A preliminary assessment of police officers' knowledge and perceptions of persons with disabilities.
Individuals with developmental disabilities are 4 to 10 times more likely to become crime victims than individuals without disabilities (D. Sobsey, D. Wells, R. Lucardie, & S. Mansell, 1995). Victimization rates for persons with disabilities is highest for sexual assault (more than 10 times as high) and robbery (more than 12 times as high). There are a number of factors related to individuals' with disabilities susceptibility to interactions with the criminal justice system. In addition to these factors, many significant barriers exist, both real and perceived, that limit investigation and prosecution of these cases. How police officers perceive and understand disability play significant roles in how these cases develop and evolve. The purpose of this study was to assess police officer knowledge and perceptions of persons with disabilities.


Self-Hybrid Transition Metal Oxide Nanosheets Synthesized by a Facile Programmable and Scalable Carbonate-Template Method.
2D transition metal oxides (TMO) nanosheets have attracted considerable attention in both fundamental research and practical applications. Herein, a convenient programmable and scalable carbonate crystals templating synthesis is developed to produce high-quality self-hybrid TMO nanosheets (Si-WO3- x , Tax Oy , Mnx Oy ) and their respective polymetallic oxide hybrid nanosheets with tunable composition, low-cost and high-yield. Taking tungsten oxide nanosheets as example, silicotungstic acid precursor is in situ converted into tungsten oxide nanosheets like scales on the surface of calcium carbonate crystals through the simple soaking-drying-calcination process, and after selectively dissolving calcium carbonate by etching, the dispersive tungsten oxide nanosheets with unique self-hybrid Si-doped h-WO3 /ε-WO3 /WO2 compositions are obtained, which show excellent acetone gas-sensing performances at low temperatures. This carbonate-template method opens up the possibility to economically produce various functional TMO nanosheets with specific compositions for diverse applications.


Virological safety of the UK blood supply in the era of individual risk assessments and HIV PrEP.
A more individualised donor selection policy was implemented in the UK in 2021, which replaced the previous 3-month deferral for men who have sex with men (MSM). Other blood services have a variety of policies in place to ensure the virological safety of blood components, ranging from an indefinite ban on MSM, to a defined period of exclusion, or to an individualised risk assessment that is not based on gender or sexual orientation. Justification of these policies should be based on scientific evidence including assessment of lengths of virological window periods, infectious disease epidemiology within donor populations and donation screening assay sensitivities. Developments in molecular technology and assays which can detect both antibodies and antigens in the very early stages of infection have significantly reduced the risk in most developed countries. However, the increasing usage of pre-exposure prophylaxis (PrEP) to prevent acquisition of HIV infection after possible high-risk sexual contact within the UK blood donor population has been recently noted. It has brought with it new diagnostic challenges within blood screening, notably possible non-detection of HIV RNA and serological markers following PrEP use despite potential infectivity. The use of other testing strategies such as detection of HIV DNA and screening for non-declared PrEP usage should be investigated further.


Quantifying mammary duct carcinoma in situ: a wild-goose chase?
Duct carcinoma in situ (DCIS) is a malignant neoplasm of the breast that is limited to the glandular component. The introduction of mammographic screening allows for earlier detection of carcinoma, at the stage of DCIS, before it invades the surrounding stroma. Although DCIS has been studied extensively, its quantification remains a dilemma. Several methods for measuring DCIS exist, including clinical measurement, radiographic assessment, and gross pathologic assessment. Other methods have been employedfor this purpose, such as counting the number of tissue sections involved, direct measuring of DCIS from glass slides, and even counting the number of ducts involved. Furthermore, there is no consensus for assessing adequacy of margins. The myriad of techniques for quantifying DCIS has profound implications for treatment and for prognostic evaluation. The inherent difficulties in quantifying DCIS are multifactorial, and the need to establish a standardized approach for reporting the extent of DCIS by correlating radiographic, clinical, gross, and histologic findings is imperative.


Lability of GABAA receptor function in human partial epilepsy: possible relationship to hypometabolism.
The function of the gamma-aminobutyric acid type A receptor (GABA(A)R) is maintained by endogenous phosphorylation. We have shown that the corresponding kinase is the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), using the locally produced glycolytic ATP. In addition, using cerebral tissue obtained during curative surgery for epilepsy, we showed that both the endogenous phosphorylation and the GABA(A)R function are significantly reduced in the "epileptogenic" cerebral cortex when compared to "control" tissue. This dysfunction likely contributes to seizure generation and/or transition from the interictal to the ictal state. Glucose utilization is decreased in the epileptogenic cortex of patients with partial epilepsy in the interictal state, but the relationship to the disorder remains unclear. We propose that this hypometabolism is related to the deficiency in the endogenous phosphorylation of GABA(A)R and the resulting greater lability of GABAergic inhibition. Several lines of evidences indeed suggest that GABAergic inhibition is costly in terms of metabolic consumption. The deficiency of this glycolysis-dependent mechanism may thus link epileptogenicity to glucose hypometabolism. The antiepileptic effect of ketogenic diets may be mediated by the subsequent rise in the NADH/NAD(+) index, which favors GABA(A)R endogenous phosphorylation and should contribute to restoration of GABAergic inhibition in the epileptogenic zone.


MicroRNA-199a-3p, microRNA-193b, and microRNA-320c are correlated to aging and regulate human cartilage metabolism.
MicroRNAs (miRNAs) are small RNAs of ∼22 base pairs that regulate gene expression. We harvested cartilage tissue from patients with polydactylism, anterior cruciate ligament injury, and osteoarthritis undergoing total knee arthroplasty and used microarrays to identify miRNAs whose expression is upregulated or downregulated with age. The results were assessed by real-time PCR and MTT assay in a mimic group, in which synthetic double-stranded RNA from the isolated miRNA was transfected to upregulate expression, and in an inhibitor group, in which the miRNA was bound specifically to downregulate expression. The expression of two miRNAs (miR-199a-3p and miR-193b) was upregulated with age and that of one miRNA (miR-320c) was downregulated with age. A real-time PCR assay showed that type 2 collagen, aggrecan, and SOX9 expression were downregulated in the miR-199a-3p mimic group but was upregulated in the inhibitor group. Similar results were observed for miR-193b. By contrast, ADAMTS5 expression was downregulated in the miR-320c mimic group and upregulated in the inhibitor group. Cell proliferative activity was upregulated significantly in the miR-193b inhibitor group compared with the control group. We believe that miR-199a-3p and miR-193b are involved in the senescence of chondrocytes, and miR-320c is involved in the juvenile properties of chondrocytes.


Triiodothyronine--binding immunoglobulin in a euthyroid patient.
We describe a clinically euthyroid 60-year old woman with a past history of 1311 therapy for treatment of possible toxic nodular goitre. She had an elevated thyroxine level of 188 microgram/L (normal range 50-125 microgram/L) following her therapy, and her TSH was within normal limits at 4.7 mU/L. However her T3 level, as determined by an RIA technique employing charcoal to separate bound and free T3, was not measurable. T3 added to the patient's serum could not be recovered, therefore the presence of an unusual protein capable of binding T3 was suspected. To avoid this interference, T3 analysis was performed on an ethanol extract of the patient's serum and was found to be 17 microgram/L (normal range 0.8-1.8 microgram/L). At this time her thyroid microsomal antibody titre was 1:100,000. A protein, capable of binding more than 70% of the patient's T3, was demonstrated in the gamma globulin fraction by agarose gel electrophoresis. This protein did not bind T4. Scatchard analysis for T3 binding revealed a protein, presumably IGG, with a binding affinity of 2 x 109 L/mole and binding capacity of 50 microgram/L. This case exemplifies the caution that must be taken in interpreting thyroid function tests. When thyroid hormone levels are inappropriate to the clinical status of the patient the presence of circulating antibodies which can bind the thyroid hormones should be considered.


Cell response in rabbits infected with T. pallidum as measured by the leucocyte migration inhibition test.
Leucocyte migration in agarose was used to examine cell response in 48 rabbits infected with the Nichols strain of T. pallidum for 1 week to 16 months. The response of the peripheral leucocytes to T. pallidum antigen (TpAg), 3 and 15 mug/ml., Reiter antigen (RAg) 6 mug./ml., and VDRL reagent 1:500 was examined. The cells in the presence of RAg, TpAg--3 mug./ml.--and the VDRL reagent demonstrated a biphasic response; in the early stage of infection (until the 4th week) stimulation of leucocyte migration and in the later stage of disease inhibition of leucocyte migration was observed. The higher concentration of TpAg--15 mug./ml.--caused only inhibition of leucocyte migration. The leucocyte response in vitro could not be confirmed by intradermal skin tests with 5 x 10(7) heat-killed T. pallidum. No correlation between the cell response and the treponemal antibodies was observed.


[Study on the incidence and spatiotemporal dynamic variation of hemorrhagic fever with renal syndrome in Shandong province].
To study the incidence and spatiotemporal dynamic variation of hemorrhagic fever with renal syndrome (HFRS) in Shandong province. According to surveillance data on HFRS epidemics and host animals, a 'contour area multifractal model' was estimated on the HFRS' incidence and multi-analysis model was applied to study spatiotemporal dynamic variation. The process could be classified into 5 periods: 1st period (1974-1981) when HFRS was in completely natural focal state in Shandong, and the nature of focus was typical Apodemus type. 2nd period (1982-1986) indicated the process of expanding and merging of the Apodemus type focus in the southeastern part of Linyi district and the Rattus type focus was in the southern part of Jining city. 3rd period (1987-1990) indicated that through the expanding and merging of the two epidemic focuses,one mixed focus dominated by the Apodemus type had been formed in the hilly area of the southern and middle part of Shandong while another one dominated by the Rattus type in the Yellow River valley of the northwestern part of Shandong. 4th period (1991-1993) showed that the process of the spatial pattern of the mixed focus dominated by the Rattus type in Shandong. 5th period (1994-2004) referred to the spatial pattern of the mixed focus dominated by the Rattus became stabilized. Evolution of the characteristics of HFRS focus in Shandong province experienced the following three processes: the simple Apodemus type and the simple Rattus type were seen separately to the mixed foci with the Apodemus type dominant and the Rattus dominant type coexisted and merged to the stable state of the mixed focus with Rattus as the dominant one.


Seasat low-rate data system.
The Seasat low-rate data system is a distributed, nonreal-time, magnetic-tape system for information processing. Its function is to apply the necessary calibrations, corrections, and conversions to yield geophysically meaningful products from raw spacecraft telemetry data. It also provides a remotely accessible catalog of satellite data.


Progress in video microscopy.
The progress in video microscopy is reviewed from its early inception, especially with respect to improvements of the microscope image quality. Very recent advances that provide serial optical sections and depth of field as thin as 0.1 micron and that make possible the recording of birefringent images of individual microtubules (25 nm in diameter) directly in live, dividing cells are also documented.


Ultrastructural correlates of synapse withdrawal at axotomized neuromuscular junctions in mutant and transgenic mice expressing the Wld gene.
We carried out an ultrastructural analysis of axotomized synaptic terminals in Wld(s) and Ube4b/Nmnat (Wld) transgenic mice, in which severed distal axons are protected from Wallerian degeneration. Previous studies have suggested that axotomy in juvenile (< 2 months) Wld mice induced a progressive nerve terminal withdrawal from motor endplates. In this study we confirm that axotomy-induced terminal withdrawal occurs in the absence of all major ultrastructural characteristics of Wallerian degeneration. Pre- and post-synaptic membranes showed no signs of disruption or fragmentation, synaptic vesicle densities remained at pre-axotomy levels, the numbers of synaptic vesicles clustered towards presynaptic active zones did not diminish, and mitochondria retained their membranes and cristae. However, motor nerve terminal ultrastructure was measurably different following axotomy in Wld transgenic 4836 line mice, which strongly express Wld protein: axotomized presynaptic terminals were retained, but many were significantly depleted of synaptic vesicles. These findings suggest that the Wld gene interacts with the mechanisms regulating transmitter release and vesicle recycling.


RETINAL-CHOROIDAL ANASTOMOSIS IN MACULAR TELANGIECTASIA TYPE 2.
To investigate the deep retinal vascular changes potentially present in macular telangiectasis Type 2 (MacTel 2) with projection resolved optical coherence tomography angiography including volume rendering. Retrospective consecutive evaluation of patients with MacTel 2 in a community-based retinal referral practice with a comprehensive ophthalmologic examination to include optical coherence tomography and projection-resolved optical coherence tomography angiography with volume rendering. Main outcome measures were the characterization of vessel presence and anatomical arrangement in the outer retina. There were 26 eyes of 13 patients with a mean age of 64.9 (±11.3) years, and 6 were men. The mean visual acuity was logMAR 0.4 (Snellen equivalent 20/50). No eye had signs of choroidal neovascularization or exudation. Focal hyperpigmentation was seen in 13 (50%) and right-angle veins in 17 (65%) eyes. Retinal-choroidal anastomoses were seen in 17 (65%) eyes. These anastomoses typically occurred in multiple clusters of small vessels. The presence of anastomoses was associated with pigment (P < 0.001), although the anastomoses did not necessarily colocalize with the pigment, and right-angle veins (P < 0.001), which were found in every eye with a retinal-choroidal anastomosis. Retinal-choroidal anastomoses were commonly observed in eyes with MacTel 2 using projection-resolved optical coherence tomography angiography. One animal model for MacTel 2 uses very low-density lipoprotein receptor mutant mice and shows multiple retinal-choroidal anastomoses in the disease pathogenesis as well. These findings suggest MacTel 2 is more than just a neurodegenerative disease with secondary vascular abnormalities, as the choroid may be involved in the disease process.


Reaction between Nickel Hydroxide and Cerium(IV) Ammonium Nitrate in Aqueous Solution.
Cerium(IV) ammonium nitrate (CAN) has been extensively used as a sacrificial oxidant to study water-oxidation catalysts (WOCs). Although nickel hydroxide has been extensively investigated as WOCs, the water-oxidation reaction (WOR) and mechanistic studies in the presence of CAN and nickel hydroxide were rarely performed. Herein, using in situ Raman spectroscopy, in situ X-ray absorption spectroscopy, and in situ electron paramagnetic resonance spectroscopy, WOR in the presence of CAN and β-Ni(OH)2 was investigated. The proposed WOR mechanism involves the oxidation of β-Ni(OH)2 by CAN, leading to the formation of γ-NiO(OH). γ-NiO(OH), in the presence of acidic conditions, evolves oxygen and is reduced to Ni(II). In other words, the role of β-Ni(OH)2 is the storage of four oxidizing equivalents by CAN, and then a four-electron reaction could result in a WOR with low activation energy. β-Ni(OH)2 in CAN at concentrations of 0.10 M shows WOR with a maximum turnover frequency and a turnover number (for 1000 s) of 5.5 × 10-5/s and 2.0 × 10-2 mol (O2)/mol(Ni), respectively. In contrast to β-Ni(OH)2, Ni(OH2)62+ (aq) could not be oxidized to γ-NiO(OH). Indeed, Ni(OH2)62+ (aq) is the decomposition product of β-Ni(OH)2/CAN.


Pathobiology of obesity and osteoarthritis: integrating biomechanics and inflammation.
Obesity is a significant risk factor for developing osteoarthritis in weight-bearing and non-weight-bearing joints. Although the pathogenesis of obesity-associated osteoarthritis is not completely understood, recent studies indicate that pro-inflammatory metabolic factors contribute to an increase in osteoarthritis risk. Adipose tissue, and in particular infrapatellar fat, is a local source of pro-inflammatory mediators that are increased with obesity and have been shown to increase cartilage degradation in cell and tissue culture models. One adipokine in particular, leptin, may be a critical mediator of obesity-associated osteoarthritis via synergistic actions with other inflammatory cytokines. Biomechanical factors may also increase the risk of osteoarthritis by activating cellular inflammation and promoting oxidative stress. However, some types of biomechanical stimulation, such as physiologic cyclic loading, inhibit inflammation and protect against cartilage degradation. A high percentage of obese individuals with knee osteoarthritis are sedentary, suggesting that a lack of physical activity may increase the susceptibility to inflammation. A more comprehensive approach to understanding how obesity alters daily biomechanical exposures within joint tissues may provide new insight into the protective and damaging effects of biomechanical factors on inflammation in osteoarthritis.


Egg substitutes: chemical and biologic evaluations.
The total lipid, cholesterol, phospholipid, and fatty acid content of dried whole egg (DWE), a refrigerated liquid egg substitute, a powdered egg substitute, and a commercial egg yolk replacer (EYR) were compared. All substitutes contained less total lipid, cholesterol, and phospholipid than DWE. The powdered substitute contained only half the total lipid content reported by the producers and only a fifth of the cholesterol of DWE, while the percentage distribution of fatty acids was similar to that of DWE. The liquid substitute and EYR had fatty acid distributions similar to soybean oil. Rat growth and lipid response were compared for diets containing either DWE or a mixture of EYR and egg white. Both diets were fed with and without vitamin and mineral supplements. Rat growth response was greatest on the DWE diets, either with or without the supplements, was intermediate on the supplemented EYR diets, and was least on the unsupplemented EYR diets. The consumption of DWE-containing diets, when compared with the EYR-containing diets, caused greater liver weight, greater liver total lipid and total cholesterol content, and slightly higher serum cholesterol.


Independent occurrence of hepatocellular and cholangiocellular cancer nodules in the liver.
We treated a patient in whom hepatocellular and cholangiocellular cancer nodules in the liver were of independent occurrence. A 57-year-old Japanese male was admitted with a diagnosis of liver tumour, detected by a scan on a follow-up study of chronic liver disease. Computed tomography and hepatic angiography demonstrated two nodules located on different sites of the right lobe of the liver and which were suggestive of primary liver cancers. He underwent hepatic resection and each tumour was histologically proved to arise independently from hepatocellular and bile duct origins. This may be the first report of patient surgically treated for two different types of carcinoma in the liver.


Development of (Trifluoromethyl)zinc Reagent as Trifluoromethyl Anion and Difluorocarbene Sources.
The trifluoromethylation of carbonyl compounds is accomplished by the stable (trifluoromethyl)zinc reagent generated and then isolated from CF3I and ZnEt2, which can be utilized as a trifluoromethyl anion source (CF3(-)). The reaction proceeds smoothly with diamine as a ligand and ammonium salt as an initiator, providing the corresponding trifluoromethylated alcohol products. Moreover, the (trifluoromethyl)zinc reagent can also be employed as a difluorocarbene source (:CF2) not only for gem-difluoroolefination of carbonyl compounds with phosphine but also for gem-difluorocyclization of alkenes or alkynes via the thermal decomposition, respectively.


The murine mutation jaundiced is caused by replacement of an arginine with a stop codon in the mRNA encoding the ninth repeat of beta-spectrin.
The jaundiced, ja/ja, mouse mutant has a severe hemolytic anemia associated with a deficiency of beta-spectrin in erythrocyte ghosts. Genes for the disease phenotype and beta-spectrin colocalize on Chromosome 12. beta-Spectrin mRNA is not detected in reticulocytes or in brain from newborn mutant mice. To locate the nucleotide sequence alteration, the erythroid beta-spectrin transcript from mutant spleen was amplified by reverse transcription PCR and sequenced. A C-to-T alteration is present in the mutant transcript and produces a premature stop codon from an arginine codon in mRNA encoding repeat 9 of beta-spectrin at amino acid position 1160. The point mutation introduces a Dde I site that is present in PCR-amplified DNA of ja/ja and ja/+ mice but not of +/+ control mice from the strain of origin, 129/Sv, or from the two strains, WB/Re and C57BL/6J, in which the mutation has been fixed by over 53 generations of backcrossing. The genetic data confirm that the point mutation is responsible for the severe reductions in beta-spectrin mRNA of jaundiced mice.


Ocular manifestations in renal allograft recipients: An Indian perspective.
The aim of this study was to report the ocular findings in renal allograft recipients in India. A cross-sectional, comprehensive ophthalmic evaluation was performed, at least three months postrenal transplant, in 152 renal allograft recipients for the ocular findings. In addition, ocular findings were assessed for an association with the clinical variables like major etiologies of end-stage renal disease, pre-transplant dialysis duration, post-transplant duration, and dosage of immunosuppressive drugs. 72.36% of the recipients (mean age, 38.16 ± 10.04 years) had at least one ocular finding at 3 ± 2.6 years (range, 0.3-14 years), postrenal transplant. Hypertensive retinopathy was the commonest ocular finding followed by posterior subcapsular cataract (20.4%), nuclear sclerosis (19.7%), diabetic retinopathy (15.1%), dry eye (11.2%), allergic conjunctivitis (9.9%), pterygium (6.6%), open-angle glaucoma (3.3%), meibomitis (3.3%), pinguicula (2.6%), chalazion (1.3%), subconjunctival haemorrhage (1.7%), central serous chorioretinopathy (1.7%), healed ocular toxoplasmosis (1.7%), papilledema (1.7%), and dry ARMD (1.7%). In addition, a significant association existed between some of the ocular findings with major aetiologies of ESRD, post-transplant duration, and dosage of immunosuppressive drugs. However, no association existed between the ocular findings and pre-transplant dialysis duration. Ocular findings are seen in 72.36% of the renal transplant recipients with hypertensive retinopathy being the commonest one. Hence, a mandatory regular ophthalmic screening of the recipients is recommended for an early detection and timely intervention to improve the quality of life.


A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region.
We used a covariate-based linkage method to reanalyze genome scan data from affected sibships collected by the Alzheimer Disease (AD) Genetics Initiative of the National Institute of Mental Health. As reported in an earlier article, the amyloid-beta precursor protein (APP) region is strongly linked to affected sib pairs of the oldest current age (i.e., age either at last exam or at death) who lack E4 alleles at the apolipoprotein E (ApoE) locus. We now report that a region on 20p shows the same pattern. A model that includes current age and the number of E2 alleles as covariates gives a LOD score of 4.1. The signal on 20p is near the location of the gene coding for cystatin-C, previously shown to be associated with late-onset AD and to codeposit with APP in the brains of patients with AD. Two-locus analysis provides evidence of strong epistasis between 20p and the APP region, limited to the oldest age group and to those lacking ApoE4 alleles. We speculate that high-risk polymorphisms in both regions produce a biological interaction between these two proteins that increases susceptibility to a very-late-onset form of AD.


The Master of Medical Management (MMM) degree: an analysis of alumni perceptions.
Innovation in health administration education stimulates administrators and faculty to identify unmet educational needs within the health sector. In 1997, the inaugural class of the Master of Medical Management (MMM) at Tulane University graduated, signaling an individual achievement for all graduates and an accomplishment in innovation and collaboration in health administration education. Tulane University, in partnership with The American College of Physician Executives (ACPE), designed a unique health administration degree to meet the distinctive needs of physicians serving in executive and managerial roles or seeking to serve in such roles in the future. Since 1997, there are nearly 700 MMM graduates who hail from Carnegie Mellon, Tulane University, and the University of Southern California. ACPE administered a survey to 500 MMM alumni in the fall of 2005. The response rate was 47% (235 of 500). The findings from this survey describe the reasons why physicians decided to enroll in the MMM, their experiences as MMM students, and their perceptions of how the MMM had an impact on their careers. Moreover, in this article, recommendations are offered related to the design and delivery of innovative educational programs for emerging disciplines within the health sector.


Factors Influencing Residency Program Selection by Medical Students Pursuing Obstetrics and Gynecology.
Little is known about the factors that influence medical student selection of obstetrics and gynecology (ob-gyn) residency programs. We assessed the factors influencing residency program selection by fourth-year medical students pursuing ob-gyn training. A voluntary, anonymous, 19-question survey of residency selection factors was distributed to all fourth-year medical students interviewing at 1 of 5 academic ob-gyn departments for a residency position during the 2013-2014 interview season. Participants were surveyed about the relative importance (not important, somewhat important, important) of various residency selection factors, including operative experience, exposure to subspecialties, curricular experience, access to fellowships, and administrative aspects of residency, including adherence to duty hour restrictions. Of 322 potential respondents, 262 (81%) completed the survey. Surgical training and training in laparoscopic surgery were deemed "important" by nearly all respondents (98%, 258 of 262, and 97%, 253 of 262, respectively). Factors that were considered "not important" by a significant group of respondents included maternity/paternity leave policies (22%, 58 of 259); opportunity for international rotations/electives (20%, 51 of 259); exposure to quality and safety initiatives (13%, 34 of 259); and training in abortion (13%, 34 of 262). Fourth-year medical students identified surgical training as the most important factor in selecting an ob-gyn residency, a finding that is particularly relevant as decreasing and changing surgical volumes affect residency training in this specialty.


[The implications of family lack of concern and perception of obesity in childhood in the city of Curitiba, State of Paraná, Brazil].
The scope of this study was to relate child obesity with the family's perception of the child's silhouette's and concern with excess weight in childhood A cross-sectional study was conducted among children aged between 20 and 48 months who frequent Health Units or are preschoolers in the city of Curitiba from June to December 2014. A questionnaire was used to collect data relating to family income, weight, height, perception of child silhouette's and assess concern about obesity by parents. Overweight and obesity was not correctly perceived by relations (kappa = 0,11) and the vast majority of parents did not know the child's height and weight and were not even concerned with childhood obesity. In the population studied, children from lower income family were more likely to suffer from overweight in childhood (p = 0,02). It is necessary to invest in the sensitization of families, since it is extremely important to pay attention to obesity from childhood onwards, thus preventing new cases and avoiding problems in adult life.


[The development of standards for ophthalmologic ultrasound diagnosis].
The performance data of ultrasonic apparatus and transducer probes are decisive in view of the information content of the echograms. Clinically applicable measurement methods, therefore, were developed already in the early sixties for ophthalmic ultrasonography. The sensitivity of each probe apparatus combination was measured first by means of a variable absorption path, the working frequency by counting the oscillations per microsecond in the rf echo signal of a plane reflector. Depth and lateral resolution were determined using monofil filaments mounted to a micrometer gauge. These measurements resulted in marked improvement of safety of diagnosis. In view of the IEC document 854, we developed a test reflector. It reflects a standard echo which can be measured within the control range of most diagnostic machines without need of additional dB-calibrated attenuators. Now, each echo amplitude can be referred to this standard echo (whose difference to the ideal reflector echo is-17 dB). An electronic device (echo simulator) permits additional checking of distinct equipment parts (especially of the dB control, time scale and amplifier dynamics). The entirely empirical use of ultrasonic diagnostic apparatus without measurement of the diagnostically relevant performance data and without readjustment and documentation of comparable examination conditions is, in our opinion, an outdated approach. Repeated measurements at regular intervals and especially after repairs or change of transducer probes are mandatory.


Ginsenoside Rh2 enhances the antitumor immunological response of a melanoma mice model.
The treatment of malignant tumors following surgery is important in preventing relapse. Among all the post-surgery treatments, immunomodulators have demonstrated satisfactory effects on preventing recurrence according to recent studies. Ginsenoside is a compound isolated from panax ginseng, which is a famous traditional Chinese medicine. Ginsenoside aids in killing tumor cells through numerous processes, including the antitumor processes of ginsenoside Rh2 and Rg1, and also affects the inflammatory processes of the immune system. However, the role that ginsenoside serves in antitumor immunological activity remains to be elucidated. Therefore, the present study aimed to analyze the effect of ginsenoside Rh2 on the antitumor immunological response. With a melanoma mice model, ginsenoside Rh2 was demonstrated to inhibit tumor growth and improved the survival time of the mice. Ginsenoside Rh2 enhanced T-lymphocyte infiltration in the tumor and triggered cytotoxicity in spleen lymphocytes. In addition, the immunological response triggered by ginsenoside Rh2 could be transferred to other mice. In conclusion, the present study provides evidence that ginsenoside Rh2 treatment enhanced the antitumor immunological response, which may be a potential therapy for melanoma.


[New methods for the evaluation of bone quality. Bone Quality Evaluation by QUS.]
The conventional ultrasonic bone densitometry systems(quantitative ultrasound:QUS)are now popular for the initial screening of osteoporosis. These systems can give us velocity(SOS)and broadband attenuation(BUA)of ultrasonic waves, which propagated in the heel. This paper describes the physical meaning of these parameters and introduces the idea of standardization, s-SOS and s-BUA. In addition, new QUS techniques for the further investigation of bone quality are also introduced. These techniques, two wave phenomenon and Axial Transmission(AT)can induce the individual properties of cortical and cancellous bones by the ultrasonic measurements.


A heat-shock response regulated by the PfAP2-HS transcription factor protects human malaria parasites from febrile temperatures.
Periodic fever is a characteristic clinical feature of human malaria, but how parasites survive febrile episodes is not known. Although the genomes of Plasmodium species encode a full set of chaperones, they lack the conserved eukaryotic transcription factor HSF1, which activates the expression of chaperones following heat shock. Here, we show that PfAP2-HS, a transcription factor in the ApiAP2 family, regulates the protective heat-shock response in Plasmodium falciparum. PfAP2-HS activates the transcription of hsp70-1 and hsp90 at elevated temperatures. The main binding site of PfAP2-HS in the entire genome coincides with a tandem G-box DNA motif in the hsp70-1 promoter. Engineered parasites lacking PfAP2-HS have reduced heat-shock survival and severe growth defects at 37 °C but not at 35 °C. Parasites lacking PfAP2-HS also have increased sensitivity to imbalances in protein homeostasis (proteostasis) produced by artemisinin, the frontline antimalarial drug, or the proteasome inhibitor epoxomicin. We propose that PfAP2-HS contributes to the maintenance of proteostasis under basal conditions and upregulates specific chaperone-encoding genes at febrile temperatures to protect the parasite against protein damage.


Classification of micro-calcification in mammograms using scalable linear Fisher discriminant analysis.
Breast cancer is one of the major causes of death in women. Computer Aided Diagnosis (CAD) systems are being developed to assist radiologists in early diagnosis. Micro-calcifications can be an early symptom of breast cancer. Besides detection, classification of micro-calcification as benign or malignant is essential in a complete CAD system. We have developed a novel method for the classification of benign and malignant micro-calcification using an improved Fisher Linear Discriminant Analysis (LDA) approach for the linear transformation of segmented micro-calcification data in combination with a Support Vector Machine (SVM) variant to classify between the two classes. The results indicate an average accuracy equal to 96% which is comparable to state-of-the art methods in the literature. Graphical Abstract Classification of Micro-calcification in Mammograms using Scalable Linear Fisher Discriminant Analysis.


Genetic-Variation-Driven Gene-Expression Changes Highlight Genes with Important Functions for Kidney Disease.
Chronic kidney disease (CKD) is a complex gene-environmental disease affecting close to 10% of the US population. Genome-wide association studies (GWASs) have identified sequence variants, localized to non-coding genomic regions, associated with kidney function. Despite these robust observations, the mechanism by which variants lead to CKD remains a critical unanswered question. Expression quantitative trait loci (eQTL) analysis is a method to identify genetic variation associated with gene expression changes in specific tissue types. We hypothesized that an integrative analysis combining CKD GWAS and kidney eQTL results can identify candidate genes for CKD. We performed eQTL analysis by correlating genotype with RNA-seq-based gene expression levels in 96 human kidney samples. Applying stringent statistical criteria, we detected 1,886 genes whose expression differs with the sequence variants. Using direct overlap and Bayesian methods, we identified new potential target genes for CKD. With respect to one of the target genes, lysosomal beta A mannosidase (MANBA), we observed that genetic variants associated with MANBA expression in the kidney showed statistically significant colocalization with variants identified in CKD GWASs, indicating that MANBA is a potential target gene for CKD. The expression of MANBA was significantly lower in kidneys of subjects with risk alleles. Suppressing manba expression in zebrafish resulted in renal tubule defects and pericardial edema, phenotypes typically induced by kidney dysfunction. Our analysis shows that gene-expression changes driven by genetic variation in the kidney can highlight potential new target genes for CKD development.


Discrimination between arabica and robusta coffee species on the basis of their amino acid enantiomers.
This work reports the results for the composition of robusta and arabica coffee species in terms of their amino acid enantiomers in the green and roasted states. The analyses were conducted for the free amino acids, as well as for the amino acids obtained after acid hydrolysis. The amino acids were extracted/hydrolyzed and isolated by SPE on strong cation exchange columns, derivatized to their N-ethoxycarbonylheptafluorobutyl esters, and analyzed by gas chromatography/FID on a Chirasil l-Val column. Multivariate analyses applied to the results showed that the free amino acids can be used as a tool for discrimination between coffee species, with a special reference to l-glutamic acid, l-tryptophan, and pipecolic acid. There is also some evidence that these compounds can be used for discrimination between green coffees subjected to different postharvest processes. It is also shown that the amino acid levels observed after acid hydrolysis can be used for the same purposes, although displaying less discriminatory power.


Phosphorylation of the p33 replication protein of Cucumber necrosis tombusvirus adjacent to the RNA binding site affects viral RNA replication.
Replication of the nonsegmented, plus-stranded RNA genome of Cucumber necrosis tombusvirus (CNV) requires two essential overlapping viral-coded replication proteins, the p33 replication co-factor and the p92 RNA-dependent RNA polymerase. In this paper, we demonstrate that p33 is phosphorylated in vivo and in vitro by a membrane-bound plant kinase. Phosphorylation of p33 was also demonstrated in vitro by using purified protein kinase C. The related p28 replication protein of Turnip crinkle virus was also found to be phosphorylated in vivo, suggesting that posttranslational modification of replication proteins is a general feature among members of the large Tombusviridae family. Based on in vitro studies with purified recombinant p33, we show evidence for phosphorylation of threonine and serine residues adjacent to the essential RNA-binding site in p33. Phosphorylation-mimicking aspartic acid mutations rendered p33 nonfunctional in plant protoplasts and in yeast, a model host. Comparable mutations within the prereadthrough portion of p92 did not abolish replication. The nonphosphorylation-mimicking alanine mutants of CNV were able to replicate in plant protoplasts and in yeast, albeit with reduced efficiency when compared to the wild type. These alanine mutants also showed altered subgenomic RNA synthesis and a reduction in the ratio between plus- and minus-strand RNAs produced during CNV infection. These findings suggest that phosphorylation of threonine/serine residues adjacent to the essential RNA-binding site in the auxiliary p33 protein likely plays a role in viral RNA replication and subgenomic RNA synthesis during tombusvirus infections.


Scrapie-induced changes in the percentage of polymorphonuclear neutrophils in mouse peripheral blood.
A decrease in the percentage of polymorphonuclear neutrophils (PMN) in the peripheral blood of mice appeared 3 days after intracerebral (IC) inoculation with scrapie mouse brain homogenate. Mice inoculated IC with normal mouse brain had PMN percentages similar to those found for uninoculated mice. This difference between normal and scrapie-inoculated mice continued throughout the preclinical phase of the disease. In the clinical phase of the disease, the percentage of PMN was either higher or lower than that found in normals. The factor causing the decrease in PMN percentages was found in the filtrates from 220-, 100-, and 50-nm filters, but not in the filtrates from a 25-nm filter. Sodium periodate treatment of the scrapie brain samples eliminated their ability to cause the decrease in PMN percentages, whereas sodium iodate had no effect. In addition to two genetically different scrapie mouse brain isolates, homogenates of mouse spleen, sheep brain, and sheep spleen from scrapie-affected animals caused a decrease in percent PMN, whereas the corresponding normal tissue homogenates did not.


RNA-Binding Proteins Implicated in Mitochondrial Damage and Mitophagy.
The mitochondrial lifecycle comprises biogenesis, fusion and cristae remodeling, fission, and breakdown by the autophagosome. This cycle is essential for maintaining proper cellular function, and inhibition of any of these processes results in deterioration of bioenergetics and swift induction of apoptosis, particularly in energy-craving cells such as myocytes and neurons. Regulation of gene expression is a fundamental step in maintaining mitochondrial plasticity, mediated by (1) transcription factors that control the expression of mitochondrial mRNAs and (2) RNA-binding proteins (RBPs) that regulate mRNA splicing, stability, targeting to mitochondria, and translation. More recently, RBPs have been also shown to interact with proteins modulating the mitochondrial lifecycle. Importantly, misexpression or mutations in RBPs give rise to mitochondrial dysfunctions, and there is strong evidence to support that these mitochondrial impairments occur early in disease development, constituting leading causes of pathogenesis. This review presents key aspects of the molecular network of the disease-relevant RBPs, including transactive response DNA-binding protein 43 (TDP43), fused in sarcoma (FUS), T-cell intracellular antigen 1 (TIA1), TIA-related protein (TIAR), and pumilio (PUM) that drive mitochondrial dysfunction in the nervous system.


Targeting tumor perfusion and oxygenation to improve the outcome of anticancer therapy.
Radiotherapy and chemotherapy are widespread clinical modalities for cancer treatment. Among other biological influences, hypoxia is a main factor limiting the efficacy of radiotherapy, primarily because oxygen is involved in the stabilization of the DNA damage caused by ionizing radiations. Radiobiological hypoxia is found in regions of rodent and human tumors with a tissue oxygenation level below 10 mmHg at which tumor cells become increasingly resistant to radiation damage. Since hypoxic tumor cells remain clonogenic, their resistance to the treatment strongly influences the therapeutic outcome of radiotherapy. There is therefore an urgent need to identify adjuvant treatment modalities aimed to increase tumor pO(2) at the time of radiotherapy. Since tumor hypoxia fundamentally results from an imbalance between oxygen delivery by poorly efficient blood vessels and oxygen consumption by tumor cells with high metabolic activities, two promising approaches are those targeting vascular reactivity and tumor cell respiration. This review summarizes the current knowledge about the development and use of tumor-selective vasodilators, inhibitors of tumor cell respiration, and drugs and treatments combining both activities in the context of tumor sensitization to X-ray radiotherapy. Tumor-selective vasodilation may also be used to improve the delivery of circulating anticancer agents to tumors. Imaging tumor perfusion and oxygenation is of importance not only for the development and validation of such combination treatments, but also to determine which patients could benefit from the therapy. Numerous techniques have been developed in the preclinical setting. Hence, this review also briefly describes both magnetic resonance and non-magnetic resonance in vivo methods and compares them in terms of sensitivity, quantitative or semi-quantitative properties, temporal, and spatial resolutions, as well as translational aspects.


TGR5: a novel target for weight maintenance and glucose metabolism.
TGR5, an emerging G protein-coupled receptor, was identified as a membrane receptor for bile acids. The expression of TGR5 and its function are distinct from the previously identified nuclear bile acid receptor, farnesoid X receptor (FXR). These two bile acid receptors complement with each other for maintaining bile acid homeostasis and mediating bile acid signaling. Both receptors are also shown to play roles in regulating inflammation and glucose metabolism. An interesting finding for TGR5 is its role in energy metabolism. The discovery of TGR5 expression in brown adipocyte tissues (BATs) and the recent demonstration of BAT in adult human body suggest a potential approach to combat obesity by targeting TGR5 to increase thermogenesis. We summarize here the latest finding of TGR5 research, especially its role in energy metabolism and glucose homeostasis.


Regulatory Eosinophils in Inflammation and Metabolic Disorders.
Eosinophils are potent effector cells implicated in allergic responses and helminth infections. Responding to stimuli, they release their granule-derived cytotoxic proteins and are involved in inflammatory processes. However, under homeostatic conditions, eosinophils are abundantly present in the intestine and are constantly in contact with the gut microbiota and maintain the balance of immune responses without inflammation. This situation indicates that intestinal eosinophils have an anti-inflammatory function unlike allergic eosinophils. In support of this notion, some papers have shown that eosinophils have different phenotypes depending on the site of residence and are a heterogeneous cell population. Recently, it was reported that eosinophils in the small intestine and adipose tissue, respectively, contribute to homeostasis of intestinal immune responses and metabolism. Accordingly, in this review, we summarize new functions of eosinophils demonstrated in recent studies and discuss their homeostatic functions.


The Surgical Management of Skeletal Disproportion with Lingual Orthodontics and Three-dimensional Planning.
This case report describes the successful treatment of a 26-year-old Caucasian male with skeletal and dental Class III malocclusion associated with mild maxillary and mandibular crowding. The patient had anteroposterior and transverse discrepancies with a reverse overjet and bilateral posterior crossbites. The nonextraction treatment plan included aligning and leveling of the teeth in both arches, Le Fort I and bilateral sagittal split osteotomies, and postsurgical correction of the malocclusion. Orthodontic treatment was initiated with custom lingual appliances followed by orthognathic surgery planned with virtual surgical planning. Treatment was concluded with detailed orthodontic finishing, achieving optimum esthetics and function.


[Alzheimer's Therapeutic Research Institute].
The Alzheimer's Therapeutic Research Institute (ATRI) was established in 2015 after ATRI director, Paul Aisen, and his fellow experts in therapeutic interventions for Alzheimer's disease (AD) moved from the Alzheimer's Disease Cooperative Study (ADCS) at the University of California to the Keck School of Medicine of the University of Southern California. The National Institute on Aging (NIA) decided to commit $14 million to the ATRI via an Alzheimer's Clinical Trials Consortium (ACTC). The ATRI supports various studies such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer's study ("A4 study"), Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3), Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN), and The Alzheimer's Disease Neuroimaging Initiative-Depression Project (ADNI-D). The ATRI will share all relevant data and materials with the academic community, corporations, and government organizations. The ATRI is overseen by a Data and Safety Monitoring Board (DSMB), which comprises of leading experts in the field of Alzheimer's research and acts independently. The ATRI is slated to play a central role in clinical dementia research in the US in near future.


Northern bobwhite select for shrubby thickets interspersed in grasslands during fall and winter.
Resource selection is a key component in understanding the ecological processes underlying population dynamics, particularly for species such as northern bobwhite (Colinus virginianus), which are declining across their range in North America. There is a growing body of literature quantifying breeding season resource selection in bobwhite; however, winter information is particularly sparse despite it being a season of substantial mortality. Information regarding winter resource selection is necessary to quantify the extent to which resource requirements are driving population change. We modeled bobwhite fall and winter resource selection as a function of vegetation structure, composition, and management from traditionally (intensively) managed sites and remnant (extensively managed) grassland sites in southwest Missouri using multinomial logit discrete choice models in a Bayesian framework. We captured 158 bobwhite from 67 unique coveys and attached transmitters to 119 individuals. We created 671 choice sets comprised of 1 used location and 3 available locations. Bobwhite selected for locations which were closer to trees during the winter; the relative probability of selection decreased from 0.45 (85% Credible Interval [CRI]: 0.17-0.74) to 0.00 (85% CRI: 0.00-0.002) as distance to trees ranged from 0-313 m. The relative probability of selection increased from near 0 (85% CRI: 0.00-0.01) to 0.33 (85% CRI: 0.09-0.56) and from near 0 (85% CRI: 0.00-0.00) to 0.51 (85% CRI: 0.36-0.71) as visual obstruction increased from 0 to 100% during fall and winter, respectively. Bobwhite also selected locations with more woody stems; the relative probability of selection increased from near 0.00 (85% CRI: 0.00-0.002) to 0.30 (85% CRI: 0.17-0.46) and near 0.00 (85% CRI: 0.00-0.001) to 0.35 (85% CRI: 0.22-0.55) as stem count ranged from 0 to 1000 stems in fall and winter, respectively. The relative probability of selection also decreased from 0.35 (85% CRI: 0.20-0.54) to nearly 0 (85% CRI: 0.00-0.001) as percent grass varied from 0 to 100% in fall. We suggest that dense shrub cover in close proximity to native grasslands is an important component of fall and winter cover given bobwhite selection of shrub cover and previously reported survival benefits in fall and winter.


Clinical profile of autoimmune pancreatitis and its histological subtypes: an international multicenter survey.
The objective of this study was to clarify the clinical and pathophysiological characteristics of autoimmune pancreatitis (AIP) and its subtypes (lymphoplasmacytic sclerosing pancreatitis [LPSP] and idiopathic duct-centric pancreatitis [IDCP]) seen around the world. An international multicenter survey of AIP was conducted in 15 institutes from 8 countries. We compared clinical and pathologic profiles of AIP (n = 731) and the clinical profiles of LPSP (n = 204) and IDCP (n = 64) patients. Patients with LPSP were approximately 16 years older than IDCP patients. Obstructive jaundice was a more frequent presentation in LPSP versus IDCP (75% vs 47%, P < 0.001), whereas abdominal pain (41% vs 68%, P < 0.001) and acute pancreatitis (5% vs 34%, P < 0.001) were more frequent in IDCP patients. Patients with LPSP were more likely to have diffuse swelling of the pancreas (40% vs 25%, P = 0.037) and elevated serum IgG4 levels (63% vs 23%, P < 0.001) but less likely to be associated with ulcerative colitis (1% vs 16%, P < 0.001). Clinical profiles of non-histologically confirmed AIP from Asia, the United States, and United Kingdom corresponded with that of LPSP, whereas those from Italy and Germany suggested a mixture of LPSP and IDCP. Autoimmune pancreatitis is seen all around the world, with regional differences in the pathologic and clinical features. Lymphoplasmacytic sclerosing pancreatitis and IDCP have distinct clinical profiles.


Luttinger liquid of trimers in Fermi gases with unequal masses.
We investigate one dimensional attractive Fermi gases in spin-dependent optical lattices. We show that three-body bound states--"trimers"--exist as soon as the two tunneling rates are different. We calculate the binding energy and the effective mass of a single trimer. We then show numerically that for finite and commensurate densities n(up) = n(down)/2 an energy gap appears, implying that the gas is a one-component Luttinger liquid of trimers with suppressed superfluid correlations. The boundaries of this novel phase are given. We discuss experimental situations to test our predictions.


Psychedelics: preclinical insights provide directions for future research.
Recently, psychedelics have emerged as promising therapeutics for numerous neuropsychiatric disorders. While their potential in the clinic has yet to be fully elucidated, understanding their molecular and biological mechanisms is imperative as these compounds are becoming widely used both in therapeutic and recreational contexts. This review examines the current understanding of basic biology, pharmacology, and structural biology in an attempt to reveal both the knowns and unknowns within the field.


Captopril in hypertension after renal transplantation.
Eight hypertensive renal allograft recipients who had received captopril are presented. Captopril in a maximal daily dose of 250 mg enabled the withdrawal of large doses of beta-blocking agents and vasodilators. Blood pressure was satisfactorily controlled in all except one. No adverse side effects were observed other than the 'first dose' effect which resulted in transient anuria in one patient. Captopril appears to be a useful agent in the management of severe hypertension after renal transplantation.


[The quality and safety of rendering emergency and urgent medical care in hospitals].
The article presents the results of external auditing on the section "The organization of emergency and urgent medical care in hospital. Organization of admitting office functioning" in 30 medical organizations of the Russian Federation based on "The proposals (practical guidelines) of Roszdravnadzor for organizing internal quality control and safety of medical activity in medical organization (hospital)". The level of compliance with requirements of the Proposals is determined. The complex and structural problems of organization of rendering of emergency and urgent medical care.


Increase in phagocytosis after geldanamycin treatment or heat shock: role of heat shock proteins.
The response to injury is activated at the systemic and cellular levels. At the systemic level, phagocytosis plays a key role in controlling infections and clearing necrotic and apoptotic cells. The expression of heat shock proteins (Hsp), which is a well-conserved process, is a major component of cellular response to stress. This study investigated the relationship between Hsps and phagocytosis. An increase in the phagocytosis of opsonized bacteria particles and latex beads was observed upon incubation of murine macrophages with geldanamycin (GA), a specific inhibitor of the Hsp90 family of proteins. The effect of GA on phagocytosis was blocked by coincubation with inhibitors of transcription (actinomycin D) or translation (cycloheximide), suggesting that gene expression was required. Because expression of Hsps has been observed after GA treatment, the effect of heat shock on phagocytosis was investigated. Similar to GA treatment, heat shock resulted in an actinomycin D-sensitive elevation of phagocytosis, which suggests that Hsps are involved. The increase in phagocytosis after GA treatment was not due to increased binding of opsonized particles to their respective receptors on the macrophage surface or to elevated oxidative stress. However, it was correlated with a rapid polymerization of actin in proximity to the plasma membrane. These results suggest that Hsps play a role in the modulation of the phagocytic process, which is part of the stress response.


Resistance changes in lipid bilayers: immunological applications.
The electrical resistance of a bimolecular lipid membrane in 0.1 molar NaCl decreases if antibody and complement are present on one side of the membrane and the homologous antigen is added to the other side. The reaction occurs within minutes and requires less than 0.1 microliter of antiserum.


Treatment of young patients with pilonidal sinus disease with the original (unmodified) Limberg flap standardized for the first time.
Pilonidal sinus disease (PSD) is commonly seen in young adults but may also affect adolescents. Our goal was to present results from operated patients, with a focus on the original Limberg flap, which we standardized for the first time. This study was a retrospective review of 60 teenage patients who underwent surgery in a single pediatric surgery center over approximately 15 years. Of the 60 patients, 33 (55%) were male and the mean age was 14.20 ± 1.31 (9-17) years. After pilonidal sinus excision, primary repair and Limberg flap were performed in 45 (75%) and 15 (25%) patients respectively. There were no complications in the patients who underwent the Limberg flap technique, whereas 49% of the patients who underwent primary repair exhibited complications. The mean follow-up was 6.7 ± 4.8 years. We standardized the Limberg flap for the first time in children with measurements and consider that it meets expectations: it is not difficult to perform, it has low complication and recurrence rates, it requires an acceptable period to return to normal activities, and gives satisfactory cosmetic results. We did not identify any complications in patients treated with the Limberg flap excision and post-operative epilation. We consider that findings achieved by the treatment of original, standardized Limberg flap excision is comparable with all of the treatment methods reported in the literature related with children.


A Comprehensive Review on the Diagnosis of Knee Injury by Deep Learning-Based Magnetic Resonance Imaging.
The continual improvement in the field of medical diagnosis has led to the monopoly of using deep learning (DL)-based magnetic resonance imaging (MRI) for the diagnosis of knee injury related to meniscal injury, ligament injury including the cruciate ligaments, collateral ligaments and medial patella-femoral ligament, and cartilage injury. The present systematic review was done by PubMed and Directory of Open Access Journals (DOAJ), wherein we finalised 24 studies conducted on the accuracy of DL MRI studies for knee injury identification. The studies showed an accuracy of 72.5% to 100% indicating that DL MRI holds an equivalent performance as humans in decision-making and management of knee injuries. This further opens up future exploration for improving MRI-based diagnosis keeping in mind the limitations of verification bias and data imbalance in ground truth subjectivity.


Baseline serum lipids and renal function in chronic kidney disease patients entering the LORD trial.
Previous studies investigating associations between serum lipids and renal disease have generally not taken into account dietary intake or physical activity both known to influence circulating lipids. Furthermore, inclusion of patients on HMG-CoA reductase inhibitors may also have influenced findings due to the pleiotropic effect of this medication. Therefore, the aim of this study is to determine the relationships between serum lipids and renal function in a group of patients not taking lipid-lowering medication and taking into account dietary intake and physical activity. Data from 100 patients enrolled in the Lipid Lowering and Onset of Renal Disease (LORD) trial were used in this study. Patients were included with serum creatinine > 120 micromol/l, and excluded if they were taking lipid-lowering medication. Unadjusted and adjusted relationships were determined between fasting serum lipid concentrations (total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol/HDL ratio) and measures of renal function (estimated glomerular filtration rate (eGFR), creatinine clearance and serum creatinine) and urinary protein excretion. Significant (p < 0.05) negative unadjusted relationships were found between lipids (total cholesterol, LDL and HDL cholesterol) and serum creatinine. In support of these findings, logarithmically-transformed lipids (total cholesterol, LDL and HDL cholesterol) were significantly associated with eGFR and creatinine clearance although the effects were of a smaller magnitude. Adjustment for dietary saturated fat intake and physical activity did not substantially change these effects. These data do not support the premise that lipids are associated with renal dysfunction in patients with normocholesterolemia.


[Staging 915 cases of nasopharyngeal carcinoma after simple radical radiotherapy--checkout of Fuzhou staging system (1992)].
Along with the development of treatments, different tumor staging systems are coexisted and have been modified. This study was to validate the rationality of the Fuzhou staging system (1992) of nasopharyngeal carcinoma (NPC), and to provide some suggestions. A total of 915 NPC patients received radical radiotherapy alone in Cancer Center of Sun Yat-sen University from Jan. 1997 to Dec. 1998. The 1-, 3-, and 5-year follow-up rates were 98.7%, 95.2%, and 91.7%, respectively. The survival data were analyzed with Life table, Cox regression, Kaplan-Meier, and log-rank methods. The 1-, 3-, and 5-year overall survival rates of the 915 patients were 87.69%, 72.73%, and 64.44%; the 1-, 3-, and 5-year disease-freely survival rates were 86.87%, 69.72%, and 58.33%, respectively. Cox regression analysis showed that the 5-year survival statuses of the 915 patients were significantly correlated with their age and the tumor stage classified by the Fuzhou staging system (1992); the 5-year survival statuses of the 803 patients no more than 60 years old were only significantly correlated with tumor stage, and had no correlation with their age. Life table analysis validated that the tumor stage classified by Fuzhou staging system (1992) can roughly predict the prognosis, but the difference between the 5-year survival rates of stage I and II patients was not significant. Kaplan-Meier analysis showed no significant difference between survival statuses of stage T1 and T2 patients when adjusted by N classification. Therefore, we adjusted stage T2 without parapharyngeal space invasion to stage T1, stage T3 with carotid vagina invasion to stage T2, stage T4 with paranasal sinus involvement to stage T3, stage T3 with cranial nerve injury to stage T4, and stage N1 with bilateral lymph nodes involvement to stage N2. After the modifications, the differences among stage I to IVa, stage T1 to T4 (adjusted by N stage), or stage N0 to N3 (adjusted by T stage) were significant. Taking the impact of age on the prognosis and the interaction between T stage and N stage into consideration, the above modifications of should be included when renewing the Fuzhou staging system (1992).


Antimalarial drug resistance in the Central and Adamawa regions of Cameroon: Prevalence of mutations in P. falciparum crt, Pfmdr1, Pfdhfr and Pfdhps genes.
The spread of Plasmodium falciparum resistant parasites remains one of the major challenges for malaria control and elimination in Sub Saharan Africa. Monitoring of molecular markers conferring resistance to different antimalarials is important to track the spread of resistant parasites and to optimize the therapeutic lifespan of current drugs. This study aimed to evaluate the prevalence of known mutations in the drug resistance genes Pfcrt, Pfmdr1, Pfdhfr and Pfdhps in two different epidemiological settings in Cameroon. Dried blood spots collected in 2018 and 2019 from asymptomatic individuals were used for DNA extraction and then the Plasmodium infection status was determined byPCR. Detection of SNPs was performed by nested PCR followed by allele-specific restriction analysis (ASRA). The prevalence of each genotype was compared between sites using the Chi square and Fisher's exact tests. A high prevalence of the Pfcrt K76 wild type allele was found in both sites (88.5 and 62.29% respectively; P< 0,0001). The prevalence of Pfmdr1 mutations 86Y and 1246Y was respectively 55.83 and 1.45% in Mfou and 45.87 and 5.97% in Tibati, with significant difference between the studied areas (P<0.0001). Overall, the Pfdhfr triple-mutant genotype (51I/59R/108N) was highly prevalent (> 96%), however no SNP was detected at codon 164. In Pfdhps, the prevalence of the 437G mutation reached (90%) and was at higher frequency in Mfou (P< 0.0001). Overall, the Pfdhps mutations 540E and 581G were less common (0.33 and 3.26%, respectively). The quadruple resistant genotype (Pfdhfr 51I/59R/108N+Pfdhp437G) was found almost 90% of the samples. The wild-type genotype (Pfdhfr N51/C59/S108/164I+Pfdhps A437/K540/A581) was never identified and the sextuple mutant (Pfdhfr 51I/59R/108N+Pfdhp437G/540E/581G), kwon as super resistant appeared in two samples from Tibati. These findings demonstrate declining trends in the prevalence of mutations conferring resistance to 4-aminoquinolines, especially to chloroquine. However, a high level of mutations in P. falciparum genes related to SP resistance was detected and this raises concerns about the future efficacy of IPTp-SP and SMC in Cameroon.


Characterization of the autophagy marker protein Atg8 reveals atypical features of autophagy in Plasmodium falciparum.
Conventional autophagy is a lysosome-dependent degradation process that has crucial homeostatic and regulatory functions in eukaryotic organisms. As malaria parasites must dispose a number of self and host cellular contents, we investigated if autophagy in malaria parasites is similar to the conventional autophagy. Genome wide analysis revealed a partial autophagy repertoire in Plasmodium, as homologs for only 15 of the 33 yeast autophagy proteins could be identified, including the autophagy marker Atg8. To gain insights into autophagy in malaria parasites, we investigated Plasmodium falciparum Atg8 (PfAtg8) employing techniques and conditions that are routinely used to study autophagy. Atg8 was similarly expressed and showed punctate localization throughout the parasite in both asexual and sexual stages; it was exclusively found in the pellet fraction as an integral membrane protein, which is in contrast to the yeast or mammalian Atg8 that is distributed among cytosolic and membrane fractions, and suggests for a constitutive autophagy. Starvation, the best known autophagy inducer, decreased PfAtg8 level by almost 3-fold compared to the normally growing parasites. Neither the Atg8-associated puncta nor the Atg8 expression level was significantly altered by treatment of parasites with routinely used autophagy inhibitors (cysteine (E64) and aspartic (pepstatin) protease inhibitors, the kinase inhibitor 3-methyladenine, and the lysosomotropic agent chloroquine), indicating an atypical feature of autophagy. Furthermore, prolonged inhibition of the major food vacuole protease activity by E64 and pepstatin did not cause accumulation of the Atg8-associated puncta in the food vacuole, suggesting that autophagy is primarily not meant for degradative function in malaria parasites. Atg8 showed partial colocalization with the apicoplast; doxycycline treatment, which disrupts apicoplast, did not affect Atg8 localization, suggesting a role, but not exclusive, in apicoplast biogenesis. Collectively, our results reveal several atypical features of autophagy in malaria parasites, which may be largely associated with non-degradative processes.


Ancient genes can be served as pan-cancer diagnostic and prognostic biomarkers.
One important challenge for cancer is efficient biomarkers monitoring its formation and developments remain greatly limited. Although the accumulated big omics data provide great opportunities to the above purpose, the biomarkers identified by the data-driven strategy often do not work well in new datasets, which is one of the main bottlenecks limiting their utilities. Given that atavistic phenotype is generally observed in cancer cells, we have been suggested that the activity of progenitor genes in tumour could serve as an efficient cancer biomarker. For doing so, we first curated 77 progenitor genes and then proposed a quantitative score to evaluate cancer progenitorness. After applying progenitorness score to ~ 22 000 samples, 33 types of cancers from 81 datasets, this method generally performs well in the diagnosis, prognosis and therapy monitoring of cancers. This study proposed a potential pan-cancer biomarker and revealed a significant role of atavism in the formation and development of cancers.


Honokiol and magnolol stimulate glucose uptake by activating PI3K-dependent Akt in L6 myotubes.
Honokiol and magnolol, ingredients of Magnolia officinalis, which is used in traditional Chinese and Japanese medicines, have been reported to have antioxidant, anticancer, and antiangiogenic effects. Effects of these compounds on glucose metabolism in adipocytes have also been reported. However, their effects on skeletal muscle glucose uptake and the underlying molecular mechanisms are still unknown. Here, we investigated the direct effects and signaling pathways activated by honokiol and magnolol in skeletal muscle cells using L6 myotubes. We found that honokiol and magnolol dose-dependently acutely stimulated glucose uptake without synergistic effects of combined administration in L6 myotubes. Treatment with honokiol and magnolol also stimulated glucose transporter-4 translocation to the cell surface. Honokiol- and magnolol-stimulated glucose uptake was blocked by the phosphatidylinositol-3 kinase inhibitor, wortmannin. Both honokiol and magnolol stimulated Akt phosphorylation, a key element in the insulin signaling pathway, which was completely inhibited by wortmannin. These results suggest that honokiol and magnolol might have beneficial effects on glucose metabolism by activating the insulin signaling pathway.


Localization of ionotropic glutamate receptors to invaginating dendrites at the cone synapse in primate retina.
The separation of OFF pathways that signal light decrements from ON pathways that signal light increments occurs at the first retinal synapse. The dendrites of OFF bipolar cells abut the cone pedicle at basal positions distal to the site of glutamate release and express ligand-gated or ionotropic glutamate receptors (GluR). The dendrites of ON bipolar cells penetrate narrow invaginations of the cone pedicle proximal to the site of release and express the G-protein-coupled, metabotropic glutamate receptor, mGluR6. However, recent studies demonstrating the expression of GluR subunits in the rodent rod bipolar cell, known to yield an ON response to light, call this basic segregation of receptors into question. The light-microscopic distribution of many glutamate receptors in the primate retina is now well established. We reexamined their ultrastructural localization in the outer retina of Macaca fascicularis to test systematically whether invaginating dendrites at the cone synapse, presumably from ON bipolar cells, also express one or more ionotropic subunits. Using preembedding immunocytochemistry for electron microscopy, we quantified the distribution of the AMPA-sensitive subunits GluR2/3 and GluR4 and of the kainate-sensitive subunits GluR6/7 across 207 labeled dendrites occupying specific morphological loci at the cone pedicle. We report, in agreement with published investigations, that the majority of labeled processes for GluR2/3 (70%) and GluR4 (67%) either occupy basal positions or arise from horizontal cells. For GluR6/7, we find a significantly lower fraction of labeled processes at these positions (47%). We also find a considerable number of labeled dendrites for GluR2/3 (10%), GluR4 (21%), and GluR6/7 (18%) at invaginating positions. Surprisingly, for each subunit, the remainder of labeled processes corresponds to "fingers" of presynaptic cytoplasm within the cone invagination.


Improved antibacterial efficiency of inhaled thiamphenicol dry powders: Mathematical modelling of in vitro dissolution kinetic and in vitro antibacterial efficacy.
Thiamphenicol (TAP) is reported to be effective against many respiratory pathogens including methicillin-resistant Staphylococcus aureus (MRSA). However, its poor solubility in water remains as one of the obstacles hindering the preparation of inhalable TAP formulations. The aim of this study was to improve the dissolution rate of TAP by micronization, and investigate whether variations in the dissolution rates of TAP would affect its in vitro antibacterial activity. Inhalable dry powders composed of TAP microcrystals (MDP) or nanocrystals (NDP) were prepared by using a wet ball milling method followed by spray drying. The morphology, solid state and in vitro dissolution of these dry powders were characterized. In vitro antibacterial activities of the inhalable TAP dry powders against a MRSA strain were evaluated. A dissolution-efficacy model relating antibacterial activity with time and dissolution rate was established via modified time-kill assays. Upon being spray dried, the volumetric mean diameters of MDP and NDP were found to be around 5 µm. Solid state analyses showed that MDP and NDP possess the same crystalline form as the raw materials. NDP exhibited faster in vitro dissolution rate as compared to MDP. The in vitro antibacterial efficiency of NDP and MDP were superior to raw TAP when the test was performed at a TAP concentration of 32 mg/L. Simulated colony forming units predictions were consistent with the result measured in the time-kill experiments with Raw TAP, MDP and NDP. This study characterized the effect of the dissolution rate of TAP dry powders on in vitro antibacterial activity against MRSA, and an enhanced antibacterial activity of TAP was observed with an increase in the dissolution rate of TAP from the dry powders at certain concentration ranges.


Evaluation of CYFRA 21.1 as a Dedifferentiation Marker of Advanced Thyroid Cancer.
Well-differentiated thyroid carcinomas have good prognosis, but as it de-differentiates, the survival rates go down. Early identification of such patients needs a marker which indicates the dedifferentiation process. CYFRA 21.1 has also shown to be increased in patients with 131I refractory thyroid cancer. We tested whether CYFRA 21.1 can differentiate between 131I avid and refractory tumors. Well-differentiated thyroid cancer patients with known distant metastases were accrued and tested for stimulated and unstimulated thyroglobulin and CYFRA 21.1. All patients underwent 131I whole-body scan, 131I post therapy scan, and 18F-Fluorodeoxyglucose positron emission tomography-computed tomography. Those with even a single 131I nonavid lesion were considered 131I refractory disease. CYFRA 21.1 of both 131I avid and nonavid was compared, and CYFRA 21.1 levels against disease extent were analyzed. CYFRA 21.1 levels were significantly elevated in 131I refractory group. A cutoff value of 2.07 ng/ml distinguished between 131I avid and refractory disease with high sensitivity and specificity (88% and 89. 7%, respectively). However, CYFRA 21.1 levels were similar in patients when analyzed based on disease sites. CYFRA 21.1 can be utilized to differentiate between 131I avid and refractory diseases. Further long-term studies are required to use it as a predictive and prognostic marker.


Role of serotonergic and noradrenergic systems in a model of visceral pain.
The effects of selective manipulations of activity of the serotonergic and noradrenergic systems were examined in the rat model of visceral pain. It was found that neither p-chlorophenylalanine(p-CPA)- nor N-chloro-ethyl-2,2--bromo-benzylamine(DSP-4)-induced strong and selective depletion of the brain and spinal cord serotonin and noradrenaline, respectively, changed in a significant way rat visceral pain perception. On the other hand, 8-OH-DPAT, a full selective 5-HT1A receptor agonist, prazosin, an alpha1-adrenoceptor antagonist, clonidine, an alpha2-adrenoceptor agonist, and two beta-adrenoceptor antagonists: propranolol and metoprolol, dose-dependently reduced the number of body writhes induced by intraperitoneally administered 2% solution of acetic acid (the writhing test). The results obtained with selective receptor ligands, DSP-4 and p-CPA, indicate that the noradrenergic and serotonergic innervation of the central nervous system contribute in a complex way to the animal behavior in the writhing test. The 5-HT1A receptors and alpha2-adrenoceptors play an inhibitory role in the expression of rat behavior in this model of visceral pain. On the other hand, adrenergic alpha1 and beta1 receptors facilitate the behavioral effects of the irritant agent.


Human T lymphocyte surface antigens: partial purification and characterization utilizing a high-titer heteroantiserum.
A high-titer human T lymphocyte-specific antiserum (A99) has been prepared by immunization of rabbits with a preparation partially purified from membranes of the T cell line, CEM. The specificities recognized by this antiserum included those recognized by TH1 and HTL antisera. Several experiments indicated that these antisera recognized several different proteins. A partial purification of material recognized by A99 serum was obtained by 1) isolation of plasma membranes, 2) detergent solubilization and chromatography on DEAE-cellulose, and 3) affinity chromatography on a wheat germ lectin-Sepharose 4B column. These three steps yielded material about 100-fold purified, and an estimate was made in several ways that on overall purification of 3500-fold would be required to achieve homogeneity. Immunoprecipitation of 125I-labeled 100-fold purified material showed that the major bands recognized by A99 serum had m.w. of 52,000, 96,000 (seen only after reduction), 120,000, 152,000, and 195,000. These data are compared to other published reports of human T lymphocyte-specific proteins.


Matricellular Proteins Play a Potential Role in Acute Primary Angle Closure.
To quantify levels of matricellular proteins in aqueous humor samples from acute primary angle closure (APAC) and non-glaucomatous cataract eyes and investigate their correlation with intraocular pressure (IOP) fluctuation. Aqueous humor samples were collected from 63 eyes including 29 current APAC eyes, 12 previous APAC eyes, and 22 cataract eyes. Concentrations of four main matricellular proteins (SPARC, tenascin-C, thrombospondin-2, and osteopontin) were measured using multiplexed immunoassay kits. Correlations between matricellular proteins and age, sex, and IOP were then detected using Spearman's rank correlation coefficient. The levels of SPARC, thrombospondin-2, and osteopontin were significantly elevated in the APAC group as compared to the cataract group (p < 0.001, p < 0.001, and p = 0.009, respectively). Further separation of the APAC group into current and previous APAC groups showed that only the differences of SPARC and thrombospondin-2 between the current APAC and cataract groups were significant (both p < 0.001). All four matricellular proteins were found to have a positive correlation with IOP in the current APAC group but no correlation was found in the previous APAC or cataract groups. The levels of matricellular proteins were significantly elevated in the current APAC eyes and positively correlated to IOP. Further studies are necessary to investigate the molecular mechanisms and histological evidence of pathogenesis in matricellular proteins in APAC.


Recommendations for the registration of drugs used in the treatment of rheumatoid arthritis. Group for the Respect of Ethics and Excellence in Science (GREES): rheumatoid arthritis section.
Rheumatoid arthritis (RA) is the commonest form of chronic inflammatory joint disease and a major target for symptom-modifying and disease-modifying drug therapy. New approaches to the treatment of RA using biological agents targeted to cellular receptors, cytokines and other mediators of inflammation, together with the availability of new methods of outcome assessment, make it timely to reconsider the classification of anti-rheumatic drugs and the requirements for the registration of new drug entities. Under the auspices of GREES (Group for the Respect of Ethics and Excellence in Science), a European Working Group of clinicians with experience in rheumatology, scientists and representatives from industry and national drug licensing authorities have formulated recommendations for the requirements for registration of anti-rheumatic drugs designed for symptom modification, structural modification and the suppression of inflammation, with particular emphasis placed on quality of life assessment by generic and disease-specific validated methods. This paper outlines the group's advice for pre-clinical testing, and Phase I, Phase II and Phase III trials to allow licences to be granted for each indication, while recognizing that a single drug may have reason to be approved under several headings.


The impacts of partnering with cancer patients in palliative care research: a systematic review and meta-synthesis.
Palliative care (PC) is an added layer of support provided concurrently with cancer care and serves to improve wellbeing and sustain quality of life. Understanding what is meaningful and a priority to patients, their families, and caregivers with lived experience of cancer and PC is critical in supporting their needs and improving their care provision. However, the impacts of engaging cancer patients within the context of PC research remain unknown. To examine the impacts of engaging individuals with lived experience of cancer and PC as partners in PC research. An a priori systematic review protocol was registered with PROSPERO (CRD42021286744). Four databases (APA PsycINFO, CINAHL, EMBASE, and MEDLINE) were searched and only published, peer-reviewed primary English studies aligned with the following criteria were included: (1) patients, their families, and/or caregivers with lived experience of cancer and PC; (2) engaged as partners in PC research; and (3) reported the impacts of engaging cancer PC patient partners in PC research. We appraised the quality of eligible studies using the Critical Appraisal Skills Program (CASP) and GRIPP2 reporting checklists. Three studies that included patient partners with lived experience of cancer and PC engaged at all or several of the research stages were identified. Our thematic meta-synthesis revealed impacts (benefits and opportunities) on patient partners (emotional, psychological, cognitive, and social), the research system (practical and ethical) and health care system (service improvements, bureaucratic attitudes, and inaction). Our findings highlight the paucity of evidence investigating the impacts of engaging patients, their families and caregivers with lived experience of cancer and PC, as partners in PC research. The results of this review and meta-synthesis can inform the more effective design of cancer patient partnerships in PC research and the development of feasible and effective strategies given the cancer and PC context patient partners are coming from.


Latency of muscle chemoreflex to vascular occlusion of active muscle during dynamic exercise.
When oxygen delivery to active muscle is too low for the ongoing rate of metabolism, metabolites accumulate and activate a muscle chemoreflex that raises arterial pressure. During static muscular contractions, the latency of the onset of increments in sympathetic activity attributed to the muscle chemoreflex is long (1-2 min). This long latency might be caused by slow accumulation of metabolites attributable to low rates of metabolism. Because shortening contractions at a given force per unit time have a much higher energy cost than do static contractions, the muscle chemoreflex should have a much shorter latency during dynamic exercise than during static contractions, and the latency should shorten further with rising exercise intensity. To test these ideas, the latency to the onset of the rise in arterial pressure induced by the muscle chemoreflex following vascular occlusion of active muscle was measured in four dogs exercising on a treadmill. During steady-state exercise of mild to moderate intensity, pressor responses to muscle ischemia were elicited by rapid, complete occlusion of the terminal aorta; this procedure mimics the blockage of muscle blood flow that occurs normally during static contractions. There was a statistically significant effect of exercise intensity on latency (P < 0.001). The latency was 23.5 +/- 4.5, 16.4 +/- 5.6, and 10.1 +/- 2.3 s (means +/- SE) at 3.2 km/h 0% grade, 6.5 km/h 0% grade, and 6.5 km/h 10% grade, respectively. Also, the rate of rise of arterial pressure during chemoreflex activation increased progressively with rising exercise intensity from 0.8 +/- 0.2 mmHg/s during exercise at 3.2 km/h 0% grade to 2.0 +/- 0.5 mmHg/s during exercise at 6.5 km/h 10% grade. Thus the latency of the muscle chemoreflex in response to vascular occlusion during mild dynamic exercise is shorter than has been reported during static contractions of moderate intensity.


A remote cis-acting variant at 3q links glomerular NCK1 to diabetic nephropathy.
We have previously reported genetic association of a single nucleotide polymorphism (SNP), rs1866813, at 3q locus with increased risk of diabetic nephropathy (DN). The SNP is located approximately 70 kb downstream of a cluster of four genes. This raises a question how the remote noncoding polymorphism affects the risk of DN. In this study, we tested a long-range regulatory potential of this variant by a series of experiments. In a luciferase assay, two alleles of the SNP showed differential effects on the luciferase activity in transfected cells in vitro. Using transgenic zebrafish, we further demonstrated in vivo that two alleles of the SNP differentially regulated GFP expression in zebrafish podocytes. Immunofluorescence staining and Western blotting verified that only Nck1 of the four nearby genes was predominantly expressed in mouse glomeruli as well as in podocytes. Furthermore, genotypes of the SNP rs1866813 were correlated with NCK1 expression in immortalized lymphocytes from diabetic patients. The risk allele was associated with increased NCK1 expression compared to the non-risk allele, consistent with the results of the reporter-based studies. Interestingly, differential expression of glomerular Nck1 between mouse strains carrying the nephropathy-prone 129/Sv allele and nephropathy-resistant C57BL/6 allele was also observed. Our results show that the DN-associated SNP rs1866813 is a remote cis-acting variant differentially regulating glomerular NCK1 expression. This finding implicates an important role for glomerular NCK1 in DN pathogenesis under hyperglycemia.


The Rapid Escalation of Fentanyl in Illicit Drug Evidence in Allegheny County, Pennsylvania, 2010-2016.
Opioid overdose deaths in the United States quadrupled from 1999 (n = 8050 deaths) to 2015 (n = 33 091 deaths), and the number of deaths associated with synthetic opioids, such as fentanyl, increased from 3105 deaths in 2013 to nearly 20 000 deaths in 2016. Given this rapid increase, timely surveillance for drugs in circulation is crucial. However, current surveillance systems used to track drug overdoses do not detect new drugs in circulation quickly. We studied the change in the presence of fentanyl in "stamp bag" drug evidence in Allegheny County, Pennsylvania, from 2010 through 2016. Stamp bags are small wax packets with individual stamps that contain mixtures of drugs, most commonly heroin, that law enforcement officers seize and retain as legal evidence. The proportion of stamp bags determined to contain fentanyl or a fentanyl analog was 2.1% in 2014 and rose sharply to 17.1% in 2016. Monitoring the chemical makeup of drug evidence items could help public health authorities identify drug use trends in their jurisdictions.


Incidence of hepatocellular carcinoma in chronic hepatitis C after interferon therapy.
We investigated the rate of occurrence and the risk factors for hepatocellular carcinoma in chronic hepatitis C patients who received interferon therapy. We followed 413 chronic hepatitis C patients for more than 6 years after interferon therapy and assessed the following patient characteristics: age, sex, platelet count, response to interferon, hepatitis C virus RNA level, hepatitis C virus genotype, liver histology, and changes in serum alanine aminotransferase levels. Hepatocellular carcinoma was found in 21 patients after interferon therapy. The factor most related to the occurrence of hepatocellular carcinoma was changes in serum alanine aminotransferase levels (univariate analysis, P < 0.0001; multivariate analysis, P = 0.0013), followed by age (univariate analysis, P = 0.0003; multivariate analysis, P = 0.0029). A significant difference was observed in the platelet count and response to interferon based on univariate analysis alone (P = 0.0096, P = 0.0241, respectively), however no significant differences were noted in the other factors. The course of serum alanine aminotransferase levels following interferon therapy rather than the eradication of hepatitis C virus was found to be the factor most profoundly involved in liver carcinogenesis. Even if interferon therapy fails to eradicate the hepatitis C virus, maintaining low serum alanine aminotransferase levels post-interferon therapy would reduce the risk of hepatocellular carcinoma in chronic hepatitis C.


Automatic epicardial adipose tissue segmentation in pulmonary computed tomography venography using nnU-Net.
Epicardial adipose tissue (EAT) is a key aspect in the investigation of cardiac pathophysiology. We sought to develop a deep learning (DL) model for fully automatic extraction and quantification of EAT through pulmonary computed tomography venography (PCTV) images. In this retrospective study, we included 128 patients with atrial fibrillation and PCTV from 2 hospitals. A DL model for automated EAT segmentation was developed from a training set of 51 patients and a validation set of 13 patients from hospital A. The algorithm was further validated using an internal test set of 16 patients from hospital A and an external test set of 48 patients from hospital B. The consistency and measurement agreement of EAT quantification were compared between the DL model and the conventional manual protocol using the Dice score coefficient (DSC), Hausdorff distance (HD95), Pearson correlation coefficient, and Bland-Altman plot. In the internal and external test set, automated segmentation with DL was successful in all cases. The total analysis time was shorter for DL than for manual reconstruction (5.43±2.52 vs. 106.20±15.90 min; P<0.001). The EAT segmented with the DL model had good consistency with manual segmentation (the DSC of the internal and external test sets were 0.92±0.02 and 0.88±0.03, respectively). The quantification of EAT evaluated with the 2 methods showed excellent correlation (all correlation coefficients >0.9; all P values <0.001) and minimal measurement difference. The proposed DL model achieved fully automatic quantification of EAT from PCTV images. The yielded results were highly consistent with those of manual quantification.


Atomic model of human cystic fibrosis transmembrane conductance regulator: membrane-spanning domains and coupling interfaces.
We describe herein an atomic model of the outward-facing three-dimensional structure of the membrane-spanning domains (MSDs) and nucleotide-binding domains (NBDs) of human cystic fibrosis transmembrane conductance regulator (CFTR), based on the experimental structure of the bacterial transporter Sav1866. This model, which is in agreement with previous experimental data, highlights the role of some residues located in the transmembrane passages and directly involved in substrate translocation and of some residues within the intracellular loops (ICL1-ICL4) making MSD/NBD contacts. In particular, our model reveals that D173 ICL1 and N965 ICL3 likely interact with the bound nucleotide and that an intricate H-bond network (involving especially the ICL4 R1070 and the main chain of NBD1 F508) may stabilize the interface between MSD2 and the NBD1F508 region. These observations allow new insights into the ATP-binding sites asymmetry and into the molecular consequences of the F508 deletion, which is the most common cystic fibrosis mutation.


Rationale for the use of mitoxantrone in multiple sclerosis.
Mitoxantrone is a member of the anthracendione family developed to treat malignancies and increasingly used to treat multiple sclerosis (MS). It has been studied as a treatment for MS since the late 1980s, and is licensed in a number of countries for progressive and worsening MS. Review of the published earlier open-label, and more recently of controlled trials suggests that mitoxantrone is efficacious in cases of worsening MS that have an inflammatory component as evidenced by progression with or without superimposed relapses and/or gadolinium (Gd) enhancing magnetic resonance (MR) lesions. Today there is no robust evidence of efficacy in primary progressive MS or in later stages of secondary progressive MS beyond an EDSS score of 6. Relevant immunomodulatory mechanisms act both on T- and B-cell function, and mitoxantrone has selective immune effects in MS by decreasing levels of TNF-alpha, IL-2, IL-2R-beta1, IL-10 and IFN-gamma. Adverse events include nausea, alopecia, infections, menstrual disorders, risk of cardiotoxicity and malignancy. Different regimens are used according to different regulatory demands in different countries. The two most commonly used regimens are every 3 months intravenous (i.v.) 12 mg/m2 for 2 years or 20 mg mitoxantrone (i.v.) combined with 1 g methylprednisolone (i.v.) every 4 weeks for 6 months. The cumulative life dose in MS patients is 140 mg/m2. Mitoxantrone is currently used as a second line drug in MS patients whose disease is not controlled by beta-interferon or glatiramer acetate. In this review, we will discuss the clinical disease patterns of MS patients who are most likely to benefit from mitoxantrone, its magnitude of clinical effect, and limitations of using mitoxantrone in MS. Mitoxantrone as a second line therapy in non-responders of beta-interferon and glatiramer acetate will be assessed. Recent strategies of combination therapy, and the optimal dose regimen will also be discussed.


Acute coronary syndrome: assessment and management.
Acute coronary syndrome is a serious condition that requires urgent assessment and management. This article outlines the nature of the condition, and discusses its underlying pathophysiology. It discusses three types of acute coronary syndrome: unstable angina, ST elevation myocardial infarction and non-ST elevation myocardial infarction. Research and guidelines are used to guide the reader through approaches to initial nursing assessment and the immediate management of patients with suspected acute coronary syndrome.


Astrocytic response in the rodent model of global cerebral ischemia and during reperfusion.
The present study investigated alterations in astrocytic cells after global cerebral ischemia resulting from cardiac arrest immediately and at several intervals after reperfusion when excessive formation of highly cytotoxic free radicals is known to occur. The cellular fraction of astrocytic origin (glial plasmalemmal vesicles - GPV) was examined by biochemical and immunochemical procedures. A tendency towards an elevation in immunocontent of glial fibrillary acidic protein (GFAP) was noticed after 24 hours whereas a significant increase was observed 7 days post ischemic event. The features of astrocytic stimulation were also observed in electron microscopy studies. An enhanced amount of gliofilaments was noticed in brain sections obtained from rats after 7 days of recovery. Simultaneously, a gradual decrease of total glutathione level, depending on the duration of reperfusion, was observed in brain homogenates and in fractions of astroglial origin. The most considerable reduction was observed on day 1 (52%) and day 7 (65%) after reperfusion in brain homogenates and on day 7 (47%) in GPV fraction. The results indicate an enhanced reactivity of astrocytic cells in ischemic conditions concomitantly with a long lasting decrease of total glutathione. Obviously, the inability of astrocytic glutathione system to detoxify free radicals formed during ischemic/reoxidation conditions may lead to damage to cerebral neurons by oxidative stress.


Genotyping--from genomic DNA to genotype in a single tube.
Nucleotide variations in the human genome, such as single-nucleotide polymorphisms, have been researched more intensively since it became apparent that these deviations are linked to various diseases and also several side effects of drugs. The investigation of genomic DNA in the laboratory requires routine methods that are time-, labour-, and cost-effective. These criteria are fulfilled by so-called closed-tube methods, which are applied directly to isolated genomic DNA without any preamplification.