Prevalence of articular chondrocalcinosis in elderly subjects in a rural area of Catalonia.
To undertake an epidemiological survey of the prevalence of radiological chondrocalcinosis in the elderly population of Osona, a rural area of Catalonia, north east Spain. Knee and wrist radiographs were performed on 261 subjects (141 women, 120 men) aged at least 60 years, who attended a series of 35 general practitioners for various medical problems. Twenty seven subjects had articular chondrocalcinosis, which represents a crude prevalence of 10%. Articular chondrocalcinosis was more often observed in women than in men (14 v 6%). Articular chondrocalcinosis increases in occurrence with age, rising from 7% in subjects aged 60-69 years to 43% in subjects older than 80 years. A similar occurrence of articular chondrocalcinosis was noted in the indigenous population, in which several cases of familial chondrocalcinosis have previously been reported, and in subjects born in other areas of Spain. All but one subject with articular chondrocalcinosis had chondrocalcinosis of the knee. The occurrence of rheumatic disorders did not differ significantly between subjects with articular chondrocalcinosis and those without. Articular chondrocalcinosis is an age related disorder, which could partly explain the discrepancies in its prevalence reported in previous studies. In most subjects with articular chondrocalcinosis recruited from an unselected population the clinical manifestations are probably mild or even absent.


The microplastic pattern of wild-caught Mediterranean mussels from the Marmara Sea.
The Sea of Marmara suffers from pollutants that come from municipal/industrial discharges and the Black Sea. Microplastic (MP)s, a rising environmental concern with consequences for seafood safety, are one of these contaminants. Thus, the abundance and feature of MPs in wild populations of the Mediterranean mussel (Mytilus galloprovincialis) from 20 sites along the sea of Marmara coastlines were analyzed herein. In total, 812 MPs were detected in 412 mussels. The MPs ranged from 0.30 to 7.53 MP individual-1 and 0.11 to 4.58 MP g-1 fresh weight. The most common shape of the MPs detected was fiber (81.16%), the majority of which were smaller than 1 mm. Polymer types were verified by FTIR, and 14 different polymers have been identified; the dominant was polyethylene terephthalate (PET, 66.38%). When one is served by a mussel meal weekly, the risk statistics project that the exposure will be 252 MPs per portion. Yet, the risk associated with the MP-contaminated mussel consumption is insignificant according to hypothetical calculations using a chemical additive (bisphenol A).


Differences in the pressures of canal anal and rectal sensitivity in patients with fecal incontinence, chronic constipation and healthy subjects.
There exists a great variability in the manometric findings between patients with anal incontinence (AI) and healthy subjects. The correlation between the pressures of the anal canal and the AI is not exact by the wide rank of normal values. Prospective study to evaluate differences in the pressures of the anal canal and in rectal sensitivity in patients with AI, chronic constipation (CC) and healthy subjects. Ninety four patients with AI, 36 patients with CC and 15 healthy subjects were included. The following data were obtained: age, sex, resting pressure, anal canal length (ACL), squeeze maximum pressure (SMP), squeeze pressure duration (SPD), first sensation, urge and maximum tolerated volume (MTV). Statistical study: test of Kruskal-Wallis, test of Mann-Whitney, and multinomial logistic regression test. There were significant differences in the resting pressure (p < 0.001), the ACL (p < 0.001) and the SMP (p < 0.01) in the group of AI with respect to the other two groups. The volume for the first sensation was significantly lower in the healthy subjects than that in the other two groups (p < 0.05). The urge volume and the MVT were smaller in the group with AI with respect to the other groups (p < 0.001). In multivariate analysis the age, the resting pressure and the volume for the first sensation and urge increase the relative risk for AI. The greater age, the decrease in anal canal resting pressure and the alteration of rectal sensation increase the risk for AI.


Using quantile regression to assess disparities in medication adherence.
To examine racial/ethnic disparities in medication adherence between Asian and Pacific Islander Americans and Whites. This retrospective data analysis included diabetes patients enrolled in a health plan in Hawaii (N = 43,445). For anti-diabetic, lipid-lowering, and anti-hypertensive medications, quantile regression was estimated at 25(th), 50(th), and 75(th) quantiles to examine the association with race and ethnicity, controlling for other patient characteristics. Consistently, Filipinos, Native Hawaiians, and other Pacific Islanders were significantly less adherent than Whites. The greatest disparities were found for other Pacific Islanders using lipid-lowering medications, with adjusted differences in medication adherence, with reductions relative to Whites of as much as 19% for lipid-lowering medications for the 25(th) quantile of adherence. Whereas the large sample size undoubtedly contributed to the statistical significance, the large magnitude of the disparities, particularly for Filipinos, Native Hawaiians, and other Pacific Islanders, which suggests that these are meaningful differences that need to be addressed. The largest disparities were found at the lowest quantile suggests that they may be occurring among the most vulnerable populations with potentially poor access to care.


Comparative observation on effect of electric acupuncture of neiguan (P 6) at chen time versus xu time on left ventricular function in patients with coronary heart disease.
Paired experimental design was adopted in this experiment for comparative observation on effect of electric acupuncture (EA) of Neiguan (P 6) at Chen Time (7 a.m. to 9 a.m.) versus Xu Time (7 p.m. to 9 p.m.) on left ventricular function in patients with coronary heart disease (CHD). The results show that EA performed at Chen Time could improve the left ventricular function of CHD patients as indicated by shortening of PEPI and decrease of PEPI/LVETI ratio; on the contrary, EA performed at Xu Time prolonged PEPI and raised PEPI/LVETI ratio in CHD patients, suggesting impairment of left ventricular function.


Developmental origin of the rat adenohypophysis prior to the formation of Rathke's pouch.
In amphibians, it has already been shown that the adenohypophysis originates from the anterior neural ridge. During the migration and morphogenesis of this organ, the anterior neural ridge transiently forms a Rathke's pouch-like structure by attaching itself to the rostral tip of the foregut, and finally gives rise to the adenohypophysis by detaching from the foregut and becoming connected to the infundibulum of the hypothalamus. In order to identify the origin of the adenohypophyseal cells in mammalian embryos prior to the formation of Rathke's pouch (RP), we labeled the rostral end of the neural plate and the adjacent area focally with DiI at the open neurula stage (9.5 dpc). After a 48-hours culture of the whole embryos, strongly labeled cells were detected in the RP only when DiI was applied to a small area situated just anterior to the rostral end of the neural plate. By explanting the labeled RP for a further 7 days, we confirmed immunohistochemically that the labeled cells developed into the secretory cells of the adenohypophysis. The developmental origin of the adenohypophysis is identified for the first time in the early mammalian embryo before the formation of RP.


Validity and reliability of the Turkish version of the Michigan Neuropathy Screening Instrument
The aim of this study was to demonstrate the validity and reliability of the Turkish version of the Michigan Neuropathy Screening Instrument (MNSI-TR). The study included 127 patients aged 45–76 years who were previously diagnosed with type 1 or 2 diabetes. Stability of the instrument was assessed by intraclass correlation coefficient. Reliability of the MNSI-TR was assessed using the Kuder– Richardson formula 20 test, item-total correlations, and floor/ceiling effect. Validity was evaluated with receiver operating characteristic curve analysis. A logistic regression model was used to determine to what degree the MNSI-TR explain nerve conduction study (NCS) results in the prediction of neuropathy. With a cut-off value of 3.5 for the questionnaire, sensitivity and specificity of the MNSI-TR were 75.5% and 68.1%, respectively. A cut-off of 2.75 for the physical assessment part of the scale resulted in 87.5% sensitivity and 93.6% specificity. The scale was able to diagnose neuropathy in the rate of 71.5% of the patients diagnosed with neuropathy by NCS. The MNSI-TR is a valid and reliable method for evaluating diabetic peripheral neuropathy in Turkish speaking societies. It must be obtained a minimum of 4 points from the questionnaire part and a minimum of 2.5 points from the physical assessment part for the diagnosis of neuropathy


Plasmid-Borne and Chromosomal ESBL/AmpC Genes in Escherichia coli and Klebsiella pneumoniae in Global Food Products.
Plasmid-mediated extended-spectrum beta-lactamase (ESBL), AmpC, and carbapenemase producing Enterobacteriaceae, in particular Escherichia coli and Klebsiella pneumoniae, with potential zoonotic transmission routes, are one of the greatest threats to global health. The aim of this study was to investigate global food products as potential vehicles for ESBL/AmpC-producing bacteria and identify plasmids harboring resistance genes. We sampled 200 food products purchased from Finland capital region during fall 2018. Products originated from 35 countries from six continents and represented four food categories: vegetables (n = 60), fruits and berries (n = 50), meat (n = 60), and seafood (n = 30). Additionally, subsamples (n = 40) were taken from broiler meat. Samples were screened for ESBL/AmpC-producing Enterobacteriaceae and whole genome sequenced to identify resistance and virulence genes and sequence types (STs). To accurately identify plasmids harboring resistance and virulence genes, a hybrid sequence analysis combining long- and short-read sequencing was employed. Sequences were compared to previously published plasmids to identify potential epidemic plasmid types. Altogether, 14 out of 200 samples were positive for ESBL/AmpC-producing E. coli and/or K. pneumoniae. Positive samples were recovered from meat (18%; 11/60) and vegetables (5%; 3/60) but were not found from seafood or fruit. ESBL/AmpC-producing E. coli and/or K. pneumoniae was found in 90% (36/40) of broiler meat subsamples. Whole genome sequencing of selected isolates (n = 21) revealed a wide collection of STs, plasmid replicons, and genes conferring multidrug resistance. bla CTX-M-15-producing K. pneumoniae ST307 was identified in vegetable (n = 1) and meat (n = 1) samples. Successful IncFII plasmid type was recovered from vegetable and both IncFII and IncI1-Iγ types from meat samples. Hybrid sequence analysis also revealed chromosomally located beta-lactamase genes in two of the isolates and indicated similarity of food-derived plasmids to other livestock-associated sources and also to plasmids obtained from human clinical samples from various countries, such as IncI type plasmid harboring bla TEM-52C from a human urine sample obtained in the Netherlands which was highly similar to a plasmid obtained from broiler meat in this study. Results indicate certain foods contain bacteria with multidrug resistance and pose a possible risk to public health, emphasizing the importance of surveillance and the need for further studies on epidemiology of epidemic plasmids.


Youth with problematic sexualized behaviors in the child welfare system: a one-year longitudinal study.
This study assessed continuity of problematic sexualized behaviors (PSB) over a 1-year period. Ninety-seven 10-12-year-olds in either foster boarding homes or a residential treatment center participated at Time 1. Twelve months later, 78 youth were available for a second data collection assessment. At both data collection phases, researchers interviewed foster parents or primary therapists about the youths' sexual behavior. Findings revealed significant continuity in PSB over time, with children who at Time 1 exhibited PSB significantly more likely to exhibit PSB at Time 2. The reverse was also true in that the absence of PSB at Time 1 was associated with the absence of PSB at Time 2. In addition, a subset of specific PSB behaviors was noted to be most stable, although this varied across the groups. Youth with PSB exhibited several patterns of persistence in specific behaviors over time, including continuity, a mix of continuity and change, and complete discontinuity. The persistence of PSB over time was most true for the children living in a residential treatment center, the more disturbed group studied. We conclude that the persistence of PSB is more likely when the child has other problematic behaviors.


Identification and characterization of a prevacuolar compartment in stigmas of nicotiana alata
The stigmas of the ornamental tobacco plant Nicotiana alata accumulate large quantities of a series of 6-kD proteinase inhibitors (PIs) in the central vacuole that are derived from a 40-kD precursor protein, Na-PI. The sorting information that directs Na-PI to the vacuole is likely to reside in a C-terminal propeptide domain of 25 amino acids that forms an amphipathic alpha helix. Using cell fractionation techniques, we have examined transit of Na-PI through the endomembrane system and have identified a prevacuolar compartment that contains Na-PI with an intact targeting signal. In contrast, the targeting signal is not present on the predominant form of Na-PI in the vacuole. The prevacuolar compartment is marked by the presence of homologs of both the t-SNARE, PEP12p, and the putative vacuolar sorting receptor BP-80. Cross-linking and affinity precipitation studies revealed that Na-PI associates with BP-80 within this compartment, providing in vivo evidence for the function of BP-80 as a sorting receptor for a protein with a C-terminal vacuolar targeting signal.


Patient selection determines the prostate cancer yield of dynamic contrast-enhanced magnetic resonance imaging-guided transrectal biopsies in a closed 3-Tesla scanner.
To evaluate the cancer yield of transrectal prostate biopsies in a 3-T magnetic resonance imaging (MRI) scanner in patients with elevated prostate specific antigen (PSA) levels and recent negative transrectal ultrasonography (TRUS)-guided prostate biopsies. Between July 2004 and November 2005, patients with at least one previous negative prostate biopsy within the previous 12 months had MRI-guided biopsy of the prostate in a 3-T MRI scanner. Patients with previous positive biopsies for cancer were excluded. Target selection was based on T2-weighted imaging and dynamic contrast-enhanced (DCE) imaging studies. Thirteen patients were eligible; their median (range) age was 61 (47-74) years and PSA value 4.90 (1.3-12.3) ng/mL. Most patients had one previous negative biopsy (range 1-4). Four patients had a family history of prostate cancer. There were 37 distinct targets based on T2-weighted imaging. Fifteen of 16 distinct DCE abnormalities were co-localized with a target based on T2-weighted imaging. Despite this correlation, only one of 13 patients had a directed biopsy positive for cancer. Including systematic biopsies, two of 13 patients had a biopsy positive for prostate cancer. One patient had prostate intraepithelial neoplasia and one had atypical glands in the specimen. The prostate-cancer yield of transrectal biopsies in a 3-T MRI scanner, among patients with recent negative TRUS-guided prostate biopsies, is similar to repeat systematic TRUS-guided biopsy. DCE correlates with T2-imaging but does not appear to improve prostate cancer yield in this population.


Hyperglycemia disrupted the integrity of the blood-brain barrier following diffuse axonal injury through the sEH/NF-κB pathway.
We aimed to investigate the role of soluble epoxide hydrolase for hyperglycemia induced-disruption of blood-brain barrier (BBB) integrity after diffuse axonal injury (DAI). Rat DAI hyperglycemia model was established by a lateral head rotation device and intraperitoneal injection of 50% glucose. Glial fibrillary acidic protein, ionized calcium-binding adapter molecule-1, β-amyloid precursor protein, neurofilament light chain, and neurofilament heavy chain was detected by immunohistochemistry. Cell apoptosis was examined by terminal deoxynucleotidyl transferase nick-end labeling (TUNEL) assay. The permeability of blood-brain barrier (BBB) was assessed by expression of tight junction proteins, leakage of Evans blue and brain water content. The soluble epoxide hydrolase (sEH) pathway was inhibited by 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) and the nuclear transcription factor kappa B (NF-κB) pathway was inhibited by pyrrolidine dithiocarbamate and activated by phorbol-12-myristate-13-acetate in vivo and/or vitro, respectively. The inflammatory factors were detected by enzyme-linked immunosorbent assay. Hyperglycemia could exacerbate axonal injury, aggravate cell apoptosis and glial activation, worsen the loss of BBB integrity, increase the release of inflammatory factors, and upregulate the expression of sEH and NF-κB. Inhibition of sEH could reverse all these damages and protect BBB integrity by upregulating the expression of tight junction proteins and downregulating the levels of inflammatory factors in vivo and vitro, while the agonist of NF-κB pathway abrogated the protective effects of TPPU on BBB integrity in vitro. sEH was involved in mediating axonal injury induced by hyperglycemia after DAI by disrupting BBB integrity through inducing inflammation via the NF-κB pathway.


Introduction to Metamodeling for Reducing Computational Burden of Advanced Analyses with Health Economic Models: A Structured Overview of Metamodeling Methods in a 6-Step Application Process.
Metamodels can be used to reduce the computational burden associated with computationally demanding analyses of simulation models, although applications within health economics are still scarce. Besides a lack of awareness of their potential within health economics, the absence of guidance on the conceivably complex and time-consuming process of developing and validating metamodels may contribute to their limited uptake. To address these issues, this article introduces metamodeling to the wider health economic audience and presents a process for applying metamodeling in this context, including suitable methods and directions for their selection and use. General (i.e., non-health economic specific) metamodeling literature, clinical prediction modeling literature, and a previously published literature review were exploited to consolidate a process and to identify candidate metamodeling methods. Methods were considered applicable to health economics if they are able to account for mixed (i.e., continuous and discrete) input parameters and continuous outcomes. Six steps were identified as relevant for applying metamodeling methods within health economics: 1) the identification of a suitable metamodeling technique, 2) simulation of data sets according to a design of experiments, 3) fitting of the metamodel, 4) assessment of metamodel performance, 5) conducting the required analysis using the metamodel, and 6) verification of the results. Different methods are discussed to support each step, including their characteristics, directions for use, key references, and relevant R and Python packages. To address challenges regarding metamodeling methods selection, a first guide was developed toward using metamodels to reduce the computational burden of analyses of health economic models. This guidance may increase applications of metamodeling in health economics, enabling increased use of state-of-the-art analyses (e.g., value of information analysis) with computationally burdensome simulation models.


Low-Intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction in Diabetic Patients.
The cause of erectile dysfunction (ED) in diabetic patients is complex and involves both neurogenic and vasculogenic components and is often hard to treat. To study the effect of low-intensity extracorporeal shock wave therapy (Li-ESWT) therapy on a subgroup of diabetic patients with ED who are responders (PDE5I-R) and non-responders (PDE5I-NR) to phosphodiesterase 5 inhibitors (PDE5I). Analysis of pooled data from 5 double-blind, sham-controlled trials was performed. In this sub-analysis, of 350 patients in the PDE5I-R group and with vasculogenic ED, we found 61 patients with diabetes mellitus who underwent LI-ESWT. Another 48 patients (of 53) belonged to the PDE5I-NR group. Baseline efficacy was evaluated with the International Index of Erectile Function-Erectile Function domain questionnaire (IIEF-EF) for the PDE5I-R and with Erection Hardness Score, IIEF-EF, and flow-mediated dilation technique for the PDE5I-NR. Change in the IIEF-EF score after treatment of diabetes-induced ED with Li-ESWT in the PDE5i-R group vs the PDE5i-NR group. LI-ESWT therapy was found to be effective in both subgroups of diabetic patients. Minimally clinical important difference in IIEF-EF score was achieved in 50%, 79.5%, 77.3%, and 65.9% of the subjects in the active group in after the sixth shockwave (SW) treatment evaluation (just before initiating the seventh SW session) and at 1 month, 6 months, and 12 months after the last SW treatment, respectively. The difference among the groups was significant (P < .05) after the sixth treatment and in all the follow-up periods. In the PDE5I-NR group, 55% of the active group were converted to PDE5I-5-R after LI-ESWT. The difference between the active and sham groups was statistically significant in all the tested measures (P < .001). LI-ESWT is safe and effective for the treatment of ED in PDE5I-R and PDE5I-NR groups. Spivak L, Shultz T, Appel B, et al. Low-Intensity Extracorporeal Shockwave Therapy for Erectile Dysfunction in Diabetic Patients. Sex Med Rev 2021;9:619-627.


Method of Developing a Culturally Tailored Diabetes Intervention for American Indians.
American Indians have the highest prevalence of type 2 diabetes compared with any other racial or ethnic group. Developing a culturally tailored diabetes prevention and management intervention is one way to reduce diabetes-related health disparities among American Indian populations. The purpose of this article is to describe our approach for developing a diabetes prevention and management intervention study using Kolb's Experiential Learning Theory as the framework. To ensure the intervention study was culturally meaningful and relevant we used community-based participatory principles by partnering with a team of nurse researchers, tribal diabetes educators, tribal leaders, and tribal community members who were involved in all aspects of the study process. We conducted seven focus groups predominantly in rural American Indian communities in Oklahoma. Using focus group findings, the team collaboratively designed and developed a multi-generational diabetes prevention and management intervention study. The intervention group sessions will focus on ways to prevent and manage diabetes while the control group sessions will focus on general health education topics that have been identified by the team as important and relevant. Family interventions that involve multiple generations and provide emotional and behavioral support to those with type 2 diabetes and family members at risk may provide our best chance at improving diabetes-related outcomes and reducing health disparities in this critical population.


Diagnosing neurofibromatosis type I in children.
Neurofibromatosis is the single most common genetic disease of the neurologic system. Because neurofibromatosis type 1 (NF-1) is often diagnosed early in life, it is essential that health care providers deepen their understanding of this common genetic disorder. Children who meet particular criteria, as formulated by the National Institutes of Health, must be worked-up for NF-1 in order to initiate appropriate treatment implementation and evaluation. This article provides a review of the literature regarding the pathophysiology, clinical manifestations, and plan of treatment related to NF-1, specifically as it affects children. Clear guidelines for health care providers in primary care are outlined.


Total blindness after trivial frontal head trauma: bilateral indirect optic nerve injury.
A 10-year-old girl developed bilateral blindness and partial third nerve paresis immediately following a closed head injury. Bilateral optic atrophy developed subsequently. This is the first report of an association between second and third nerve injuries after minor head trauma in the absence of a preexisting lesion. The pathophysiology of indirect injury to the optic nerve under these circumstances is uncertain, but the lesions in this patient seemed to be due to ischemia.


Fluorescent sensing of fluoride in cellular system.
Fluoride ions have the important roles in a lot of physiological activities related with biological and medical system, such as water fluoridation, caries treatment, and bone disease treatment. Great efforts have been made to develop new methods and strategies for F(-) detection in the past decades. Traditional methods for the detection of F(-) including ion chromatography, ion-selective electrodes, and spectroscopic techniques have the limitations in the biomedicine research. The fluorescent probes for F(-) are very promising that overcome some drawbacks of traditional fluoride detection methods. These probes exhibit high selectivity, high sensitivity as well as quick response to the detection of fluoride anions. The review commences with a brief description of photophysical mechanisms for fluorescent probes for fluoride, including photo induced electron transfer (PET), intramolecular charge transfer (ICT), fluorescence resonance energy transfer (FRET), and excited-state intramolecular proton transfer (ESIPT). Followed by a discussion about common dyes for fluorescent fluoride probes, such as anthracene, naphalimide, pyrene, BODIPY, fluorescein, rhodamine, resorufin, coumarin, cyanine, and near-infrared (NIR) dyes. We divide the fluorescent probes for fluoride in cellular application systems into nine groups, for example, type of hydrogen bonds, type of cleavage of Si-O bonds, type of Si-O bond cleavage and cylization reactions, etc. We also review the recent reported carriers in the delivery of fluorescent fluoride probes. Seventy-four typical fluorescent fluoride probes are listed and compared in detail, including quantum yield, reaction medium, excitation and emission wavelengths, linear detection range, selectivity for F(-), mechanism, and analytical applications. Finally, we discuss the future challenges of the application of fluorescent fluoride probes in cellular system and in vivo. We wish that more and more excellent fluorescent fluoride probes will be developed and applied in the biomedicine field in the future.


Multispecialty medical groups: adapting to capitation.
Capitation payments are becoming a significant source of revenue for many multispecialty medical groups. These medical groups are discovering that financial success under capitation requires proper prospective evaluation and planning, diligent monitoring, and a sound understanding of insurance and risk concepts. The most successful groups will be those that can deliver quality medical care in the most cost-efficient manner.


p53 and bcl-2 overexpression as associated risk factors in patients 40 years old or less with transitional cell carcinoma of the bladder.
Transitional cell carcinoma (TCC) of the bladder in younger patients has historically a favourable prognosis. bcl-2 and p53 genes are implicated in cell cycle regulation with roles on programmed cell death. Presence of nuclear accumulation of p53 and cytoplasmic accumulation of bcl-2 were proposed to confer a growth advantage to tumour cells. In this study, we investigated the roles of p53 and bcl-2 as prognostic factors in TCC of bladder in patients younger than 40 years. From 1986 to 1998, 25 patients younger than 40 years were treated for TCC of bladder in our hospital. Of the tumour specimens, 24 were adequate for evaluating p53 and bcl-2 oncoproteins (group I). As a control (group II), we randomly selected 30 patients older than 50 years treated for bladder cancer in this period. Two oncoproteins were detected by immunohistochemical analysis in paired tumour tissue specimens in both groups. Retrospectively obtained clinical follow-up data were available, with a mean follow-up of 44 and 25.5 months in groups I and II, respectively. Relations between tumour recurrences and progression with positivity of bcl-2 and p53 were investigated. Expression of bcl-2 was observed in 13 (54.1%) and 11 (36.7%) and nuclear p53 accumulation in 9 (37.5%) and 17 (56.7%) of groups I and II, respectively. In the presence of p53 expression, tumours showed significantly more progression in group I (55 vs. 6.7%) and group II (41.1 vs. 0%). Recurrence rates were not significantly different in tumours with and without nuclear p53 overexpression in both groups. Also, recurrence and progression rates were not significantly different in tumours with and without cytoplasmic bcl-2 overexpression in both groups. Grade (G) and stage appeared as important prognostic factors in both groups since 60% of GIII tumours showed progression in group I, but none of GI and GII tumours. Similarly, 75% of T3 tumours progressed, while these rates were 25 and 25% for T1-T2 tumours in group I. In group II, 31.2, 25 and 0% of GIII, GII and GI tumours progressed, while 50, 41.6 and 0% of T3, T2 and T1 tumours progressed, respectively. Nuclear p53 expression in TCC appears to be associated with a poorer prognosis in both younger and older patients. Although cytoplasmic bcl-2 overexpression is found in the majority of tumours in the younger group, it is not associated with tumour progression and recurrence.


Mitochondria-associated gene expression perturbation predicts clinical outcomes and shows potential for targeted therapy in neuroblastoma.
Mitochondria have long been considered a potential target in cancer therapy because malignant cells are known for their altered energy production. However, there is a lack of comprehensive research on the involvement of mitochondria-associated proteins (MAPs) in neuroblastoma (NB), and their potential as therapeutic targets is yet to be fully explored. MAP genes were defined based on the protein-coding genes with mitochondrial localization. The mRNA expression patterns and dynamics of MAP genes associated with NB were investigated by integrating publicly available transcriptional profiles at the cellular and tissue levels. Multivariate Cox regression analysis was conducted to reveal the association of MAP genes with the overall survival (OS) and clinical subgroups of NB patients. The single-cell RNA-seq dataset and gene dependency screening datasets were analyzed to reveal the therapeutic potential of targeting MAP genes. We compiled a total of 1,712 MAP genes. We found the global and cell type-specific mRNA expression changes of the MAP genes associated with NB status and survival. Our analyses revealed a group of MAP gene signatures independent of MYCN-amplification status associated with NB outcome. We provided computational evidence with selected MAP genes showing good performance in predicting long-term prognosis. By analyzing gene dependency of the MAP genes in NB cell lines and ex vivo human primary T cells, we demonstrated the therapeutic potential of targeting several MAP genes in NB tumors. Collectively, our study provides evidence for the MAP genes as extended candidates in NB tumor stratification and staging, prognostic prediction, and targeted drug development.


Targeted disruption of S100P suppresses tumor cell growth by down-regulation of cyclin D1 and CDK2 in human hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The number of cases of HCC has continued to increase in recent decades. Previous studies have suggested that S100P, a member of the S100P calcium-binding protein family, is aberrantly regulated in several malignant neoplasms. However, the underlying molecular mechanisms of the dysregulation of S100P remain to be elucidated. To investigate biological effects of S100P on hepatocarcinogenesis, aberrant expression of S100P was investigated by immunohistochemistry (IHC), Western blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) in HCC tissues and cell lines. Endogenous expression of S100P was disrupted by the RNA interference-mediated protein knockdown method in the human Hep3B liver cancer cell line. Then, cell growth and cellular apoptosis were compared with control siRNA transfectants. The effects of S100P-silencing on the major components of cell cycle regulation were assessed by Western blot analysis. As results, elevated levels of S100P were observed in the HCC tissues compared to the corresponding normal tissues. Targeted disruption of S100P suppressed cell growth and augmented cellular apoptosis. In addition, inhibition of S100P resulted in the down-regulation of cyclinD1 and CDK2. In conclusion, this study showed over-expression of S100P in HCC. The aberrant regulation of S100P in HCC might activate cyclin D1 and CDK expression and contribute to the mitogenic potential of tumor cells during HCC carcinogenesis. These findings provide information that suggests new therapeutic strategies for the treatment of liver cancer.


[Evaluation of a new Israel infant soy formula].
A new infant soy formula has recently been developed in Israel and is being produced (Materna Tsimchit, Trima Industries, Kibbutz Ma'aborot). We compared its efficacy with that of a well-known imported soy formula (Isomil, Ross Laboratories, USA) in a prospective, randomized, double-blind study. 45 normal infants, aged 1-6 months, were monitored for over 2 months after the soy formula was started either because of cow-milk allergy or lactose intolerance. 22 received Materna Tsimchit and 23 Isomil. The study revealed no significant differences between the products with regard to compliance, behavior, symptoms, physical examination (including growth parameters and nutritional assessment), stool characteristics and complete blood counts. We conclude, given the limitations of the present study, that the new Israeli product is as effective as the foreign product.


Pathogenicity evaluation and the genotype-phenotype analysis of OPA1 variants.
Autosomal dominant optic atrophy (ADOA) is an important cause of irreversible visual impairment in children and adolescents. About 60-90% of ADOA is caused by the pathogenic variants of OPA1 gene. By evaluating the pathogenicity of OPA1 variants and summarizing the relationship between the genotype and phenotype, this study aimed to provide a reference for clinical genetic test involving OPA1. Variants in OPA1 were selected from the exome sequencing results in 7092 cases of hereditary eye diseases and control groups from our in-house data. At the same time, the urine cells of some optic atrophy patients with OPA1 variants as well as their family members were collected and oxygen consumption rates (OCR) were measured in these cells to evaluate the pathogenicity of variants. As a result, 97 variants were detected, including 94 rare variants and 3 polymorphisms. And the 94 rare variants were classified into three groups: pathogenic (33), variants of uncertain significance (19), and likely benign (42). Our results indicated that the frameshift variants at the 3' terminus might be pathogenic, while the variants in exon 7 and intron 4 might be benign. The penetrance of the missense variants was higher than that of truncation variants. The OCR of cells with pathogenic OPA1 variants were significantly lower than those without pathogenic variants. In conclusion, some variants might be benign although predicted pathogenic in previous studies while some might have unknown pathogenesis. Measuring the OCR in urine cells could be used as a method to evaluate the pathogenicity of some OPA1 variants.


Autocorrelation analysis for the unbiased determination of power-law exponents in single-quantum-dot blinking.
We present an unbiased and robust analysis method for power-law blinking statistics in the photoluminescence of single nanoemitters, allowing us to extract both the bright- and dark-state power-law exponents from the emitters' intensity autocorrelation functions. As opposed to the widely used threshold method, our technique therefore does not require discriminating the emission levels of bright and dark states in the experimental intensity timetraces. We rely on the simultaneous recording of 450 emission timetraces of single CdSe/CdS core/shell quantum dots at a frame rate of 250 Hz with single photon sensitivity. Under these conditions, our approach can determine ON and OFF power-law exponents with a precision of 3% from a comparison to numerical simulations, even for shot-noise-dominated emission signals with an average intensity below 1 photon per frame and per quantum dot. These capabilities pave the way for the unbiased, threshold-free determination of blinking power-law exponents at the microsecond time scale.


The vaginal microbiome amplifies sex hormone-associated cyclic changes in cervicovaginal inflammation and epithelial barrier disruption.
Susceptibility to HIV is associated with the menstrual cycle and vaginal microbiome, but their collective impact on vaginal inflammation remains unclear. Here, we characterized the cervicovaginal proteome, inflammation, and microbiome community structure and function during the menstrual cycle. Cervicovaginal secretions were collected from regularly cycling women (n = 16) at median day 10, 16, and 24 of each menstrual cycle and analyzed by mass spectrometry, 16S rRNA gene sequencing, and a multiplex bead array immunoassay. Follicular, ovulatory, and luteal phases were defined by serum sex hormone levels. Ovulation showed the largest mucosal proteome changes, where 30% and 19% of the 406 human proteins identified differed compared to the luteal and follicular phases, respectively. Neutrophil/leukocyte migration pathways were lowest during ovulation and peaked in the luteal phase, while antimicrobial and epithelial barrier promoting proteins were highest during ovulation. Vaginal microbial community structure and function did not vary significantly during the menstrual cycle, with the majority consistently Lactobacillus-dominant (63%) or non-Lactobacillus-dominant (25%). Fluctuations in the epithelial barrier protein RPTN between the ovulatory and luteal phase were amplified in women with Gardnerella vaginalis and anaerobic bacteria and reduced when Lactobacillus was dominant. This small study demonstrates that sex hormones modulate neutrophil/leukocyte inflammation, barrier function, and antimicrobial pathways in the female genital tract with the strongest changes occurring during ovulation. The data further suggest a microbiome context for hormone-driven changes in vaginal immunity which may have implications for HIV susceptibility.


Mothers' knowledge of and attitudes toward human milk banking in South Australia: a qualitative study.
The beneficial effects of breastfeeding for mothers and babies are well recognized. When maternal breast milk is not available in sufficient quantity, donor breast milk is recommended as an alternate source of nutrition, particularly in preterm and other high-risk infants. Australia lags behind the rest of the developed world in establishing and promoting human milk banks; there is no human milk bank in South Australia and little is known concerning mothers' perceptions of using human milk banks in that state. This study explored mothers' knowledge of and attitudes toward human milk banks, to inform the development of human milk banking policies and guidelines in South Australia should a milk bank be established. In-depth semistructured interviews were conducted with 12 mothers who were breastfeeding and/or had preterm or sick babies. In addition, 2 focus groups were conducted-1 with breastfeeding mothers as potential donors (n = 5) and the other with mothers of preterm or high-risk infants (n = 4)-to answer questions raised by early analysis of the individual interview data. Breastfeeding mothers, as potential donors, unanimously supported donating their breast milk to a human milk bank, provided it would be easy (especially if required to drop off milk) and not overly time consuming. Mothers of preterm or sick infants would use a human milk bank if they were assured the milk was safe and appropriate for their babies. Study participants would welcome having access to a human milk bank for both donating and receiving milk in South Australia.


Physiologically Based Pharmacokinetic Modelling of Cabotegravir Microarray Patches in Rats and Humans.
Microarray patches (MAPs) are currently under investigation as a self-administered, pain-free alternative used to achieve long-acting (LA) drug delivery. Cabotegravir is a potent antiretroviral that has demonstrated superior results over current pre-exposure prophylaxis (PrEP) regimens. This study aimed to apply physiologically based pharmacokinetic (PBPK) modelling to describe the pharmacokinetics of the dissolving bilayer MAP platform and predict the optimal dosing strategies for a once-weekly cabotegravir MAP. A mathematical description of a MAP was implemented into a PBPK model, and empirical models were utilised for parameter estimation. The intradermal PBPK model was verified against previously published in vivo rat data for intramuscular (IM) and MAP administration, and in vivo human data for the IM administration of LA cabotegravir. The verified model was utilised for the prediction of 300 mg, 150 mg and 75 mg once-weekly MAP administration in humans. Cabotegravir plasma concentrations >4 × protein-adjusted 90% inhibitory concentration (PA-IC90) (0.664 µg/mL) and >8 × PA-IC90 (1.33 µg/mL) were set as targets. The 75 mg, 150 mg and 300 mg once-weekly cabotegravir MAP regimens were predicted to sustain plasma concentrations >4 × PA-IC90, while the 300 mg and 150 mg regimens achieved plasma concentrations >8 × PA-IC90. These data demonstrate the potential for a once-weekly cabotegravir MAP using practical patch sizes for humans and inform the further development of cabotegravir MAPs for HIV PrEP.


The Utility of Ambulatory Blood Pressure Monitoring for Diagnosing White Coat Hypertension in Older Adults.
The beneficial effect of antihypertensive medication on reducing the risk of cardiovascular disease (CVD) events is supported by data from randomized controlled trials of older adults with hypertension. However, in clinical practice, overtreatment of hypertension in older adults may lead to side effects and an increased risk of falls. The diagnosis and treatment of hypertension is primarily based on blood pressure measurements obtained in the clinic setting. Ambulatory blood pressure monitoring (ABPM) complements clinic blood pressure by measuring blood pressure in the out-of-clinic setting. ABPM can be used to identify white coat hypertension, defined as elevated clinic blood pressure and non-elevated ambulatory blood pressure. White coat hypertension is common in older adults but does not appear to be associated with an increased risk of CVD events among this population. Herein, we review the current literature on ABPM in the diagnoses of white coat hypertension in older adults, including its potential role in preventing overtreatment.


Molecular surveillance of HIV-1 field strains in Nigeria in preparation for vaccine trials.
We conducted a national molecular epidemiologic survey of HIV-1 strains in Nigeria to determine the most prevalent subtype(s) for use in developing candidate vaccines. A total of 230 HIV-1-positive blood samples collected from 34 of the 36 Nigerian states were analyzed by our modified env gp41-based heteroduplex mobility assay (HMA) and/or gp41 sequencing and analysis. Overall, 103 (44.8%) were subtype A, 125 (54.3%) were subtype G, one (0.4%) was subtype C, and one (0.4%) was subtype J, and one (0.4%) was unclassifiable. To further characterize Nigerian viruses to aid in strain selection for candidate vaccines, one gp41 subtype G and five gp41 subtype A strains were selected for full envelope sequencing. The one subtype G sequence had consistent phylogenies throughout gp160, using programs to detect recombination. However, all five sequences that were primarily subtype A in gp41 were found to be recombinant viruses. Two of the five (40%) were A/G/J mosaics with common breakpoints. The remaining three gp160 recombinants all had their own unique break points: two A/? and one A/?/G, however, all five had the majority of their mosaic breakpoints occurring in gp41. None of the five were consistent with the circulating recombinant form (CRF)02_AG strain previously reported to be prevalent in West Africa. In conclusion, we showed a clear dominance and widespread distribution of gp41 subtypes A and G in fairly equal proportions, suggesting that vaccines designed for use in this geographic locale should incorporate the gene(s) of both subtypes. However, appreciating the magnitude of diversity of HIV-1 strains in Nigeria may require sequencing and analysis of longer gene regions for the identification of prevalent or emerging CRFs.


Calcium-ion efflux from brain tissue: power-density versus internal field-intensity dependencies at 50-MHz RF radiation.
In previous experiments changes were found in calcium-ion efflux from chick-brain tissue that had been exposed in vitro to 147-MHz radiation across a specific range of power densities when the field was amplitude modulated at 16 Hz. In the present study, 50-MHz radiation, similarly modulated as a sinusoid, was found to produce changes in calcium-ion efflux from chick brains exposed in vitro in a Crawford cell. Exposure conditions were optimized to broaden any power-density window and to enhance the opportunity to detect changes in the calcium-ion efflux. The results of a power-density series demonstrated two effective ranges: One spanning a range from 1.44 to 1.67 mW/cm2, and the other including 3.64 mW/cm2, which were bracketed by no-effect results at 0.72, 2.17, and 4.32 mW/cm2. peaks of positive findings are associated with near-identical rates of energy absorption: 1.4 microW/g at 147 MHz, and 1.3 microW/g at 50 MHz, which indicates that the enhanced-efflux phenomenon is more dependent on the intensity of fields in the brain than on the power density of incident radiation. In addition, the phenomenon appears to occur at multiples of some, as yet unknown, rate of radiofrequency (RF) energy absorption. Because of the extremely small increments of temperature associated with positive findings (less than 4 X 10(-4) degrees C), and the existence of more than one productive absorption rate, a solely thermal explanation appears extremely unlikely.


Effect of Postactivation Potentiation Induced by Elastic Resistance on Kinematics and Performance in a Roundhouse Kick of Trained Martial Arts Practitioners.
Aandahl, HS, Von Heimburg, E, and Van den Tillaar, R. Effect of postactivation potentiation induced by elastic resistance on kinematics and performance in a roundhouse kick of trained martial arts practitioners. J Strength Cond Res 32(4): 990-996, 2018-The aim of this study was to examine whether kicking with elastic resistance during warm-up could initiate postactivation potentiation (PAP), and thereby positively influence kinematics and performance on subsequent explosive roundhouse kicking. Five women and 11 men (n = 16) with a background in kickboxing (n = 10) or taekwondo (n = 6) performed 2 warm-up strategies with 3 subsequent test kicks 5-8 minutes after a PAP-inducing exercise. Kicking performance, defined as roundhouse kicking velocity with the foot, was measured using 3D motion capture (500 Hz) with a 15 marker lower-body 3D model. In addition, electromyography of the prime movers-vastus lateralis, vastus medialis, and rectus femoris muscles-was measured to confirm the presence of PAP. Kicking velocity of the foot increased by 3.3% after performing a warming-up strategy including kicking with elastic resistance (p = 0.009, η = 0.32). Increases were also recorded in muscle activity in vastus medialis (35.2%, p = 0.05, η = 0.18) and rectus femoris (43.9%, p = 0.04, η = 0.20). These findings indicate that performing a warm-up strategy including kicking with elastic resistance can have a positive effect on kicking performance in a roundhouse kick.


The general stress response factor EcfG regulates expression of the C-2 hopanoid methylase HpnP in Rhodopseudomonas palustris TIE-1.
Lipid molecules preserved in sedimentary rocks facilitate the reconstruction of events that have shaped the evolution of the Earth's biosphere. A key limitation for the interpretation of many of these molecular fossils is that their biological roles are still poorly understood. Here, we use Rhodopseudomonas palustris TIE-1 to identify factors that induce biosynthesis of 2-methyl hopanoids (2-MeBHPs), progenitors of 2-methyl hopanes, one of the most abundant biomarkers in the rock record. This is the first dissection of the regulation of hpnP, the gene encoding the C-2 hopanoid methylase, at the molecular level. We demonstrate that EcfG, the general stress response factor of alphaproteobacteria, regulates expression of hpnP under a variety of challenges, including high temperature, pH stress, and presence of nonionic osmolytes. Although higher hpnP transcription levels did not always result in higher amounts of total methylated hopanoids, the fraction of a particular kind of hopanoid, 2-methyl bacteriohopanetetrol, was consistently higher in the presence of most stressors in the wild type, but not in the ΔecfG mutant, supporting a beneficial role for 2-MeBHPs in stress tolerance. The ΔhpnP mutant, however, did not exhibit a growth defect under the stress conditions tested except in acidic medium. This indicates that the inability to make 2-MeBHPs under most of these conditions can readily be compensated. Although stress is necessary to regulate 2-MeBHP production, the specific conditions under which 2-MeBHP biosynthesis is essential remain to be determined.


Novel genes influencing the expression of the yellow locus and mdg4 (gypsy) in Drosophila melanogaster.
We used a system with a mobilized Stalker transposable element, sometimes in combination with P-M hybrid dysgenesis, in the search for new mutations interfering with the y2 mutation induced by mdg4 (gypsy) insertion into the yellow locus. A novel gene, modifier of mdg4, was detected in chromosome 3. The mutation mod(mdg4) either enhanced or suppressed phenotypic changes in different mutations induced by mdg4 insertions. Thus, mod(mdg4) seems to be involved in the control of mdg4 expression. Six other loci designated as enhancers of yellow were also detected. The e(y)n (with n from 1-6) mutations enhanced the expression of several y mutations induced by different insertions into the yellow locus. The major change is a damage of bristle and hair pigmentation which is not suppressed by su(Hw) mutations. On the other hand, e(y)n alleles do not interact with mdg4 induced mutations in other loci. All e(y)n genes are located in different regions of the X chromosome. One may speculate that e(y)n genes are involved in trans-regulation of the yellow locus and possibly of some other loci.


Mutations in alpha-tubulin promote basal body maturation and flagellar assembly in the absence of delta-tubulin.
We have isolated suppressors of the deletion allele of delta-tubulin, uni3-1, in the biflagellate green alga Chlamydomonas reinhardtii. The deletion of delta-tubulin produces cells that assemble zero, one or two flagella and have basal bodies composed primarily of doublet rather than triplet microtubules. Flagellar number is completely restored in the suppressed strains. Most of the uni3-1 suppressors map to the TUA2 locus, which encodes alpha2-tubulin. Twelve independent tua2 mutations were sequenced. Amino acids D205 or A208, which are nearly invariant residues in alpha-tubulin, were altered. The tua2 mutations on their own have a second phenotype - they make the cells colchicine supersensitive. Colchicine supersensitivity itself is not needed for suppression and colchicine cannot phenocopy the suppression. The suppressors partially restore the assembly of triplet microtubules. These results suggest that the delta-tubulin plays two roles: it is needed for extension or stability of the triplet microtubule and also for early maturation of basal bodies. We suggest that the mutant alpha-tubulin promotes the early maturation of the basal body in the absence of delta-tubulin, perhaps through interactions with other partners, and this allows assembly of the flagella.


Spur-of-the-Moment Modification in National Treatment Policies Leads to a Surprising HCV Viral Suppression in All Treated Patients: Real-Life Egyptian Experience.
The aim of this study was to retrospectively analyze the outcome of an unscheduled change in national Egyptian policies for the treatment of hepatitis C virus (HCV), which was transpired as a result of a reduction in interferon supplies, and to manage patients who already started interferon-based therapy. After completing a priming 4-weeks course of sofosbuvir/pegylated interferon/ribavirin (SOF/PEG IFN/RBV), a 12-weeks course of sofosbuvir/daclatasvir (SOF/DCV) combination was initiated. We evaluated the sustained virologic response at 12 weeks posttreatment (SVR12) for 2 groups of patients; Group 1, which included patients who had the previous regimen with IFN priming, and group 2, which included the first consecutive group of patients who received SOF/DCV for 12 weeks from the start without IFN priming. All group 1 patients (1,214 patients) achieved SVR12 (100%) and this was statistically significant when compared with the overall SVR12 in group 2 [8,869 patients with sustained virologic response [SVR] of 98.9%] (P value <0.001). No serious adverse events were reported in both groups. In this real-life treatment experience, interferon-based directly acting antiviral treatment with SOF/PEG IFN/RBV as a priming for 4 weeks, followed by SOF/DCV combination for 12 weeks, led to HCV viral suppression in all treated patients.


Shared Decision-Making in Palliative Care: A Maternalistic Approach.
During goals of care conversations, palliative care clinicians help patients and families determine priorities of care and align medical care with those priorities. The style and methods of communicating with families and negotiating a care plan can range from paternalistic to entirely patient driven. In this paper, we describe a case in which the palliative care clinician approached decision-making using a paradigm that is intuitive to many clinicians and which seems conceptually sound, but which has not been fully explored in the bioethics literature. This paradigm, termed maternalism, allows the clinician to direct decision-making within a relationship such that best interests and autonomy are mutually reinforced, thus reflecting relational autonomy as opposed to individual autonomy. We explore whether this method is appropriate in this case and explain how it captures significant ethical features of the case that might be missed by other approaches.


Review of direct-acting antiviral agents for the treatment of chronic hepatitis C.
Rapid breakthroughs in the treatment of hepatitis C virus (HCV) infection have dramatically altered the treatment landscape for this chronic disease. In 2011, the protease inhibitors (PIs) boceprevir and telaprevir in combination with peginterferon (peg-IFN) and ribavirin (RBV) were the first direct-acting antivirals (DAAs) approved in the United States for treatment of genotype (GT) 1 HCV. Several DAAs currently in late-stage clinical trials, including NS3/NS4A serine PIs, NS5A inhibitors, NS5B polymerase inhibitors (both nucleoside and non-nucleoside) and cyclophilin inhibitors, both with and without peg-IFN and RBV, are promising for the treatment of HCV. DAA regimens offer several advantages including that they specifically target HCV viral replication and thus appear to be less dependent on host characteristics, very high SVR rates accompanied by fewer side effects (SE) and lower pill burdens. A review on the treatment of HCV is important and timely as the development on DAAs is progressing rapidly and the health-care providers need to be aware about this as these regimens are anticipated to become clinically available soon. The literature was searched and reviewed using PubMed as well as data gathered from those presented at the international liver meetings, AASLD and EASL as well as CROI. With the potential of eliminating IFN and RBV, several DAAs under clinical development appear to be promising using novel approaches with good antiviral effects, shorter duration and lower SE profile.


Bridging Tumorigenesis and Therapy Resistance With a Non-Darwinian and Non-Lamarckian Mechanism of Adaptive Evolution.
Although neo-Darwinian (and less often Lamarckian) dynamics are regularly invoked to interpret cancer's multifarious molecular profiles, they shine little light on how tumorigenesis unfolds and often fail to fully capture the frequency and breadth of resistance mechanisms. This uncertainty frames one of the most problematic gaps between science and practice in modern times. Here, we offer a theory of adaptive cancer evolution, which builds on a molecular mechanism that lies outside neo-Darwinian and Lamarckian schemes. This mechanism coherently integrates non-genetic and genetic changes, ecological and evolutionary time scales, and shifts the spotlight away from positive selection towards purifying selection, genetic drift, and the creative-disruptive power of environmental change. The surprisingly simple use-it or lose-it rationale of the proposed theory can help predict molecular dynamics during tumorigenesis. It also provides simple rules of thumb that should help improve therapeutic approaches in cancer.


Hepatitis B and C viruses: molecular identification and targeted antiviral therapies.
Four agents are in clinical development for the treatment of chronic hepatitis B infection. These nucleoside analogs are incorporated into the growing DNA chain and terminate replication. Lamivudine, a cytadine analog that inhibits the synthesis of negative strand DNA from pre-genomic RNA, predictably inhibits replication and improves liver enzymes and histology in infected individuals. Following cessation of treatment, relapse is common, and genetic causes of viral resistance have been described. Other drugs for HBV infection include famciclovir, a guanosine analog that has also shown to suppress replication in immunocompetent as well as in immunocompromised patients; lobucavir, a guanosine analog; and adevfovir, an adenine nucleotide analog. The future of drug therapy against HBV likely includes combination agents with one or more nucleoside/nucleotide analogs and immune stimulants, such as interferon, or therapeutic vaccines. Recent advances in the treatment of HCV have been less impressive. An effective vaccine is greatly needed yet development in the near future is unlikely. Recommendations for therapy of chronic HCV have been proposed following the National Institutes of Health Consensus Conference. Interferon alpha is advised in patients with elevated serum alanine aminotransferases and liver histology demonstrating active hepatitis, regardless of level of pretreatment viremia or infecting genotype. Therapy should be continued for three months, at which time response should be assessed. If a biochemical and/or virological response has been achieved, treatment should be continued for a year. Trials are underway to evaluate interferon in combination with ribavirin. Recent identification of the crystalline structure of the HCV NS3 protease promises development of effective inhibitors of this critical viral enzyme.


[The evolutionary problems of the family of human and animal macroglobulins].
Studies have been made on physicochemical and immunochemical properties of macroglobulins, as well as of associated with pregnancy glycoproteins, from human subjects, mammals, birds, fishes and invertebrates. It was shown that these proteins exhibit similar composition, structure and capacity to bind proteinases inhibiting the latter. Using immunochemical methods, reactions of antigenic identity of these proteins were investigated. A hypothesis of evolutionary formation of macroglobulin family is discussed.


Intracellular ion content of skeletal muscle measured by instrumental neutron activation analysis.
The intracellular contents of sodium (Na+), potassium (K+), calcium (Ca2+), magnesium (Mg2+), and chloride (Cl-) in rat hindlimb muscles (soleus, plantaris, white and red gastrocnemii) were measured by instrumental neutron activation analysis (INAA) and atomic absorption spectrophotometry (AAS). Muscle extracellular fluid volume (ECFV) was determined using [3H]mannitol, [14C]mannitol, [3H]polyethylene glycol (PEG, mol wt 900, PEG-900) or the chloride (Cl) method and intracellular fluid volume (ICFV) calculated. Rats were anesthetized with pentobarbital sodium. The muscles were biopsied, frozen in liquid nitrogen, freeze-dried, weighed, and transferred to vials for analysis. For a given muscle, ion contents measured by the two methods showed a consistent small difference which could not be explained. The PEG-900 space and the Cl method yielded a larger ECFV than did mannitol; it is concluded that PEG-900 and Cl overestimate ECFV. There were significant differences in total tissue water (TTW), ECFV, ICFV, and intracellular ion contents between the different muscle types. The fast glycolytic muscles (white gastrocnemius, plantaris) had lower TTW (758 ml/kg wet wt) and ECFV (6.5-8.5% TTW) but the highest ICFV; the soleus (slow oxidative fibers) had the highest TTW (766 ml/kg wet wt) and ECFV (10-15% TTW) but the lowest ICFV. The fast-twitch white gastrocnemius and plantaris muscles have a higher intracellular content of K+ and lower Na+ and Cl- than the slow-twitch soleus muscle. The technique of INAA provides a rapid and accurate means of determining intramuscular ion content in small samples of tissue.


The SilenT AtRial FIBrillation (STAR-FIB) study programme - design and rationale.
Anticoagulation of patients with screen-detected atrial fibrillation may prevent ischaemic strokes. The STAR-FIB study programme aims to determine the age- and sex-specific prevalence of silent atrial fibrillation and to develop a clinical prediction model to identify patients at risk of undiagnosed atrial fibrillation in a hospitalised patient population. The STAR-FIB study programme includes a prospective cohort study and a case-control study of hospitalised patients aged 65–84 years, evenly distributed for both age and sex. We recruited 795 patients without atrial fibrillation for the cohort study (49.2% females; median age 74.8 years). All patients had three serial 7-day Holter ECGs to screen for silent atrial fibrillation. The primary endpoint will be any episode of atrial fibrillation or atrial flutter of ≥30 seconds duration. The age- and sex-specific prevalence of newly diagnosed atrial fibrillation will be estimated. For the case-control study, 120 patients with paroxysmal atrial fibrillation were recruited as cases (41.7% females; median age 74.6 years); controls will be randomly selected from the cohort study in a 2:1 ratio. All participants in the cohort study and all cases were prospectively evaluated including clinical, laboratory, echocardiographic and electrical parameters. A clinical prediction model for undiagnosed atrial fibrillation will be derived in the case-control study and externally validated in the cohort study. The STAR-FIB study programme will estimate the age- and sex-specific prevalence of silent atrial fibrillation in a hospitalised patient population, and develop and validate a clinical prediction model to identify patients at risk of silent atrial fibrillation.


Preparation of polysulfone microcapsules containing 1-octanol for the recovery of caprolactam.
Polysulphone (PSF) microcapsules containing 1-octanol were prepared with solvent extraction method for the recovery of caprolactam. One-step and two-step processes were, respectively, applied to prepare microcapsules. In order to get high extractant loading, a loading method with the assistance of ultrasound has been developed. With the two-step preparation process the extractant loss can be avoided. A very high extractant loading ratio of 5.96 g g(-1) and the maximum uptake to caprolactam of 65.6 mg g(-1) were achieved. Under the action of ultrasound the extractant loading efficiency is greatly intensified. With the one-step process 1-octanol loading ratio is highly limited. Only 1.74 g g(-1) loading ratio and 29.9 mg g(-1) uptake to caprolactam were realized. Meanwhile the extractant loss in the one-step process is serious. Considering extraction capacity and extractant loss in the preparation process, it is suggested that PSF microcapsules containing 1-octanol should be prepared with the two-step process. To fasten mass transfer rate, microcapsules with relatively smaller size are desired.


[The Dutch nursing concepts framework in registration and record systems].
This article reports on the results and method used in a literature review which was performed as a partial study in the Dutch National Pilot Research in Nursing Terminology. In this study literature stands for documents which are being used in nursing practice. The analysis of these documents points out that the Dutch practical nursing terminology is very heterogeneous. Concepts related to nursing diagnosis and nursing problems are used in many different ways. The arrangement of nursing terminology in general and of nursing diagnosis or nursing problems in particular, shows many dissimilarities. Indications for known classifications are small in number. There is a prodigious conceptual confusion. Community health care and mental health care show interesting efforts concerning classification, acute hospital care however only in a limited way. Community health care seems more advanced in establishing and systematizing nursing data. The results of this literature research indicate a large similarity with the results gathered at the other parts of the National Pilot Research in Nursing Terminology. The credibility of the results of this literature study is considered very high.


The RING-H2 gene LdXERICO plays a negative role in dormancy release regulated by low temperature in Lilium davidii var. unicolor.
Dormancy regulation is the basis of the sustainable development of the lily industry. Therefore, basic research on lily dormancy is crucial for innovation in lily cultivation and breeding. Previous studies revealed that dormancy release largely depends on abscisic acid (ABA) degradation. However, the key genes and potential regulatory network remain unclear. We used exogenous ABA and ABA inhibitors to elucidate the effect of ABA on lily dormancy. Based on the results of weighted gene coexpression network analysis (WGCNA), the hub gene LdXERICO was identified in modules highly related to endogenous ABA, and a large number of coexpressed genes were identified. LdXERICO was induced by exogenous ABA and expressed at higher levels in tissues with vigorous physiological activity. Silencing LdXERICO increased the low-temperature sensitivity of bulblets and accelerated bulblet sprouting. LdXERICO rescued the ABA insensitivity of xerico mutants during seed germination in Arabidopsis, suggesting that it promotes seed dormancy and supporting overexpression studies on lily bulblets. The significant increase in ABA levels in transgenic Arabidopsis expressing LdXERICO indicated that LdXERICO played a role by promoting ABA synthesis. We generated three transgenic lines by overexpressing LdICE1 in Arabidopsis thaliana and showed that, in contrast to LdXERICO, LdICE1 positively regulated dormancy release. Finally, qRT-PCR confirmed that LdXERICO was epistatic to LdICE1 for dormancy release. We propose that LdXERICO, an essential gene in dormancy regulation through the ABA-related pathway, has a complex regulatory network involving temperature signals. This study provides a theoretical basis for further exploring the mechanism of bulb dormancy release.


Heterogeneity in collagen biosynthesis by sprouting retinal endothelial cells.
Bovine retinal microvascular endothelial cells can display two distinct and reversible morphologies in culture: 'cobblestone' and 'sprouting'. The cobblestone morphology resembles the resting cells lining the lumen of mature vessels while the sprouting morphology resembles the angiogenic cells involved in the formation of new vessels. Retinal cells displayed some heterogeneity in the shape of the cells making up the cobblestone monolayer. In contrast, all cell lines displayed an identical sprouting morphology. We have investigated the synthesis of matrix macromolecules by retinal endothelial cells displaying either the cobblestone or the sprouting morphology. Type IV was the only collagen synthesised by eight different lines of early-passage (between one and six) cobblestone endothelial cells. Collagen types I and III were not detected in these cultures. In contrast, heterogeneity was observed in the types of collagen synthesized by four lines of early-passage cells displaying the sprouting morphology. That is, two lines synthesised collagen types, II, III and IV, whereas two other lines continued to synthesise only type IV collagen. Both cobblestone and sprouting cells synthesised fibronectin and thrombospondin, although the relative amounts of these macromolecules varied with culture conditions. The pattern of collagen synthesis by cobblestone cells was also affected by in vitro "ageing": 4/5 lines examined above passage eight synthesised collagen types I, III and IV. Our results indicate that there is heterogeneity in the sprouting phenotype displayed by retinal endothelial cells, and that this phenotype is not necessarily associated with the synthesis of type I collagen. We suggest that differences in the spectrum of matrix macromolecules synthesised by sprouting endothelial cells may play a role in the control of angiogenesis.


Cancer education interventions for rural populations.
To respond to major needs expressed by 15 farm family focus group participants, education interventions were designed to overcome barriers to primary prevention for skin cancer. Farmers are at high risk for developing skin cancer because of occupational exposure. In an attempt to increase skin cancer prevention education in a rural population, three demonstration projects were developed and field tested. Projects were designed to overcome barriers defined by the focus groups. One project evaluated a school-based education intervention. A second project evaluated a family-based education intervention. Knowledge gain was the evaluation endpoint of these two projects. Significant knowledge gain was demonstrated for these projects. A third project was designed to deliver skin cancer information directly to farmers using veterinarians. Farmers found this method of delivery acceptable.


Comparison of methodologies in determining bone marrow fat percentage under different environmental conditions.
The use of bone marrow fat percentage has been recommended in assessing body condition at the time of death in wild and domestic ruminants, but few studies have looked at the effects of time and exposure on animal bone marrow. We investigated the utility of bone marrow fat extraction as a tool for establishing antemortem body condition in postmortem specimens from sheep and cattle, particularly after exposure to high heat, and compared different techniques of fat extraction for this purpose. Femora were collected from healthy and "skinny" sheep and cattle. The bones were either frozen or subjected to 40°C heat; heated bones were either wrapped in plastic to minimize desiccation or were left unwrapped. Marrow fat percentage was determined at different time intervals by oven-drying, or by solvent extraction using hexane in manual equipment or a Soxhlet apparatus. Extraction was performed, where possible, on both wet and dried tissue. Multiple samples were tested from each bone. Bone marrow fat analysis using a manual, hexane-based extraction technique was found to be a moderately sensitive method of assessing antemortem body condition of cattle up to 6 d after death. Multiple replicates should be analyzed where possible. Samples from "skinny" sheep showed a different response to heat from those of "healthy" sheep; "skinny" samples were so reduced in quantity by day 6 (the first sampling day) that no individual testing could be performed. Further work is required to understand the response of sheep marrow.


Effect of high-dose thymidine infusions in patients with mycosis fungoides.
The antitumor effect of thymidine has been demonstrated in patients with leukemia and lymphoma. This report summarizes the treatment of three patients with mycosis fungoides, a chronic T-cell lymphoma. Four courses of thymidine (75 g/m2/day) were administered by continuous infusion for 4-7 days. Steady-state serum thymidine levels were in the range of 1-3 mM. Associated toxicities were minimal and consisted of milk headache and anorexia. Myelosuppression was manifested by transient declines in the peripheral leukocyte count. One patient had extensive clearing of diffuse erythematous plaques on the trunk and extremities that persisted for over one month. A second patient had partial clearing of plaques that persisted for two weeks following therapy and a third patient had a minimal response with 25% reduction in lymphadenopathy and noduloulcerative lesions. These responses indicate the effectiveness of thymidine as a single agent in the treatment of mycosis fungoides.


Structural basis for the coiled-coil architecture of human CtIP.
The DNA repair factor CtIP has a critical function in double-strand break (DSB) repair by homologous recombination, promoting the assembly of the repair apparatus at DNA ends and participating in DNA-end resection. However, the molecular mechanisms of CtIP function in DSB repair remain unclear. Here, we present an atomic model for the three-dimensional architecture of human CtIP, derived from a multi-disciplinary approach that includes X-ray crystallography, small-angle X-ray scattering (SAXS) and diffracted X-ray tracking (DXT). Our data show that CtIP adopts an extended dimer-of-dimers structure, in agreement with a role in bridging distant sites on chromosomal DNA during the recombinational repair. The zinc-binding motif in the CtIP N-terminus alters dynamically the coiled-coil structure, with functional implications for the long-range interactions of CtIP with DNA. Our results provide a structural basis for the three-dimensional arrangement of chains in the CtIP tetramer, a key aspect of CtIP function in DNA DSB repair.


Recovery of metagenomic data from the Aedes aegypti microbiome using a reproducible snakemake pipeline: MINUUR.
Background: Ongoing research of the mosquito microbiome aims to uncover novel strategies to reduce pathogen transmission. Sequencing costs, especially for metagenomics, are however still significant. A resource that is increasingly used to gain insights into host-associated microbiomes is the large amount of publicly available genomic data based on whole organisms like mosquitoes, which includes sequencing reads of the host-associated microbes and provides the opportunity to gain additional value from these initially host-focused sequencing projects. Methods: To analyse non-host reads from existing genomic data, we developed a snakemake workflow called MINUUR (Microbial INsights Using Unmapped Reads). Within MINUUR, reads derived from the host-associated microbiome were extracted and characterised using taxonomic classifications and metagenome assembly followed by binning and quality assessment. We applied this pipeline to five publicly available Aedes aegypti genomic datasets, consisting of 62 samples with a broad range of sequencing depths. Results: We demonstrate that MINUUR recovers previously identified phyla and genera and is able to extract bacterial metagenome assembled genomes (MAGs) associated to the microbiome. Of these MAGS, 42 are high-quality representatives with >90% completeness and <5% contamination. These MAGs improve the genomic representation of the mosquito microbiome and can be used to facilitate genomic investigation of key genes of interest. Furthermore, we show that samples with a high number of KRAKEN2 assigned reads produce more MAGs. Conclusions: Our metagenomics workflow, MINUUR, was applied to a range of Aedes aegypti genomic samples to characterise microbiome-associated reads. We confirm the presence of key mosquito-associated symbionts that have previously been identified in other studies and recovered high-quality bacterial MAGs. In addition, MINUUR and its associated documentation are freely available on GitHub and provide researchers with a convenient workflow to investigate microbiome data included in the sequencing data for any applicable host genome of interest.


Domoic Acid-Induced Neurotoxicity Is Mainly Mediated by the AMPA/KA Receptor: Comparison between Immature and Mature Primary Cultures of Neurons and Glial Cells from Rat Cerebellum.
Domoic acid (DomA) is a naturally occurring shellfish toxin that can induce brain damage in mammalians. Neonates have shown increased sensitivity to DomA-induced toxicity, and prenatal exposure has been associated with e.g. decreased brain GABA levels, and increased glutamate levels. Here, we evaluated DomA-induced toxicity in immature and mature primary cultures of neurons and glial cells from rat cerebellum by measuring the mRNA levels of selected genes. Moreover, we assessed if the induced toxicity was mediated by the activation of the AMPA/KA and/or the NMDA receptor. The expression of all studied neuronal markers was affected after DomA exposure in both immature and mature cultures. However, the mature cultures seemed to be more sensitive to the treatment, as the effects were observed at lower concentrations and at earlier time points than for the immature cultures. The DomA effects were completely prevented by the antagonist of the AMPA/KA receptor (NBQX), while the antagonist of the NMDA receptor (APV) partly blocked the DomA-induced effects. Interestingly, the DomA-induced effect was also partly prevented by the neurotransmitter GABA. DomA exposure also affected the mRNA levels of the astrocytic markers in mature cultures. These DomA-induced effects were reduced by the addition of NBQX, APV, and GABA.


Characterisation of the T-cell response to Ebola virus glycoprotein amongst survivors of the 2013-16 West Africa epidemic.
Zaire ebolavirus (EBOV) is a highly pathogenic filovirus which can result in Ebola virus disease (EVD); a serious medical condition that presents as flu like symptoms but then often leads to more serious or fatal outcomes. The 2013-16 West Africa epidemic saw an unparalleled number of cases. Here we show characterisation and identification of T cell epitopes in surviving patients from Guinea to the EBOV glycoprotein. We perform interferon gamma (IFNγ) ELISpot using a glycoprotein peptide library to identify T cell epitopes and determine the CD4+ or CD8+ T cell component response. Additionally, we generate data on the T cell phenotype and measure polyfunctional cytokine secretion by these antigen specific cells. We show candidate peptides able to elicit a T cell response in EBOV survivors and provide inferred human leukocyte antigen (HLA) allele restriction. This data informs on the long-term T cell response to Ebola virus disease and highlights potentially important immunodominant peptides.


Myeloablative radiochemotherapy followed by reinfusion of purged autologous stem cells for Waldenström's macroglobulinaemia.
Waldenström's macroglobulinaemia (WM) is an incurable lymphoproliferative disorder. The purpose of this study was to investigate the role of autologous peripheral blood stem cell transplantation (ASCT) for the treatment of WM. Seven patients (untreated or after first-line therapy) with symptomatic WM underwent two or three cycles of Dexa-BEAM chemotherapy + G-CSF with stem cell harvesting and proceeded to total body irradiation and high-dose cyclophosphamide followed by reinfusion of ex-vivo B-cell-depleted stem cells. Engraftment was prompt, and procedure-related deaths did not occur. A strong reduction or normalization of BM infiltration and serum IgM levels occurred in all evaluable patients, but immunofixation electrophoresis revealed persistent paraproteinaemia in five of them. With 3-30 months of follow-up, all patients are alive without clinical or serological signs of disease progression. This pilot trial shows for the first time that high-dose radiochemotherapy with purged stem cells is effective and may improve the course of patients with WM. In the majority of cases, however, complete eradication of the disease does not appear to be possible with ASCT alone.


Usefulness Of Glucocorticoids In The Management Of Foreign Body Aspiration.
Foreign body aspiration can be a life-threatening emergency. An aspirated solid or semi-solid object may lodge in the larynx, trachea or other breathing airways. If the object is large enough to cause nearly complete obstruction of the airway, asphyxia may rapidly cause death. We report a 19-year old man admitted with right lower lobe pneumonia who spontaneously expelled a foreign body, one day after admission and glucocorticoids administration. Glucocorticoids should be considered in foreign body aspiration management because improvement of the inflammatory reaction may facilitate expontaneous expulsion or foreign body extraction


Divergent subgenome evolution after allopolyploidization in African clawed frogs (Xenopus).
Whole genome duplication (WGD), the doubling of the nuclear DNA of a species, contributes to biological innovation by creating genetic redundancy. One mode of WGD is allopolyploidization, wherein each genome from two ancestral species becomes a 'subgenome' of a polyploid descendant species. The evolutionary trajectory of a duplicated gene that arises from WGD is influenced both by natural selection that may favour redundant, new or partitioned functions, and by gene silencing (pseudogenization). Here, we explored how these two phenomena varied over time and within allopolyploid genomes in several allotetraploid clawed frog species (Xenopus). Our analysis demonstrates that, across these polyploid genomes, purifying selection was greatly relaxed compared to a diploid outgroup, was asymmetric between each subgenome, and that coding regions are shorter in the subgenome with more relaxed purifying selection. As well, we found that the rate of gene loss was higher in the subgenome under weaker purifying selection and that this rate has remained relatively consistent over time after WGD. Our findings provide perspective from recently evolved vertebrates on the evolutionary forces that likely shape allopolyploid genomes on other branches of the tree of life.


Digital gene expression signatures for maize development.
Genome-wide expression signatures detect specific perturbations in developmental programs and contribute to functional resolution of key regulatory networks. In maize (Zea mays) inflorescences, mutations in the RAMOSA (RA) genes affect the determinacy of axillary meristems and thus alter branching patterns, an important agronomic trait. In this work, we developed and tested a framework for analysis of tag-based, digital gene expression profiles using Illumina's high-throughput sequencing technology and the newly assembled B73 maize reference genome. We also used a mutation in the RA3 gene to identify putative expression signatures specific to stem cell fate in axillary meristem determinacy. The RA3 gene encodes a trehalose-6-phosphate phosphatase and may act at the interface between developmental and metabolic processes. Deep sequencing of digital gene expression libraries, representing three biological replicate ear samples from wild-type and ra3 plants, generated 27 million 20- to 21-nucleotide reads with frequencies spanning 4 orders of magnitude. Unique sequence tags were anchored to 3'-ends of individual transcripts by DpnII and NlaIII digests, which were multiplexed during sequencing. We mapped 86% of nonredundant signature tags to the maize genome, which associated with 37,117 gene models and unannotated regions of expression. In total, 66% of genes were detected by at least nine reads in immature maize ears. We used comparative genomics to leverage existing information from Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa) in functional analyses of differentially expressed maize genes. Results from this study provide a basis for the analysis of short-read expression data in maize and resolved specific expression signatures that will help define mechanisms of action for the RA3 gene.


[Descriptive epidemiology of suicide in Spain (1906-1990)].
In Spain, suicide as a cause of death is increasing in different age groups in both sexes. The aim of the present work is to characterize the phenomenon of suicide. A retrospective descriptive epidemiological study was carried out. Data periodically published by the National Institute of Statistics (INE) on the statistical Incidence of Suicides in Spain (1906-1990) were analyzed, processed and tabulated. Suicide increases with age and this increase is more pronounced as from 40 years of age. The ratio between sexes is 3:1 in favour of men, although with a tendency to decrease. The most important causes of suicide are: physical suffering (27%), psychopathy (18%) and Daily Activities (DA) (17.5%). The method most used is hanging, which has been the case of 37% of the suicides committed in Spain during the study period (1906-1990). The risk factors associated with suicide are age, male sex, and physical and mental suffering.


Cardiorespiratory consequences of sleep apnoea syndrome in patients with massive obesity.
Assessment of cardiorespiratory consequences of sleep apnoea syndrome (SAS) is difficult owing to confounding factors, especially obesity, that are strongly associated with SAS. This study was designed to assess the cardiorespiratory consequences of SAS by comparing the results of a comprehensive cardiorespiratory evaluation in apnoeic and nonapnoeic patients with massive obesity. In a retrospective chart-review study, we studied 60 patients with massive obesity defined by a body mass index (BMI) >40 kg.m(-2), presenting no chronic respiratory disease, who underwent an extensive assessment of cardiorespiratory consequences of obesity, including overnight polysomnography, lung function tests, arterial blood gas analysis, evaluation of vascular risk factors, myocardial scintigraphy with dipyridamole stress-test, isotopic ventriculography, Doppler echocardiography and Holter electrocardiogram recording. SAS defined by an apnoea + hypopnoea index (AHI) > or = 10 was diagnosed in 42% of patients (25 out of 60). Mean+/-SD AHI of SAS-positive (SAS+) patients was 38+/-24. Age, BMI, ventilatory function parameters, prevalence of smoking history and diabetes mellitus did not differ significantly in SAS+ versus SAS-negative (SAS-) groups. The following complications were observed more frequently in SAS+ than in SAS- patients: daytime hypoxaemia (35 vs 9%, p<0.02), pulmonary arterial hypertension (36 vs 7%, p<0.05) and increased interventricular septal thickness (50 vs 15%, p<0.03). No association was found between SAS on the one hand and systemic arterial hypertension, coronary artery disease, left ventricular dysfunction and nocturnal cardiac arrhythmias on the other. Nocturnal apnoeas in massive obesity may thus be associated with moderate daytime hypoxaemia, mild pulmonary arterial hypertension and moderate left ventricular hypertrophy, but not with severe cardiorespiratory complications.


Real life treatment of diabetes mellitus type 2 patients: an analysis based on a large sample of 394,828 German patients.
The aim of this claims-based data analysis was to describe the care of German T2DM patients and to determine which subgroups could be differentiated in terms of the achieved T2DM-related treatment results, the underlying comorbidities, and the achieved comorbidity-related treatment results. We included all T2DM patients insured by a large sickness fund in 2010/2011. We defined 12 subgroups according to observed HbA1C, blood pressure and Charlson Comorbidity Index (CCI). For each subgroup, available sociodemographic and clinical information were reported. Different treatment variables were described. T2DM-related events leading to acute hospitalisations were reported. We included 394,828 T2DM patients in our analysis; for 228,703 patients' detailed data as basis for subgroup classification were available. For 4.5% of these patients, a HbA1C >9% was observed. 21,833 of the T2DM patients were affected by a T2DM-related event; the risk was 5.53% per patient year; 1.74% of the patients suffered from more than one event. Most frequent event types were hospitalisation with T2DM as primary diagnosis (2.39%), vascular interventions/stent implantations (1.92%), and ischaemic stroke (1.19%). There were significant differences between the observed subgroups in terms of T2DM-related event risk. Overall, our data indicate that the typically treated T2DM patient has a number of comorbidities and thus treatment focused solely on T2DM is neither possible nor clinically meaningful. Particularly those patients who reached HbA1C goals, but had also achieved relevant additional treatment goals reached low yearly T2DM event rates whereas subgroups failing to achieve one or several treatment goals are facing much higher event risks.


Coronary artery and mitral valve surgery in Takayasu's arteritis: a case report.
Concomitant coronary artery disease and mitral valve disease are rare in Takayasu's Arteritis. Our patient had Takayasu's Arteritis diagnosed 9 years ago. She had an inferior myocardial infarction and double stent implantation 8 months ago. She was admitted to the hospital for chest pain, and 3 vessel diseases were diagnosed with significant mitral regurgitation due to anterior leaflet prolapse. In this report, we present perioperative management of our patient who underwent coronary artery bypass grafting and mitral valve replacement.


Safety of the One Step Percutaneous Endoscopic Gastrostomy (Push-PEG) Button in Pediatric Patients.
Percutaneous Endoscopic Gastrostomy (PEG) - Systems are essential tools for enteral feeding in a broad variety of pediatric patients. The One Step ("Push-PEG") technique allows the direct introduction of a PEG-Button. The aim of the study was to investigate the safety and parental view of the Push-PEG technique. We conducted a single-center retrospective data and questionnaire (SDC, http://links.lww.com/MPG/D296 ) based study including all pediatric patients receiving a PEG via push or pull technique between 2015 until end of 2020 and compared these two groups. The primary outcome was the detection of minor and major complications. Secondary outcomes were growth, thriving and parental contentment using a likert-scaled questionnaire . 83 patients were included in the analysis. There were no significant differences in the basic data regarding age, weight or diagnosis category. Overall complication rate was 34,9%. The Push-PEG group showed a lower rate of complications (32,7% vs 38,7%) and a lower rate of major complications (4.1% vs 8,8%), although the difference is not significant. 34 families completed the questionnaire (SDC, http://links.lww.com/MPG/D296 ) (response rate 40%). There were no significant differences between the two groups regarding answers of the likert-scaled questions. Push-PEG placement seems to be as safe as placement via traditional pull technique, even in small infants more than 2.8 months and 4 kg. As Push-PEG placement requires less follow-up interventions it may show significant advantages and could be the method of first choice in many cases.


Association of MDR1 gene SNPs and haplotypes with the tacrolimus dose requirements in Han Chinese liver transplant recipients.
This work seeks to evaluate the association between the C/D ratios (plasma concentration of tacrolimus divided by daily dose of tacrolimus per body weight) of tacrolimus and the haplotypes of MDR1 gene combined by C1236T (rs1128503), G2677A/T (rs2032582) and C3435T (rs1045642), and to further determine the functional significance of haplotypes in the clinical pharmacokinetics of oral tacrolimus in Han Chinese liver transplant recipients. The tacrolimus blood concentrations were continuously recorded for one month after initial administration, and the peripheral blood DNA from a total of 62 liver transplant recipients was extracted. Genotyping of C1236T, G2677A/T and C3435T was performed, and SNP frequency, Hardy-Weinberg equilibrium, linkage disequilibrium, haplotypes analysis and multiple testing were achieved by software PLINK. C/D ratios of different SNP groups or haplotype groups were compared, with a p value<0.05 considered statistically significant. Linkage studies revealed that C1236T, G2677A/T and C3435T are genetically associated with each other. Patients carrying T-T haplotype combined by C1236T and G2677A/T, and an additional T/T homozygote at either position would require higher dose of tacrolimus. Tacrolimus C/D ratios of liver transplant recipients varied significantly among different haplotype groups of MDR1 gene. Our studies suggest that the genetic polymorphism could be used as a valuable molecular marker for the prediction of tacrolimus C/D ratios of liver transplant recipients.


Latitudinal Effect in the Transfer of Radiocarbon from Stratosphere to Troposphere.
Latitudinal variations in the descent of bomb-produced radiocarbon from the stratosphere is suggested by differences in tropospheric carbon-14 activity. The magnitude of a similar latitudinal effect in the pre-bomb steady state is estimated. This effect may be part of the explanation of the short-term oscillations in carbon-14 activity found in treerings from the last 1300 years.


Overexpression of ANAC046 Promotes Suberin Biosynthesis in Roots of Arabidopsis thaliana.
NAC (NAM (no apical meristem), ATAF1/2, and CUC2 (cup-shaped cotyledon)) proteins are one of the largest families of plant-specific transcription factors, and this family is present in a wide range of land plants. Here, we have investigated the role of ANAC046 in the regulation of suberin biosynthesis and deposition in Arabidopsis. Subcellular localization and transcriptional activity assays showed that ANAC046 localizes in the nucleus, where it functions as a transcription activator. Analysis of the PANAC046:GUS lines revealed that ANAC046 is mainly expressed in the root endodermis and periderm, and is also induced in leaves by wounding. The transgenic lines overexpressing ANAC046 exhibited defective surfaces on the aerial plant parts compared to the wild-type (WT) as characterized by increased permeability for Toluidine blue stain and greater chlorophyll leaching. Quantitative RT-PCR analysis showed that the expression of suberin biosynthesis genes was significantly higher in the roots and leaves of overexpression lines compared to the WT. The biochemical analysis of leaf cuticular waxes showed that the overexpression lines accumulated 30% more waxes than the WT. Concurrently, overexpression lines also deposited almost twice the amount of suberin content in their roots compared with the WT. Taken together, these results showed that ANAC046 is an important transcription factor that promotes suberin biosynthesis in Arabidopsis thaliana roots.


PAX7 target genes are globally repressed in facioscapulohumeral muscular dystrophy skeletal muscle.
Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to hypomethylation of D4Z4 repeats on chromosome 4q causing expression of the DUX4 transcription factor. However, DUX4 is difficult to detect in FSHD muscle biopsies and it is debatable how robust changes in DUX4 target gene expression are as an FSHD biomarker. PAX7 is a master regulator of myogenesis that rescues DUX4-mediated apoptosis. Here, we show that suppression of PAX7 target genes is a hallmark of FSHD, and that it is as major a signature of FSHD muscle as DUX4 target gene expression. This is shown using meta-analysis of over six FSHD muscle biopsy gene expression studies, and validated by RNA-sequencing on FSHD patient-derived myoblasts. DUX4 also inhibits PAX7 from activating its transcriptional target genes and vice versa. Furthermore, PAX7 target gene repression can explain oxidative stress sensitivity and epigenetic changes in FSHD. Thus, PAX7 target gene repression is a hallmark of FSHD that should be considered in the investigation of FSHD pathology and therapy.