Comparative analysis of foetal calf and human low density lipoprotein: relevance for pharmacodynamics of photosensitizers.
The effects of differences in lipoprotein content on the distribution of the novel hydrophobic photosensitizer n-butyl-3-[18-(2-butylcarbamoyl-ethyl)-3,7,12,17-tetramethyl-18,13-divinyl-22,24-dihydro-porphin-2-yl]propionamide (PP-N-3) and haematoporphyrin ester (HpE), a relatively hydrophilic photosensitizer, in human (HS) and foetal calf sera (FCS), were investigated. The binding characteristics of human and foetal calf low-density lipoprotein (LDL) were characterised using a human fibroblast line (Vag 12). The uptake into cells of HpE and PP-N-3 was also examined. A comparison of the lipoprotein content, composition and receptor-binding characteristics of foetal calf and human serum was also carried out. LDL content was measured directly using sequential ultracentrifugation to isolate LDL. In our study, we found haematoporphyrin ester to bind to human very low-density lipoprotein (VLDL), LDL and high-density lipoprotein (HDL) in the ratio 2:31:65. In the case of PP-N-3 this ratio was 56:10:33. As VLDL was not detected in foetal calf serum, only binding to LDL and HDL was observed. Using the sequential ultracentrifugation technique, foetal calf serum was found to contain LDL which in turn did bind to human LDL receptors. The uptake of PP-N-3 and HpE in the presence of low density lipoprotein from foetal calf serum (FC-LDL) was not significantly different to values observed in the presence of human serum low density lipoprotein (HS-LDL).


Below- or above-elbow immobilization in conservative treatment of distal radius fractures: a systematic review and meta-analysis.
There is no consensus regarding the range of immobilization in the conservative treatment of distal radius fractures (DRFs). Therefore, this systematic review and meta-analysis aimed to compare the clinical outcome of patients with DRFs treated conservatively with below- or above-elbow immobilization. Following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines, two independent reviewers searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform in April 2020; a subsequent update search was conducted in April 2021. We identified all randomised controlled trials comparing two immobilization methods in DRFs. The primary outcome measures were the Disabilities of the Arm, Shoulder and Hand (DASH) or QuickDASH questionnaire scores in the short- and long-term (≤ and >six weeks, respectively) follow-up as well as the treatment failure rate. The secondary outcome measures were radiographic outcome, patient-rated wrist evaluation (PRWE) score, pain score and adverse events. Risk of bias was evaluated using the Cochrane Risk of Bias tool version 2. We used the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate the quality of evidence. The initial search revealed 1,775 records, and ten studies with 909 participants in total were included. There was no significant difference in DASH score in the short-term follow-up (4.99 lower, 95% confidence interval (CI): 10.45 lower to 0.46 higher; very low certainty) and treatment failure (risk ratio: 0.91, 95% CI: 0.59 to 1.40; low certainty). A clinically irrelevant but significant mean difference (0.83 lower, 95%CI: 1.64 lower to 0.03 lower; low certainty) was found in the DASH score in favour of below-elbow immobilization in the long-term follow-up. The overall risk of bias in DASH scores was high based on the measurement bias. Furthermore, there was no significant difference in secondary outcome measures. This meta-analysis did not demonstrate clinically meaningful difference between below- and above-elbow immobilization in terms of DASH score both in the short- and long-term follow-ups. However, overall certainty of evidence was considered very low, based on the very serious risk of bias, inconsistency and imprecision. Hence, there is a need for further higher quality research. UMIN000040134 (4/14/2020).


Case-Control Study to Investigate the Association Between Serum Apolipoprotein B/A1 Ratio and Atrial Fibrillation by Sex in 920 Patients from China.
BACKGROUND The serum apolipoprotein B/A1 ratio (APOB/APOA1) has been shown to predict cardiovascular events, whereas the effect of the APOB/APOA1 ratio on atrial fibrillation (AF) is less known. We investigated the association between the APOB/APOA1 ratio and AF by sex in 920 patients from China. MATERIAL AND METHODS We reviewed clinical data on 1840 hospitalized patients, including 920 patients with AF (male/female: 460/460, age: 68.62±10.36 years) and 920 age- and sex-matched patients without AF with sinus rhythm in China between January 2019 and September 2021. Pearson correlation analysis was performed to investigate the correlation between APOB/APOA1 ratio and AF-related metabolic factors. Logistic regression analysis was used to determine the odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS Low serum APOB/APOA1 ratios in male and female patients were significantly associated with AF after adjusting for confounding factors (OR 0.159, 95% CI 0.058-0.432, P<0.05). Serum APOB/APOA1 ratio was positively correlated with triglyceride (TG) (r=0.146, P<0.05) and total cholesterol (TC) (r=0.227, P<0.05) and was negatively correlated with albumin (ALB) (r=-0.128, P<0.05) and prealbumin (PAB) (r=-0.107, P<0.05). There was no significant difference of APOB/APOA1 ratio in different subtypes, complications, and statin use in patients with AF (P>0.05). CONCLUSIONS A low serum APOB/APOA1 ratio in male and female patients from China was significantly related to AF. This finding implies that a low serum APOB/APOA1 ratio may be associated with the causes of AF. Further studies are needed to determine causalities.


Hierarchical rupture growth evidenced by the initial seismic waveforms.
The ability to predict the eventual size of an earthquake during its early growth stage is a crucial component of earthquake early warning systems. Recent studies have revealed that the onsets of small and large earthquakes are variable but statistically indistinguishable. However, it is unknown whether small and large earthquakes can share the same processes at the same location. Here we show clear evidence of almost identical growth processes shared by repeating earthquakes of various sizes that have occurred in the Naka region, eastern Japan. Our results indicate that a large earthquake is a failure with a large characteristic spatial scale that is initially triggered by a failure with a small characteristic scale, which may also occur independently controlled by subtle differences in the physical conditions, suggesting the existence of a hierarchical structure on the plate interface. Earthquakes are random, but they may also be controlled by such structures.


[The rate of repair of a radiation lesion of the central nervous system during protracted and fractionated irradiation].
In experiments with fractionated and prolonged irradiation of guinea pigs and dogs it was shown that the recovery of CNS from acute radiation affection may be approximated, for different animal species, by an exponential function at a rate of 0.02 h-1 and a half-life period of approximately 30 h.


Vaccines for parasitic and bacterial diseases.
The first decade of the millennium should mark the beginning of a new era in vaccine development, reaping the rewards of advances in genome characterization, antigen identification, understanding the molecular bases of protective immune responses, and adjuvant design and development. Advances in all of these areas have culminated in vaccine candidates entering clinical testing. These include vaccines against two of humankind's oldest and deadliest diseases, tuberculosis and malaria. Several vaccine candidates for each of these diseases will be tested in humans during the next few years. A candidate vaccine for leishmaniasis, an infection that has taught us much about T-cell regulation of protection and disease in animal models, has been developed and is now in the clinic. There are indications both in animal models and in patients that vaccines may be used not only to protect but also to treat leishmania infections.


Progesterone increases oligodendroglial cell proliferation in rat cerebellar slice cultures.
We have previously demonstrated that progesterone significantly increases the rate of myelination in organotypic slice cultures of 7-day-old rat and mouse cerebellum. Here, we show that progesterone (20microM) stimulates the proliferation of oligodendrocyte precursors in cultured cerebellar slices of 7-day-old rats. The steroid increased the number of pre-oligodendrocytes (NG2(+), O4(+)) and to some extent of oligodendrocyte precursors, corresponding to an earlier developmental stage (nestin(+), PDGFalphaR(+), NG2(+), O4(-)). Progesterone stimulated the proliferation of both NG2(+) and O4(+) cells as shown by increased double-immunolabeling with the cell proliferation marker Ki67. The mitogenic effect of progesterone was inhibited by the progesterone receptor antagonist mifepristone (10microM) and could not be mimicked by its GABA-active metabolite 3alpha,5alpha-tetrahydroprogesterone (allopregnanolone), even at the high concentration of 50microM. Results indicate that progesterone first strongly and transiently stimulates the proliferation of oligodendrocyte precursors, and that it may thereafter accelerate their maturation into myelinating oligodendrocytes. Although oligodendrocyte precursors may be a direct target for the actions of progesterone, their number may also be indirectly influenced by the effects of the steroid on neurons and microglial cells, since treatment of the cerebellar slices with progesterone enhanced staining of the neuronal cytoskeleton marker microtubule-associated protein-2 and increased the number of OX-42(+) microglia. A small percentage (about 0.1%) of the NG2(+) cells transiently became OX-42(+) in response to progesterone. These results point to novel mechanisms by which progesterone may promote myelination in the CNS, specifically by stimulating the proliferation and maturation of oligodendrocyte precursors into myelinating oligodendrocytes.


A simple, accurate and universal method for quantification of PCR.
Research into gene expression enables scientists to decipher the complex regulatory networks that control fundamental biological processes. Quantitative real-time PCR (qPCR) is a powerful and ubiquitous method for interrogation of gene expression. Accurate quantification is essential for correct interpretation of qPCR data. However, conventional relative and absolute quantification methodologies often give erroneous results or are laborious to perform. To overcome these failings, we developed an accurate, simple to use, universal calibrator, AccuCal. Herein, we show that AccuCal quantification can be used with either dye- or probe-based detection methods and is accurate over a dynamic range of ≥10(5) copies, for amplicons up to 500 base pairs (bp). By providing absolute quantification of all genes of interest, AccuCal exposes, and circumvents, the well-known biases of qPCR, thus allowing objective experimental conclusions to be drawn. We propose that AccuCal supersedes the traditional quantification methods of PCR.


Adolescents living with HIV, complex needs and resilience in Blantyre, Malawi.
Adolescents living with HIV (ALHIV) in Malawi experience multiple challenges associated with their illness and various social, environmental, economic and cultural factors. In exploring their various medical concerns and social vulnerabilities, we consider the role of multiple services in creating a pathway for resilience. Multiple methods and case studies allowed for triangulation of evidence and provided a holistic understanding of resilience among adolescents with complex needs. The research methods included: (1) a survey to identify examples of young people with complex needs, (2) qualitative interviews and field notes to further explore these needs, (3) patient files and health passports to identify clinical challenges, and (4) ecomapping exercises to personalize cases and identify resilience-enabling resources and supports. We present four case studies to highlight the complex experiences and access to services of ALHIV, and to illustrate their growing power and decision-making capacity over time. Adversity experienced by ALHIV varied by gender, family situation, years of schooling, and use of teen-clubs for support. The two female adolescents emphasised their need to be accepted and how this impacted sexuality and reproduction. The two males illustrated how ideas of masculinity influenced their sexual practice and involvement with health services and the correctional justice system. Multiple risks (alcohol use, sexual activities) and complex needs (belonging, having a purpose in life/productive activities, autonomy, desire for offspring) influence pathways to resilience. ALHIV were able to strengthen their own wellbeing by resisting negative behaviours and peer pressure and caregiver interactions through 'strategic silence'. ALHIV experienced self-transformation as a result of taking ART, with fewer severe episodes of illness and distressing skin conditions. Continuous engagement at the teen-club clinic transformed both productive activities and social relationships among ALHIV as they set life goals, gained a sense of empowerment, requested SRH services, and formed intimate relationships. These transformative opportunities allowed them to learn ways of minimizing risk of reinfection and violence, and of navigating health worker-caregiver-adolescent interactions.


Tunable Multipolar Fano Resonances and Electric Field Enhancements in Au Ring-Disk Plasmonic Nanostructures.
We theoretically research the characteristics of tunable multipolar Fano resonances in novel-designed Au ring-disk plasmonic nanostructures. We systematically study some structural parameters that influence the multipolar Fano resonances of the nanostructures. Adjustment of the radius (R₁ and R₂) of the Au ring, the radius (R₃) of the Au disk and the thickness (H) of the Au ring-disk can effectively adjust the multipolar Fano resonances. The complex field distributions excited by a Au ring-disk can produce dark resonance modes. At the frequency of the multipolar Fano resonances, strong localized field distributions can be obtained. The Fano resonances exhibit strong light-extinction properties in Au ring-disk nanostructures, which can be applied to an optical tunable filter and optical switch.


The multidimensional driving style inventory--scale construct and validation.
Two studies were conducted in order to develop a multidimensional instrument of driving style. In Study 1, we developed a self-report scale assessing four broad domains of driving style-the multidimensional driving style inventory (MDSI). A factor analysis revealed eight main factors, each one representing a specific driving style--dissociative, anxious, risky, angry, high-velocity, distress reduction, patient, and careful. In addition, significant associations were found between the eight factors, on the one hand, and gender, age, driving history, and personality measures of self-esteem, need for control, impulsive sensation seeking, and extraversion, on the other. In Study 2, further associations were found between the eight driving style factors and measures of trait anxiety and neuroticism. The discussion focused on the validity and utility of a multidimensional conceptualization of driving style.


Blood pressure, heart rate, pressure-rate product and electrocardiographic changes in healthy children during treadmill exercise.
Heart rate, systolic and diastolic blood pressure, rate-pressure product and electrocardiographic changes were measured in 288 healthy children during treadmill exercise. A constant speed (3.5 miles/hour) protocol was used to facilitate the measurements of physiologic data during exercise. Because responses to exercise vary with size, the children were separated into four groups according to body surface area. Comparisons were also made between male and female and between black and white children. The values for heart rate and systolic pressure showed excellent reproducibility in repeated tests. These data establish for clinical use reference values for children during treadmill exercise.


Surgical therapy for multiple sclerosis tremor: a 12-year follow-up study.
Severe multiple sclerosis (MS) tremor causes disability poorly responsive to medication. Deep brain stimulation (DBS) or thalamotomy can suppress tremor, but long-term outcomes are unclear. Nine patients with MS tremor underwent disability measures at baseline and 12 months post-surgery (six thalamotomy, three DBS) in 1997-1998 (previously reported, Matsumoto et al., Neurology 2001;57:1876-82). We report the prospective 12-year follow-up of this cohort for tremor, disability, and death. Surgery was initially successful in all. Tremor recurred in all patients within median 3 months, although two DBS patients were tremor-free for 5 years. Median tremor-free survival (tremor-free time/survival time) was 4.3%. At 12-year follow-up, four survivors (two thalamotomy, two DBS) (Expanded Disability Status Scale scores 8-8.5) were severely disabled. Five patients were dead (four thalamotomy, one DBS) median 5.8 years post-operative. Surgery benefit for severe tremor was overall short-lived (median 3 months), with long-term poor prognosis. Although two DBS patients had sustained 5-year tremor-suppression, the observed progressive disability and death in this cohort bear importance for long-term success in future MS tremor surgery trials.


The role of protein kinase CK2 in the regulation of the insulin production of pancreatic islets.
An appropriate regulation of the insulin production and secretion in pancreatic β-cells is necessary for the control of blood glucose homeostasis. The pancreatic duodenal homeobox factor-1 (Pdx-1) is among the various factors and signals which are implicated in the regulation of the insulin synthesis and secretion in the pancreatic β-cells. Recently, we identified Pdx-1 as a substrate for protein kinase CK2. Since CK2 is implicated in the regulation of many different cellular signaling pathways we now asked whether it might also be involved in the regulation of the insulin regulation in β-cells. Here, we show that insulin treatment of β-cells resulted in an elevated CK2 kinase activity. On the other hand down-regulation of CK2 activity by quinalizarin led to an elevated level of insulin. These results demonstrate that CK2 is implicated in the insulin regulation on pancreatic β-cells.


Infant mortality, ethnicity, and genetically determined disorders in The Netherlands.
Infant mortality of ethnic minorities in The Netherlands (10% of the population) is twice as high as in the indigenous Dutch population. Causes of death are different for the diverse migrant groups. Hospital records of nearly 600 infants who died in the four major cities between 1995 and 1998 were analysed according to the cause of death, ethnicity, and possible heredity. There was a four to five times higher proportion of hereditary causes of death in the Moroccan and Turkish population, compared with the Surinamese/Antillians and indigenous Dutch. This might be explained by a high inbreeding coefficient as three-quarters of the marriage partners are recruited from the home villages and between a quarter and a third of these marriages are between first cousins. Health promotion activities in The Netherlands have not been successful so far. Preconception genetic counselling might help in reducing these differences.


HGA: de novo genome assembly method for bacterial genomes using high coverage short sequencing reads.
Current high-throughput sequencing technologies generate large numbers of relatively short and error-prone reads, making the de novo assembly problem challenging. Although high quality assemblies can be obtained by assembling multiple paired-end libraries with both short and long insert sizes, the latter are costly to generate. Recently, GAGE-B study showed that a remarkably good assembly quality can be obtained for bacterial genomes by state-of-the-art assemblers run on a single short-insert library with very high coverage. In this paper, we introduce a novel hierarchical genome assembly (HGA) methodology that takes further advantage of such very high coverage by independently assembling disjoint subsets of reads, combining assemblies of the subsets, and finally re-assembling the combined contigs along with the original reads. We empirically evaluated this methodology for 8 leading assemblers using 7 GAGE-B bacterial datasets consisting of 100 bp Illumina HiSeq and 250 bp Illumina MiSeq reads, with coverage ranging from 100x- ∼200x. The results show that for all evaluated datasets and using most evaluated assemblers (that were used to assemble the disjoint subsets), HGA leads to a significant improvement in the quality of the assembly based on N50 and corrected N50 metrics.


Cell physiological aspects of the plasma membrane electrogenic H+ pump.
This article deals with cell physiological aspects of the plasma membrane electrogenic proton (H+) pump and emphasizes the contribution of the giant algal cells of the Characeae in elucidating the mechanism of the pump. First, a history of the development of intracellular perfusion techniques in characean internodal cells is described, including preparation of tonoplast-free cells. Then, an outline of the hypothesis of the electrogenic H+ pump proposed by Kitasato is introduced, who prophesied the existence of an electric potential generated by an active H+ efflux. Subsequently, a history of finding ATP as the direct energy source of the electrogenic ion pump is presented. Quantitative agreement between the pump current and the ATP-dependent H+ efflux supports the notion that the ion carried by the electrogenic ion pump is H+. The role of the H+ pump in regulation of the cytosolic pH is discussed. Mechanisms of light-induced potential change through photosynthesis-controlled activation of the H+ pump are discussed in terms of changes in the levels of adenine nucleotides and in modulation of the Km value for the ATP of H+-ATPase. Recent progress in the molecular mechanism of the blue-light-induced activation of the H+-ATPase in guard cells is presented. However, there are cases where H+-ATPase activity is inhibited by blue light, indicating the flexibility of the control mechanisms of H+-ATPase activity. Finally, modulation of H+-pumping or H+-ATPase activities in response to environmental factors, such as anoxia, membrane excitation, osmotic and salt stresses, nutrient deficiencies and aluminum toxicity are described. Discussions are presented on the regulation of the electrogenic H+ pump.


Analysis of serum insulin-like growth factor-1, fibroblast growth factor 23, and Klotho levels in girls with rapidly progressive central precocious puberty.
To study the levels of serum insulin-like growth factor 1 (IGF-1), fibroblast growth factor 23 (FGF23), and Klotho, and to study their relationship with girls with rapidly progressive central precocious puberty (RP-CPP). This is a cross-sectional study on the progression rate of central precocious puberty in girls, who complained of breast development before the age of 8 years and were followed between June 2021 and June 2022. At the same time, 28 healthy girls less than 8 years old who had not started puberty were recruited as the control group. The physical examination and laboratory evaluation of each group was completed. Only patients with CPP received pelvic ultrasound examination and bone age test. Bone age index (BAI), basal LH levels (BLH), basal LH levels/basal FSH levels (BFSH), peak LH (PLH)/peak FSH (PFSH), IGF-1, Klotho, FGF23, and ovarian volume in the RP-CPP group were higher than those in slowly progressive CPP (SP-CPP) group. In the RP-CPP group, IGF-1 was correlated with Klotho, FGF23, and BLH; Klotho was correlated with FGF23 and BLH; FGF23 was correlated with BLH. The BLH, FGF23, Klotho, and IGF-1 have a certain correlation with RP-CPP, which may play an important role in the speed of girls' sexual development. • The association between IGF-1 and RP-CPP. • We found the association between FGF23, Klotho and RP-CPP.


Substance P release from the rat substantia nigra.
The characteristics of substance P release have been investigated in the rat substantia nigra, in vitro, using a sensitive radioimmunoassay method. The spontaneous efflux of substance P represented approximately 0.5% of tissue stores released per minute. Addition of potassium to the superfusion medium produced a concentration-dependent increase in substance P release which was linear over the range 15--60 mM potassium. The potassium-evoked release of substance P was almost totally abolished by removal of calcium from the superfusion medium, and was linearly related to an increase in calcium concentration with a corresponding decrease in the magnesium concentrations over the range 0.1--3.0 mM calcium. Veratridine (50 micrometer) also evoked the release of substance P in a calcium- and tetrodotoxin-sensitive manner. Superfusion of substantia nigra slices with GABA produced a concentration-dependent inhibition in the K+-evoked release of substance P which could be abolished by continuous superfusion with picrotoxin. Bicuculline was less effective than picrotoxin in blocking the effects of GABA. The GABA agonist muscimol also produced an inhibition of substance P release, whereas baclofen was without effect. These results support the concept that substance P may function as a neurotransmitter within the substantia nigra, and suggest that GABA may have a role in the regulation of substance P release.


Disgust- and not fear-evoking images hold our attention.
Even though disgust and fear are both negative emotions, they are characterized by different physiology and action tendencies. The aim of this study was to examine whether fear- and disgust-evoking images would produce different attention bias effects, specifically those related to attention (dis)engagement. Participants were asked to identify a target which was briefly presented around a central image cue, which could either be disgusting, frightening, or neutral. The interval between cue onset and target presentation varied within blocks (200, 500, 800, 1100 ms), allowing us to investigate the time course of attention engagement. Accuracy was lower and reaction times were longer when targets quickly (200 ms) followed disgust-evoking images than when they followed neutral- or fear-evoking images. For the other, longer interval conditions no significant image effects were found. These results suggest that emotion-specific attention effects can be found at very early visual processing stages and that only disgust-evoking images, and not fear-evoking ones, keep hold of our attention for longer. We speculate that this increase in early attention allocation is related to the need to perform a more comprehensive risk-assessment of the disgust-evoking images. The outcomes underline not only the importance of examining the time course of emotion induced attention effects but also the need to look beyond the dimensions of valence and arousal.


Antipyretic and anticonvulsant activity of n-hexane fraction of Viola betonicifolia.
To investigate the antipyretic and anticonvulsant activities of n-hexane fraction of Viola betonicifolia (V. betonicifolia). The antipyretic effect was scrutinized using brewer's yeast induced pyrexia and anticonvlsion effect was tested using pentylenetetrazol and strychnine induced convulsion in mice. N-hexane fraction of V. betonicifolia demonstrated highly significant antipyretic activity during various assessment times (1-5 h) when challenged in yeast induced pyrexia test. The effect was in a dose dependent manner with maximum attenuation (82.50%) observed at 300 mg/kg i.p. When tested in pentylenetetrazol induced convulsion test, the 1st stage (Ear and facial twitching) and 2nd stage (Convulsive wave through the body) was 100% protected during 24 h at all the test doses (300, 400 and 500 mg/kg i.p.), while the latency time of remaining stages was significantly increased. The maximum effect was observed by n-hexane fraction of V. betonicifolia at 400 and 500 mg/kg i.p., as the latency time for generalized clonic-tonic seizure (5th stage) was increased up to 25.34 min. However, n-hexane fraction of V. betonicifolia had no protection in strychnine induced convulsion test. In conclusion, phytopharmacological studies provide scientific foundation to the folk uses of the plant in the treatment of pyrexia and neurological disorders.


High prevalence of food sensitisation in young children with liver disease: a clue to food allergy pathogenesis?
The pathogenesis of food allergy is not completely understood - animal models suggest hepatic mechanisms may be important for immune tolerance to orally ingested antigens, but there is little direct evidence for this in humans. We investigated whether there is an association between liver dysfunction or transplantation in young children and IgE sensitisation to food. We evaluated paired pre- and post- liver transplant sera from children aged 0-36 months treated at a single centre during 2001-2008. Sera were assayed for total IgE and cow's milk, egg and peanut-specific IgE. We quantified hepatic dysfunction pre-transplant using the Paediatric End-stage Liver Disease (PELD) score. We also assessed 70 children after renal transplant to establish whether any association between liver transplant and food sensitisation was organ specific. Paired sera were available from 50 of 94 children who had a liver transplant during the study period. 35 of 50 (70%) had IgE sensitisation (≥ 0.35 kUa/l) to ≥ 1 food pre-transplant and 18 (36%) post-transplant (p = 0.001). Ten (20%) children had food-specific IgE levels that carry high probability of challenge-confirmed food allergy pre-transplant. Food sensitisation pre-transplant was associated with severity of liver dysfunction [mean (s.d.) pre-transplant PELD score 1.52 (0.13) in food sensitised, 0.77 (0.22) in non-sensitised children p = 0.004]. Total IgE level was raised in 34/42 (81%) pre-transplant and fell significantly post-transplant. Interview assessment of the parents of 40 children revealed that 13 (33%) had a history consistent with food allergy. These findings were not replicated in the renal transplant group. Young children with severe liver dysfunction appear to have a high prevalence of food sensitisation. Hepatic mechanisms may therefore be important for establishing immune tolerance to dietary antigens in humans.


Unexpected versus all-cause mortality as the endpoint for investigating the effects of a Rapid Response System in hospitalized patients.
The purpose of this study was to assess the effect of replacing all-cause mortality by death without limitation of medical treatments (LOMT) as the endpoint in a study of rapid response teams (RRTs) in hospitalized patients. We also described the time course of LOMT orders in patients dying on a general ward and the influence of RRTs on such orders. This study is a secondary analysis of the COMET trial, a pragmatic prospective Dutch multicenter before-after study. We repeated the original analysis of the influence of RRTs on death before hospital discharge by replacing all-cause mortality by death without an LOMT order. In a subgroup of all patients dying before hospital discharge, we documented patient demographics, admission characteristics and LOMT orders of each patient. Patients age 18 ears or above were included. In total, 166,569 patients were included in the study. The unadjusted ORs were 0.865 (95 % CI 0.77-0.98) in the original analysis using all-cause mortality and 0.557 (95 % CI 0.40-0.78) when choosing death without LOMT as the endpoint. In total, 3408 patients died before discharge. At time of death, 2910 (85 %) had an LOMT order. Median time from last change in LOMT status and death was 2 days (IQR 1-5) in the before-phase and median time after introduction of the RRT was 1 day (IQR 1-4) (p value not significant). The improvement in survival of hospitalized patients after introduction of a rapid response team in the COMET study was more pronounced when choosing death without limitation of medical treatment, rather than all deaths as the endpoint. Most patients who died during hospitalization had limitation of medical treatments ordered, often shortly before death. Rapid response teams did not influence the institution of limitation of medical treatments.


Molecular cloning and characterization of equine Toll-like receptor 9.
Innate immunity relies on a series of germline-encoded pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), to detect conserved microbial components. TLR9 is typically expressed intracellularly in immune cells such as dendritic cells and recognizes unmethylated bacterial or viral cytosine-phosphate-guanine DNA (CpG-DNA). To investigate innate immune responses through TLR9 signaling pathway in horses, we cloned and characterized equine TLR9. Protein sequence analysis shows that equine TLR9 has a typically conserved cytosolic Toll/interleukin-1 receptor (TIR) domain, three leucine-rich repeat (LRR) motifs, with greater than 82% identity to human, monkey, bovine, canine, feline, porcine and ovine orthologs. Equine TLR9 mRNA expression was characterized for spleen, lymph node, and peripheral blood leukocyte samples. Flow cytometric analysis of equine TLR9 expression using a cross-reactive TLR9 mAb identified high constitutive expression of equine TLR9 in PMNs, CD4(+) and CD8(+) T-lymphocytes as well as other leukocytes; similar to human TLR9 expression. The conservation of equine TLR9 and high expression profile in leukocytes suggests that equine TLR9 is a frequent target for unmethylated CpG-DNA, an essential mechanism for the activation of innate immunity.


TDP-43 differentially propagates to induce antero- and retrograde degeneration in the corticospinal circuits in mouse focal ALS models.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by TDP-43 inclusions in the cortical and spinal motor neurons. It remains unknown whether and how pathogenic TDP-43 spreads across neural connections to progress degenerative processes in the cortico-spinal motor circuitry. Here we established novel mouse ALS models that initially induced mutant TDP-43 inclusions in specific neuronal or cell types in the motor circuits, and investigated whether TDP-43 and relevant pathological processes spread across neuronal or cellular connections. We first developed ALS models that primarily induced TDP-43 inclusions in the corticospinal neurons, spinal motor neurons, or forelimb skeletal muscle, by using adeno-associated virus (AAV) expressing mutant TDP-43. We found that TDP-43 induced in the corticospinal neurons was transported along the axons anterogradely and transferred to the oligodendrocytes along the corticospinal tract (CST), coinciding with mild axon degeneration. In contrast, TDP-43 introduced in the spinal motor neurons did not spread retrogradely to the cortical or spinal neurons; however, it induced an extreme loss of spinal motor neurons and subsequent degeneration of neighboring spinal neurons, suggesting a degenerative propagation in a retrograde manner in the spinal cord. The intraspinal degeneration further led to severe muscle atrophy. Finally, TDP-43 induced in the skeletal muscle did not propagate pathological events to spinal neurons retrogradely. Our data revealed that mutant TDP-43 spread across neuro-glial connections anterogradely in the corticospinal pathway, whereas it exhibited different retrograde degenerative properties in the spinal circuits. This suggests that pathogenic TDP-43 may induce distinct antero- and retrograde mechanisms of degeneration in the motor system in ALS.


Experimental fluid percussion brain injury: vascular disruption and neuronal and glial alterations.
Because of the potential relationship between vascular disturbances and secondary tissue damage, we identified areas of brain which exhibited hemorrhage and leakage of protein during the acute stage after experimental brain injury and subsequently studied the development of pathologic changes, including cavity formation, neuronal necrosis, and gliosis within these regions. The development of pathologic changes was evaluated at 1, 6, and 24 h and 1, 2, and 4 weeks after lateral, fluid percussion (FP) brain injury of moderate severity in the rat. Vascular disruption in the acute stages, as evidenced by hemorrhage and leakage of Evans blue albumin, was most prominent 6 h postinjury and was maximal in the parieto-occipital cortex. From 1 to 24 h after injury, regions of the injured hemisphere, including the cortex and hippocampus, exhibited abnormal neurons which stained with acid fuchsin and Alizarin red, histochemical markers for injured neurons and calcium, respectively. These same regions suffered significant neuronal cell loss from 1 to 4 weeks after injury. The distribution of reactive astrocytes was also evaluated by immunocytochemical localization of glial fibrillary acidic protein (GFAP). By 2 weeks postinjury, a prominent cavity was present in the frontoparietal and occipital cortices. Although astrogliosis was most pronounced in the cortex surrounding the cavity, prominent reactive astrocytes were widely distributed throughout the injured hemisphere. This study characterized the pathological changes which occur after experimental traumatic brain injury. In particular, we propose that neuronal cell injury in the hippocampus serves as a useful 'window' to assess beneficial efficacy of pharmacological intervention in the treatment of brain injury.


Review and analysis on the meridian research of China over the past sixty years.
The meridian research situation and various meridian hypotheses of China in the past sixty years between 1950 and 2013 are summarized in the paper; possible existed problems in the process of current meridian research are analyzed. Based on previous research results, we proposed that the essence of meridian can not be explained by the reductive analysis method, meridian research should be carried out under the guidance of overall concept of Chinese medicine theory. In this paper, combined with coherence theory of biophoton, we put forward the quantum interference hypothesis of meridian, which provides a possible research idea for meridian study.


Sombor spectra of chain graphs.
We study the Sombor index and the Sombor spectral properties of chain graphs. In particular, an explicit formula for the Sombor index is given, the Sombor eigenvalues are discussed, bounds on the largest and the smallest Sombor eigenvalues are presented, chain graphs with the simple Sombor eigenvalue are characterized, formulae for the Frobenius norm and the determinant of the Sombor quotient matrix of chain graphs are given, the Sombor spread bound and the Sombor energy bounds are presented along with the characterization of graphs attaining them.


Biological availability of nickel arsenides: toxic effects of particulate Ni5As2.
To determine if fugitive nickel arsenides from an oil shale retort could pose a threat to living organisms, we studied the effects of particulate Ni5As2 on cultured mammalian cells. Culture growth rate was greatly reduced at the lowest suspension concentration tested (10 microM), even though much of the Ni5As2 powder remained insoluble. FCM analysis indicated Ni5As2 arrested cell-cycle traverse in G1 and G2. Cell survival studies indicated cells could overcome this toxicity if exposure levels were low (less than or equal to 25 microM in suspension) and restricted to less than or equal to 24 h. At higher powder levels, survival was greatly reduced. Transmission electron microscopy (TEM) demonstrated that cells exposed to less than or equal to 100 microM powder did not phagocytize the Ni5As2 particles. At higher concentrations, TEM X-ray microanalysis demonstrated that As was preferentially extracted from the Ni5As2 particle surface and free Ni was deposited inside the cell. These observations suggest that the toxicity of Ni5As2 particles may be caused by some soluble product of Ni5As2.


Tubular cytoplasmic inclusions in a case of childhood dermatomyositis with migratory subcutaneous nodules.
A boy with dermatomyositis which began at the age of one year and five months showed multiple migratory subcutaneous nodules, which have seldom been described. Histological and electron microscopic studies of muscles and subcutaneous nodules demonstrated the following interesting findings. 1. Light microscopy. The migratory subcutaneous nodules consisted of non-suppurative panniculitis and ischaemic adipo-necrosis as a sequel to vascular lesions. This finding suggests that the nodules may have arisen from the subcutaneous adipose tissue which had been severely damaged by systemic angiopathy. 2. Electron microscopy. Examination of the vessels in muscle and subcutaneous nodules showed tubular cytoplasmic inclusions with a diameter of approximately 250 A in the endoplasmic reticulum of vascular endothelial cells. These observations provide strong support for the concept that the fundamental pathologic process in childhood dermatomyositis is of a vascular nature, and the primary lesion is in the walls of the intramuscular blood vessels.


Technique of ultrasound examination during laparoscopic cholecystectomy.
Intracorporeal ultrasonography was used as a new method to examine the bile ducts during laparoscopic cholecystectomy. A prototype rigid 7.5-MHz ultrasound probe, 10 mm in diameter and 50 cm in length, was introduced during 25 laparoscopic cholecystectomies. A dual scanning technique was developed for complete examination of the bile duct. This entailed transverse scanning via the subxyphoid trocar and longitudinal scanning via the umbilical trocar. The intrahepatic ducts were also visualized by placing the probe on the liver surface. Color Doppler imaging was useful to quickly distinguish the duct from vascular structures. Laparoscopic ultrasonography clearly delineated the bile ducts in all operations except one. The time required for imaging was significantly shorter for ultrasonography than for cholangiography. Our preliminary experience demonstrates that a complete examination of the bile ducts can be performed with intracorporeal ultrasonography in a relatively short period of time.


The Myb-p300-CREB axis modulates intestine homeostasis, radiosensitivity and tumorigenesis.
The gastrointestinal (GI) epithelium is constantly renewing, depending upon the intestinal stem cells (ISC) regulated by a spectrum of transcription factors (TFs), including Myb. We noted previously in mice with a p300 mutation (plt6) within the Myb-interaction-domain phenocopied Myb hypomorphic mutant mice with regard to thrombopoiesis, and here, changes in GI homeostasis. p300 is a transcriptional coactivator for many TFs, most prominently cyclic-AMP response element-binding protein (CREB), and also Myb. Studies have highlighted the importance of CREB in proliferation and radiosensitivity, but not in the GI. This prompted us to directly investigate the p300-Myb-CREB axis in the GI. Here, the role of CREB has been defined by generating GI-specific inducible creb knockout (KO) mice. KO mice show efficient and specific deletion of CREB, with no evident compensation by CREM and ATF1. Despite complete KO, only modest effects on proliferation, radiosensitivity and differentiation in the GI under homeostatic or stress conditions were evident, even though CREB target gene pcna (proliferating cell nuclear antigen) was downregulated. creb and p300 mutant lines show increased goblet cells, whereas a reduction in enteroendocrine cells was apparent only in the p300 line, further resembling the Myb hypomorphs. When propagated in vitro, crebKO ISC were defective in organoid formation, suggesting that the GI stroma compensates for CREB loss in vivo, unlike in MybKO studies. Thus, it appears that p300 regulates GI differentiation primarily through Myb, rather than CREB. Finally, active pCREB is elevated in colorectal cancer (CRC) cells and adenomas, and is required for the expression of drug transporter, MRP2, associated with resistance to Oxaliplatin as well as several chromatin cohesion protein that are relevant to CRC therapy. These data raise the prospect that CREB may have a role in GI malignancy as it does in other cancer types, but unlike Myb, is not critical for GI homeostasis.


Does dantrolene influence central dopamine and serotonin metabolism in the neuroleptic malignant syndrome? A retrospective study.
Homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) levels in the cerebrospinal fluid (CSF) were determined twice in nine cases of neuroleptic malignant syndrome (NMS) during the active phase. During the test period, three cases received no dantrolene and six cases received dantrolene prior to the second CSF examination. In the group not administered dantrolene, the levels of HVA and 5-HIAA were lower on the second examination compared to the first, suggesting that the levels of these substances decreased during the course of NMS. In the group receiving dantrolene, the levels of HVA and 5-HIAA increased after administration compared with the preadministration levels. In particular, a significant difference in the changes in HVA was demonstrated between the two groups. This suggests that dantrolene influences central dopaminergic metabolism in the active phase of NMS.


[Fluoride concentration and enamel solubility of deciduous and young permanent teeth after application of topical fluoride solutions].
The aim of this article was to compare, through the distillation method, the incorporated amount of fluoride and the reduction of solubility in the enamel of both deciduous and young permanent teeth, following topical application of a 2% neutral sodium fluoride solution, according to the Knutson's technique and a 1.23% of acidulated solution, according to the Wellock & Brudevold's technique. The greatest fluoride incorporation was observed in the deciduous teeth after the usage of the 2% neutral solution. The amount of calcium and phosphorus liberation by the acid solution was greatest in the control group, followed by the group of teeth treated in acidulated solution and, finally, by those treated in 2% sodium fluoride solution.


Digital micelles of encoded polymeric amphiphiles for direct sequence reading and ex vivo label-free quantification.
Identification and quantification of synthetic polymers in complex biological milieu are crucial for delivery, sensing and scaffolding functions, but conventional techniques based on imaging probe labellings only afford qualitative results. Here we report modular construction of precise sequence-defined amphiphilic polymers that self-assemble into digital micelles with contour lengths strictly regulated by oligourethane sequences. Direct sequence reading is accomplished with matrix-assisted laser desorption/ionization (MALDI) tandem mass spectrometry, facilitated by high-affinity binding of alkali metal ions with poly(ethylene glycol) dendrons and selective cleavage of benzyl-carbamate linkages. A mixture of four types of digital micelles could be identified, sequence-decoded and quantified by MALDI and MALDI imaging at cellular, organ and tissue slice levels upon in vivo administration, enabling direct comparison of biological properties for each type of digital micelle in the same animal. The concept of digital micelles and encoded amphiphiles capable of direct sequencing and high-throughput label-free quantification could be exploited for next-generation precision nanomedicine designs (such as digital lipids) and protein corona studies.


[Thrombosis and antiprothrombinase in children. Apropos of 2 cases].
Two cases of arterial and venous thrombosis associated with lupus anticoagulant are reported. The first case was observed in the context of a systemic lupus erythematosus. In the second case, no underlying disease was found. From these 2 cases and a review of the literature, the particularities of this association in children is discussed.


Hindbrain lactate regulates preoptic gonadotropin-releasing hormone (GnRH) neuron GnRH-I protein but not AMPK responses to hypoglycemia in the steroid-primed ovariectomized female rat.
Steroid positive-feedback activation of the gonadotropin-releasing hormone (GnRH)-pituitary luteinizing hormone (LH) neuroendocrine axis propagates the pre ovulatory LH surge, a crucial component of female reproduction. Our work shows that this key event is restrained by inhibitory metabolic input from hindbrain A2 noradrenergic neurons. GnRH neurons express the ultra-sensitive energy sensor adenosine 5'-monophosphate-activated protein kinase (AMPK); here, we investigated the hypothesis that GnRH nerve cell AMPK and peptide neurotransmitter responses to insulin-induced hypoglycemia are controlled by hindbrain lack of the oxidizable glycolytic end-product L-lactate. Data show that hypoglycemic inhibition of LH release in steroid-primed ovariectomized female rats was reversed by coincident caudal hindbrain lactate infusion. Western blot analyses of laser-microdissected A2 neurons demonstrate hypoglycemic augmentation [Fos, estrogen receptor-beta (ER-β), phosphoAMPK (pAMPK)] and inhibition (dopamine-beta-hydroxylase, GLUT3, MCT2) of protein expression in these cells, responses that were normalized by insulin plus lactate treatment. Hypoglycemia diminished rostral preoptic GnRH nerve cell GnRH-I protein and pAMPK content; the former, but not the latter response was reversed by lactate. Results implicate caudal hindbrain lactoprivic signaling in hypoglycemia-induced suppression of the LH surge, demonstrating that lactate repletion of that site reverses decrements in A2 catecholamine biosynthetic enzyme and GnRH neuropeptide precursor protein expression. Lack of effect of lactate on hypoglycemic patterns of GnRH AMPK activity suggests that this sensor is uninvolved in metabolic-inhibition of positive-feedback-stimulated hypophysiotropic signaling to pituitary gonadotropes.


The ins and outs of body piercing.
PATIENTS WITH BODY PIERCINGS present a challenge for today's perioperative nurses. The need to prepare these patients for surgery while promoting safety, preserving body image, and respecting cultural values has gone beyond the routine practice of jewelry removal. BODY ART (ie, tattooing, piercing) has been practiced by men, women, and children from ancient times to the present. It was used then, as it is now, for many purposes, including personal expression, rite of passage, and fashion trends. THE EXPANDING POPULARITY of body piercing increases the likelihood that patients will arrive for surgery with body jewelry in place. This article provides perioperative nurses with the proper tools to deliver culturally sensitive care to patients with body piercings.


Intravenous self-administration of diazepam in rats.
Diazepam 0.5-2.0 mg/kg per injection was self-administered intravenously by rats on a continuous reinforcement schedule in a dose-dependent manner over a 30 day period. The rates of diazepam self-administration were relatively stable after responding was established, in comparison with rats self-administering morphine 0.5 mg/kg per injection whose rates continued to increase. At a fixed ratio 4 or 8 schedule, higher maximum rates of responding were seen with diazepam than with morphine. During withdrawal, reductions in body weight tended to occur in a manner dependent on the preceding rates of diazepam self-administration and were possibly caused by physical dependence. These findings suggest that diazepam acts as an intravenous reinforcer in rats and that the procedure we describe is of use to predict the dependence liability of drugs considered to have only a weak potential for abuse.


Fryns syndrome: a lethal birth defect with variable phenotypic expressions in siblings.
Fryns syndrome (FS) is a multiple congenital anomaly syndrome, inherited as an autosomal recessive defect with variable expression. The authors report a newborn with FS, whose mother had two previous affected pregnancies with the infants having variable phenotypic expression. FS is characterized by craniofacial dysmorphism, diaphragmatic hernia and distal limb hypoplasia. This is the first published report from India describing a case of FS with familial recurrence, which would serve further to illustrate the clinical variability of this disorder.


An organic psychosis due to a venlafaxine-propafenone interaction.
An extraordinary case of an organic psychosis during the treatment of a patient with a bipolar affective disorder. Clinical observation and further investigations including monitoring of serum levels (case report). A significant interaction between venlafaxine and propafenone causes markedly increased serum levels of venlafaxine correlating with unexpected psychopathological changes. There is a potentially dangerous interaction between venlafaxine and propafenone. Serum levels of venlafaxine should be monitored if propafenone is added.


HSA: integrating multi-track Hi-C data for genome-scale reconstruction of 3D chromatin structure.
Genome-wide 3C technologies (Hi-C) are being increasingly employed to study three-dimensional (3D) genome conformations. Existing computational approaches are unable to integrate accumulating data to facilitate studying 3D chromatin structure and function. We present HSA ( http://ouyanglab.jax.org/hsa/ ), a flexible tool that jointly analyzes multiple contact maps to infer 3D chromatin structure at the genome scale. HSA globally searches the latent structure underlying different cleavage footprints. Its robustness and accuracy outperform or rival existing tools on extensive simulations and orthogonal experiment validations. Applying HSA to recent in situ Hi-C data, we found the 3D chromatin structures are highly conserved across various human cell types.


Congenital ureteric cyst--rare anomaly.
A rare example of a congenital cyst of the ureter is described and the embryologic development of the abnormality discussed. The world literature relevant to the case is reviewed.


Photocatalytic performances of heterojunction catalysts of silver phosphate modified by PANI and Cr-doped SrTiO3 for organic pollutant removal from high salinity wastewater.
In this work, Ag3PO4/PANI/Cr:SrTiO3 photocatalysts were designed to effectively eliminate organic pollutants including Rhodamine B and phenol from high salinity wastewater under visible light. The phase composition, optical properties, and morphology of powders were studied, and the effects of inorganic salts on removal performance of the as-prepared particles were also tested. Results showed that the photocatalytic activities of Ag3PO4/PANI/Cr:SrTiO3 composites for Rhodamine B and phenol reached 100% within 10 min and 18 min, respectively. The reaction rate of pure Ag3PO4 was 7 times less than that of the ternary composite with the adding of PANI and Cr:SrTiO3. The activity of Ag3PO4/PANI/Cr:SrTiO3 remained at 92.25% after five cycles, so the photocatalytic and recyclable performance of ternary composite was greatly improved. In addition, when there was SO42- with a content of ranging from 1% to 21%, the degradation activity of the ternary catalyst under visible light was not changed for Rhodamine B, which indicated that the ternary catalyst exhibited the excellent sulfate resistance ability. Results from ESR and radical trapping experiments showed that O2- and h+ made an important contribution to visible-light photocatalytic activities.


Reconstitution of selenocysteine incorporation reveals intrinsic regulation by SECIS elements.
Selenoproteins are present in all three domains of life and are responsible for a major part of a cell's antioxidant defense against reactive oxygen species. Synthesis of selenoproteins requires the decoding of a UGA codon as selenocysteine (Sec) instead of translation termination. Sec is incorporated into the growing polypeptide chain during translation elongation and is known to require a set of highly specific factors: the Sec insertion sequence (SECIS) element in the 3' untranslated region, Sec-tRNA(Sec), the Sec-specific elongation factor eEFSec, and SECIS binding protein 2. Since reconstitution has not been reported, whether these factors are sufficient is unknown. Here, we report a novel in vitro translation system in which Sec incorporation has been reconstituted from purified components introduced into a Sec naive system. In addition, we developed a novel method to purify Sec-tRNA(Sec) and active eEFSec/GTP/tRNA ternary complex. We found that the known basal factors are sufficient for Sec incorporation in vitro. Using this highly manipulable system, we have also found that ribosomes from non-Sec-utilizing organisms cannot support Sec incorporation and that some SECIS elements are intrinsically less efficient than others. Having identified the essential set of factors, this work removes a significant barrier to our understanding of the mechanism of Sec incorporation.


Glutamine metabolism in human lymphocytes.
The data indicate that glutamine plays a critical role in the metabolism of human lymphocytes stimulated in vitro and in vivo. The understanding of these processes is a prerequisite if one is to substitute glutamine under conditions of compromised lymphocyte function.


Resolution and quantification of arginine, monomethylarginine, asymmetric dimethylarginine, and symmetric dimethylarginine in plasma using HPLC with internal calibration.
N(G) ,N(G) -dimethyl-l-arginine (asymmetric dimethylarginine, ADMA),N(G) -monomethyl-l-arginine (l-NMMA) and N(G) ,N(G') -dimethyl-l-arginine (symmetric dimethylarginine, SDMA) are released during hydrolysis of proteins containing methylated arginine residues. ADMA and l-NMMA inhibit nitric oxide synthase by competing with l-arginine substrate. All three methylarginine derivatives also inhibit arginine transport. To enable investigation of methylarginines in diseases involving impaired nitric oxide synthesis, we developed a high-performance liquid chromatography (HPLC) assay to simultaneously quantify arginine, ADMA, l-NMMA and SDMA. Our assay requires 12 μL of plasma and is ideal for applications where sample availability is limited. We extracted arginine and methylarginines with mixed-mode cation-exchange columns, using synthetic monoethyl-l-arginine as an internal standard. Metabolites were derivatized with ortho-phthaldialdeyhde and 3-mercaptopropionic acid, separated by reverse-phase HPLC and quantified with fluorescence detection. Standard curve linearity was ≥0.9995 for all metabolites. Inter-day coefficient of variation (CV) values were ≤5% for arginine, ADMA and SDMA in human plasma and for arginine and ADMA in mouse plasma. The CV value for l-NMMA was higher in human (10.4%) and mouse (15.8%) plasma because concentrations were substantially lower than ADMA and SDMA. This assay provides unique advantages of small sample volume requirements, excellent separation of target metabolites from contaminants and validation for both human and mouse plasma samples.


Steatotic hepatocyte-derived extracellular vesicles promote β-cell apoptosis and diabetes via microRNA-126a-3p.
Extracellular vesicles (EVs) have emerged as a unique mediator of interorgan communications, playing important roles in the pathophysiologic process of various diseases, including diabetes and other metabolic diseases. Here, we reported that the EVs released by steatotic hepatocytes exerted a detrimental effect on pancreatic β cells, leading to β-cell apoptosis and dysfunction. The effect was profoundly attributable to an up-regulation of miR-126a-3p in the steatotic hepatocyte-derived EVs. Accordingly, overexpression of miR-126a-3p promoted, whereas inhibition of miR-126a-3p prevented β-cell apoptosis, through a mechanism related to its target gene, insulin receptor substrate-2. Moreover, inhibition of miR-126a-3p by its specific antagomir was able to partially reverse the loss of β-cell mass and ameliorate hyperglycaemia in diabetic mice. Thus, the findings reveal a novel pathogenic role of steatotic hepatocyte-derived EVs, which mechanistically links nonalcoholic fatty liver disease to the development of diabetes.


Use of radioactive gold in the treatment of pleural effusions caused by metastatic cancer.
This paper presents a series of 12 patients suffering from advanced gynecological cancer with the occurrence of pleural effusions. All patients received at least one intrapleural dose of radioactive gold (100 m Ci Au198) when the necessity for thoracentesis became more than once every three weeks. Three showed no recurrence of fluid, five a significant slowing down of effusion, and four did not show any response. Severe complications were minimal, and were comparable to those resulting from thoracentesis in general.


Pralatrexate is an effective treatment for relapsed or refractory transformed mycosis fungoides: a subgroup efficacy analysis from the PROPEL study.
Transformed mycosis fungoides (tMF) is an aggressive disease with a median survival of 12-24 months. In this retrospective analysis of 12 patients with tMF, treatment with pralatrexate resulted in an objective response of 25% per independent central review and 58% per investigator assessment. Pralatrexate was well tolerated, with no toxicity-related discontinuations, which makes this an additional option for tMF treatment. Transformed mycosis fungoides (tMF) is an aggressive disease, with poor prognosis and a median survival of 24 months. In the Pralatrexate in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma (PROPEL) study, 12 patients with tMF were treated with a median of 10 pralatrexate doses (starting dose of 30 mg/m(2)) administered weekly for 6 weeks in a 7-week cycle. The median number of prior systemic therapies was 3. This retrospective analysis showed that the objective response rate in this subgroup was 25% (n = 3) per independent central review and 58% (n = 7) per investigator assessment, with this discrepancy likely attributed to challenges with photodocumentation of cutaneous lesions. The median duration of response and the median progression-free survival were 2.2 and 1.7 months, respectively, per central review, whereas median duration of response was 4.4 months, and median progression-free survival was 5.3 months per investigator assessment. Median survival was 13 months. Grade 1-3 mucositis was reported in 7 (58%) patients. Grade 4 adverse events were fatigue (n = 1) and thrombocytopenia (n = 1). Pralatrexate was well tolerated, with no toxicity-related discontinuations. Based on these results, pralatrexate may be a treatment option for patients with relapsed or refractory tMF.


Noradrenergic innervation of the pineal gland--histochemical basis of scintigraphic imaging?
There is first evidence that the adult human pineal gland may be equipped with noradrenergic fibers as is the case in a variety of mammalian species. It therefore appears worthwhile to investigate the capacity of pineal noradrenergic nerves to take up 123I-MIBG, a prerequisite for scintigraphic imaging.


Current therapy of hypertension. A pharmacologic approach.
Adequate treatment of hypertension requires that the physician understand the pharmacologic actions of antihypertensive agents. Although no drug is without adverse reactions, it should be possible to choose an agent or combination of agents which can effectively lower blood pressure and be tolerated by the patient. The indications, proposed mechanisms of actions and adverse effects of the following antihypertensive drugs are discussed: thiazide diuretics, spironolactone, triamterene, trimethaphan, Rauwolfia alkaloids. guanethidine, bethanidine, methyldopa, clonidine, pargyline, propranolol, hydrazaline, minoxidil, guancydine, diazoxide and sodium nitroprusside.


[Experimental study on carcinogenic activity of the organic extracts from water of the sifangtai section of songhua river].
To study the carcinogenic activity and potential mechanism of the organic extracts from the Songhua River in vitro. The in vitro cell transformation and single cell gel electrophoresis (SCGE) tests were detected with the ether extracts of water. The expression of anticancer genes p53, p16, and p21 measured by immunohistochemical assays and the apoptosis by TUNEL assay were also studied. The extracts from the water induced malignant transformation of BALB/C mouse embryo fibroblast cells and induce DNA damage. p53, p16 and p21 failed to express in transformed cells induced by the water extracts, and the apoptosis rate of transformed cells decreased. This study demonstrates that the organic extracts from the Songhua River has potential carcinogenicity.


The effect of metformin on neuronal activity in the appetite-regulating brain regions of mice fed a high-fat diet during an anorectic period.
Metformin reduces body weight by decreasing food intake in humans and animals. However, the brain regions involved in metformin-induced anorexia remain unclear. Therefore, we investigated c-Fos expression (FOS), a marker of neuronal activity, in the appetite-regulating brain regions after oral administration of metformin (PO, 300mg/kg daily for 1 or 3days) or vehicle. The body weight and food intake decreased in mice treated with metformin for 3days (RM group) and mice that had the same amount of food as the RM group (Pair-fed group; PF) compared to the control group. FOS expression levels increased in the paraventricular nucleus, area postrema, and central amygdala of mice administered an acute single dose of metformin (SM group) compared to the control mice. In the nucleus tractus solitarius, the FOS expression levels increased in both the SM and RM groups compared to the control group. The FOS expression levels also increased in the nucleus accumbens of the RM group compared to other groups. The FOS expression levels decreased in the ventromedial hypothalamic nucleus in the PF group, but not the RM group, compared to the control group, suggesting a potential hypothalamic area involvement for metformin-induced anorexia. These results suggest that both the hypothalamic and extra-hypothalamic regions are associated with metformin-induced anorexia, which is dependent on metformin treatment duration.


Cerebral endothelial regeneration following experimental brain injury. Variation in the regeneration process according to the severity of injury.
It is still unknown when and in which area endothelial regeneration occurs after brain injury, and to what extent such changes depend on the severity of the injury. We have, therefore, studied bromodeoxyuridine (BrdU) uptake by regenerating endothelial cells in two different groups of rats given cold lesions using immunohistochemistry employing anti-BrdU monoclonal antibody, anti-factor VIII-related antigen antibody and anti-glial fibrillary acidic protein antibody. The earliest evidence for the presence of BrdU-positive endothelial cells (BrdU + end) was observed at 2 days after injury, the injured endothelial cells regenerating from the edge toward the center of the lesion in both groups. We considered that edema fluid could act as an important factor, since at 2 days post-injury BrdU + end were not in contact with macrophages and were always found in Evans blue-stained areas. Study of endothelial cell kinetics also confirmed that the repair of injured endothelial cells was intimately involved in the reconstruction of the blood-brain barrier, since the time of disappearance of BrdU + end coincided with the disappearance of Evans blue-stained areas. The difference in the process of endothelial regeneration was first apparent on the 3rd day, there being no difference at 2 days.


Evolutionary dynamics under partner preferences.
The fact that people often have preference rankings for their partners is a distinctive aspect of human behavior. Little is known, however, about how this talent as a powerful force shapes human behavioral traits, including those which should not have been favored by selection, such as cooperation in social dilemma situations. Here we propose a dynamic model in which network-structured individuals can switch their interaction partners within neighborhoods based on their preferences. For the partner switching, we propose two interruption regimes: dictatorial regime and negotiating regime. In the dictatorial regime, focal individuals are able to suspend interactions out of preferences unilaterally. In the negotiating regime, either focal individuals or the associated partners agree to suspend, then these interactions can be successfully suspended. We investigate the evolution of cooperation under both preference-driven partner switching regimes in the context of both the weakened variant of the donation game and the standard one. Specifically, we theoretically approximate the critical conditions for cooperation to be favored by weak selection in the weakened donation game where cooperators bear a unit cost to provide a benefit for each active neighbor and simulate the evolutionary dynamics of cooperation in the standard donation game to test the robustness of the analytical results. Under dictatorial regime, selection of cooperation becomes harder when individuals have preferences for either cooperator or defector partners, implying that the expulsion of defectors by cooperators is overwhelmed by the chasing of defectors towards cooperators. Under negotiating regime, both preferences for cooperator and defector partners can significantly favor the evolution of cooperation, yet underlying mechanisms differ greatly. For preferences over cooperator partners, cooperator-cooperator interaction relationships are reinforced and the associated mutual reciprocity can resist and assimilate defectors. For preferences over defector partners, defector-defector interaction relationships are anchored, weakening defectors' exploitation over cooperators. Cooperators are thus offered much time space to interact among cospecies and spread. Our work may help better understand the critical role of preference-based adaptive partner switching in promoting the evolution of cooperation.


Clarification of Cliff and Caruso (1998).
In response to N. Cliff and J. C. Caruso (1998), the author clarifies that it is the sum of the reliabilities of the components that remains invariant under rotation in reliable component analysis.


Extensive lesions and a positive cone margin are strong predictors of residual disease in subsequent hysterectomy following conization for squamous intraepithelial lesion grade 2 or 3 study design.
This study aimed to determine the predictive factors for post-conization of residual disease in subsequent hysterectomy for cervical intraepithelial neoplasia grade 2 or 3. This retrospective study included 267 patients with histologically confirmed cervical intraepithelial neoplasia grade 2 or 3 who underwent hysterectomy within 7 months after conization. Clinical data (e.g., age, menopausal status, gravidity, parity, type of transformation zone, conization method) as well as pathological data pertaining to conization and hysterectomy were collected from medical records. A logistic regression model was used to analyze the relationship between the variables and risk of residual lesions in hysterectomy samples. Overall, 70 (26.2%) patients had residual lesions in their hysterectomy specimens. Univariate analyses revealed that age ≥ 50 years (p=0.019), endocervical gland involvement(p=0.013), positive margin(p < 0.001), and involvement of 3-4 quadrants(p < 0.001) were risk factors for residual lesions. Conversely, postmenopausal status, gravidity ≥ 3, parity ≥ 2, loop electrosurgical excision procedure, and type III transformation zone were not risk factors for residual lesions. A positive margin(p < 0.001) and multiple-quadrant involvement(p < 0.001) were identified as independent risk factors for residual lesions on multivariate analysis. Multiple-quadrant involvement and a positive cone margin were reliable predictive factors for residual disease. Total hysterectomy or repeated cervical conization should be considered for patients with these two risk factors. The identification of high-risk patients with extensive lesions by colposcopic examination before conization is indispensable, as it will enable surgeons to perform conization with consideration of risk factors and possibly improve the approach used for the excisional procedure. For high-risk patients, colposcope-guided cold-knife conization is preferred when resources permit.


Distinctive clinical phenotype and treatment outcome of type 1 autoimmune hepatitis in the elderly.
Autoimmune hepatitis is classically a disease of young women. Our aims were to determine its occurrence, clinical phenotype, and outcome in elderly patients and contrast findings to young adults. Two-hundred-and-five white North American adults with definite type 1 autoimmune hepatitis were grouped according to age at presentation and the groups compared. Forty-seven patients (23%) were aged > or = 60 years (median age, 68 years), and 31 patients (15%) were aged < or = 30 years (median age, 25 years). The patients > or = 60 years had a higher frequency of cirrhosis at presentation than the patients < or = 30 years (33% versus 10%, P = .03). They also had thyroid or rheumatic diseases more commonly (42% vs. 13%, P = .006). HLA DR3 occurred more frequently in the patients < or = 30 years than in those > or = 60 years (58% vs. 23%, P = .004), and HLA DR4 occurred more often in the patients > or = 60 years (47% vs. 13%, P = .003). Patients aged > or = 60 years failed corticosteroid treatment less commonly than those aged < or = 30 years (5% vs. 24%, P = .03). Autoimmune hepatitis occurred in patients aged 18-30 years (15%), 31-39 years (15%), 40-49 years (21%), 50-59 years (25%), and > or = 60 years (23%). Differences in age distribution, HLA frequencies, and treatment outcome occurred after age > or = 40 years. In conclusion, elderly patients have a greater frequency of cirrhosis at presentation and HLA DR4 than patients < or = 30 years, and they have a lower occurrence of treatment failure. Transitions in clinical and genetic phenotypes occur after age > or = 40 years. Genetic susceptibilities may favor etiologic factors that are age-related.


Application of high-intensity focused ultrasound for fetal therapy: experimental study using an animal model of lower urinary tract obstruction.
The purpose of this study is to investigate whether high-intensity focused ultrasound (HIFU) exposure is able to produce a fistula between the bladder and abdominal wall of a fetus with lower urinary tract obstruction (LUTO). We constructed a prototype HIFU transducer in combination with an imaging probe. HIFU was applied to the lower abdomen of a rabbit neonate that was complicated by LUTO as an experimental model to produce a fistula; HIFU was applied in a tank filled with degassed water. Exposed lesions were assessed by histological analysis at necropsy. When HIFU was applied at 5.5 kW/cm(2) of spatial-peak temporal average intensity (SPTA), a fistula was created between the lower abdominal wall and the urinary bladder; urine gushed out from the bladder through the fistula within 60 s after HIFU exposure. The findings suggest that fetal diseases such as LUTO can be non-invasively treated using HIFU exposure from even outside the maternal body, though this study was performed in a water tank.


Identification of biomarkers for preterm delivery in mid-trimester amniotic fluid.
We investigated whether the level of vascular endothelial growth factor (VEGF) and inflammatory markers in mid-trimester amniotic fluid have predictive value for spontaneous preterm birth in singleton pregnancy. Our subjects were 72 pregnant women who were undertaken with amniocentesis from 16 to 19 weeks of gestation. 36 cases were women with preterm delivery, and other 36 cases were matched women with full-term delivery. Stored amniotic fluid was investigated after the delivery. The levels of matrix metalloproteinases-8 (MMP-8), interleukin-6 (IL-6), C-reactive protein (CRP), and VEGF were measured by enzyme-linked immunosorbent assay (ELISA) and Western blot. The levels of MMP-8 and IL-6 in preterm group were significantly higher than control group (5.76 ± 1.53 ng/ml vs 4.89 ± 1.77 ng/ml and 170.54 ± 55.69 pg/ml vs 141.92 ± 57.21 pg/ml, respectively) (p < 0.05). In terms of VEGF, the levels were elevated in preterm group (30.76 ± 4.06 pg/ml vs 22.36 ± 7.03 pg/ml) (p < 0.05). This study suggests that elevated levels of IL-6 and MMP-8 in amniotic fluid at mid-trimester are predictive of preterm delivery, and that VEGF which is representative of angiogenesis can be a new and useful predictor of preterm delivery.


Early adaptation of human lower extremity vein grafts: wall stiffness changes accompany geometric remodeling.
To quantitatively describe the temporal changes in elastic properties and wall dimensions in lower-extremity vein grafts after implantation. This is a prospective study of patients (N = 38) undergoing lower extremity bypass grafts (N = 41) with autologous veins. Pulse wave velocity (PWV), luminal diameter, and wall thickness measurements were obtained by duplex ultrasound scan intraoperatively and at 1, 3, and 6 months postoperatively for assessment of graft dimensions and wall stiffness. Lower extremity vein grafts showed an increase in PWV (from 16 +/- 1 to 21 +/- 3 cm/s; mean +/- SEM; P =.08), reflecting an increase in wall stiffness (from 1.2 +/- 0.2 to 2.5 +/- 0.7 x 10(6) dynes/cm; P =.02) and wall thickness (from 0.47 +/- 0.03 to 0.61 +/- 0.004 mm; P =.04) over the first 6 months after implantation. Changes in lumen diameter were positively correlated with changes in external graft diameter (P <.01) and negatively correlated with initial lumen diameter (P <.01) but not with changes in the wall thickness. These results suggest complex remodeling of vein grafts during the first several months after implantation, with increased wall thickness occurring independent of variable changes in lumen diameter. Simultaneously, a marked increase in wall stiffness over this interval suggests a likely role for collagen deposition.


Pose prediction and virtual screening performance of GOLD scoring functions in a standardized test.
The performance of all four GOLD scoring functions has been evaluated for pose prediction and virtual screening under the standardized conditions of the comparative docking and scoring experiment reported in this Edition. Excellent pose prediction and good virtual screening performance was demonstrated using unmodified protein models and default parameter settings. The best performing scoring function for both pose prediction and virtual screening was demonstrated to be the recently introduced scoring function ChemPLP. We conclude that existing docking programs already perform close to optimally in the cognate pose prediction experiments currently carried out and that more stringent pose prediction tests should be used in the future. These should employ cross-docking sets. Evaluation of virtual screening performance remains problematic and much remains to be done to improve the usefulness of publically available active and decoy sets for virtual screening. Finally we suggest that, for certain target/scoring function combinations, good enrichment may sometimes be a consequence of 2D property recognition rather than a modelling of the correct 3D interactions.


Implementing a collaborative framework for academic support for registered nurses.
This paper describes the collaboration between a national health service acute hospital trust and a higher education institution, to implement a framework for academic support for registered nurses undertaking learning beyond registration. A small percentage of the educational budget was utilised to fund two academic staff (0.6 whole time equivalent) to work within the trusts' own learning and development department. The initial aim of the project was to maximise the utilisation of the funding available for learning beyond registration study. The focus of the project was at both a strategic level and with individual staff. Embedding within the culture of the trust was important for the academic staff to understand and gain the service/user perspective to some of the barriers or issues concerning learning beyond registration. Following a scoping exercise, the multiplicity of issues that required action led to the creation of an academic support framework. This framework identified potential for intervention in 4 phases: planning for study, application and access to learning, during study and outcome of study. Interventions were identified that were complimentary and adjuncts to the academic support provided by the higher education institution. New resources and services were also developed such as pathway planning support and study skill workshops. One important resource was a dedicated point of contact for staff. A "live" database also proved useful in tracking and following-up students.


Parathyroid cryopreservation after parathyroidectomy: a worthwhile practice?
Parathyroid cryopreservation is often utilized for patients having parathyroidectomy. This allows for future autotransplantation if a patient becomes permanently hypocalcemic after surgery. However, the practice of cryopreservation is costly and time-consuming, while the success rate of delayed autotransplantation is highly variable. We sought to determine the rate and outcomes of parathyroid cryopreservation and delayed autotransplantation at our institution to further evaluate its utility. At our institution, 2,083 parathyroidectomies for hyperparathyroidism (HPT) were performed from 2001 to 2010. Of these, parathyroid cryopreservation was utilized in 442 patients (21 %). Patient demographics, preoperative diagnoses, and other characteristics were analyzed, as well as the rate and success of delayed autotransplantation. Of the 442 patients with cryopreservation, the mean age was 55 ± 1 years and 313 (70.8 %) were female. A total of 308 (70 %) had primary HPT, 46 (10 %) had secondary HPT, and 88 (20 %) had tertiary HPT. Delayed autotransplantation of cryopreserved parathyroid tissue was used in 4 (1 %) patients at an average time of 9 ± 4 months after initial surgery. Three of the 4 patients remained hypoparathyroid after this procedure. The single cured patient underwent the procedure only 4 days after the initial parathyroidectomy. Although cryopreservation was used in over one-fifth of patients undergoing parathyroidectomy, the need for parathyroid reimplantation was very low (1 %). Furthermore, the success rate of parathyroid autotransplantation was poor in these patients. Therefore, the continued practice of parathyroid cryopreservation is questionable.


High temperature tolerance and heat acclimation of Opuntia bigelovii.
The tolerance of Opuntia bigelovii Engelm. (Cactaceae) to high temperature was investigated by subjecting stems to temperatures ranging from 25°C to 65°C for a 1-h period, after which various properties of chlorenchyma cells were examined. The temperatures at which activities depending on membrane integrity decreased by 50% were 60°C for electrolyte leakage, 52°C for staining by neutral red, and 51°C for plasmolysis for plants maintained at day/night air temperatures of 30°C/20°C. Nocturnal acid accumulation, which depends on stomatal opening and enzymatic reactions as well as membrane properties, was half-inactivated at a lower temperature, 46°C. Visual observation indicated that 50% of the stems subjected to a heat treatment of 52°C became necrotic in 2 weeks.Heat acclimation, which is apparently necessary for survival of O. bigelovii in the field, was investigated by raising the day/night air temperatures from 12°C/2°C to 60°C/50°C in 10°C steps every 2 weeks. The heat tolerance of the cellular properties increased with increasing air temperature; for a 10°C temperature increase, the half-inactivation temperature increased 2.9°C for electrolyte leakage, 3.0°C for staining, 3.8° C for stem survival, and fully 6.1°C for nocturnal acid accumulation. The relative order of these four properties with respect to heat tolerance did not change during the hardening, nocturnal acid accumulation remaining the most heat sensitive. The upper temperature for 50% survival was 59° for O. bigelovii when acclimated to day/night air temperatures of 50°C/40°C.


Comparative spine imaging in leptomeningeal metastases.
Sixty-one patients (34 men; 27 women) ranging in age from 1-74, median 40 years with leptomeningeal metastases (LM) as defined by either positive CSF cytology (85%) or a clinical syndrome and compatible neuroradiographic findings (15%) underwent CT-myelographic (CT-M), spine MR (S-MR) and 111Indium-DTPA CSF flow studies (FS). Each patient underwent sequential spine imaging (CT-M, S-MR and FS) over a median of 5 days. In 57% of patients, all 3 spine imaging modalities were normal. 43% of patients demonstrated abnormalities on spine imaging; 33% had abnormal FS, 34% showed abnormalities on S-MR and 33% had abnormalities by CT-M. FS were most sensitive for detecting interruption of CSF flow whereas CT-M and S-MR better demonstrated nerve root thickening (CT-M approximately S-MR), cord enlargement (CT-M > S-MR), subarachnoid nodules (S-MR > CT-M), intraparenchymal cord tumor (S-MR > CT-M) and epidural spinal cord compression (S-MR = CT-M). In conclusion, patients with LM frequently require spine imaging and the results of this study suggest both S-MR and FS provide the best radiographic assessment wherein S-MR is superior for detecting bulky disease and FS best demonstrates interruption of CSF flow.


Microphthalmia with linear skin defects: a case report and review.
Microphthalmia with linear skin defects syndrome is an X-linked dominant disorder characterized by microphthalmia and other ocular anomalies as well as linear, jagged skin defects typically involving the scalp, face, neck, and upper trunk. Other associated characteristics include short stature, developmental delay, congenital heart defects, diaphragmatic hernia, agenesis of the corpus callosum, anencephaly, hydrocephalus, and seizures. Microphthalmia with linear skin defects syndrome is now known to be associated with a deletion of the X chromosome at Xp22. This is an area that has been found to include the HCCS gene, which encodes a holocytochrome c-type synthase believed to be critical in the regulation of apoptosis. We present a patient with classic clinical and genetic findings of MLS syndrome and discuss the primary characteristics and management of this disorder.


Early rotation of a cross-lip flap to repair a defect caused by a human bite.
A case is presented of loss of half of the lower lip from a human bite. An Estlander flap was used on the fifth day for reconstruction, with no infection and a good result. This shows the advantage of a "delayed primary closure" in some of these badly contaminated wounds.


N6-methyladenosine (m6A) in cancer stem cell: From molecular mechanisms to therapeutic implications.
The emergence of drug resistance and metastasis has long been a difficult problem for cancer treatment. Recent studies have shown that cancer stem cell populations are key factors in the regulation of cancer aggressiveness, relapse and drug resistance. Cancer stem cell (CSC) populations are highly plastic and self-renewing, giving them unique metabolic, metastatic, and chemotherapy resistance properties. N6-methyladenosine (m6A) is the most abundant internal modification of mRNA and is involved in a variety of cell growth and development processes, including RNA transcription, alternative splicing, degradation, and translation. It has also been linked to the development of various cancers. At present, the important role of m6A in tumour progression is gradually attracting attention, especially in the tumour stemness regulation process. Abnormal m6A modifications regulate tumour metastasis, recurrence and drug resistance. This paper aims to explore the regulatory mechanism of m6A in CSCs and clinical therapy, clarify its regulatory network, and provide theoretical guidance for the development of clinical targets and improvement of therapeutic effects.


Imaging of Mischievous Intra-abdominal Fat Presenting with Abdominal Pain: A Pictorial Review.
To briefly discuss the imaging features of different types of intra-abdominal fat necrosis. Trauma and ischemic insult may result in intra-abdominal fat necrosis. Fat necrosis may present with acute abdomen, clinically simulating with other etiologies, such as acute diverticulitis and acute appendicitis. Imaging plays a crucial role in making the exact diagnosis and differentiating it from other pathologies that may require surgical intervention. Computed tomography (CT) is the most commonly used imaging modality. A small fat attenuation lesion with a hyperattenuating rim in contact with the ventral surface of the sigmoid colon indicates epiploic appendagitis while a larger fat-attenuation lesion on the right side of the abdomen in between the colon and anterior abdominal wall indicates omental infarction. Fat stranding at the root of the mesentery with fat ring sign represents inflammatory mesenteric panniculitis while retractile or sclerosing mesenteritis appears as a fibrotic spiculated mass with or without calcification, mimicking mesenteric carcinoid. In patients with acute pancreatitis, the amount of inflamed fat correlates with clinical severity and outcome. Familiarity with the imaging features of different types of intraabdominal fat necrosis helps in establishing an accurate diagnosis, thus avoiding unnecessary intervention. Patel RK, Mittal S, Singh S. Imaging of Mischievous Intra-abdominal Fat Presenting with Abdominal Pain: A Pictorial Review. Euroasian J Hepato-Gastroenterol 2022;12(1):45-49.


Propofol Suppresses LPS-induced BBB Damage by Regulating miR-130a-5p/ZO-1 Axis.
The blood-brain barrier (BBB) is a highly selective semi-permeable barrier that separates circulating blood from the extracellular fluid of the brain and central nervous system, which is crucial for maintaining brain homeostasis. This study aimed to explore the role of propofol in BBB damage and further evaluate the underlying molecular mechanism. Lipopolysaccharide (LPS) was administered to mice to create an in vivo BBB damage mice model. Additionally, hCMEC/D3 cells as brain microvascular endothelial cells (BMECs) were treated with LPS to establish the in vitro BBB damage cell model. Subsequently, propofol was used for the BBB damage model. Evans blue staining and fluorescein sodium were utilized in the in vivo experiments to demonstrate BBB leakage and BBB permeability. Cell counting kit-8 (CCK-8) assay was used to assess cell viability and the trans-endothelial electrical resistance (TEER) value was measured using an epithelial voltmeter. Furthermore, enzyme-linked immunosorbent assay was performed to measure the levels of the inflammatory cytokines such as interleukin-1β (IL-1β) and tumor necrosis factor-alpha (TNF-α). The levels of miR-130a-5p and zonula occludens-1 (ZO-1) in brain tissues and cells were detected using reverse transcription-quantitative polymerase chain reaction, western blot, or immunofluorescence staining. Furthermore, a dual-luciferase reporter assay was used to demonstrate the association between miR-130a-5p and ZO-1. Propofol treatment suppressed BBB leakage, the amount of fluorescein sodium, and the levels of IL-1β and TNF-α in the LPS-induced BBB damage mice model. Meanwhile, propofol treatment increased the TEER value in the LPS-induced hCMEC/D3 cells. Additionally, propofol treatment significantly down-regulated miR-130a-5p and up-regulated ZO-1. More importantly, miR-130a-5p directly targeted ZO-1 and negatively regulated ZO-1 expression in hCMEC/D3 cells. Furthermore, miR-130a-5p mimic partially reversed the effect of propofol on the TEER value and the levels of inflammatory cytokines such as IL-1β and TNF-α in the LPS-induced hCMEC/D3 cells. Propofol suppressed LPS-induced BBB damage by regulating miR-130a-5p/ZO-1 axis. These findings suggested a potentially effective treatment approach for BBB damage.


Functional polymorphisms in the IL6 gene promoter and the risk of urinary bladder cancer in India.
Interleukin-6 is a multifunctional cytokine, which plays a key role in tumor proliferation and differentiation. Variations in its gene (IL6) sequence may affect the risk of developing various cancers, including urinary bladder cancer. The present study was done to find the association of functional polymorphisms in the IL6 promoter with urinary bladder cancer. Single nucleotide polymorphisms were genotyped in histologically confirmed 232 cases of urinary bladder cancer and 250 healthy controls. The controls subjects were matched to the cases by age, sex, and ethnicity. Genotyping of the polymorphisms (-174G>C; -572G>C, -596A>G) was undertaken by direct DNA sequencing. The level of association between the genotypes and urinary bladder cancer risk was estimated by odds ratios and 95% confidence intervals generated by applying the chi-square test. Linkage disequilibrium (LD) between SNPs and haplotype analysis were performed using Haploview software. Significantly higher number of smokers (p=0.047), tobacco chewers (p=<0.001) and those with non-vegetarian food habits (p=0.016) were seen in the case group. The distribution of genotypes at -174G>C locus differed significantly between cases and controls and the variant genotypes GC+CC were significantly rarer in the cases (p=0.00073; OR=0.52 95% CI 0.35-0.75). Variant genotypes (GC+CC) were more common in grade I than grade III tumors (p=0.032), further suggesting a protective effect. No LD was found between the SNPs; however, the frequency of haplotype AGC was significantly lesser in the cases than controls (p=0.0103), suggesting a protective effect. Genotype distribution at the other two loci (-572G>C and -596A>G) did not show association with bladder cancer. IL6 (-174G>C) substitution confers significant protection against the risk of urinary bladder cancer in the study population, while other substitutions in this gene (-572G>C and -596A>G) do not affect the risk. In general, there is a lack of studies on the cytokine gene polymorphisms in urinary bladder cancer.


Current Programs and Incentives to Overcome Rural Physician Shortages in the United States: A Narrative Review.
Access to healthcare continues to be a top priority and prominent challenge in rural communities, with 20% of the total U.S. population living in rural areas while only 10% of physicians practice in rural areas. In response to physician shortages, a variety of programs and incentives have been implemented to recruit and retain physicians in rural areas; however, less is known about the types and structures of incentives that are offered in rural areas and how that compares to physician shortages. The purpose of our study is to conduct a narrative review of the literature to identify and compare current incentives that are offered by rural physician shortage areas to better understand how resources are being allocated to vulnerable areas. We reviewed published peer-reviewed articles from 2015-2022 to identify incentives and programs designed to address physician shortages in rural areas. We augment that review by examining the gray literature, including reports and white papers on the topic. Identified incentive programs were aggregated for comparison and translated into a map that depicts high, medium, and low levels of geographically designated Health Professional Shortage Areas (HPSAs) and the number of incentives offered by state. Surveying current literature regarding different types of incentivization strategies while comparing to primary care HPSAs provides general insights on the potential influence of incentive programs on shortages, allows easy visual review, and may provide greater awareness of available support for potential recruits. Providing a broad overview of the incentives offered in rural areas will help illuminate whether diverse and appealing incentives are offered in the most vulnerable areas and guide future efforts to address these issues.


Neonatal Glucose Homeostasis.
Hypoglycemia is a common condition in the newborn period. Several intrinsic and extrinsic factors play a role in the degree/duration of hypoglycemia. Multiple thresholds have been proposed as a potential point whereby hypoglycemia may have short and long-term adverse effects. Rather than a "numerical" threshold, treatment approaches should be individualized and tailored to the etiology, symptoms, and neonatal underlying conditions. Hyperglycemia in the newborn period is commonly seen in preterm infants and can exert gluco-toxic effects in organs at critical periods of development. Considering the peripheral insulin resistance (IR) of prematurity and contributing factors is key to achieving euglycemia.


gyrA mutations and phenotypic susceptibility levels to ofloxacin and moxifloxacin in clinical isolates of Mycobacterium tuberculosis.
To compare mutations in the quinolone resistance-determining region of the gyrA gene and flanking sequences with the MICs of ofloxacin and moxifloxacin for Mycobacterium tuberculosis. The presence of mutations in 177 drug-resistant M. tuberculosis isolates was determined by DNA sequencing and the MICs quantified by MGIT 960. Single nucleotide polymorphisms were detected at codons 94 (n = 30), 90 (n = 12), 91 (n = 3), 89 (n = 1), 88 (n = 1) and 80 (n = 1). Four isolates with double mutations D94G plus A90V (n = 2) and D94G plus D94N (n = 2) reflect mixed populations. Agreement between genotypic and phenotypic susceptibility was high (≥97%) for both drugs. Mutant isolates had an MIC(50) of 8.0 mg/L and an MIC(90) of >10 mg/L for ofloxacin compared with an MIC(50) and MIC(90) of 2.0 mg/L for moxifloxacin. Codons 94 and 88 were linked to higher levels of fluoroquinolone resistance compared with codons 90, 91 and 89. The MIC distributions for the wild-type isolates ranged from ≤0.5 to 2.0 mg/L for ofloxacin and from ≤0.125 to 0.25 mg/L for moxifloxacin. However, 96% of the isolates with genetic alterations had MICs ≤2.0 mg/L for moxifloxacin, which is within its achievable serum levels. This study provides quantitative evidence that the addition of moxifloxacin to extensively drug-resistant tuberculosis (XDR-TB) regimens based on a clinical breakpoint of 2.0 mg/L has merit. The use of moxifloxacin in the treatment of multidrug-resistant tuberculosis may prevent the acquisition of additional mutations and development of XDR-TB.