aPTT significantly more than 100 U. No difference was found between the aPTT obtained from the 100 U and the 100 U plus pretreatment group, as aspirin and clopidogrel do not affect the coagulation cascade. One hundred units of heparin can achieve anticoagulation in a similar magnitude as needed in interventional procedures in humans. This fact enhances suitability of the rabbit animal model for the testing of intravascular devices.


HIV testing and access to HIV medical care among people who inject drugs and their intimate partners in Kazakhstan.
Growing rates of HIV and high rates of injection drug use in Kazakhstan call for examining access to testing and treatment among people who inject drugs and their intimate partners. We examine how access to health and drug treatment services as well as risk environment factors are associated with ever being tested for HIV and ever receiving any general HIV medical care among 728 male and female intimate partners where at least one partner injects drugs. Multivariate random effects logistic regression with random effects for couple were conducted to examine associations between access to health and drug treatment services, risk environment factors, and HIV testing and HIV medical care outcomes. Analyses indicate that accessing needle exchange services and having a regular physician were associated both with access to HIV testing and HIV medical care. Receiving drug treatment was associated with accessing HIV testing but not HIV medical care. Being arrested and charged with a criminal offense was also associated with accessing HIV testing but not HIV medical care. Study findings highlight the need for increased scale-up of HIV testing efforts, as well as integrated HIV treatment and care in Kazakhstan.


Clinical and patient-reported outcomes of bilateral implantation of a +2.5 diopter multifocal intraocular lens.
To assess the effectiveness and safety of a multifocal intraocular lens (IOL) with +2.5 diopter (D) additional power compared with a monofocal IOL. Fifteen sites in the United States. Prospective randomized patient- and observer-masked clinical trial. Randomized patients received multifocal or monofocal IOLs bilaterally. Visual acuity (33 cm, 40 cm, 53 cm, 60 cm, 4 m) was measured; safety was assessed through adverse event rates. Patient-reported visual outcomes were evaluated using the Visual Tasks questionnaire. The frequency and severity of visual disturbances were evaluated using the Assessment of Photic Phenomena and Lens EffectS questionnaire. The multifocal IOL (n = 155) provided better corrected distance visual acuity at 53 cm than the monofocal IOL (n = 165) (0.322 versus 0.512 logMAR; between-group difference, -0.190 logMAR; P < .0001) and 40 cm but not at 4 m. Ocular adverse event rates were less than 3.84% in both groups. Serious adverse event rates were comparable between the 2 IOL types. Patients with multifocal IOLs reported less difficulty with near tasks (with and without correction) and intermediate tasks (without correction). Difficulty with extended-intermediate and distance tasks was similar between groups. The most frequently reported self-rated severe phenomena were halos, starbursts, and glare. Most patients (monofocal ≥72%; multifocal ≥73%) reported never experiencing blurred, distorted, or double vision. The +2.5 D multifocal IOL provided better vision at 40 cm and 53 cm and similar vision at 4 m compared with the monofocal IOL. Safety profiles and visual phenomena were comparable between groups.


[Who makes decisions--the dilemma of decision-making within the framework of job-sharing in a hospital].
By means of a case report on a 44-year-old female patient, we show how, with changing personnel and places of care, decisions as well as the kind of decision-making during illness influence the quality of care. The patient was receiving immunosuppressive therapy after kidney transplantation and then suffered from a carcinomatous ovary. At first she refused postoperative chemotherapy, but then returned with a very advanced state of metastatic growth. The lack of continuity, a missing overall interdisciplinary concept of medical case, as well as the failure to document decision processes and the patient's attitude to life and suffering made it difficult for the caring team to accompany her in the last weeks of life. A possible solution to such a complex problem will be the introduction of ethical case deliberation.


MGNREGA in the Times of COVID-19 and Beyond: Can India do More with Less?
Covid-19 has ushered in a renewed focus on health, sanitisation and, in unexpected ways, on the need for productive employment opportunities in rural India. MGNREGA, the rural employment guarantee programme, has had a mixed track record in terms of providing adequate employment to those who need it the most, the quality of asset creation and adequacy of wages offered. This paper makes a case for reorienting a small portion of MGNREGA spending to create micro-entrepreneurs out of the 'reverse migrating' masons, electricians, plumbers and others in rural areas who can directly contribute to augmenting health and sanitization infrastructure in the likely new normal. This will provide relief to those whose livelihoods have been severely impacted and eventually lower dependence on public finances. We propose approval of a new work type for sanitization works without any hard asset creation under MGNREGA and roping in the private sector for its project management skills to quickly skill up the returning migrants as well as to match work with workers on an ongoing basis.


Ethics training at mental health centers.
Eighteen (78.26% response rate) mental health centers in Colorado responded to a survey about the nature of ethics training. Mental health centers spent an average of 1.27 hours during the previous year on ethics training. Centers rated their staff as less prepared to deal with ethical issues than programs rated their students, representing a split between classrooms and applied settings. There may be some confusion of ethical and legal issues. Several recommendations are made, including interdisciplinary and continuing ethics training, and teaching a process of thinking rather than merely cases and rules.


Regulation of the surface activity of carbon anodes for rationalization of potassium storage.
The gradient temperature was manipulated to construct hollow irregular carbon spheres with regulated intrinsic defects and surface area targeting favorable potassium storage. An enlarged surface area, increased intrinsic defects, and superior conductivity induced more surface-active interfaces. These actions facilitated a high reversible capacity as well as excellent cycling stability.


Pleomorphic xanthoastrocytoma. Ultrastructural and immunohistochemical study of a case with a rapidly fatal outcome following surgery.
In 1979, researchers described a series of young patients with clinically and histologically distinctive supratentorial gliomas which were designated pleomorphic (meningocerebral) xanthoastrocytomas (PXA). Significantly, patients with these neoplasms were reported to have a relatively favorable prognosis. The authors present a new case of PXA in a 32-year-old man. This case is unique for two reasons: (1) a relatively rapid fatal outcome with death 21 months after diagnosis; and (2) the presence, at autopsy, of extensive recurrent tumor with features of a malignant astrocytoma. Detailed electron microscopic and immunohistochemical studies, supporting the proposed subpial astrocytic origin of PXA, are presented. Literature pertaining to PXA is reviewed. This report illustrates the unique features of PXA and demonstrates its potential for aggressive behavior.


The differing perspectives of doctors and nurses in end-of-life decisions in the intensive care unit: A qualitative study.
End-of-life (EOL) decision-making in the intensive care unit (ICU) can be emotionally challenging for both doctors and nurses, who are sometimes placed in difficult positions where they are required to make decisions on behalf of patients. With an ageing population and advances in medical technology, there is an increase in such decisions being made in ICUs. The objective of this study was to explore the perspectives of doctors and nurses involved in the EOL decision-making process in an ICU. This study used a qualitative methodology based on naturalistic inquiry. Intensive care nurses and doctors from a large Sydney metropolitan public hospital were purposively selected, and data saturation was reached after a total of eight nurses and four doctors were interviewed. Data were collected through semistructured interviews, either face-to-face or over the telephone. Interviews were then transcribed verbatim, and themes were identified and coded through a line-by-line analysis of each transcript (manual thematic analysis). The findings revealed two main themes: 'Doctors' and nurses' roles in decision-making' and 'Managing family expectations'. These themes highlighted key differences in decision-making processes, in that doctors tended to aim to meet the family's needs, while the nurses tended to advocate on behalf of the patient and what they interpreted as the patient's best interests. Furthermore, nurses tended to feel undervalued in decision-making during family conferences, when in reality, the doctors were making decisions based on all information obtained, primarily from nursing staff. EOL decision-making is complex and affects doctors and nurses involved in different ways. More emphasis on interprofessional education and collaboration between the two disciplines may enhance future decision-making processes.


Antiparallel alignment of the two protomers of the regulatory subunit dimer of cAMP-dependent protein kinase I.
The purified type I regulatory subunit of cAMP-dependent protein kinase is a dimeric protein, and the two protomers of the dimer are linked by two interchain disulfide bonds. The disulfide linkages that join these two polypeptide chains have been identified in order to provide a structural basis for the orientation of the two chains in the asymmetric dimer. Disulfide bonds were found to exist exclusively between Cys-16 and Cys-37, and this assignment, thus, establishes a general antiparallel alignment of the two chains. Two other homologous proteins, the type II regulatory subunit and the cGMP-dependent protein kinase also are dimeric proteins. In all three proteins, a relatively small, nonhomologous, amino-terminal segment of the polypeptide chain is essential for maintaining the dimeric aggregation state.


Hypertension and renal impairment in patients with cystinuria: findings from a specialist cystinuria centre.
Higher blood pressures (mean systolic difference 16.8 mmHg) when compared to matched individuals are already reported in patients with calcium urolithiasis. We present the prevalence of hypertension and renal impairment in patients with cystinuria from our specialist single centre. We analysed our prospective database of adult patients with cystinuria who attend our cystinuria service. This included details of the medical and operative management of their disease. Descriptive statistics were used to analyse and present the data. 120 patients were included with a median age of 40 (19-76) years, 66 were male (55%) and 54 were female (45%). 54/120 patients (45%) were taking medications to prevent stone formation. 78% (94/120) patients reported having undergone one or more stone-related procedure. 59% (55/94) of these having required at least one PCNL or open procedure during their lifetime. Prevalence of hypertension was 50.8% (61/120), and double in males compared to females (62.1% vs. 37.0%, P = 0.0063). Mean baseline creatinine was 88.2 (49-153) µmol/l and eGFR was 77.6 (32-127) ml/min/1.73 m2. When categorized by CKD stage, only 24.6% (27% vs. 21%, M vs. F) patients had normal renal function (being an eGFR > 89 ml/min/1.73 m2). 57.6% patients were CKD stage 2 and 17.8% CKD stage 3. Females had a slightly greater incidence of renal impairment. All patients who have previously undergone a nephrectomy (n = 10) or have a poorly functioning kidney (n = 19) have renal impairment (CKD stage 2 or 3). Incidence of hypertension in patients with cystinuria is 51%, with a male preponderance. Only 25% of patients with cystinuria have normal renal function. This highlights the long-term cardiovascular and renal risks that the metabolic effects of cystinuria pose, in addition to the challenges of managing recurrent urolithiasis in a young population.


Neck mass due to pedicle ossification after oromandibular reconstruction.
To determine the radiographic incidence of heterotopic ossification and the clinical incidence of neck masses secondary to heterotopic ossification in a series of patients who underwent fibula free flap oromandibular reconstruction. Retrospective review at a university medical center. Patient database of 520 consecutive fibula free flaps from 1995 to 2010 was reviewed to identify patients who had postoperative computed tomography (CT) scans of the neck to further investigate the radiologic presence of heterotopic ossification. Patient chart review was also performed to identify patients who had clinical evidence of neck masses consistent with heterotopic ossification. Of the 66 patients who had postoperative CT scans available for radiologic assessment, 43 (65%) showed heterotopic ossification of the fibula periosteum. Clinically, 14 of 520 patients (2.6%) presented with firm, level I or II neck masses that proved to be secondary to heterotopic ossification. Development of a firm neck mass after treatment of head and neck cancer often indicates recurrent tumor. Heterotopic ossification has not been previously reported as a potential etiology of neck masses after fibula free flap oromandibular reconstruction in the head and neck surgery literature. The radiographic incidence of this phenomenon is high, and the clinical incidence of neck masses secondary to heterotopic ossification is low. Heterotopic ossification can be distinguished from recurrent tumor on the basis of physical examination, radiographic assessment, and/or fine-needle aspiration biopsy. Awareness of heterotopic ossification should be included in the differential diagnosis of patients with a neck mass who have undergone fibula free flap reconstructions.


[Probiotics in broilers' rearing: A strategy for intensive production models].
The broiler industry has become an important economic activity in Argentina. Global production of broiler meat has been growing in Argentina faster than for any other meats, possibly due to declining poultry prices and increasing incomes. Modern rearing systems can produce broilers ready to slaughter in 50 days, with the required 2.7kg of weight and a feed conversion of about 1.6kg feed/kg of meat. Nevertheless, broilers raised under these intensive conditions are exposed to various stressors every day. For many years, feed supplementation with antibiotics was widely used to stabilize the gut flora, improve general parameters and prevent avian diseases. However, the utility of antibiotics has been questioned because of the emergence and spread of antibiotic-resistant bacteria in meat. Therefore, there is a renewed interest in finding viable alternatives to antibiotics. One potential method is the supplementation of broiler diets with probiotics. This review provides an updated summary of the use of probiotics to improve sanitary conditions and enhance performance in broilers, demonstrating the role of probiotics as a reliable option to replace antimicrobial growth promoters.


Blocking effect of twin boundaries on partial dislocation emission from void surfaces.
Recent discovery that nanoscale twin boundaries can be introduced in ultrafine-grained metals to improve strength and ductility has renewed interest in the mechanical behavior and deformation mechanisms of these nanostructured materials. By controlling twin boundary spacing, the effect of twin boundaries on void growth is investigated by using atomistic simulation method. The strength is significantly enhanced due to the discontinuous slip system associated with these coherent interfaces. Atomic-scale mechanisms underlying void growth, as well as the interaction between twin boundaries and the void, are revealed in details.


Pretend play-based training improves some socio-emotional competences in 5-6-year-old children: A large-scale study assessing implementation.
The purpose of this study is to evaluate the effect of a pretend play-based training in 5-6-year-old children in a large scale school context on emotion comprehension, emotion regulation, prosocial behaviour and on their pretend play competences. The analysis of implementation variables was carried out in order to ensure program implementation quality in the experimental group. Results show an improvement in emotion comprehension and a decrease in aggressive behavioural responses in children in the experimental group (n = 101) compared to those in the control group (n = 79). Findings are discussed in regard to implementation outcomes and the influence of this form of play on the improvement of these variables.


Effect of dentin adhesives on contraction of restorative resins in cavities surrounded by acid-etched enamel.
Enamel-surrounded cavities prepared in extracted human teeth were treated with an enamel-bonding agent, one of two commercial dentin adhesives (Scotchbond 2 and Tenure), or one of two recent modifications of the Gluma system. In all cases the enamel margins were subjected to some form of acid etching. The cavities were filled with one of two different light-cured posterior resins, and the wall-to-wall polymerization contraction was assessed in the enamel surface level and, after grinding, measured and presented as linear shrinkage in the dentin surface level. The linear shrinkage varied from 0.66% in the control group, in which only composite resin was applied, to 0.28% in a group in which the cavities were pretreated with dentin adhesive. No difference could be demonstrated between the dentin adhesives or between the dentin adhesives and the enamel-bonding agent.


Early-life environmental intervention may increase the number of neurons, astrocytes, and cellular proliferation in the hippocampus of rats.
Neonatal handling reduces the stress response in adulthood due to a feedback mechanism. The present study analyzed the effects of repeated neonatal environmental intervention (daily handling during the first 10 days after birth) on neuron-, astroglial cell density, and cellular proliferation of the hippocampal (CA1, CA2, and CA3) pyramidal cell layers in female rats. Pups were divided into two groups, nonhandled and handled, which were submitted to repeated handling sessions between postnatal days 1 and 10. Histological and immunohistochemical procedures were used to determine changes in neuron density, astroglial cell density, and cellular proliferation. We found an increase in neuron density in each pyramidal cell layer of the hippocampus (CA1, CA2, and CA3) in female rats (11 and 90 day old) that were handled during the neonatal period. Furthermore, we found an increase in astroglial cell density in both hemispheres of the brain in the handled group. Finally, we observed an increase in cellular proliferation in both hippocampi (CA1, CA2, and CA3) of the brain in female pups (11 days old) handled during the neonatal period. This study demonstrates that an early-life environmental intervention may induce morphological changes in a structure involved with several functions, including the stress response. The results of the current study suggest that neonatal handling may influence the animals' responses to environmental adversities later in life.


Usefulness of magnetic motor evoked potentials in the surgical treatment of hemiplegic patients with intractable epilepsy.
Five hemiplegic patients with intractable epilepsy were studied with transcranial magnetic stimulation (TMS) before and after various surgical treatments. These patients had unilateral widespread cerebral lesions acquired at various times, including congenital, infantile and childhood injury. Motor evoked potentials (MEPs) of the abductor pollicis brevis (APB) muscles were simultaneously recorded on both sides following TMS of the motor cortex in the respective hemisphere using a figure-8 or circular coil. In all patients with congenital disease, the abolition of motor function in the affected hemisphere was estimated by magnetic MEPs, and the hemiplegia did not deteriorate after functional hemispherectomy (HS) was performed in two of them. In two patients with acquired disease, HS was not performed because it was shown by magnetic maps that the motor function in the affected hemisphere remained. Furthermore, it was shown by electric MEPs using subdural electrodes that a patient who had had encephalitis in early childhood had a reorganised motor area in the parietal cortex of the affected hemisphere. The present findings indicate that magnetic MEPs are a very useful non-invasive method of assessing whether the motor area in the affected hemisphere can be resected in hemiplegic patients with intractable epilepsy.


Bayesian integrated testing strategy (ITS) for skin sensitization potency assessment: a decision support system for quantitative weight of evidence and adaptive testing strategy.
The presented Bayesian network Integrated Testing Strategy (ITS-3) for skin sensitization potency assessment is a decision support system for a risk assessor that provides quantitative weight of evidence, leading to a mechanistically interpretable potency hypothesis, and formulates adaptive testing strategy for a chemical. The system was constructed with an aim to improve precision and accuracy for predicting LLNA potency beyond ITS-2 (Jaworska et al., J Appl Toxicol 33(11):1353-1364, 2013) by improving representation of chemistry and biology. Among novel elements are corrections for bioavailability both in vivo and in vitro as well as consideration of the individual assays' applicability domains in the prediction process. In ITS-3 structure, three validated alternative assays, DPRA, KeratinoSens and h-CLAT, represent first three key events of the adverse outcome pathway for skin sensitization. The skin sensitization potency prediction is provided as a probability distribution over four potency classes. The probability distribution is converted to Bayes factors to: 1) remove prediction bias introduced by the training set potency distribution and 2) express uncertainty in a quantitative manner, allowing transparent and consistent criteria to accept a prediction. The novel ITS-3 database includes 207 chemicals with a full set of in vivo and in vitro data. The accuracy for predicting LLNA outcomes on the external test set (n = 60) was as follows: hazard (two classes)-100 %, GHS potency classification (three classes)-96 %, potency (four classes)-89 %. This work demonstrates that skin sensitization potency prediction based on data from three key events, and often less, is possible, reliable over broad chemical classes and ready for practical applications.


Effects of deoxynivalenol (DON) on growth performance, nutrient digestibility and DON metabolism in pigs.
Wheat infected naturally withFusarium, contaminated mainly with 18.53 mg DON per kg, was added to a total constant wheat proportion of 400g/kg diet. Control and DON contaminated feed was fed for 11 weeks underad libitum and restrictive feeding conditions to 48 pigs of both sexes, which were randomly divided into 4 groups. Effects on performance (live weight range between 26 and 100kg), duration of feed intake and blood parameters were investigated. Parallel to this study, a balance study was carried out to examine the effects on nutrient digestibility and DON metabolism.The group fed the DON contaminated rationad libitum consumed 15% less feed and gained 14% less live weight compared to thead libitum control group, while the feed to gain ratio was unaffected. Under restrictive feeding conditions (DON and control) pigs exhibited 33%, 25% and 10% lower feed consumption, live weight gain and feed to gain ratio, respectively, than the control group fedad libitum. Metabolizability of energy, digestibility of organic matter, crude protein, crude fat and N-retention were significantly increased by 4, 3, 6, 11 and 10%, respectively, in the DON group of the restrictively fed pigs.In average up to 43.2% of the ingested DON, as the parent toxin in both groups, was eliminated with the urine and up to 3.0% with faeces. DON fed animals needed more time to consume the restrictive ration than the control group.


Extracorporeal photopheresis affects interleukin (IL)-10 and IL-12 production by monocytes in patients with chronic graft-versus-host disease.
Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic bone marrow transplantation. Extracorporeal photopheresis (ECP) has recently been introduced as an alternative treatment for cases of cGVHD refractory to conventional immunosuppressive treatment, but its mechanism of action is not yet clear. To investigate in seven patients with cGVHD the effects of ECP on resistance of monocytes to apoptosis and on monocyte cytokine production. We designed an in vitro model that could mimic the potential in vivo effect of reinfusion of peripheral blood mononuclear cells treated by ECP. The model was based on coculture of ECP-treated lymphocytes with untreated monocytes from the same patient. ECP did not accelerate spontaneous apoptosis of monocytes. However, ECP-treated monocytes produced increased amounts of interleukin (IL)-12. In contrast, IL-12 production by monocytes did not increase in cocultures, but IL-10 production was upregulated. These results suggest that reinfusion of large numbers of autologous apoptotic lymphocytes is significant for the therapeutic outcome of ECP through upregulation of IL-10, which is an immunosuppressive cytokine.


Aziridine Opening via a Phenonium Ion Enables Synthesis of Complex Phenethylamine Derivatives.
We report that the treatment of unsymmetrical 2,3-disubstituted aziridines with TiCl4 yields β-phenethylamine products via the intermediacy of a phenonium ion. Derivatization of the products obtained via this method is demonstrated. Computational analysis of the reaction pathway provides insight into the reaction mechanism, including the selectivity of the phenonium opening.


DNA interaction with platinum-based cytostatics revealed by DNA sequencing.
The main mechanism of action of platinum-based cytostatic drugs - cisplatin, oxaliplatin and carboplatin - is the formation of DNA cross-links, which restricts the transcription due to the disability of DNA to enter the active site of the polymerase. The polymerase chain reaction (PCR) was employed as a simplified model of the amplification process in the cell nucleus. PCR with fluorescently labelled dideoxynucleotides commonly employed for DNA sequencing was used to monitor the effect of platinum-based cytostatics on DNA in terms of decrease in labeling efficiency dependent on a presence of the DNA-drug cross-link. It was found that significantly different amounts of the drugs - cisplatin (0.21 μg/mL), oxaliplatin (5.23 μg/mL), and carboplatin (71.11 μg/mL) - were required to cause the same quenching effect (50%) on the fluorescent labelling of 50 μg/mL of DNA. Moreover, it was found that even though the amounts of the drugs was applied to the reaction mixture differing by several orders of magnitude, the amount of incorporated platinum, quantified by inductively coupled plasma mass spectrometry, was in all cases at the level of tenths of μg per 5 μg of DNA.


Expression of upstream and downstream targets of mTOR pathway in seven cases of secretory carcinoma of salivary gland origin.
To investigate the expression of upstream and downstream targets of mTOR signalling pathway in the secretory carcinoma of salivary gland origin (SCsg). Seven cases of secretory carcinoma diagnosed by a combination of immunohistochemistry and/or molecular testing were retrieved from our pathology files. For comparison purposes, 27 other salivary carcinomas were selected. Immunohistochemical staining was performed against phospho-Akt, PTEN, phospho-mTOR, phospho-4E-BP, eIF4E and phospho-S6 ribosomal protein. With the exception of Akt, all the other proteins were present at some level in the SCsg and in other salivary carcinomas. PTEN was diffusely expressed in 57.1% of SCsg, but only in 14.8% of other salivary carcinomas. mTOR is expressed in more than half of the cases both for SCsg and other salivary tumour types. Most cases of SCsg showed negative expression for S6 ribosomal protein (71.4%) and 4E-BP1 (57.1%). For both groups evaluated, eIF4E was the most expressed protein. SCsg shows different expression patterns for the mTOR signalling molecules, but only eIF4E was highly expressed. This may suggest alternative signalling pathways other than Akt and mTOR in this group of tumours.


Comparison of adrenocorticotropic hormone efficacy between aetiologies of infantile spasms.
We aimed to study the efficacy of adrenocorticotropic hormone (ACTH) treatment on infantile spasms with different aetiologies. In particular, we were interested in patients with structural-acquired aetiology. Patients with infantile spasms, who were treated with ACTH, were divided into three groups based on the aetiologies: unknown aetiology with normal development (unknown-normal), structural-acquired, and combined-congenital aetiologies that included genetic, metabolic, structural-congenital, or unknown aetiology with developmental delay. Of the 107 patients included (58 males, 49 females), 25 patients had unknown-normal aetiology [median age at onset 5 months, standard deviation (SD) 3.12, range 2-16 months]; 20 patients had structural-acquired aetiology (median age at onset 6.5 months, SD 3.85 months, range 4-17 months); and 62 patients had combined-congenital aetiologies (median age at onset 5 months, SD 2.73 months, range 2-16 months). The efficacy of ACTH was 64.0 %, 65 %, and 30.6 % in the unknown-normal aetiology, structural-acquired aetiology, and combined-congenital aetiologies, respectively (p < 0.01). Multivariate analysis showed a statistically significant higher efficacy in the unknown-normal aetiology [Odds ratio (OR) 4.63, 95 % confidence interval (CI) 1.60-13.30] and structural-acquired aetiology (OR 3.41, 95 % CI 1.01-11.50) compared to that in the combined-congenital aetiologies. Infantile spasms with structural-acquired aetiology had greater response to ACTH treatment than those with combined-congenital aetiologies. The efficacy of standard therapy of infantile spasms should be considered based on aetiology.


Subcutaneous immunisation with zymosan generates mucosal IgA-eliciting memory and protects mice from heterologous influenza virus infection.
Immunoglobulin A (IgA) is the most abundant isotype of antibodies and provides a first line of defense at the mucosa against pathogens invading the host. It has been widely accepted that the mucosal IgA response provided by vaccination requires mucosal inoculation, and intranasal inoculation has been proposed for vaccines against influenza virus. Considering the difficulty of intranasal vaccination in infants or elderly people, however, parenteral vaccination that provides the mucosal IgA response is desirable. Here, we demonstrate that subcutaneous immunisation with zymosan, a yeast cell wall constituent known to be recognised by Dectin-1 and TLR2, potentiates the production of antigen-specific IgA antibodies in the sera and airway mucosa upon intranasal antigen challenge. We confirmed that the antigen-specific IgA-secreting cells accumulated in the lung and nasal-associated lymphoid tissues after the antigen challenge. Such an adjuvant effect of zymosan in the primary immunisation for the IgA response depended on Dectin-1 signalling, but not on TLR2. The IgA response to the antigen challenge required both antigen-specific memory B and T cells, and the generation of memory T cells, but not memory B cells, depended on zymosan as an adjuvant. Finally, we demonstrated that subcutaneous inoculation of inactivated influenza virus with zymosan, but not with alum, mostly protected the mice from infection with a lethal dose of a heterologous virus strain. These data suggest that zymosan is a possible adjuvant for parenteral immunisation that generates memory IgA responses to respiratory viruses such as influenza virus.


Long term increase of mucosal mast cells in the rat induced by administration of compound 48/80.
Administration of Compound 48/80 to rats for 5 days resulted in an increase of the specific type of mucosal mast cell, while connective tissue mast cells elsewhere were almost completely degranulated. The number of mucosal mast cells increased slowly for another 5 days and then returned to the control level, in an exponential manner. The half life of the newly formed mast cells was calculated to be about 40 days. This value may be taken as an estimate of the half life of mucosal mast cells. These cells, therefore, constitute a fraction of mast cells with rapid turnover. Available evidence indicates that the classical connective tissue mast cell has a very long life span, without significant turnover in terms of cell death and cell renewal. We suggest that the increase of mucosal mast cells is an indirect effect of Compound 48/80, related to its effect on other mast cells and mediated by material(s) released from these cells during the secretory process.


Visualization of clonal expansion after massive depletion of cells carrying the bovine leukemia virus (BLV) integration sites during the course of disease progression in a BLV naturally-infected cow: a case report.
Bovine leukemia virus (BLV) infects cattle, integrates into host DNA as a provirus, and induces malignant B-cell lymphoma. Previous studies have addressed the impact of proviral integration of BLV on BLV-induced leukemogenesis. However, no studies have monitored sequential changes in integration sites in which naturally infected BLV individuals progress from the premalignant stage to the terminal disease. Here, we collected blood samples from a single, naturally infected Holstein cow at three disease progression stages (Stage I: polyclonal stage, Stage II: polyclonal toward oligoclonal stage, Stage III: oligoclonal stage) and successfully visualized the kinetics of clonal expansion of cells carrying BLV integration sites using our BLV proviral DNA-capture sequencing method. Although 24 integration sites were detected in Stages I and II, 92% of these sites experienced massive depletion in Stage III. Of these sites, 46%, 37%, and 17% were located within introns of Refseq genes, intergenic regions, and repetitive sequences, respectively. At Stage III cattle with lymphoma, only two integration sites were generated de novo in the intergenic region of Chr1, and the intron of the CHEK2 gene on Chr17 was significantly increased. Our results are the first to demonstrate clonal expansion after the massive depletion of cells carrying BLV integration sites in a naturally infected cow.


A gel-sandwich technique for the qualitative and quantitative determination of dehydrogenases in the enzyme histochemistry. I. Development of the new methods on the example of LDH (E.C. 188.8.131.52).
A gel-sandwich technique for the histochemical demonstration of dehydrogenase is introduced with LDH set up as an example. Especially suitable, of the gels examined, for this technique is 1.5% W/V agar-agar low gel strength. In it several reaction ingredients for the histochemical reaction are dissolved. Considering LDH the following gel composition showed good results: 1.5% W/V agar-agar low gel strength, 5 mM TNBT in 150 microliter DMF, 120 mM L-lactate, 3--5 mM NAD+, 10 mM amytal, 22,4--32 X 10(-5) M Meldola Blue, 160 mM soldium phosphate buffer pH 7.6 (total solution of 1 ml). After the solidification of the gel, gel-bars were frozen with CO2-snow. The 40--80 micrometer thick gel slices were gained in the cryostat. Of the three different arrangement possibilities of the gel slices and the tissue-sections a sandwich arrangement (cover-gel slice--tissue section--ground-gel slice) produced the best results. The enzyme reaction is started by thawing of the gel slices (together with the tissue sections) and by putting them between the hotplate and the evaporator-head-piece, especially developed for this technique. The gel slices also remain in combination with the tissue sections after the reaction. The influence of the gel in combination with the electron carrier Meldola Blue on the spontaneous reduction rates of ditetrazolium salts in day light, were examined as well as the diffusion rates of TNBT and NADH out of gel slices and the influence of DMF and DMSO on the LDH activity. This technique prevents both, the loss of enzymes and the loss of reduction equivalents. There are given presuppositions for qualitative and quantitative histochemical investigations as well. The advantages of the new gel technique are discussed.


Characterization of the replication origin of the myxobacterial self-replicative plasmid pMF1.
Thus far, pMF1 is the only endogenous myxobacterial plasmid whose replication mechanism is unclear. In this study, we determined that the plasmid replicates via the theta-mode. The pMF1.14 gene, located in the pMF1.13-pMF1.15 operon (repABC), encodes an essential replication initiation protein that was predicted to have no typical DNA/protein binding motifs but contains rich disordered regions. The pMF1 replication-related essential cis-acting DNA region, approximate 370bp, was located within pMF1.14, and was found to contain several directly and inverted atypical repeats. The unique characteristics of the pMF1 replicon are suggested to be the reason for its strict narrow host range in Myxococcus cells.


Atomically dispersed nickel as coke-resistant active sites for methane dry reforming.
Dry reforming of methane (DRM) is an attractive route to utilize CO2 as a chemical feedstock with which to convert CH4 into valuable syngas and simultaneously mitigate both greenhouse gases. Ni-based DRM catalysts are promising due to their high activity and low cost, but suffer from poor stability due to coke formation which has hindered their commercialization. Herein, we report that atomically dispersed Ni single atoms, stabilized by interaction with Ce-doped hydroxyapatite, are highly active and coke-resistant catalytic sites for DRM. Experimental and computational studies reveal that isolated Ni atoms are intrinsically coke-resistant due to their unique ability to only activate the first C-H bond in CH4, thus avoiding methane deep decomposition into carbon. This discovery offers new opportunities to develop large-scale DRM processes using earth abundant catalysts.


Skin-permeable liposome improved stability and permeability of bFGF against skin of mice with deep second degree scald to promote hair follicle neogenesis through inhibition of scar formation.
Excessive deposition of extracellular matrix (ECM) usually resulted in scar formation during wound healing, which caused skin dysfunction, such as hair loss. Basic fibroblast growth factor (bFGF) was very helpful for promoting hair follicle neogenesis and regulating the remodeling of ECM during wound healing. Because of its poor stability in wound fluids and low permeability against the dense wound scar, the repairing quality of bFGF on wound was hindered largely in clinical practice. To overcome these drawbacks, herein, a novel liposome with silk fibroin hydrogel core (bFGF-SF-LIP) was firstly prepared to stabilize bFGF, followed by insertion of laurocapam, a permeation enhancer, into the liposomal membrane to construct a skin-permeable liposome (SP-bFGF-SF-LIP). The encapsulated efficiency of bFGF was reaching to nearly 90% when ratio of drug/lipids above 1:300, and it activity was not compromised by laurocapam. SP-bFGF-SF-LIP exhibited a hydrodynamic diameter of 103.3 nm and Zeta potential of -2.31 mV. The stability of the encapsulated bFGF in wound fluid was obviously enhanced. After 24 h of incubation with wound fluid containing MMP-9, the remaining bFGF was as high as 65.4 ± 0.5% for SP-bFGF-SF-LIP, while only 2.1 ± 0.2% of free bFGF was remained. The skin-permeability of bFGF was significantly enhanced by SP-bFGF-SF-LIP and most of the encapsulated bFGF penetrated into the dermis. After treatment with SP-bFGF-SF-LIP, the morphology of hair follicle at wound zone was obviously improved and the hair regrew on the deep second scald mice model. The therapeutic mechanism was highly associated with inhibiting scar formation and promoting vascular growth in dermis. Conclusively, SP-bFGF-SF-LIP may a potential option to improve wound healing with high-quality.


Long-term suppression of cathepsin B levels by RNA interference retards schistosome growth.
Schistosoma mansoni is an important flatworm parasite of man that has remained intractable to experimental analyses of gene function. We have developed an approach for using dsRNA to target schistosome transcripts for RNA interference, and used it to address the role of cathepsin B (SmCB1), a cysteine protease that has been proposed to play a central role in hemoglobin digestion in the schistosome gut. Electroporation of 3 h old larval schistosomes with SmCB1-specific dsRNA (SmCB1-dsRNA) resulted in a greater than 10-fold reduction in SmCB1 transcript levels that persisted for >20 days. RNAi mediated reductions in transcript levels led to associated reductions in SmCB1 enzyme activity. Schistosomes treated with SmCB1-dsRNA were viable and developed intestinal heme pigmentation indicative of hemoglobin digestion, but showed significant growth retardation when compared to control parasites, indicating that SmCB1 function is not essential for hemoglobin digestion but is necessary for normal parasite growth. This effect on growth was apparent when parasites were maintained in culture or introduced into mammalian hosts. The report sheds new light on the role of SmCB1 and provides a template for using RNAi to examine gene function in the mammal-parasitic stages of schistosomes during early development in vitro and in vivo.


Publication performance and trends in bruxism research: A bibliometric analysis.
Bruxism is an umbrella term that encompass a multidimensional spectrum of masticatory muscle activities. The purpose of this study was to do a bibliometric analysis including citation performance in the research topic of bruxism, by using an innovative method including details of article title, author keyword, KeyWords Plus and abstracts. The data were retrieved 2022-12-19 from the Clarivate Analytics Web of Science Core Collection, and the online version of the Science Citation Index Expanded (SCI-EXPANDED) for studies published 1992 to 2021. To evaluate research trends, the distribution of keywords in the article title and author-selected keywords were used. The search yielded 3233 documents in SCI-EXPANDED, of which 2598 were of the document-type 'articles' published in 676 journals. The analysis of the articles revealed that "bruxism/sleep bruxism," "electromyography," "temporomandibular disorders" and "masticatory muscles" are the most used keywords by the authors. Further, the most frequently cited study was published 9 years ago and handles the present definition of bruxism. The most productive authors and those with the highest performance have some common features; they have several national and international collaborations; and they have published articles about the definition, aetiology/pathophysiology and prevalence of bruxism, all senior researchers in the field of TMD. Hopefully, based on this study, researchers and clinicians will have information to be stimulated to outline future research projects on bruxism-related aspects, and to initiate new international or multinational collaborations.


Quantitative analysis of trifluoroacetic acid in body fluids of patients treated with halothane.
A simple procedure for the quantitative analysis of trifluoroacetic acid (TFA) in urine and serum from patients narcotized with halothane is described. This involves addition of sodium hydroxide to the body fluid, evaporation of the aqueous phase and esterification of TFA in concentrated sulphuric acid with 2,2,2-trichloroethanol. The gaseous phases above the reaction mixture were then analyzed by gas chromatography with a nickel-63 electron-capture detector. The detection limit was 1 microgram of TFA per mililitre of body fluid (200 microgram of body fluid are analysed) and the relative standard deviation was +/-6%. Patients treated with ethrane, another commercial anaesthetic, did not produce any detectable TFA.


Degree-based topological indices and polynomials of hyaluronic acid-curcumin conjugates.
Quantitative structure-activity relationship (QSAR) represents quantitative correlation of chemical structural features called as molecular descriptors and pharmacological activity as response endpoints. Topological index is a molecular descriptor extensively used to study QSAR of pharmaceuticals to assess their molecular characteristics by numerical computation. Theoretical assessment of drug like molecules helps to expedite the drug design and discovery process by rationalizing the lead identification, lead optimization and understanding their mechanism of actions. Therefore, in this article, we have computed the general inverse sum indeg index, ISI α , β of Hyaluronic acid-curcumin conjugates by using molecular structure analysis and edge partitioning technique. Many standard topological indices are obtained as a special case of ISI α , β . We also proposed general inverse sum indeg polynomial ISI α , β ( G n , x ) of Hyaluronic acid-curcumin conjugates from which many well-known polynomials are deduced.


Relation of precurarization to suxamethonium to provide ease of intubation and to prevent post-suxamethonium muscle pains.
Tubocurarine 0.05 and 0.07 mg.kg-1, gallamine 0.1 and 0.2 mg.kg-1 and pancuronium 0.01 and 0.02 mg.kg-1 given three minutes before suxamethonium 1.0, 1.5 and 2 mg.kg-1 in groups of 10 patients each (total 210 patients) to compare ease of tracheal intubation and incidence of post-suxamethonium muscle pain. These were compared with a control group of suxamethonium 1.0, 1.5 and 2 mg.kg-1 given alone after thiopentone 5 mg.kg-1. On analysis, tubocurarine 0.07 mg.kg-1 and suxamethonium 2 mg.kg-1 was the ideal combination with the best intubation conditions and the lowest incidence of post-suxamethonium muscle pains. The second best combination was gallamine 0.2 mg.kg-1 and suxamethonium 2 mg.kg-1. Pancuronium 0.01 mg.kg-1 and 0.02 mg.kg-1 in combination with suxamethonium 2 mg.kg-1 were satisfactory, although less efficient than the combination with either tubocurarine or gallamine.


Chryseobacterium herbae Isolated from the Rhizospheric Soil of Pyrola calliantha H. Andres in Segrila Mountain on the Tibetan Plateau.
A non-motile, Gram-staining-negative, orange-pigmented bacterium called herbae pc1-10T was discovered in Tibet in the soil around Pyrola calliantha H. Andres' roots. The isolate thrived in the temperature range of 10-30 °C (optimal, 25 °C), pH range of 5.0-9.0 (optimum, pH = 6.0), and the NaCl concentration range of 0-1.8% (optimal, 0%). The DNA G+C content of the novel strain was 37.94 mol%. It showed the function of dissolving organophosphorus, acquiring iron from the environment by siderophore and producing indole acetic acid. Moreover, the genome of strain herbae pc1-10T harbors two antibiotic resistance genes (IND-4 and AdeF) encoding a β-lactamase, and the membrane fusion protein of the multidrug efflux complex AdeFGH; antibiotic-resistance-related proteins were detected using the Shotgun proteomics technology. The OrthoANIu values between strains Chryseobacterium herbae pc1-10T; Chryseobacterium oleae CT348T; Chryseobacterium kwangjuense KJ1R5T; and Chryseobacterium vrystaatense R-23566T were 90.94%, 82.96%, and 85.19%, respectively. The in silico DDH values between strains herbae pc1-10T; C. oleae CT348T; C. kwangjuense KJ1R5T; and C. vrystaatense R-23566T were 41.7%, 26.6%, and 29.7%, respectively. Chryseobacterium oleae, Chryseobacterium vrystaatense, and Chryseobacterium kwangjuense, which had 16S rRNA gene sequence similarity scores of 97.80%, 97.52%, and 96.75%, respectively, were its closest phylogenetic relatives. Chryseobacterium herbae sp. nov. is proposed as the designation for the strain herbae pc1-10T (=GDMCC 1.3255 = JCM 35711), which represented a type species based on genotypic and morphological characteristics. This study provides deep knowledge of a Chryseobacterium herbae characteristic description and urges the need for further genomic studies on microorganisms living in alpine ecosystems, especially around medicinal plants.


A dentist's guide to using the BNF: part II.
The BNF can be used as a tool to facilitate rational prescribing. In the second of this two-part series, we describe how dentists can maximise the effectiveness of their prescribing and minimise the risks involved while tailoring medicines to the individual needs of each patient.


Molecular properties of somatostatin receptors.
The neuropeptide somatostatin is widely distributed in the central nervous system and in peripheral tissues and may be involved in the regulation of a number of physiological functions including movement and cognition. Somatostatin may also have a role in the development of the central nervous system, in particular, the cerebellum and spinal cord. Somatostatin induces its actions by interacting with a family of membrane associated receptors. Recently, five somatostatin receptors have been cloned and referred to as SSTR1-SSTR5. The distribution of the expression of the mRNAs for these receptors are distinct but overlapping. Preliminary pharmacological analysis of these receptors may lead to the development of selective ligands at these receptors. These compounds may be useful in identifying the selective functions of these receptor subtypes. Some somatostatin analogues have antiproliferative actions and are used presently to treat carcinoids. Development of subtype selective somatostatin analogues could be helpful in further identifying somatostatin receptor-expressing tumors and in the treatment of cancer. The cloning of these receptors has now opened up the possibility of more clearly investigating the functions of somatostatin in the brain and peripheral tissues and will facilitate the generation of new somatostatin drugs that may be employed for the treatment of a number of diseases.


Genomic, expressional, protein-protein interactional analysis of Trihelix transcription factor genes in Setaria italia and inference of their evolutionary trajectory.
Trihelix transcription factors (TTF) play important roles in plant growth and response to adversity stress. Until now, genome-wide identification and analysis of this gene family in foxtail millet has not been available. Here, we identified TTF genes in the foxtail millet and its grass relatives, and characterized their functional domains. As to sequence divergence, TTF genes were previously divided into five subfamilies, I-V. We found that Trihelix family members in foxtail millet and other grasses mostly preserved their ancestral chromosomal locations during millions of years' evolution. Six amino acid sites of the SIP1 subfamily possibly were likely subjected to significant positive selection. Highest expression level was observed in the spica, with the SIP1 subfamily having highest expression level. As to the origination and expansion of the gene family, notably we showed that a subgroup of subfamily IV was the oldest, and therefore was separated to define a new subfamily O. Overtime, starting from the subfamily O, certain genes evolved to form subfamilies III and I, and later from subfamily I to develop subfamilies II and V. The oldest gene, Si1g016284, has the most structural changes, and a high expression in different tissues. What's more interesting is that it may have bridge the interaction with different proteins. By performing phylogenetic analysis using non-plant species, notably we showed that a subgroup of subfamily IV was the oldest, and therefore was separated to define a new subfamily O. Starting from the subfamily O, certain genes evolved to form other subfamilies. Our work will contribute to understanding the structural and functional innovation of Trihelix transcription factor, and the evolutionary trajectory.


Ferritin-nanocaged copper arsenite minerals with oxidative stress-amplifying activity for targeted cancer therapy.
We report copper(II) arsenite-encapsulated ferritin nanoparticles (CuAS-FNs) as oxidative stress-amplifying anticancer agents. The CuAS-FNs were fabricated through CuAS mineralization in the cavity of the FNs. The formation of crystalline CuAS complex minerals in the FNs was systematically identified using various analytical tools, including X-ray photoelectron spectroscopy (XPS) and transmission electron microscopy (TEM)-associated energy-dispersive X-ray spectroscopy (TEM-EDS). The CuAS-FNs showed pH-dependent release behavior, in which the CuAS mineral was effectively retained at physiological pH, in contrast, at lysosomal pH, the CuAS complex was dissociated to release arsenite and Cu2+ ions. At lysosomal pH, the release rate of arsenite (HAsO32-) and Cu2+ ions from the CuAS-FNs more accelerated than at physiological pH. Upon transferrin receptor-1-mediated endocytosis, the CuAS-FNs simultaneously released arsenite and Cu2+ ions in cells. The released arsenite ions can increase the intracellular concentration of hydrogen peroxide (H2O2), with which the Cu2+ ions can elevate the level of hydroxyl radicals (·OH) via Fenton-like reaction. Thus, the CuAS-FNs could target cancer cell through the recognizing ability of FNs and kill cancer cells by amplifying the ·OH level through the synergistic activity of Cu2+ and arsenic ions. Importantly, MCF-7 tumors were effectively suppressed by CuAS-FNs without systemic in vivo toxicity. Therefore, the CuAS-FNs is a promising class of Fenton-like catalytic nanosystem for cancer treatment.


Detection of Cortical Microbleeds in Postmortem Brains of Patients with Lewy Body Dementia: A 7.0-Tesla Magnetic Resonance Imaging Study with Neuropathological Correlates.
It is unclear whether associated cerebrovascular pathology contributes to the clinical spectrum of Lewy body dementia (LBD). The present postmortem 7.0-tesla MRI study investigates the anatomical distribution of cortical microbleeds (CoMBs) in LBD brains with and without associated Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). CoMBs predominated in the frontal section of the LBD brains and were associated to severe white matter lesions. No differences were observed when LBD brains with and without AD and CAA were compared. In LBD, there is a specific distribution of CoMBs that is different from that in other neurodegenerative diseases. The increase of frontal CoMBs is not due to the frequently associated AD and CAA features but due to the LBD itself.


Distinct sensitivities to SARS-CoV-2 variants in vaccinated humans and mice.
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has led to the development of a large number of vaccines, several of which are now approved for use in humans. Understanding vaccine-elicited antibody responses against emerging SARS-CoV-2 variants of concern (VOCs) in real time is key to inform public health policies. Serum neutralizing antibody titers are the current best correlate of protection from SARS-CoV-2 challenge in non-human primates and a key metric to understand immune evasion of VOCs. We report that vaccinated BALB/c mice do not recapitulate faithfully the breadth and potency of neutralizing antibody responses elicited by various vaccine platforms against VOCs, compared with non-human primates or humans, suggesting caution should be exercised when interpreting data obtained with this animal model.


Psychosocial factors associated with complicated grief in caregivers during COVID-19: Results from a preliminary cross-sectional study.
The COVID-19 pandemic has changed how end-of-life ceremonies are performed, affecting grief processing and bereavement experiences. In this study, caregivers of patients who died with COVID-19 during the first wave of the pandemic were asked to complete an online survey designed to detect psychosocial factors associated with the presence of complicated grief (CG). The results show CG present in 48.4% of caregivers. The marital and cohabitant status during lockdown, the perceived sense of guilt and depression levels were significantly associated with the presence of CG, whereas attendance at the funeral and social support were found to be significant protective factors.


The role of clinical drug trial methodology with respect to studies of new drugs. Clinical trials of timolol.
The use of the Randomized Clinical Trial (RCT) to assess the safety and efficacy of a new drug or treatment can provide a clear evaluation of the relative benefits and risks of the new therapy as compared to the longer-established treatment methodology. In some cases, such as insulin, the benefits are immediately apparent; in other cases, such as photocoagulation for proliferative diabetic retinopathy, the consensus is not so easily obtained, and the clinical trial can supply the answer. Furthermore, the RCT provides the opportunity to identify adverse reactions, in particular those which present with a seemingly unrelated or unexpected set of symptoms. In conducting clinical trials of timolol, researchers must be alert for beta-adrenergic antagonist effects, such as were seen with practolol, and should be especially careful to note early, mild reactions which may be the forerunners of later, more severe or irreversible adverse effects.


Evaluation of tear samples for Herpes Simplex Virus 1 (HSV) detection in suspected cases of viral keratitis using PCR assay and conventional laboratory diagnostic tools.
Herpes Simplex Virus (HSV) keratitis is a leading cause of corneal blindness. Definitive laboratory diagnosis is essential for timely management. Collection of corneal scrapings in patients with advanced epithelial keratitis and corneal thinning poses perforation risks; tear fluid is a feasible and convenient alternative but has not been widely evaluated for HSV detection. Tear fluid alone (229) or along with corneal scrapings (153) from patients of suspected herpetic keratitis was tested for HSV-1 antigen by indirect immunofluorescence assay, virus isolation in Hep 2 cells and PCR to amplify the 111bp region of the thymidine kinase (tk) coding gene and the 144bp region from the DNA polymerase coding gene of HSV. HSV 1 antigen was detected in 31/229 (13.53%) tear specimen and 35/153 (22.87%) corneal scrapings in immunofluorescence assay; virus was isolated from 12/229 (5.2%) tear and 17/153 (11.11%) corneal scrapings, and PCR was positive for both the genes in 32/229 (13.97%) tear specimen and 56/153 (36.66%) corneal scrapings. Corneal scrapings yielded a significantly better HSV positivity than tears in both the PCR assay (p<0.0005) and immunofluorescence assay. PCR was much more sensitive than immunofluorescence and virus isolation. However, tears should be tested for definitive laboratory diagnosis of HSV infection whenever corneal scraping collection is not possible.


Eradication of hepatocellular carcinoma xenografts by radiolabelled, lipiodol-inducible gene therapy.
The promoter region of the early-growth response-1(Egr-1) gene has been shown to be activated by external radiation, thus making a selective tumoricidal effect possible. A previous experiment showed that the Egr-1 promoter can be activated by internal radiation using radioisotopes as well as external radiation. Internal radiation using I-131 lipiodol (I-131-Lip) has been established as one of the most useful therapeutic strategies against hepatoma. We herein linked the Egr-1 promoter to the herpes simplex virus-thymidine kinase (HSV-TK) gene, and investigated its efficacy in hepatoma gene therapy in combination with I-131-Lip. A luciferase assay showed the Egr-1-promoter activity to be markedly increased in hepatoma tissue specimens in an I-131-dose-dependent manner, whereas a less than two-fold increase in this activity was observed in other organs. In addition, the radioactivity derived from I-131 was selectively accumulated in the tumor tissue specimens. To examine the efficacy of EgrTK/ganciclovir (GCV) gene therapy in vivo, subcutaneous hepatoma xenografts in nude mice were transfected using a hemagglutinating virus of Japan (HVJ)-liposome vector. Complete tumor regression was observed in all the EgrTK-transfected tumors following combination treatment with I-131-Lip and GCV 42 days after treatment without any side effects (n=8). In contrast, the tumors continued to grow in all control mice (n=10). Furthermore, the serum alpha-fetoprotein levels decreased in the combination therapy group, while they increased in the controls. In conclusion, these data indicate that Egr-1 promoter-based gene therapy combined with internal radiation has a selective effect on hepatoma tumors while also showing an improved in vivo efficacy. This combination therapy might, therefore, be an effective human hepatoma gene therapy, even in advanced multiple cases.


Understanding DNA replication by the bacteriophage T4 replisome.
The T4 replisome has provided a unique opportunity to investigate the intricacies of DNA replication. We present a comprehensive review of this system focusing on the following: its 8-protein composition, their individual and synergistic activities, and assembly in vitro and in vivo into a replisome capable of coordinated leading/lagging strand DNA synthesis. We conclude with a brief comparison with other replisomes with emphasis on how coordinated DNA replication is achieved.


Dynamic Rather than Static Procedures in Correcting Claw Deformities Due to Ulnar Nerve Palsy.
The theoretic disadvantage of dynamic tendon transfers is the perception that they are "more complex" than static procedures. The latter may provide a simple solution to claw deformity in a subset of patients; however, they completely disregard the disability associated with loss of the intrinsic musculature. Dynamic procedures reconstruct in part the deficient intrinsic forces and are thus capable of correcting the deformity and some disabilities associated with ulnar nerve palsy. In our practice, we have consistently achieved reasonable correction of claw deformity and improvement in tendon synchrony and grip strength with a modified Stiles-Bunnell, flexor digitorum superficialis tendon transfer.


An evaluation of the role of the intravenous urogram in the management of patients with epididymo-orchitis.
The purpose of this study was to evaluate the role of intravenous urography in patients presenting with symptoms of epididymo-orchitis. The intravenous urograms of 67 such patients were assessed retrospectively. The management of patients with acute epididymo-orchitis was not affected by intravenous urography, although a number of abnormalities were identified. Patients with additional symptoms not typical of acute epididymo-orchitis showed a higher incidence of abnormalities some of which affected management. It is concluded that urography is not warranted in the investigation of patients with uncomplicated acute epididymo-orchitis.