Intravenous enhanced 3D FLAIR imaging to identify CSF leaks in spontaneous intracranial hypotension: Comparison with MR myelography.
To evaluate the clinical utility of intravenous gadolinium-enhanced heavily T2-weighted 3D fluid-attenuated inversion recovery (HT2-FLAIR) imaging for identifying spinal cerebrospinal fluid (CSF) leaks in patients with spontaneous intracranial hypotension (SIH). Patients with SIH underwent MR myelography and post-contrast HT2-FLAIR imaging after an intravenous gadolinium injection. Two types of CSF leaks (epidural fluid collection and CSF leaks around the nerve root sleeve) at each vertebral level were compared between the 2 sequences. The total numbers of CSF leaks and vertebral levels involved were recorded for the whole spine. The sequence that was superior for the overall visualization of epidural and paraspinal fluid collection was then selected. Nine patients with SIH were included in the present study. HT2-FLAIR imaging was equivalent or superior to MR myelography at each level for detecting the 2 types of CSF leaks. In the 2 types of CSF leaks, the total numbers of CSF leaks and levels involved were higher on HT2-FLAIR images than on MR myelography, while no significant difference was observed for CSF leaks around the nerve root sleeve. In all 9 patients, HT2-FLAIR imaging was superior to MR myelography for the overall visualization of epidural and paraspinal fluid collection. Intravenous gadolinium-enhanced HT2-FLAIR imaging was superior to MR myelography for the visualization of CSF leaks in patients with SIH. This method can be useful for identifying spinal CSF leaks.


Critical care. A specialty without frontiers.
During its development, the specialty of Intensive Care has evolved from simple supportive ventilatory techniques to complex monitoring and decision making. The evidence suggests that a trained dedicated intensivist has beneficial effects on outcomes and costs compared to open units. The role of the intensivist and the need for interaction with other groups is discussed.


A new capillary tube agglutination-inhibition test for the detection of circulating immune complexes containing endogenously bound C1q.
The C1q agglutination-inhibition test (C1q-AIT) is a sensitive assay, capable of detecting circulating immune complexes (CIC) containing as little as 40 ng C1q. This non-isotopic test can be easily performed in 4 h from the receipt of the serum sample (including the isolation of CIC by PEG 6000 percipitation). The reagents are stable for at least 6 months under normal refrigeration. Because a carefully standardized C1q- anti-C1q reaction is used, CIC can be semi-quantitated by a routine titration procedure. Sera from patients with diseases reported to be associated with CIC gave significantly high test results, while diseases not normally associated with CIC (e.g. OA, gout, allergy) gave low frequencies of positive results. The C1q-AIT for CIC containing endogenously bound C1q was shown to be equivalent to and more sensitive than the [125I]C1q-BA for CIC containing exogenously bound C1q.


Towards precision oncology with patient-derived xenografts.
Under the selective pressure of therapy, tumours dynamically evolve multiple adaptive mechanisms that make static interrogation of genomic alterations insufficient to guide treatment decisions. Clinical research does not enable the assessment of how various regulatory circuits in tumours are affected by therapeutic insults over time and space. Likewise, testing different precision oncology approaches informed by composite and ever-changing molecular information is hard to achieve in patients. Therefore, preclinical models that incorporate the biology and genetics of human cancers, facilitate analyses of complex variables and enable adequate population throughput are needed to pinpoint randomly distributed response predictors. Patient-derived xenograft (PDX) models are dynamic entities in which cancer evolution can be monitored through serial propagation in mice. PDX models can also recapitulate interpatient diversity, thus enabling the identification of response biomarkers and therapeutic targets for molecularly defined tumour subgroups. In this Review, we discuss examples from the past decade of the use of PDX models for precision oncology, from translational research to drug discovery. We elaborate on how and to what extent preclinical observations in PDX models have confirmed and/or anticipated findings in patients. Finally, we illustrate emerging methodological efforts that could broaden the application of PDX models by honing their predictive accuracy or improving their versatility.


Publisher Correction: Normal-to-mildly increased albuminuria predicts the risk for diabetic retinopathy in patients with type 2 diabetes.
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.


INTRAMOLECULAR AND INTERMOLECULAR HYDROXYL REACTIVITY DIFFERENCES IN GINKGOLIDES A, B AND C AND THEIR CHEMICAL APPLICATIONS.
An investigation of the chemistry of ginkgolides A, B and C (1) has revealed an unusual interaction between the hydroxyl groups at C(1) and C(10) which activates their deprotonation to give 2 and provides a method for the interconversion of 1C and 1B. The ginkgolide 7-enol system 7 is more stable than the corresponding 7-keto form 6, which is easily made by selective Jones oxidation of ginkgolide C.


17β-estradiol and progesterone independently augment cutaneous thermal hyperemia but not reactive hyperemia.
We examined the impact of estradiol and progesterone on skin LH and RH in 25 healthy women. Subjects were studied three times over 10-12 days. Endogenous sex hormones were suppressed with a GnRHa. Subjects were studied on day 4 of suppression (study day 1), three to four days later following treatment with either 17β-estradiol or progesterone (study day 2), and another three to four days later, following treatment with both estradiol and progesterone (study day 3). Subjects underwent identical LH and RH protocols on all study days. LH is characterized by an initial peak in blood flow, followed by a prolonged plateau. A brief nadir is seen between the phases. Blood flow values are expressed as percent maximum CVC. Estradiol alone increased initial peak CVC from 71 ± 2% to 79 ± 2% (p = 0.001). Progesterone alone increased initial peak CVC from 72 ± 2% to 78 ± 2% (p = 0.046). Neither estradiol nor progesterone increased plateau CVC. No significant changes were seen between study days 2 and 3 for either group. No differences were observed in RH. Both estradiol and progesterone increased initial peak CVC during LH, without altering plateau CVC. There was no additive effect of estradiol and progesterone.


Plasmodium falciparum pfhrp2 and pfhrp3 Gene Deletions from Persons with Symptomatic Malaria Infection in Ethiopia, Kenya, Madagascar, and Rwanda.
Histidine-rich protein 2 (HRP2)-based rapid diagnostic tests detect Plasmodium falciparum malaria and are used throughout sub-Saharan Africa. However, deletions in the pfhrp2 and related pfhrp3 (pfhrp2/3) genes threaten use of these tests. Therapeutic efficacy studies (TESs) enroll persons with symptomatic P. falciparum infection. We screened TES samples collected during 2016-2018 in Ethiopia, Kenya, Rwanda, and Madagascar for HRP2/3, pan-Plasmodium lactate dehydrogenase, and pan-Plasmodium aldolase antigen levels and selected samples with low levels of HRP2/3 for pfhrp2/3 genotyping. We observed deletion of pfhrp3 in samples from all countries except Kenya. Single-gene deletions in pfhrp2 were observed in 1.4% (95% CI 0.2%-4.8%) of Ethiopia samples and in 0.6% (95% CI 0.2%-1.6%) of Madagascar samples, and dual pfhrp2/3 deletions were noted in 2.0% (95% CI 0.4%-5.9%) of Ethiopia samples. Although this study was not powered for precise prevalence estimates, evaluating TES samples revealed a low prevalence of pfhrp2/3 deletions in most sites.


Music therapy for depression: it seems to work, but how?
Evidence is beginning to emerge that music therapy can improve the mental health of people with depression. We examine possible mechanisms of action of this complex intervention and suggest that music therapy partly is effective because active music-making within the therapeutic frame offers the patient opportunities for new aesthetic, physical and relational experiences.


[Human mobile genetic elements: structure, distribution and functional role].
Data concerning human mobile genetic elements which make up 45% of the genome are reviewed. Much attention is focused on their role in genome functioning, such as recombination, regulation of gene expression and neogenes besides classification and distribution.


A progestin regulates the prostaglandin pathway in the neuroendocrine system in female mudskipper Boleophthalmus pectinirostris.
Sex hormones regulate the reproductive cycle through brain-pituitary axis, but the molecular mechanism is still enigmatic. In the reproductive season, the mudskipper Boleophthalmus pectinirostris possesses a semilunar periodicity spawning rhythm, which coincides with the semilunar periodicity variations in 17α-hydroxyprogesterone, the precursor of 17α,20β-dihydroxy-4-pregnen-3-one (DHP), a sexual progestin in teleosts. In the present study, we investigated in vitro the brain transcriptional differences between DHP-treated tissues and control groups using RNA-seq. Differential expression analysis revealed that 2700 genes significantly differentially expressed, including 1532 up-regulated and 1168 down-regulated genes. The majority of prostaglandin pathway-related genes were dramatically up-regulated, especially the prostaglandin receptor 6 (ptger6). Tissue distribution analysis revealed that ptger6 gene was ubiquitously expressed. In situ hybridization results showed that ptger6, nuclear progestin receptor (pgr), and DHP-induced c-fos mRNA were co-expressed in the ventral telencephalic area, the ventral nucleus of ventral telencephalic area, the anterior part of parvocellular preoptic nucleus, the magnocellular part of magnocellular preoptic nucleus, the ventral zone of periventricular hypothalamus, the anterior tubercular nucleus, the periventricular nucleus of posterior tuberculum, and the torus longitudinalis. DHP significantly enhanced promoter activities of ptger6 via Pgr. Together, this study suggested that DHP regulates the prostaglandin pathway in the neuroendocrine system of teleost fish.


A randomized trial of an education and support program for HIV-infected individuals.
To assess the effectiveness of an intervention for providing information and support to HIV-positive donors on changes in their sexual behavior, and to assess which donor characteristics are predictive of behavior change. Subjects were randomly assigned to a structured intervention or community referral group. Follow-up assessments were conducted every 6 months. New York City, New York, USA. A cohort of 271 HIV-infected persons who donated blood to the New York Blood Center. Donors randomized to the structured intervention program met individually with a nurse for counseling and were offered a six-session support group. The program was designed to provide information, encourage safer sexual behavior and provide support. Sexual behavior, psychological distress and psychological help seeking, and immune function. In both groups there was a large decrease over time in reports of unsafe sexual activity. However, more than 30% of participants in both groups reported unsafe sexual activity at the 1-year follow-up visit. Donors randomized to the structured intervention program did not report significantly more behavior change at the 1-year follow-up. Better programs to promote behavior change in seropositive individuals are needed.


Quantitative contributions of IgG, IgM and C3 to erythrophagocytosis and rosette formation by peritoneal macrophages, and anti-opsonin activity of dextran sulfate 500.
In vitro phagocytosis by guinea pig peritoneal macrophages of immune complexes (EA) was shown to be dependent on IgG antibody in a dose-dependent fashion. C3b enhanced phagocytosis of EA at limited IgG antibody concentrations only. When IgM antibody was used for sensitization of sheep red blood cells (SRBC), phagocytosis and rosette formation did not occur in the absence of bound C3. The polyanion, dextran sulfate 500 (DS), was shown to depress both rosette formation and phagocytosis of EAIgG, C1423 and EAIgMC1423, as well as immune adherence of human group 0 erythrocytes and hemolytic activity of C3. This effect of DS was seen only when it was actually present in the incubation medium.


Exploration of the Factors Influencing Attitudes to Breastfeeding in Public.
Negative attitudes toward breastfeeding in public have consistently been identified as a key barrier to breastfeeding continuation. In order to design effective social marketing campaigns to improve public attitude toward breastfeeding in public, it is critical to identify segments of the population who are less likely to support this activity, their underlying reasons, and the medium through which they can be reached. The aims were to (a) identify the underlying dimensions that drive acceptance or opposition to breastfeeding in public, (b) test whether specific population segments were more or less likely to support breastfeeding in public, and (c) identify suitable media outlets to reach them. A cross-sectional survey testing agreement with 60 statements was administered online between May 2016 and May 2017 and was completed by 7190 respondents. Exploratory factor analysis was used to identify 12 dimensions driving acceptance or opposition to breastfeeding in public. The influence of demographics and media consumption on attitudes toward breastfeeding in public was tested using Welch's t tests and one-way analyses of variance (ANOVAs). Acceptance of breastfeeding in public was found to differ with gender, age, religion, and parental and breastfeeding status, but not household income. Support for breastfeeding in public also varied with media consumption habits. This work lays the foundation to design effective social marketing campaigns aimed at increasing public support for breastfeeding in public.


Medical ethics' appropriation of moral philosophy: the case of the sympathetic and the unsympathetic physician.
Philosophy textbooks typically treat bioethics as a form of "applied ethics"-i.e., an attempt to apply a moral theory, like utilitarianism, to controversial ethical issues in biology and medicine. Historians, however, can find virtually no cases in which applied philosophical moral theory influenced ethical practice in biology or medicine. In light of the absence of historical evidence, the authors of this paper advance an alternative model of the historical relationship between philosophical ethics and medical ethics, the appropriation model. They offer two historical case studies to illustrate the ways in which physicians have "appropriated" concepts and theory fragments from philosophers, and demonstrate how appropriated moral philosophy profoundly influenced the way medical morality was conceived and practiced.


A new aquahydroxidocopper(II) oxovanadium(IV) vanadate, Cu(H2O)(OH)VO(VO4).
Single crystals of the title compound have been prepared hydrothermally. Vanadate tetrahedra and distorted oxovanadium octahedra form layers, linked by two independent Cu atoms located on inversion centres. Each Cu atom is surrounded by six O atoms, forming an octahedron distorted by Jahn-Teller elongation. One of the two independent interlayer spaces bridged by the Cu atoms is significantly more compact than the other.


Robotic repair for Barlow mitral regurgitation: Repairability, safety, and durability.
In Barlow disease, increased repair complexity drives decreased repair rates. We evaluated outcomes of a simplified approach to robotic mitral repair in Barlow disease. A prospective institutional registry with vital-statistics, statewide admissions and echocardiographic follow-up was used to identify 924 consecutive patients undergoing robotic surgery for degenerative mitral regurgitation (MR) between 2005 and 2020, including 12% (n = 111) with Barlow disease. Freedom from >moderate (>2+) MR was analyzed with death as a competing risk and predictors of failure were analyzed using multivariable Cox regression. Median follow-up was 5.5 years (range, 0-15 years). Patients with Barlow disease were younger (median, age 59 years; interquartile range [IQR], 51-67 vs 62; IQR, 54-70 years, P = .05) than patients without Barlow disease. Replacements were performed in 0.9% (n = 1) of patients with Barlow disease and 0.8% (n = 6) of patients without Barlow disease (P = 1). Repairs comprised simple leaflet resection and annuloplasty band in 73.9% (n = 546) of non-Barlow valves versus 12.7% (n = 14) of patients with Barlow disease who required neochordae (53.6%, n = 59), chordal transfer (20%, n = 22), and commissural sutures (37.3%, n = 41), with longer cardiopulmonary bypass time (median 133; IQR, 117-149 minutes vs 119; IQR, 106-142 minutes, P < .01). Survival free from greater than moderate MR at 5 years was 92.0% (95% confidence interval [CI], 80.2%-98.1%) in patients with Barlow disease versus 96.0% (95% CI, 93.3%-98.0%) in patients without Barlow disease (P = .40). Predictors of late failure included Barlow disease (hazard ratio, 3.9; 95% CI, 1.7-9.0) and non-Barlow isolated anterior leaflet prolapse (hazard ratio, 5.6; 95% CI, 2.3-13.4). Barlow disease may be reliably and safely repaired with acceptable long-term durability by experienced robotic mitral surgery programs.


Gene therapy for ocular neovascularization: a cure in sight.
Recent advances in the field of ocular gene transfer have led researchers pursuing treatment for age-related macular degeneration and diabetic retinopathy to turn to gene therapy for the answer. Viral vector-mediated delivery of both anti-angiogenic proteins and molecules that inhibit the eye's endogenous pro-angiogenic factors has successfully diminished the pathology of ocular diseases in rodent models. A gene-therapy solution to the debilitating blindness caused by ocular neovascularization may be on the horizon.


Motivation and willingness to increase physical activity for dementia risk reduction: Cross-Sectional UK survey with people aged 50 and over.
Attitudes to increasing physical activity to reduce risk of dementia were assessed in a national online survey promoted via online forums and public adverts. The Motivation to Change Behaviour for Dementia Risk Reduction (MOCHAD-10) scale examined motivation for lifestyle change. Multivariable logistic regression was used to identify the predictors of willingness and motivation to increase physical activity. Data from 3,948 individuals showed most people were moderately/very physically active (80%). People more likely to be physically active had better health and education, were older, male, and had a partner. People willing to increase physical activity (73%) were more likely to be younger, non-White, underweight, had better health and lifestyles, and had experience caring for someone with dementia. People with higher levels of motivation to change lifestyle (MOCHAD-10 subscales) were more likely to be female, younger, in poorer physical/mental health, had lower perceived mental activity, and were a carer for someone with dementia. Men and those with better health status were more physically active. Those who exercised less and those who were more motivated to increase physical activity were not necessarily able to be physically active. Multisectoral public health strategies should seek to use the high motivation levels among this group to mitigate the barriers related to physical activity for dementia risk reduction.


Artificial intelligence-enabled simulation of gluteal augmentation: A helpful tool in preoperative outcome simulation?
While the buttock region is considered an esthetic hallmark, the Brazilian butt lift (BBL) remains controversially discussed in the plastic surgery community. This is due to its contentious safety profile. Thus, informed consent and patient education play a key role in preoperative planning. To this end, we aimed to program an easy-to-use, widely accessible, and low-budget algorithm that produces reliable outcome simulations. The conditional generative adversarial network (GAN) was trained using pre- and postoperative images from 1628 BBL patients. To validate outcome simulation, 25 GAN-generated images were assessed deploying 67 Amazon Mechanical Turk Workers (Mturks). Mturks could not differentiate between GAN-generated and real patient images in approximately 49.4% of all trials. This study presents a free-to-use, widely accessible, and reliable algorithm to visualize potential surgical outcomes that could potentially be applied in other fields of plastic surgery.


The application of a neural network to predict hypotension and vasopressor requirements non-invasively in obstetric patients having spinal anesthesia for elective cesarean section (C/S).
Neural networks are increasingly used to assess physiological processes or pathologies, as well as to predict the increased likelihood of an impending medical crisis, such as hypotension. We compared the capabilities of a single hidden layer neural network of 12 nodes to those of a discrete-feature discrimination approach with the goal being to predict the likelihood of a given patient developing significant hypotension under spinal anesthesia when undergoing a Cesarean section (C/S). Physiological input information was derived from a non-invasive blood pressure device (Caretaker [CT]) that utilizes a finger cuff to measure blood pressure and other hemodynamic parameters via pulse contour analysis. Receiver-operator-curve/area-under-curve analyses were used to compare performance. The results presented here suggest that a neural network approach (Area Under Curve [AUC] = 0.89 [p < 0.001]), at least at the implementation level of a clinically relevant prediction algorithm, may be superior to a discrete feature quantification approach (AUC = 0.87 [p < 0.001]), providing implicit access to a plurality of features and combinations thereof. In addition, the expansion of the approach to include the submission of other physiological data signals, such as heart rate variability, to the network can be readily envisioned. This pilot study has demonstrated that increased coherence in Arterial Stiffness (AS) variability obtained from the pulse wave analysis of a continuous non-invasive blood pressure device appears to be an effective predictor of hypotension after spinal anesthesia in the obstetrics population undergoing C/S. This allowed us to predict specific dosing thresholds of phenylephrine required to maintain systolic blood pressure above 90 mmHg.


Primary B-cell malignant lymphoma of the maxilla with a sarcomatous pattern and multilobated nuclei.
Three cases of primary malignant lymphoma of the maxilla are reported. The primary intraosseous origin of these tumors was demonstrated by x-ray examination and surgical exploration. The initial interpretation as odontogenic infection led to a delay in starting therapy of 9 months in one case. Biopsies of two cases were initially interpreted as sarcoma because of a dense reactive fibrosis between the tumor cells. Subsequently, hemimaxillectomy was performed in one case. Histologically and ultrastructurally the tumor cells showed marked nuclear abnormalities with cleavage, folding, and lobulation. Immunohistochemical studies of two cases showed a monoclonal immunoglobulin expression, IgG-K; T-lymphocyte-associated antigens were not detected on the tumor cells. The findings indicate the existence of a primary B-cell malignant lymphoma of bone with multilobated nuclei. The lymphoid nature may be masked by a dense proliferation of connective tissue. The relation of these tumors to the classifications for malignant lymphoma of lymph node is discussed.


Correction of the galactocerebrosidase deficiency in globoid cell leukodystrophy-cultured cells by SL3-3 retroviral-mediated gene transfer.
Globoid cell leukodystrophy (GCL) or Krabbe disease is an autosomal recessive inherited disease caused by the deficiency of galactocerebrosidase, the lysosomal enzyme responsible for the degradation of galactocerebroside, a major component of myelin. An animal model homologue of GCL is the twitcher mouse. In the present work, using novel recombinant retroviruses harboring the SL3-3 LTR, we have been able to stably correct the galactocerebrosidase deficiency in twitcher mouse TM-2 cells and in primary human fibroblasts from a patient with globoid cell leukodystrophy. These results show the possibility of retroviral-mediated gene therapy for the treatment of GCL.


Prenatal treatment with rapamycin restores enhanced hippocampal mGluR-LTD and mushroom spine size in a Down's syndrome mouse model.
Down syndrome (DS) is the most frequent genetic cause of intellectual disability including hippocampal-dependent memory deficits. We have previously reported hippocampal mTOR (mammalian target of rapamycin) hyperactivation, and related plasticity as well as memory deficits in Ts1Cje mice, a DS experimental model. Here we characterize the proteome of hippocampal synaptoneurosomes (SNs) from these mice, and found a predicted alteration of synaptic plasticity pathways, including long term depression (LTD). Accordingly, mGluR-LTD (metabotropic Glutamate Receptor-LTD) is enhanced in the hippocampus of Ts1Cje mice and this is correlated with an increased proportion of a particular category of mushroom spines in hippocampal pyramidal neurons. Remarkably, prenatal treatment of these mice with rapamycin has a positive pharmacological effect on both phenotypes, supporting the therapeutic potential of rapamycin/rapalogs for DS intellectual disability.


Synthesis of a Bi3+-Doped Cs2HfCl6 Double Perovskite with Highly Efficient Blue Light Emission at Room Temperature.
Lead-free perovskites have been widely studied due to their environmental friendliness and high stability. In this study, Bi3+-doped Cs2HfCl6 has been synthesized at room temperature. Different from the emission of the Cs2HfCl6 host (452 nm), Bi3+:Cs2HfCl6 can produce a bright blue emission at an excitation wavelength of 350 nm, which is derived from the 3P1 → 1S0 transition of Bi ions and accompanied by the properties of self-trapped excitons. Moreover, 7%Bi3+:Cs2HfCl6 shows excellent stability with the photoluminescence quantum yield reaching up to 69.08%. Meanwhile, a light-emitting diode that is close to pure white light has been fabricated by using 7%Bi3+:Cs2HfCl6, which has a high color rendering index of 92.5. These results show that Bi3+:Cs2HfCl6 would be a potential candidate in the field of inorganic luminescent materials.


Mutations in the anticodon stem of tRNA cause accumulation and Met22-dependent decay of pre-tRNA in yeast.
During tRNA maturation in yeast, aberrant pre-tRNAs are targeted for 3'-5' degradation by the nuclear surveillance pathway, and aberrant mature tRNAs are targeted for 5'-3' degradation by the rapid tRNA decay (RTD) pathway. RTD is catalyzed by the 5'-3' exonucleases Xrn1 and Rat1, which act on tRNAs with an exposed 5' end due to the lack of certain body modifications or the presence of destabilizing mutations in the acceptor stem, T-stem, or tRNA fold. RTD is inhibited by mutation of MET22, likely due to accumulation of the Met22 substrate adenosine 3',5' bis-phosphate, which inhibits 5'-3' exonucleases. Here we provide evidence for a new tRNA quality control pathway in which intron-containing pre-tRNAs with destabilizing mutations in the anticodon stem are targeted for Met22-dependent pre-tRNA decay (MPD). Multiple SUP4οc anticodon stem variants that are subject to MPD each perturb the bulge-helix-bulge structure formed by the anticodon stem-loop and intron, which is important for splicing, resulting in substantial accumulation of end-matured unspliced pre-tRNA as well as pre-tRNA decay. Mutations that restore exon-intron structure commensurately reduce pre-tRNA accumulation and MPD. The MPD pathway can contribute substantially to decay of anticodon stem variants, since pre-tRNA decay is largely suppressed by removal of the intron or by restoration of exon-intron structure, each also resulting in increased tRNA levels. The MPD pathway is general as it extends to variants of tRNATyr(GUA) and tRNASer(CGA) These results demonstrate that the integrity of the anticodon stem-loop and the efficiency of tRNA splicing are monitored by a quality control pathway.


New potential application of hydroxypropyl-β-cyclodextrin in solid self-nanoemulsifying drug delivery system and solid dispersion.
The purpose of this study was to use hydroxypropyl-β-cyclodextrin (HP-β-CD) as a novel carrier in solid SNEDDS and solid dispersions to enhance the solubility and oral bioavailability of poorly water-soluble dexibuprofen. The novel dexibuprofen-loaded solid SNEDDS was composed of dexibuprofen, corn oil, polysorbate 80, Cremophor® EL, and HP-β-CD at a weight ratio of 45/35/50/15/100. This solid SNEDDS spontaneously formed a nano-emulsion with a size of approximately 120 nm. Unlike the conventional solid SNEDDS prepared with colloidal silica as a carrier, this dexibuprofen-loaded solid SNEDDS exhibited a spherical structure. Similar to the dexibuprofen-loaded solid dispersion prepared with HP-β-CD, the transformation of the crystalline drug to an amorphous state with no molecular interactions were observed in the solid SNEDDS. Compared to the solid dispersion and dexibuprofen powder, solid SNEDDS significantly enhanced drug solubility and AUC. Therefore, HP-β-CD is a novel potential carrier in SNEDDS for improving the oral bioavailability of dexibuprofen.


Seasonal variation of Legionnaires' disease in Scotland.
A summer and autumn peak in incidence is a characteristic epidemiological feature of Legionnaires' disease, a fact which may help in diagnosis. Previous reports from Scotland have reported a winter peak. This study examined the seasonal variation in Legionnaires' disease in Scotland in each year and by category of diagnosis. A characteristic summer/autumn peak was seen for travel-related infection. For non-travel infection, there was an autumnal peak between 1978 and 1982 but an early winter peak between 1983 and 1986. Overall, the pattern could be described as a summer/autumn plateau reaching a peak in early winter. This pattern, seen in men and women, was clearest in the Greater Glasgow area. Nosocomial cases were clustered in the months of October, November and December. In non-travel cases the classical seasonal pattern was not observed and clinicians cannot rely upon this epidemiological feature for diagnosis. However, the relative infrequency of the disease between January and May was a consistent and potentially useful feature. Most reports on seasonal variation are based on aggregated data on travel and non-travel cases. The present observations question the hypotheses developed to explain the seasonal pattern and call for further studies.


The oral microbiome and oral cancer.
The role that bacteria play in the etiology and predisposition to cancer is of increasing interest, particularly since the development of high-throughput genetic-based assays. With this technology, it has become possible to comprehensively examine entire microbiomes as a functional entity. This article focuses on the understanding of bacteria and its association with oral squamous cell carcinoma.


High potassium promotes differentiation of retinal neurons but does not favor rod differentiation.
Neural retinal cells of newborn rats were cultured under dissociated culture conditions. Differentiation of several types of retinal cells was confirmed by immunohistochemical detection of type-specific neural phenotypes. We used Thy-1.1 antigen as a ganglion cell marker, HPC-1 or GABA as an amacrine cell marker and rhodopsin as a rod cell marker. With a high concentration of potassium (38 mM), expression of the respective neural phenotypes were differentially affected. High K+ increased the number of Thy-1.1 positive cells 6 to 8 fold, and drastically promoted their neurite extension. The same culture conditions, however, reduced considerably the number of rhodopsin positive cells, possibly due to the unique membrane properties of photoreceptors. A high K+ concentration also promoted differentiation of HPC-1 positive and GABA positive cells, but to a lesser extent than the Thy-1.1 positive cells. Several possibilities were examined to understand the effect of a high K+ concentration on retinal neural cells. The total cell number in cultures with a high K+ concentration was approximately half of that in control cultures at day 3 and slightly smaller at day 11, suggesting that high K+ did not have a positive general effect on the proliferation or survival of retinal cells. Naturally occurring neuronal death (apoptosis) is a well-known phenomenon during retinal development. A histochemical method for detecting DNA fragmentation, a step preceding apoptosis, showed that high K+ had no preventive effect. BrdU (bromodeoxyuridine) immunohistochemistry showed that high K+ did not seem to enhance proliferation of neural precursor cells. These results indicate that a high K+ concentration promotes the expression of neuronal phenotypes but is not a favorable condition for rod differentiation. Since a high K+ concentration is considered to induce depolarization of nerve cells, the present results suggest an anterograde influence from surrounding neuronal cells, through chronic depolarization by elevated K+, is essential for the differentiation and maturation of retinal cells.


Action recognition is sensitive to the identity of the actor.
Recognizing who is carrying out an action is essential for successful human interaction. The cognitive mechanisms underlying this ability are little understood and have been subject of discussions in embodied approaches to action recognition. Here we examine one solution, that visual action recognition processes are at least partly sensitive to the actor's identity. We investigated the dependency between identity information and action related processes by testing the sensitivity of neural action recognition processes to clothing and facial identity information with a behavioral adaptation paradigm. Our results show that action adaptation effects are in fact modulated by both clothing information and the actor's facial identity. The finding demonstrates that neural processes underlying action recognition are sensitive to identity information (including facial identity) and thereby not exclusively tuned to actions. We suggest that such response properties are useful to help humans in knowing who carried out an action.


Current therapeutic insights regarding problematic fingernails and toenails in the Republic of Korea.
Problematic nails and toenails are infected by germs and increasingly have many causes. To investigate the types and treatment of problematic nails and toenails, we focused on bacteria that may appear in problematic nail toenail symptoms. We have searched for PubMed and Google Scholar and correlated the words Onychomycosis, Tinea ungium, Melanonychia, and ingrown toenail related to symptoms. To measure onychomycosis, KOH tests and fungal culture tests will be used. Treatment can be treated with full-body treatment using anti-fungal agents and local treatment (laser therapy) that can minimize the side effects. A biopsy should be performed when Melanonychia is diagnosed with brown or black pigments on the patient's fingernail plate. Moreover, ingrown toenail surgical treatment can be improved by acquired lifestyle. There are many different types of treatments, but many studies show that problematic nail and toenail improvement periods are long and treatment success rates are low.


Absorption of interferon alpha from patches in rats.
Interferon alpha (IFN-alpha), patch preparations composed of three layers, water-insoluble backing layer, drug containing layer with absorption enhancer and surface layer containing pH-dependent polymer were prepared. As absorption enhancer, three surfactants, Gelucire44/14 (Lauroyl macrogol-32 glycerides), Labrasol (Caprylocaproyl macrogol-8 glycerides) and HCO-60 (polyoxyethylated hydrogenerated castor oil) were used in preparing IFN-alpha patch preparations. The intestinal absorption of IFN-alpha was studied after the administration of test patch preparations into the rat jejunum, 50,000 IU/kg. The serum IFN-alpha levels were measured by an ELISA method and both C(max) and AUC were determined as the index of absorption of IFN-alpha. Gelucire44/14 preparation including Pharmasol for the stable solidification showed the higher C(max), 7.66 +/- 0.82 IU/ml, and AUC, 12.85 +/- 1.49 IU h/ml, than Labrasol (6.51 +/- 0.89 and 8.30 +/- 1.34 IU h/ml) and HCO-60 (6.02 +/- 1.14, 7.53 +/- 1.84 IU h/ml) preparations, respectively. By comparing to the AUC obtained after s.c. injection of the same dose of IFN-alpha to rats, bioavailability (BA) was estimated to be 7.8% in Gelucire44/14 preparation. In vitro release study showed that the T50%s, the time when half of the formulated IFN-alpha is released from the patches, were 3.4 +/- 0.1 min for HCO-60, 7.8 +/- 0.1 min for Gelucire44/14 and 11.4 +/- 0.1 min for Labrasol preparations. To study the effect of absorption site, Gelucire44/14 preparation was administered into the rat duodenum and ileum. However, there were not significant differences on AUC among the three absorption sites. By reducing the IFN-alpha dose from 50,000 to 25,000 IU/kg, the serum IFN-alpha levels vs time profile showed a tendency of dose-dependency. When the histological examination of small intestinal mucosa was carried out in this study, the small intestinal mucosa after the Gelucire44/14 patches administered and before it was administered, could not recognize impaired. From these results, the usefulness of oral patch system for the oral delivery of IFN-alpha has been proved in rats.


PGAM5: A crucial role in mitochondrial dynamics and programmed cell death.
In response to mitochondrial damage, mitochondria activate mitochondrial dynamics to maintain normal functions, and an imbalance in mitochondrial dynamics triggers multiple programmed cell death processes. Recent studies have shown that phosphoglycerate mutase 5 (PGAM5) is associated with mitochondrial damage. PGAM5 activates mitochondrial biogenesis and mitophagy to promote a cellular compensatory response when mitochondria are mildly damaged, whereas severe damage to mitochondria leads to PGAM5 inducing excessive mitochondria fission, disruption to mitochondrial movement, and amplification of apoptosis, necroptosis and mitophagic death signals, which eventually evoke cell death. PGAM5 functions mainly through protein-protein interactions and specific Ser/Thr/His protein phosphatase activity. PGAM5 is also regulated by mitochondrial proteases. Detection of PGAM5 and its interacting protein partners should enable a more accurate evaluation of mitochondrial damage and a more precise method for the diagnosis and treatment of diseases.


Radioimmunotherapy of glioblastoma multiforme - Current status and future prospects.
Glioblastoma multiforme (GBM) or grade IV astrocytoma is the most diagnosed form of primary brain tumours in adults. Radioimmunotherapy (RIT), mostly in combination with conventional therapies, is presented in the current review as a therapeutic strategy of high potential in the management of GBM. A systematic literature search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) to identify clinical studies that employed a form of radioimmunotherapy using alpha- or beta-emitting radioisotopes. The available literature on RIT in GBM and high-grade gliomas is presented and discussed. The results suggest that this promising treatment approach merits further investigation in future clinical studies.


Simultaneous determination of some ultraviolet-absorbing chemicals in sunscreen cosmetics using a high-performance liquid chromatography method.
A method of gradient elution high-performance liquid chromatography (HPLC) for simultaneous determination of 11 different ultraviolet-absorbing chemicals of phenylbenzlmldazole sulphonic acid, 4-aminobenzoic acid, benzophenone-4, benzophenone-3, isoamyl p-methoxycinnamate, 4-methylbenzylidene camphor, octocrylene, ethylhexyl methoxycinnamate, homosalate, ethylhexyl salicylate, methylene bis-benzotriazolyl tetramethylbutyl phenol was developed for the application to sunscreen cosmetic products. In this study, an Agilent SB-C18 analytical column (250 × 4.6 mm, 5 μm) was utilized and methanol, tetrahydrofuran and perchloric acid aqueous solution (0.2 mL HClO(4) + 300 mL H(2)O) were used for gradient elution at a total flow rate of 1.0 mL min(-1). The optimum conditions for 11 different ultraviolet-absorbing chemicals analyses were investigated. All calibration curves showed good linear regression with UV detection (311 nm) within test ranges. The correlation coefficients were better than 0.999 in all cases. The assay was simple, selective, convenient and reproducible and is suitable for the determination of ultraviolet-absorbing chemicals in commercial sunscreen cosmetic products. The use frequency of 11 different ultraviolet absorbents in 100 sunscreen cosmetics was investigated and statistically analysed. The ultraviolet absorbent of maximum use frequency was ethylhexyl methoxycinnamate.


Time Off Work After Childbirth and Breastfeeding Supportive Workplaces: Associations with Near-Exclusive Breastfeeding Trajectory Membership.
We aimed to determine whether the association between time off work and a near-exclusive breastfeeding trajectory is moderated by perceived employer support for breastfeeding. We conducted a secondary analysis of working mothers (n = 1,468) from the Infant Feeding Practices Study II, a longitudinal observational (2005-2007) study of U.S. infant feeding behaviors. Previous studies have found four latent infant feeding subgroups in the Infant Feeding Practices Study II sample, each following a distinct breastfeeding intensity trajectory. Multivariate least-squares regression was conducted to estimate whether time off work after delivery predicted increased membership in the subgroup characterized by near-exclusive breastfeeding, and whether this association was moderated by perceived employer support for workplace breastfeeding. Both time off work and perception of more breastfeeding support were independently, positively related to probability of membership in the near-exclusive breastfeeding trajectory (β = 0.16, p = .019, and β = 0.14, p = .004, respectively). The interaction of these two factors suggests an attenuation effect. The addition of paid leave to the model did not change the estimates. The positive relationship between time off and trajectory membership was significant only for mothers who perceived their workplaces to be unsupportive of breastfeeding.


Transcriptome analysis revealed the roles of long non-coding RNA and mRNA in the bursa of Fabricius during pigeon (Columba livia) development.
The bursa of Fabricius (BF) is the critical humoral immune organ to birds, playing an essential role in B lymphocyte differentiation. However, unlike other poultries, surgical removal of pigeon BF did not limit humoral immune responsiveness. To investigate the expression profiles and the potential role of mRNA and long non-coding RNA (LncRNA) in squab BFs, transcriptome analysis was performed by RNA-Sequencing (RNA-Seq) over three developmental stages (1-day, 13 and 26 days old). We identified 13,072 mRNAs and 19,129 lncRNAs, of which 2,752 mRNAs and 1,515 lncRNAs were differential expressed (DE) in pigeon BFs over three developmental stages. Cluster analysis presented different expression patterns in DE mRNAs and lncRNAs. Functional enrichment analysis revealed that DE lncRNAs and mRNAs with distinct expression patterns might play crucial roles in the immune system process and tissue morphogenesis. In particular, some DE genes and lncRNAs with higher expression levels in 13D or 26D are related to lymphocyte activation and differentiation, adaptive immune response, positive regulation of immune response, leukocyte migration, etc. Protein-protein interaction (PPI) network and Molecular Complex Detection (MCODE) analysis sreened six significant modules containing 37 genes from immune-related DE gene cluster, which is closely linked in B cell activation, lymphocyte differentiation, B cell receptor signaling pathway, etc. Our study characterizes mRNA and lncRNA transcriptomic variability in pigeon BFs over different developmental stages and enhances understanding of the mechanisms underlying physiological functions of pigeon BF.


Natural epigenetic variation in plant species: a view from the field.
Researchers are beginning to use wild plant populations to survey and assess cytosine methylation polymorphisms in a population and ecological genetic framework. These studies support the plausibility of adaptive epigenetic alleles, but uncertainty remains due to the difficulty in untangling genetic and epigenetic variation in wild populations. The increasing emphasis on stress-induced epigenetic alterations and transgenerational phenomena among researchers focused on epigenetic mechanisms should push practitioners of this subfield to consider the questions and tools of colleagues grappling with epigenetics from ecological and evolutionary perspectives.


Sequential triage in the first trimester may enhance advanced ultrasound scanning in population screening for trisomy 21.
To design a trisomy 21 screening protocol for sequential triage in the first trimester, and to evaluate whether it reduces the need for advanced ultrasound scanning to such an extent that this could be dealt with by a limited number of well-trained sonographers only. Screening results of 31 trisomy 21 affected pregnancies and 16 096 unaffected pregnancies from the first trimester screening program of Algemeen Medisch Laboratorium in Antwerp, Belgium, were used to define high-risk, intermediate-risk and low-risk groups. A serum screening result (age, pregnancy-associated plasma protein-A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG)) of >or=1 : 30 and/or a nuchal translucency thickness (NT) measurement of >or= 3.5 mm were classified as high risk. A serum screening result of < 1 : 1000 together with an NT of < 3.5 mm were classified as low risk. Other results were considered intermediate risk, for which further advanced ultrasound screening would be indicated. This protocol was then evaluated prospectively in another population of 13 493 first-trimester pregnancies. Of the total population, 1.9% was identified as being high risk (14 trisomy 21 pregnancies and 222 unaffected pregnancies; prevalence, 1 : 17), 59.6% was identified as being low risk (three trisomy 21 pregnancies and 9615 unaffected pregnancies; prevalence, 1 : 3206) and 38.4% was identified as being intermediate risk (10 trisomy 21 pregnancies and 6190 unaffected pregnancies; prevalence, 1 : 620). A similar distribution was found in the prospective arm of the study. There was no reduction of overall screening performance compared with our current first-trimester combined screening program. The number of intermediate-risk pregnancies was sufficiently low as to enable advanced ultrasound scanning by well-trained sonographers only. In population screening for fetal trisomy 21, sequential triage in the first trimester can be achieved using very simple methods. Pregnancies at high or at low risk can be identified easily and the number of pregnancies at intermediate risk can be reduced sufficiently to enable advanced ultrasound scanning by well-trained sonographers only. A prospective study is needed to evaluate the performance of this approach and to compare its results with current combined or integrated screening algorithms.


Combined effect of copper and cadmium on heavy metal ion bioaccumulation and antioxidant enzymes induction in Chlorella vulgaris.
The relationships between metal uptake and antioxidant enzyme activities or a response to membrane lipid peroxidation (i.e., malondialdehyde production) in Chlorella vulgaris exposed to Cu and Cd compounds singly and in combination were investigated. The results showed that bioaccumulation of a single metal was influenced by the presence of the other metal. The activities of superoxide dismutase and peroxidase increased to more than fivefold of the control after exposure to Cu(1.5 μM) alone or to Cu(1.5 μM) with Cd mixtures. Malondialdehyde levels in C. vulgaris also increased to approximately twofold of the control after exposure to high concentration of Cu(1.5 μM) alone or to Cu and Cd mixtures. However, Cd alone did not significantly increase the levels of antioxidant enzymes or malondialdehyde.


A comparative study between McKee-Farrar and Charnley arthroplasty with long-term follow-up periods.
One hundred seventy-seven consecutive total hip arthroplasties on 169 patients, 107 with a McKee-Farrar prosthesis and 70 with a Charnley low-friction arthroplasty, were followed in a prospective study. Fifty-five patients (31%) representing 55 hips died during the study period. Four (2%), two McKee-Farrar and two Charnley, were lost to follow-up study. The remaining 55 McKee-Farrar and 41 Charnley hips were evaluated after a mean follow-up period of 11.5 years (range, 10.1-13.5 years). Twenty-two (12%) of the hips had been revised. A survival study was performed and the two techniques were compared with regard to walking ability, Harris hip score, and radiologic assessment. No major differences were observed. The mean annual revision rate in this series was 1.3%. Walking distance increased from 200 m before operation to 2,000 m 1 year after operation and then remained constant during the observation time. The results, using the Harris hip score, were good or excellent (greater than 80 points) in 47%. Thirty hips (32%) showed signs of prosthetic loosening; 17 of these caused pain on weightbearing occasionally or regularly and 13 caused no pain at all.


Identification and characterization of the myeloid differentiation factor 88 gene in yellow catfish.
Myeloid differentiation factor 88 (MyD88) is an important adapter protein of the innate immune system, but it has never before been reported in yellow catfish (Pelteobagrus fulvidraco). In this study, we cloned and characterized the yellow catfish MyD88 gene. The gene was 1230 bp in length and contained an 876-bp open reading frame which encodes a polypeptide of 291 amino acid residues. The theoretical molecular mass and isoelectric point of this polypeptide were 33.4341 kDa and 5.17, respectively. Furthermore, bioinformatic and phylogenetic analyses grouped yellow catfish MyD88 with MyD88 of other fish. We found that the deduced amino acid sequence showed that the conserved N-terminal death domain and the C-terminal typical Toll/interleukin-1 receptor domain were very similar to those of other fish. Moreover, reverse transcription PCR showed that yellow catfish MyD88 is ubiquitously expressed in all tissues examined, with highest expression levels observed in the spleen and lowest levels in the intestine. Importantly, MyD88 was shown to be significantly up-regulated in the intestines after 30-day dietary supplement of Clostridium butyricum. Collectively, these results indicate that yellow catfish MyD88 has a conserved structure and is probably an important component of innate immunity in yellow catfish. This study is the first to identify and characterize MyD88 in yellow catfish, thereby providing a reference for further research into the yellow catfish innate immune system.


Efficacy of Intra-articular Versus Extra-articular Bupivacaine Injection in Arthroscopic Partial Meniscectomy: A Prospective, Randomized, Double-Blind Clinical Trial.
Immediate postoperative pain relief following arthroscopic partial meniscectomy remains a critical contributor to improved patient experience, early recovery of range of motion, and enhanced rehabilitation. To evaluate the effect of intra-articular versus extra-articular bupivacaine on pain intensity and analgesic intake after arthroscopic partial meniscectomy. Randomized controlled trial; Level of evidence, 1. This was a prospective double-blind, randomized clinical trial. All patients included underwent arthroscopic partial meniscectomy under general anesthesia. Patients were randomized into 2 groups, with 20 patients in each group. At the conclusion of the arthroscopic procedure, the intra-articular group received 10 mL 0.5% bupivacaine introduced intra-articularly and 10 mL isotonic saline 0.9% infiltrated subcutaneously around the portals. The extra-articular group received the isotonic saline intra-articularly and the bupivacaine around the portals. The primary outcome was the visual analog scale (VAS) for pain. Assessments were performed 0 to 0.5, 1 to 2, 2 to 4, and at 24 and 48 hours postoperatively. In addition, analgesic and narcotic consumption was monitored. There were no differences between the groups in terms of patient demographics. VAS scores for the intra-articular group were 6, 8, 3.25, 4.3, and 4.5 at 0 to 0.5, 1 to 2, 2 to 4, 24, and 48 hours postoperatively, respectively. VAS scores for the extra-articular group were 3.8, 5, 2.9, 5.2, and 5.25, respectively. No statistically significant differences were observed between the 2 groups regarding pain intensity at all time points. There was also no statistically significant difference in analgesic consumption. Dipyrone was the preferred drug by patients from the intra-articular group, while the extra-articular group preferred to use opioids and nonsteroidal anti-inflammatory drugs. There were no differences in pain severity and analgesic intake between intra- or extra-articular bupivacaine administration after arthroscopic partial meniscectomy.


Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: A longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects.
Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD). Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years). Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these. The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death.


Local anesthetic sympathectomy restores fMRI cortical maps in CRPS I after upper extremity stellate blockade: a prospective case study.
Patients with complex regional pain syndrome type I (CRPS I) show a cortical reorganization with contralateral shrinkage of cortical maps in S1. The relevance of pain and disuse for the development and the maintenance of this shrinkage is unclear. Aim of the study was to assess whether short-term pain relief induces changes in the cortical representation of the affected hand in patients with CRPS type I. Case series analysis of prospectively collected data. We enrolled a case series of 5 consecutive patients with CRPS type I (disease duration 3 - 36 months) of the non-dominant upper-limb and previously diagnosed sympathetically maintained pain (SMP) by reduction of the pain intensity of more than > 30% after prior diagnostic sympathetic block. We performed fMRI for analysis of the cortical representation of the affected hand immediately before as well as one hour after isolated sympathetic block of the stellate ganglion on the affected side. Wilcoxon-Test, paired t-test, P < 0.05. Pain decrease after isolated sympathetic block (pain intensity on the numerical rating scale (0 - 10) before block: 6.8 ± 1.9, afterwards: 3.8 ± 1.3) was accompanied by an increase in the blood oxygenation level dependent (BOLD) response of cortical representational maps only of the affected hand which had been reduced before the block, despite the fact that clinical and neurophysiological assessment revealed no changes in the sensorimotor function. The interpretation of the present results is partly limited due to the small number of included patients and the missing control group with placebo injection. The association between recovery of the cortical representation and pain relief supports the hypothesis that pain could be a relevant factor for changes of somatosensory cortical maps in CRPS, and that these are rapidly reversible.


Chromosome breakage and ultrasound.
Human lymphocyte cultures were examined for chromosome damage after exposure to ultrasound. Control and treated slides were scored "blind" and showed no evidence of damage due to ultrasound. Neither was there evidence of chromosome damage in blood cultures from six infants whose mothers had ultrasound during pregnancy when compared with that from six infants whose mothers had not. Our results suggest that if diagnostic ultrasound causes chromosome damage it does so with less frequency than acceptable levels of diagnostic x-irradiation.


Residual Site Radiotherapy After Immunochemotherapy in Primary Mediastinal B-Cell Lymphoma: A Monoinstitutional Retrospective Study.
To evaluate the efficacy of residual site radiation therapy (RSRT) on local control (LC), progression-free (PFS) and overall (OS) survival in patients with primary mediastinal lymphoma (PMBCL), following rituximab and chemotherapy treatment (ICHT). The study included 34 patients with PMBCL treated between 2006 and 2014 with ICHT with/without autologous stem cell transplantation and RSRT. Between the end of ICHT/stem cell transplantation and RSRT, patients were evaluated with 18F-fluorodeoxyglucose positron-emission tomography. The gross tumor volume included morphological mediastinal residual disease after ICHT/SCT. The percentage of LC, PFS and OS were assessed. All patients received RSRT with a median dose of 30 Gy. Median follow-up was 82 months. One patient out of 34 (3%) showed progressive disease 9 months from diagnosis. The 10-year PFS and OS were 97% and 97% respectively. RSRT in patients with PMBCL treated with ICHT did not impact unfavorably on LC and patient survival.


Silencing of Glutathione S-Transferase Pi Inhibits Cancer Cell Growth via Oxidative Stress Induced by Mitochondria Dysfunction.
Antitumor drug development based on the concept of intervening in the antioxidant system of cancer cells has been gaining increased interest. In this study, we propose a promising strategy for cancer treatment using modulation of oxidative stress by suppression of glutathione S-transferases (GSTs), a typical antioxidant enzyme. siRNA which can be applied to the development of nucleic acid drugs, enabling them to eliminate unwanted side effects, increase specificity, and avoid the problem of drug resistance, was employed for GSTP-silencing at the transcriptional level. The silencing of the pi class of GST (GSTP) that displayed the most characteristic expression profile in 13 kinds of cancer cell lines has shown significant impairment in the growth of cancer cells due to oxidative stress caused by excess ROS accumulation. Comparative proteomics between normal cells and GSTP-silenced pancreatic cancer cell PANC-1 suggested that GSTP-silencing facilitated the mitochondrial dysfunction. These findings show promise for the development of strategies toward cancer therapy based on the mechanism that allows genetic silencing of GSTP to promote oxidative stress through mitochondria dysfunction.


Effects of captopril and propanolol on bradykinin-induced changes in vascular pressures, lymph total protein concentration, and weight in canine forelimbs.
Sixty-minute local intraarterial infusions of bradykinin (0.8, 5, or 10 micrograms base/min) produced transient forelimb vasodilation and dose-related increases in lymph flow, lymph total protein concentration, total protein transport, and weight in forelimbs perfused at a controlled flow rate. Mean aortic pressure was not affected by these infusion rates of bradykinin. Following pretreatment with captopril, the local intraarterial infusion of these same doses of bradykinin produced sustained systemic hypotension. The increase in protein efflux and edema formation produced by local infusions of bradykinin following pretreatment with captopril was markedly increased during the infusion of the low dose of bradykinin (0.8 micrograms base/min, ia), but was attenuated during the local infusion of the larger dose of bradykinin (5 micrograms base/min, ia). Following pretreatment with both captopril and propranolol, the increase in protein efflux and edema formation produced by this larger dose of bradykinin (5 micrograms base/min) was greater than that produced by infusions of this dose of bradykinin alone or after pretreatment with captopril. Moreover, the increase in protein efflux and edema formation was greater during the infusion of the higher dose of bradykinin than during the infusion of the low dose of this autacoid under these conditions. The 60-min infusion of a massive dose of bradykinin into the left ventricular chamber (280 micrograms base/min) produced sustained decreases in aortic and forelimb perfusion pressure, but little edema formation relative to that produced by local intraarterial infusions of this agent. In contrast, the 60-min intravenous infusion of only 5 micrograms base/min of bradykinin following pretreatment with both captopril and propranolol produced profound systemic hypotension and marked increases in protein efflux and edema formation in forelimbs perfused at a controlled flow rate comparable to that produced by the local intraarterial infusion of this dose of bradykinin alone. These data demonstrate that endogenous kininases and catecholamines may dramatically affect the increase in protein efflux and edema formation produced by either local or systemic infusions of bradykinin by modulating the magnitude of the increase in macromolecular permeability.


Two Sides of the Same Coin? A Dual Multiple Criteria Decision Analysis of Novel Treatments Against Rheumatoid Arthritis in Physicians and Patients.
Available treatment options for rheumatoid arthritis (RA) differ in important aspects. In this sense, each RA treatment option is accompanied by a spectrum of characteristics that collectively constitute its comprehensive "value," as viewed from the physician's or the patient's perspective. The objective of this study was to perform a multiple criteria decision analysis of different RA treatments from the perspective of physicians and patients and to outline the respective aspects of value for each treatment METHODS: A literature review was performed for constructing a set of criteria (N = 8) for the multiple criteria decision analysis. Workshops for the elicitation of preferences occurred separately for physicians and patients. A performance matrix was populated via 2 network meta-analyses plus converged clinical opinion. Criteria were hierarchically classified by application of pairwise comparisons, and criteria weights were attributed by point allocation through convergence of opinions. Performances in both panels were scored by using a 100-point scale. A linear additive value function was used for the calculation of total value estimates. Both panels provided their consensus. The hierarchical classification of attributes from the physician perspective placed the highest values on the criteria of severe adverse events, clinical efficacy, route of administration, and cost per year for the third-party payer. From the patient perspective, the highest ranking criteria were clinical efficacy, severe adverse events, percentage of patients remaining with the same targeted immune modulator for 1 year ("drug survival"), and cost per year for the third-party payer. In an era of multiple options and varying preferences, RA treatments must be evaluated by taking into consideration patients' preferences as well, as to cover the full spectrum of value elements rather than simply clinical outcomes. The results of this analysis show that physicians and patients share similarities but also marked differences in terms of the aspects of treatment that they perceive as more valuable.


Complete Coding Genome Sequence of a Novel Porcine Reproductive and Respiratory Syndrome Virus 2 Restriction Fragment Length Polymorphism 1-4-4 Lineage 1C Variant Identified in Iowa, USA.
A porcine reproductive and respiratory syndrome virus 2 strain was identified in lung samples from nursery piglets associated with a 17.15% mortality rate on a swine farm in Iowa. Open reading frame 5 (ORF5) sequencing indicated that this strain is a restriction fragment length polymorphism (RFLP) 1-4-4 lineage 1C variant strain, and its complete coding genome sequence was determined.


Evidence of altered epidermal nerve fiber morphology in adults with self-injurious behavior and neurodevelopmental disorders.
The purpose of this preliminary study was to examine the morphology and neuropeptide density of epidermal nerve fibers quantified through skin biopsy samples from three adults with neurodevelopmental disorders and chronic self-injurious behavior (SIB) secondary to mental retardation compared with non-SIB normal IQ controls. A cross-sectional design was used with 3mm punch skin biopsies collected from each participant from non-self-injurious body sites and compared with site-matched existing normal control skin samples. The study was conducted at an outpatient clinic. The primary dependent measure for the morphology analyses was the coefficient of variation (CV) to quantify the mean gap length between epidermal nerve fibers for each subject. Visual microscopic examination and quantitative analysis of the microscopy images suggested there were morphological abnormalities (increased CV) in the epidermal nerve fibers among the chronic SIB cases. Substance P (SP) fiber density was increased with 2-3 times as many fibers in SIB subjects as control subjects. Additional empirical work is needed to clarify the relation between sensory innervation of the skin and self-injury to improve assessment and treatment outcomes.


Worldwide antipsychotic drug search intensities: pharmacoepidemological estimations based on Google Trends data.
Prescription patterns of antipsychotic drugs (APDs) are typically sourced from country-specific data. In this study, a digital pharmacoepidemiological approach was used to investigate APD preferences globally. Publicly available data on worldwide web search intensities in Google for 19 typical and 22 atypical APDs were temporally and spatially normalized and correlated with reported prescription data. The results demonstrated an increasing global preference for atypical over typical APDs since 2007, with quetiapine, olanzapine, risperidone, and aripiprazole showing the largest search intensities in 2020. Cross-sectional analysis of 122 countries in 2020 showed pronounced differences in atypical/typical APD preferences that correlated with gross domestic product per capita. In conclusion, the investigation provides temporal and spatial assessments of global APD preferences and shows a trend towards atypical APDs, although with a relative preference for typical APDs in low-income countries. Similar data-sourcing methodologies allow for prospective studies of other prescription drugs.


FluCAN 2009: initial results from sentinel surveillance for adult influenza and pneumonia in eight Australian hospitals.
To describe the epidemiology of adult patients hospitalised with influenza or pneumonia during a pandemic season in a sentinel network in Australia. Prospective case series of adult hospital admissions to eight acute care general public hospitals (Influenza Complications Alert Network [Flu CAN] sentinel hospitals) in six Australian jurisdictions, 1 July to 4 December 2009. Demographic, clinical and outcome measures in patients admitted with laboratory-confirmed pandemic (H1N1) 2009 influenza in the sentinel hospitals compared with data from national notifications and intensive care unit (ICU) surveillance; admissions for influenza and pneumonia over time in each jurisdiction. During 190 hospital-weeks of observation, there were 538 influenza admissions. Of these, 465 patients (86.4%) had the pandemic strain, representing 9.3% of total admissions with pandemic (H1N1) 2009 influenza (n = 4992) recorded nationally in 2009. Of these patients, 250/465 (53.8%) were women, 67/453 (14.8%) were Indigenous, and the median age was 46 years (interquartile range, 29-58 years). Comorbidities were present in 354/464 patients (76.3%), and 40 were pregnant (30.3% of women aged 15-49 years). FluCAN reported that 102 patients (21.9%) were admitted to ICUs, and of patients admitted to hospital, 26 (5.6%) died. FluCAN results were very similar to national notification data and published ICU admissions data. Of those who were followed to 30 days after discharge, 30 (6.5%) were readmitted. Of 1468 patients hospitalised with pneumonia, 718 (48.9%) were tested for influenza and 163 (11.1%) were co-infected with the pandemic strain. Sentinel surveillance systems can provide important and reliable information in a timely fashion and can monitor changes in severity of influenza during a pandemic season.


Transferable Resistance to Highest Priority Critically Important Antibiotics for Human Health in Escherichia coli Strains Obtained From Livestock Feces in Uruguay.
The aim of this work was to detect Escherichia coli isolates displaying resistance to oxyimino-cephalosporins, quinolones, and colistin in feces from livestock in Uruguay. During 2016-2019, fecal samples from 132 broiler and layer chicken flocks, 100 calves, and 50 pigs, were studied in Uruguay. Samples were cultured on MacConkey Agar plates supplemented with ciprofloxacin, ceftriaxone, or colistin. E. coli isolates were identified by mass spectrometry and antibiotic susceptibility testing was performed by disk diffusion agar method and colistin agar test. Antibiotic resistance genes were detected by polymerase chain reaction and sequencing. The most frequently detected resistance gene was qnrB19, recovered from 87 animals. Regarding plasmid-mediated quinolone resistance genes, qnrS1 was the second in prevalence (23 animals) followed by qnrE1, found in 6 chickens and two calves. Regarding resistance to oxyimino-cephalosporins, 8 different β-lactamase genes were detected: bla CTX-M-8 and bla CMY-2 were found in 23 and 19 animals, respectively; next, bla CTX-M-2 and bla SHV-12 in 7 animals each, followed by bla CTX-M-14 in 5, bla CTX-M-15 and bla SHV2a in 2, and bla CTX-M-55 in a single animal. Finally, the mcr-1 gene was detected only in 8 pigs from a single farm, and in a chicken. Isolates carrying bla CMY-2 and bla SHV-12 were also found in these animals, including two isolates featuring the bla CMY-2/mcr-1 genotype. To the best of our knowledge, this is the first work in which the search for transferable resistance to highest priority critically important antibiotics for human health is carried out in chickens and pigs chains of production animals in Uruguay.


Discriminating between cardiac and pulmonary dysfunction in the general population with dyspnea by plasma pro-B-type natriuretic peptide.
This study was designed to determine whether measurement of plasma pro-B-type natriuretic peptide (proBNP) could be used in discriminating between cardiac and pulmonary dyspnea in the general population. Natriuretic peptides are useful markers in ruling out acute cardiac dyspnea in the emergency department, but their diagnostic significance in evaluating chronic dyspnea in the general population is unknown. Within the Copenhagen City Heart Study, a large, community-based population study, dyspnea was evaluated by spirometry, oxygen saturation, echocardiography, and plasma proBNP. Of 2,929 participants, 959 reported dyspnea. The plasma proBNP concentration was higher in the group with dyspnea (mean 17.8 pmol/l; 95% confidence interval [CI] 16.3 to 19.4 pmol/l) than in the group without (10.6 pmol/l; 95% CI 10.0 to 11.4 pmol/l; p < 0.001). In the group with dyspnea, left ventricular hypertrophy and/or systolic dysfunction was associated with a 2.6-fold increase in plasma proBNP concentration (p < 0.001), whereas pulmonary dysfunction was not associated with increased plasma proBNP (p = 0.66). Using multivariable regression analysis, a model to estimate the expected concentration of plasma proBNP based on age and gender was established for dyspneic subjects: an actual plasma proBNP concentration below half of the expected value ruled out left ventricular systolic and diastolic dysfunction (sensitivity 100%, 95% CI 100% to 100%; specificity 15%, 95% CI 12% to 17%). In the general population with dyspnea, plasma proBNP concentrations are increased in left ventricular dilatation, hypertrophy, systolic dysfunction, or diastolic dysfunction, but are unaffected by pulmonary dysfunction.


Newborn screening for Fabry disease in Oregon: Approaching the iceberg of A143T and variants of uncertain significance.
Fabry disease newborn screening (NBS) has been ongoing in Oregon for over 41 months by first-tier enzyme quantitation and second-tier DNA testing. During that period the majority of abnormal referrals received (34/60) were for the presence of the controversial c.427G > A (p.Ala143Thr) aka A143T and the majority of non-A143T referrals were for other variants of uncertain significance (17/60) resulting in at least 32 infants with an inconclusive case outcome even after clinical evaluation and/or diagnostic testing. To date there has been no significant family history or onset of symptoms in individuals with an inconclusive outcome. Based on our experience, we have developed a framework for approaching A143T and other variants of uncertain clinical significance in an attempt to balance sensitivity with the unnecessary medicalization of healthy infants.


Activation of RXR-PPAR heterodimers by organotin environmental endocrine disruptors.
The nuclear receptor retinoid X receptor-alpha (RXR-alpha)-peroxisome proliferator-activated receptor-gamma (PPAR-gamma) heterodimer was recently reported to have a crucial function in mediating the deleterious effects of organotin compounds, which are ubiquitous environmental contaminants. However, because organotins are unrelated to known RXR-alpha and PPAR-gamma ligands, the mechanism by which these compounds bind to and activate the RXR-alpha-PPAR-gamma heterodimer at nanomolar concentrations has remained elusive. Here, we show that tributyltin (TBT) activates all three RXR-PPAR-alpha, -gamma, -delta heterodimers, primarily through its interaction with RXR. In addition, the 1.9 A resolution structure of the RXR-alpha ligand-binding domain in complex with TBT shows a covalent bond between the tin atom and residue Cys 432 of helix H11. This interaction largely accounts for the high binding affinity of TBT, which only partly occupies the RXR-alpha ligand-binding pocket. Our data allow an understanding of the binding and activation properties of the various organotins and suggest a mechanism by which these tin compounds could affect other nuclear receptor signalling pathways.


Modulation of the Rat Intergeniculate Leaflet of the Thalamus Network by Norepinephrine.
Circadian rhythms are regulated by a set of brain structures, one of which is the Intergeniculate Leaflet of the Thalamus (IGL). The most recognised role of the IGL is the integration of a variety of stimuli affecting rhythmicity, such as lighting conditions, received by the eye, or light-independent (non-photic) cues, the information about which is delivered via the activation of the non-specific projections. One of them is the norepinephrinergic system originating in the brainstem Locus Coeruleus (LC). In order to investigate the effect of norepinephrine (NE) on the IGL neurons we have performed ex vivo recordings using the extracellular multi-electrode array technique as well as the intracellular whole-cell patch clamp. Using both agonists and antagonists of specific NE receptor subtypes, we confirmed the presence of functional α1-, α2- and β-adrenergic receptors within the investigated structure, allowing NE to exert multiple types of effects on different IGL neurons, mainly depolarisation of the neurons projecting to the Suprachiasmatic Nuclei - the master circadian pacemaker, and various responses exhibited by the cells creating the connection with the contralateral IGL. Moreover, NE was shown to affect IGL cells both directly and via modulation of the synaptic network, in particular the miniature inhibitory postsynaptic currents. To the best of our knowledge, these are the first studies to confirm the effects of NE on the activity of the IGL network.


Xanthine oxidase levels in human brain tumors.
Xanthine oxidase is most recognized for its role as the rate-limiting enzyme in nucleic acid degradation through which all purines are channelled for terminal oxidation. The enzyme serves as a source of oxygen-derived free radicals which induce both cellular injury and edema as well as changes in vascular permeability. In the study we compared xanthine oxidase levels of human brain tumors with normal brain tissues. Statistical evaluation of our results shows significantly higher xanthine oxidase levels in tumoral brain tissues. However, xanthine oxidase has not any significance for the differentiation of tumor types among each others. The oncotypes studied were meningioma and astrocytoma.


Efficacy of transarterial chemoembolization monotherapy or combination conversion therapy in unresectable hepatocellular carcinoma: A systematic review and meta-analysis.
Hepatocellular carcinoma (HCC) is a highly malignant disease with poor prognosis, and most cases were already considered unresectable at the time of presentation. Conversion therapy, as an emerging treatment, is designed to provide patients with initially unresectable hepatocellular carcinoma (uHCC) the opportunity to undergo radical resection. At present, conversion therapy for patients with uHCC remains controversial. Transarterial chemoembolization (TACE) is currently the most widely selected treatment for uHCC, but its efficacy as a conversion therapy remains controversial. We compared and evaluated the conversion rate for and tumor response to TACE monotherapy or combination therapy. Meanwhile, postoperative complications and overall survival (OS) in uHCC patients who underwent conversion therapy were also analyzed. A total of 18 studies were included in this meta-analysis. The conversion rate for triple therapy [TACE in combination with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs)] was 42% [95% confidence interval (CI), 0.29-0.56], higher than any other group [TACE monotherapy: 10% (95% CI, 0.08-0.12), bigeminy therapy: 19% (95% CI, 0.06-0.36)]. Meanwhile, triple therapy yielded a better tumor response than TACE monotherapy or bigeminy therapy. Among the patients with successful surgical resection after conversion therapy, the pooled postoperative OS rates at 1, 2, and 5 years were 90% (95% CI, 0.81-0.97), 58% (95% CI, 0.42-0.73), and 42% (95% CI, 0.26-0.60), respectively, and the major postoperative complications were biliary leakage (7%; 95% CI, 0.03-0.12) and liver failure (3%; 95% CI, 0.00-0.07). TACE conversion therapies showed good conversion rates, especially the triple therapy of TACE in combination with TKIs and ICIs. Surgical resection after successful conversion therapy could maximize the outcome of patients with uHCC.


The association of genetic polymorphisms of bone formation genes with canine hip dysplasia.
Canine hip dysplasia (CHD) is an orthopedic disorder characterized by abnormal laxity of the hip joint. It is considered multifactorial and polygenic and affects predominantly medium and large sized dog breeds. The aim of this study was to identify CHD associated polymorphisms in chromosomal regions on CFA19, CFA24, CFA26, and CFA34. Blood samples from 60 dogs of different breeds were collected and genotyped, including 46 cases and 14 controls. After sequencing and single nucleotide polymorphism (SNP) determination of the target regions, an individual SNP analysis with a 2 statistic was performed based on the comparison of allele frequencies in cases and controls. A significant association was observed between CHD and a T/C SNP on CFA19, which harbors genes involved in bone metabolism. No other significant association was found in the study and previously identified SNPs cannot be validated as related to CHD. Further research is warranted to identify CHD-associated polymorphisms in order to develop a genotype-based diagnosis and selection approach.


The effects of lycopene supplementation on insulin-like growth factor-1 and insulin-like growth factor binding proteins: A systematic review of randomized controlled trials.
Lycopene has been posited to regulate insulin-like growth factor-1 (IGF-1). We aimed to conduct a systematic review of the effects of lycopene on circulating IGF-1 and insulin-like growth factor binding proteins (IGFBPs) in adults. A systematic search was carried out in PubMed, Scopus, ISI Web of Science, and the Cochrane Library databases for randomized controlled trials (RCTs), published from inception until March 2020. A total of 11 studies fulfilled the selection criteria. Eleven studies examined the effect of lycopene supplementation on IGF-1, one of which reported a significant reduction. Moreover, three, four, and ten studies were found for IGFBP-1, IGFBP-2, and IGFBP-3, respectively; where one study found a significant increase in these proteins. In conclusion, no consistent modifying effect of lycopene supplementation on IGF-1 and IGFBPs levels are evident in the literature. More research is needed to explore the effect of lycopene on IGF-1 system.


State-of-the-art camel care.
An international team of vets is providing expert care in the world's first dedicated camel hospital, explains Daniel Gillett.


Spectroscopic studies on heme d in the visible and infrared.
Heme d has been isolated from the terminal oxidase complex of Escherichia coli strain MR43L/F152 and purified by high-pressure liquid chromatography. The infrared spectrum indicated that carbonyls in the chlorin skeleton of this isolated heme existed as carboxylic acids. Earlier work on the iron-free chlorin had demonstrated the presence of a spirolactone substituent. This may have arisen from a cyclization reaction from a dicarboxylic acid, diol precursor. Although the free heme in extracts can exist as a diol, this does not prove that the diol as such is the precise form in the enzyme complex. Visible and fluorescence spectra are reported for a variety of derivatives and complexes of heme d to establish a spectral library that may be used to prove the presence of this structure in other enzymes or cells. Association constants have been measured for complexes of heme d with cyanide, imidazole, and pyridine and are contrasted to available data for protoheme.


Cutaneous larva migrans: an unusual souvenir from a Scottish holiday.
Cutaneous larva migrans acquired in western Scotland. A reminder that with a warming climate, conditions conventionally restricted to the tropics may be contracted in the British Isles in the absence of foreign travel.


Functional disconnection and reconnection: an alternative strategy to stoicism in public safety personnel.
Background: North American public safety personnel (PSP; e.g., police, firefighters, paramedics) training programmes often focus on the importance of controlling emotional reactions (i.e. remaining stoic) to make sound decisions in high-stress environments. Many PSP carry avoidant coping strategies into their personal lives, however, resulting in disrupted relationships and deterioration of well-being. Objective: We argue for an alternative perspective, functional disconnection and functional reconnection (FD/FR), that limits stoicism and avoidant coping in PSP work environments. FD/FR instead suggests that PSP can receive support and training focused on intentional and cognizant changes of the physical, emotional, mental, and spiritual aspects of their occupational roles; the same intention should be given to supporting reconnection when re-integrating into personal roles following the workday. Conclusion: FD/FR strategies can be incorporated into clinical treatment, existing training programmes and embraced by organizational leadership to facilitate a necessary shift towards prioritizing PSP well-being.


An enigmatic satellite.
McLaughlin and Chadwick describe an X-linked tandem repeat that is transcribed, conserved and defies X inactivation. Is it selfish, functional or just an oddity?


Randomization, blinding, data handling and sample size estimation in papers published in Veterinary Anaesthesia and Analgesia in 2009 and 2019.
To evaluate reporting of items indicative of bias and weak study design. Literature survey. Papers published in Veterinary Anaesthesia and Analgesia. Reporting of randomization, blinding, sample size estimation and data exclusion were compared for papers published separated by a 10 year interval. A reporting rate of more than 95% was considered ideal. The availability of data supporting results in a publicly accessible repository was also assessed. Selected papers were randomized and identifiers removed for review, with data from 59 (57 in 2009, two in 2008) and 56 (52 in 2019, four in 2018) papers analyzed. Items were categorized for completeness of reporting using a previously published operationalized checklist. Two reviewers reviewed all papers independently. Full reporting of randomization increased over time from 13.6% to 85.7% [95% confidence interval (CI), 57.8-86.6%; p < 0.0001], as did sample size estimation (from 0% to 20%; 95% CI, 7.6-32.4%; p = 0.002). Reporting of blinding (49.2% and 50.0%; 95% CI, -18.3% to 20.0%; p = 1.0) and exclusions of samples/animals (39.0% and 50.0%; 95% CI, -8.8% to 30.8%; p = 0.3) did not change significantly. Data availability was low (2008/2009, zero papers; 2018/2019, two papers). None of the items studied exceeded the predetermined ideal reporting rate. These results indicate that reporting quality remains low, with a risk of bias.


Changes in AMP deaminase activities in the hearts of diabetic rats.
AMP deaminase from normal and diabetic rat hearts was separated on cellulose phosphate and quantitated by HPLC. From soluble fractions three different AMP deaminase activities, according to KCl elution from cellulose phosphate and percent of total activity were: 170 mM (85%), 250 mM (8%) and 330 mM (7%) KCl. The AMP deaminase activity which eluted with 170 mM KCl was resolved to two distinct peaks by HPLC anionic exchange. After 4 weeks of diabetes the heart enzyme profile change to: 170 mM (10%), 250 mM (75%) and 330 mM (15%). Once purified the four activities were kinetically distinct: 170 mM KCl cytosolic, AMP Km = 1.78, stimulated by ATP, GTP, NADP and strongly inhibited by NAD; 170 mM KCl mitochondria AMP Km = 17.9, stimulated by ATP, ADP; 250 mM KCl isozyme, AMP Km = 0.66, stimulated by ADP; and 330 mM KCl isozyme, AMP Km = 0.97, inhibited by ATP, NAD(P).


Inflammation in the nervous system.
Earlier studies on inflammation in the CNS have largely focused on conditions with an immune component. Recent evidence has emerged, however, that the innate, acute inflammatory response in the CNS parenchyma is quite unlike that in other tissues. The meninges and ventricular compartments show more typical responses, as does the parenchyma of the brain in immature animals. It is becoming apparent that the cells of the mononuclear phagocyte lineage dominate inflammatory responses in the CNS parenchyma.


Activation of extracellular signal-regulated protein kinase 5 downregulates FasL upon osmotic stress.
Extracellular signal-regulated protein kinase (ERK) 5 is a mitogen-activated protein kinase (MAPK) that is activated by dual phosphorylation via a unique MAPK/ERK kinase 5, MEK5. The physiological importance of this signaling cascade is underscored by the early embryonic death caused by the targeted deletion of the erk5 or the mek5 genes in mice. Here, we have found that ERK5 is required for mediating the survival of fibroblasts under basal conditions and in response to sorbitol treatment. Increased Fas ligand (FasL) expression acts as a positive feedback loop to enhance apoptosis of ERK5- or MEK5-deficient cells under conditions of osmotic stress. Compared to wild-type cells, erk5-/- and mek5-/- fibroblasts treated with sorbitol display a reduced protein kinase B (PKB) activity associated with increased Forkhead box O3a (Foxo3a) activity. Based on these results, we conclude that the ERK5 signaling pathway promotes cell survival by downregulating FasL expression via a mechanism that implicates PKB-dependent inhibition of Foxo3a downstream of phosphoinositide 3 kinase.


Effect of donor-to-recipient HLA matching in low-immunological risk kidney transplant recipients without induction therapy on acute rejection, graft survival, infections, and surgical complications at 3 years: The road towards new recommendations.
Donor-to-recipient human leukocyte antigen mismatching is considered one of the strongest determinants for graft and patient survival in kidney transplant recipients (KTR). This retrospective study discusses the impact of HLA matching as low immunological risk KTR without induction therapy. Records of 80 adult kidney transplant patients were reviewed with three years of the follow-up. All patients had panel reactive antibodies (PRA) < 20%, absence of donor-specific antibodies (DSA) and did not receive the induction therapy. These patients were divided into two groups according to their HLA matching between donor and recipient: 55 patients with ≥ 3 HLA matches (Group I; low immunogenicity) were compared to 25 patients with <3 HLA matches (Group II; high immunogenicity). The primary endpoints included the rate and severity of acute rejection (AR) episodes, graft function (creatinine level), and survival at 1, 3, 6, 12, and 36 months. Secondary endpoints include the rate and type of infections at one-year, surgical complications at one-year, and patient survival at 1, 6, 12, and 36 months after kidney transplantation. Baseline demographic characteristics were comparable between the two groups except for recipient age, donor gender, and pre-transplant dialysis time. There was no significant difference observed between two groups at one-year in infection rate, the length of hospital stay, AR severity, the rate of cytomegalovirus infection, and the occurrence of delayed graft function. However, the rate of AR, the graft function upon discharge, and the rate and type of surgical complications at one-year were significantly higher in Group II (high immunogenicity). The patient and graft survival at three years, the death-censored graft survival, and the serum creatinine levels at 1, 3, 6, 12, and 36 months were similar between two groups. Two deaths occurred in each group (NS). In our center, the donor-to-recipient HLA mismatch is not considered an immunological risk factor in low-risk kidney transplant recipients (PRA < 20% and absence of DSA).


Phase-transfer energetics of small-molecule alcohols across the water-hexane interface: molecular dynamics simulations using charge equilibration models.
We study the water-hexane interface using molecular dynamics (MD) and polarizable charge equilibration (CHEQ) force fields. Bulk densities for TIP4P-FQ water and hexane, 1.0086±0.0002 and 0.6378±0.0001 g/cm(3), demonstrate excellent agreement with experiment. Interfacial width and interfacial tension are consistent with previously reported values. The in-plane component of the dielectric permittivity (ɛ(||)) for water is shown to decrease from 81.7±0.04 to unity, transitioning longitudinally from bulk water to bulk hexane. ɛ(||) for hexane reaches a maximum in the interface, but this term represents only a small contribution to the total dielectric constant (as expected for a non-polar species). Structurally, net orientations of the molecules arise in the interfacial region such that hexane lies slightly parallel to the interface and water reorients to maximize hydrogen bonding. Interfacial potentials due to contributions of the water and hexane are calculated to be -567.9±0.13 and 198.7±0.01 mV, respectively, giving rise to a total potential in agreement with the range of values reported from previous simulations of similar systems. Potentials of mean force (PMF) calculated for methanol, ethanol, and 1-propanol for the transfer from water to hexane indicate an interfacial free energy minimum, corresponding to the amphiphilic nature of the molecules. The magnitudes of transfer free energies were further characterized from the solvation free energies of alcohols in water and hexane using thermodynamic integration. This analysis shows that solvation free energies for alcohols in hexane are 0.2-0.3 kcal/mol too unfavorable, whereas solvation of alcohols in water is approximately 1 kcal/mol too favorable. For the pure hexane-water interfacial simulations, we observe a monotonic decrease of the water dipole moment to near-vacuum values. This suggests that the electrostatic component of the desolvation free energy is not as severe for polarizable models than for fixed-charge force fields. The implications of such behavior pertain to the modeling of polar and charged solutes in lipidic environments.


The mediating effect of depressive symptoms on the relationship between bullying victimization and non-suicidal self-injury among adolescents: Findings from community and inpatient mental health settings in Ontario, Canada.
Although bullying victimization has been linked to a number of behavioral and emotional problems among adolescents, few studies have investigate the mechanism through which bullying victimization affect non-suicidal self-injury. The objectives of this study were to examine the effect of bullying victimization on non-suicidal self-injury and the mediating effect of depressive symptoms on the relationship between bullying victimization and non-suicidal self-injury among adolescents. Data for this study came from the interRAI Child and Youth Mental Health dataset. A total of 1650 adolescents aged 12-18 years (M =14.56; SD =1.79; 54.2% males) were analyzed. Binary logistic and Poisson regression models were conducted to identify the mediating effect of depressive symptoms on the relationship between bullying victimization and non-suicidal self-injury. Of the 1650 adolescents studied, 611 representing 37% engaged in non-suicidal self-injury and 26.7% were victims of bullying. The effect of bullying victimization on non-suicidal self-injury was partially mediated by depressive symptoms after adjusting for the effect of demographic characteristics, history of childhood abuse, social support, and mental health diagnoses. The contribution of bullying victimization and depression to non-suicidal self-injury adds to the case for the development of trauma-focused interventions in reducing the risk of non-suicidal self-injury among adolescents.


Allogeneic stem cell transplantation for multiple myeloma.
High-dose chemotherapy (with or without total body irradiation) followed by allogenic marrow transplantation is curative for some patients with advanced multiple myeloma. A relatively high transplant-related mortality, however, limits the wider application of this approach. The challenge for future studies will be to develop less toxic preparative regimens, more efficient ways to prevent infection and graft-versus-host disease, and methods to enhance the graft-versus-leukemia effect of allografts.


Wavelength and vulnerability to atrial fibrillation: Insights from a computer model of human atria.
To explain the contradictory results related to the concept of critical cardiac wavelength in the initiation and perpetuation of atrial fibrillation (AF). A biophysically based computer model was used to: (1) study the relationship between wavelength and AF perpetuation in the presence of multiple re-entrant wavelets, (2) evaluate the performance of different existing methods for wavelength estimation in the presence of different arrhythmogenic substrates, and (3) document the impact of either heterogeneities in refractoriness or the presence of a mother rotor on wavelength estimation. The simulations confirmed that the wavelength must be below a critical value for AF to be sustained, when the perpetuation mechanism relies on multiple re-entrant wavelets. The estimated value of wavelength was not the same for all methods tested and depended in part on the nature of the spatio-temporal organization of the AF dynamics. A priori information about the underlying wavelet dynamics is needed for a correct interpretation of the cardiac wavelength as estimated by the current clinical methods.