Sorcin links calcium signaling to vesicle trafficking, regulates Polo-like kinase 1 and is necessary for mitosis.
Sorcin, a protein overexpressed in many multi-drug resistant cancers, dynamically localizes to distinct subcellular sites in 3T3-L1 fibroblasts during cell-cycle progression. During interphase sorcin is in the nucleus, in the plasma membrane, in endoplasmic reticulum (ER) cisternae, and in ER-derived vesicles localized along the microtubules. These vesicles are positive to RyR, SERCA, calreticulin and Rab10. At the beginning of mitosis, sorcin-containing vesicles associate with the mitotic spindle, and during telophase are concentrated in the cleavage furrow and, subsequently, in the midbody. Sorcin regulates dimensions and calcium load of the ER vesicles by inhibiting RYR and activating SERCA. Analysis of sorcin interactome reveals calcium-dependent interactions with many proteins, including Polo-like kinase 1 (PLK1), Aurora A and Aurora B kinases. Sorcin interacts physically with PLK1, is phosphorylated by PLK1 and induces PLK1 autophosphorylation, thereby regulating kinase activity. Knockdown of sorcin results in major defects in mitosis and cytokinesis, increase in the number of rounded polynucleated cells, blockage of cell progression in G2/M, apoptosis and cell death. Sorcin regulates calcium homeostasis and is necessary for the activation of mitosis and cytokinesis.


Increasing numbers of pediatric AIDS patients.
Few--if any--dental practitioners are unaware of the increasing changes occurring in dental and medical practices as a result of this deadly disease.


[Development of main disturbances of hemostasis in patients with obesity].
According to current views obesity especially with increased amount of visceral fat is characterized by prothrombogenic changes of hemostasis and fibrinolysis. This combined with insulin resistance, compensatory hyperinsulinemia, disturbances of carbohydrate metabolism, atherogenic dyslipidemia and hypertension substantially increases risk of origination and progression of cardiovascular diseases. Results of our study demonstrate high prevalence of various prothrombogenic abnormalities in coagulation and anticoagulation systems in patients with visceral obesity and metabolic syndrome (MS). Disturbances of hemostasis were detected by such screening methods as measurement of APTT, INR and concentration of fibrinogen in blood plasma. We received data on positive association of severity of some abnormalities of hemostasis with anthropometric and biochemical parameters of obesity and MS, parameters of lipid and carbohydrate metabolism. Revealed disturbances of hemostasis create prerequisites for development of thrombophilia and make additional contribution to increase of cardiovascular risk in this category of patients. This dictates necessity of more thorough and deepened examination of patients with visceral obesity and MS with the aim of detection and correction of pathological changes of lipid and carbohydrate metabolism, system of hemostasis and fibrinolysis at earliest stages.


Atypical presentation of histoplasmosis in a patient with psoriasis and psoriatic arthritis on infliximab therapy.
Infliximab is a chimeric monoclonal antibody to TNF-alpha which acts on both the soluble and transmembrane forms of TNF-alpha. It has been used successfully for the treatment of psoriasis and psoriatic arthritis, rheumatoid arthritis, Crohn's disease and ankylosing spondylitis either as monotherapy or in combination with drugs such as methotrexate. To date, over 20,440 patients with moderate-to-severe psoriasis have been treated with infliximab worldwide. Opportunistic infections and reactivation of underlying latent infections are an area of concern with the use of infliximab particularly when used in conjunction with other immunosuppresants. The authors report a case of histoplasmosis presenting with signs of severe hypercalcemia and renal failure in a patient on infliximab for approximately three years in combination with low dosages of methotrexate and prednisone. This report stresses the importance of maintaining a high index of suspicion for unusual pathogens while managing patients receiving TNF-alpha inhibitors, particularly when used in combination with other immunosuppressants. In addition, the authors emphasize the role of a multi-disciplinary approach and appropriate coordination among caregivers.


Sugar-Sweetened Beverages and Cardiometabolic Health: An Update of the Evidence.
Sugar-sweetened beverages (SSBs) have little nutritional value and a robust body of evidence has linked the intake of SSBs to weight gain and risk of type 2 diabetes (T2D), cardiovascular disease (CVD), and some cancers. Metabolic Syndrome (MetSyn) is a clustering of risk factors that precedes the development of T2D and CVD; however, evidence linking SSBs to MetSyn is not clear. To make informed recommendations about SSBs, new evidence needs to be considered against existing literature. This review provides an update on the evidence linking SSBs and cardiometabolic outcomes including MetSyn. Findings from prospective cohort studies support a strong positive association between SSBs and weight gain and risk of T2D and coronary heart disease (CHD), independent of adiposity. Associations with MetSyn are less consistent, and there appears to be a sex difference with stroke with greater risk in women. Findings from short-term trials on metabolic risk factors provide mechanistic support for associations with T2D and CHD. Conclusive evidence from cohort studies and trials on risk factors support an etiologic role of SSB in relation to weight gain and risk of T2D and CHD. Continued efforts to reduce intake of SSB should be encouraged to improve the cardiometabolic health of individuals and populations.


Contraceptive use among HIV-positive women in Quang Ninh province, Vietnam.
To investigate contraceptive use among HIV-positive women in Ha long city and Cam Pha town of Quang Ninh, a Northern province of Vietnam. Cross-sectional questionnaire study among HIV-positive women identified through the district HIV/AIDS register. Information on socioeconomic characteristics and contraceptive use before and after HIV diagnosis was obtained through structured questionnaires. Chi-square testing was used to assess whether the included women differed from the target population in terms of age. Crude Odds ratios (ORs) were calculated to show the association between contraceptive use and the women's socioeconomic characteristics. Logistic regression analyses were applied to adjust for possible confounding. The women's contraceptive use before HIV testing and after HIV testing was described and compared by Chi-square testing, and the association between post-test counselling and the women's use of condom was assessed by ORs. Of the 351 participants, 63% stated they had used contraception before HIV diagnosis and 89% stated they had used contraception after HIV diagnosis. Forty six per cent of the women had been using either the pill or an intrauterine device (IUD) before the diagnosis whereas the same applied for only 8% of the women after diagnosis. Thirty-nine per cent stated they had been using condom before HIV diagnosis whereas 87% stated condom use after HIV diagnosis. Condom use was more common among women who had received post-test counselling (OR 3.03, 95% CI 1.03-8.90). A change of contraceptive methods from IUD and oral contraception before HIV diagnosis to condom use after HIV diagnosis was observed. The women's use of condoms after HIV diagnosis was associated with having received post-test counselling.


Solubility of ammonium acid urate nephroliths from bottlenose dolphins (Tursiops truncatus).
Nephrolithiasis has been identified in managed populations of bottlenose dolphins (Tursiops truncatus); most of these nephroliths are composed of 100% ammonium acid urate (AAU). Several therapies are being investigated to treat and prevent nephrolithiasis in dolphins including the alkalization of urine for dissolution of nephroliths. This study evaluates the solubility of AAU nephroliths in a phosphate buffer, pH range 6.0-8.0, and in a carbonate-bicarbonate buffer, pH range 9.0-10.8. AAU nephroliths were obtained from six dolphins and solubility studies were conducted using reverse-phase high performance liquid chromatography with ultraviolet detection at 290 nm. AAU nephroliths were much more soluble in a carbonate-bicarbonate buffer, pH range 9.0-10.8 compared to phosphate buffer pH range 6.0-8.0. In the pH range 6.0-8.0, the solubility was 45% lower in potassium phosphate buffer compared to sodium phosphate buffer. When citrate was used along with phosphate in the same pH range, the solubility was improved by 13%. At pH 7 and pH 8, 150 mM ionic strength buffer was optimum for dissolution. In summary, adjustment of urinary pH alone does not appear to be a useful way to treat AAU stones in bottlenose dolphins. Better understanding of the pathophysiology of AAU nephrolithiasis in dolphins is needed to optimize kidney stone prevention and treatment.


Problems of antiarthritic therapy in the elderly.
Rheumatic diseases are prevalent in the elderly population, resulting in high morbidity caused mainly by lack of mobility. Consequently, the use of antirheumatic drugs in older persons is extensive. This review outlines some of the hazards encountered in the use of antirheumatic drugs in the elderly. Analgesics such as propoxyphene and acetaminophen are useful adjuncts to the treatment of arthritic pain, but propoxyphene has been associated with respiratory depression, and renal clearance of acetaminophen is reduced in elderly subjects. Salicylates may cause deafness, and like the other nonsteroidal anti-inflammatory drugs, may cause salt and water retention resulting in congestive cardiac failure. Phenylbutazone should not be used because of the risk of blood dyscrasia, and indomethacin has been reported as interfering with the antihypertensive effect of beta-blockers. Chloroquine levels may be raised in patients with impaired renal function, and there is increased risk of retinal damage with the drug in elderly subjects. Injectable gold compounds and penicillamine are not contraindicated in the elderly, because they are just as efficacious as in younger persons for the treatment of rheumatoid arthritis. Toxicity due to gold compound is not increased in the elderly, but skin rashes and abnormalities of taste do occur more commonly in elderly patients treated with penicillamine. Corticosteroids do not affect disease progression and therefore should be used only in acute severe disease for short periods of time. As in the younger population, treatment of gout in the elderly is dependent on renal function.(ABSTRACT TRUNCATED AT 250 WORDS)


The capital expenditure process for the health care supervisor.
Competition for health care capital dollars has increased as third-party and government reimbursement decreases, patient volume decreases, and alternative services increase. Given this rationing situation, it is more important than ever that the health care supervisor carefully document and present a capital expenditure request. This request should outline skillfully the benefits and costs of undertaking a new service or replacing an old asset. A supervisor who can quantify the costs and benefits of a project and utilize one of the four common capital budgeting techniques: payback period, net present value, profitability index, or internal rate of return, will certainly be taking a step in the right direction for ensuring a serious evaluation of his or her proposal. This article attempts to explain this process using both narrative and quantitative examples.


Enabling Electrochemical-Mechanical Robustness of Ultra-High Ni Cathode via Self-Supported Primary-Grain-Alignment Strategy.
The electrochemical-mechanical degradation of ultrahigh Ni cathode for lithium-ion batteries is a crucial aspect that limits the cycle life and safety of devices. Herein, the study reports a facile strategy involving rational design of primary grain crystallographic orientation within polycrystalline cathode, which well enhanced its electro-mechanical strength and Li+ transfer kinetics. Ex situ and in situ experiments/simulations including cross-sectional particle electron backscatter diffraction (EBSD), single-particle micro-compression, thermogravimetric analysis combined with mass spectrometry (TGA-MS), and finite element modeling reveal that, the primary-grain-alignment strategy effectively mitigates the particle pulverization, lattice oxygen release thereby enhances battery cycle life and safety. Besides the preexisting doping and coating methodologies to improve the stability of Ni-rich cathode, the primary-grain-alignment strategy, with no foreign elements or heterophase layers, is unprecedently proposed here. The results shed new light on the study of electrochemical-mechanical strain alleviation for electrode materials.


BaC: a thermodynamically stable layered superconductor.
To predict all stable compounds in the Ba-C system, we perform a comprehensive study using first-principles variable-composition evolutionary algorithm USPEX. We find that at 0 K the well-known compound BaC2 is metastable in the whole pressure range 0-40 GPa, while intercalated graphite phase BaC6 is stable at 0-19 GPa. A hitherto unknown layered orthorhombic Pbam phase of BaC has structure consisting of alternating layers of Ba atoms and layers of stoichiometry Ba2C3 containing linear C3 groups and is predicted to be stable in the pressure range 3-32 GPa. From our electron-phonon coupling calculations, the newly found BaC compound is a phonon-mediated superconductor and has a critical superconductivity temperature Tc of 4.32 K at 5 GPa. This compound is dynamically stable at 0 GPa and therefore may be quenchable under normal conditions.


Maf1-mediated regulation of yeast RNA polymerase III is correlated with CCA addition at the 3' end of tRNA precursors.
In eukaryotic cells tRNA synthesis is negatively regulated by the protein Maf1, conserved from yeast to humans. Maf1 from yeast Saccharomyces cerevisiae mediates repression of trna transcription when cells are transferred from medium with glucose to medium with glycerol, a non-fermentable carbon source. The strain with deleted gene encoding Maf1 (maf1Δ) is viable but accumulates tRNA precursors. In this study tRNA precursors were analysed by RNA-Seq and Northern hybridization in wild type strain and maf1Δ mutant grown in glucose medium or upon shift to repressive conditions. A negative effect of maf1Δ mutant on the addition of the auxiliary CCA nucleotides to the 3' end of pre-tRNAs was observed in cells shifted to unfavourable growth conditions. This effect was reduced by overexpression of the yeast CCA1 gene encoding ATP(CTP):tRNA nucleotidyltransferase. The CCA sequence at the 3' end is important for export of tRNA precursors from the nucleus and essential for tRNA charging with amino acids. Data presented here indicate that CCA-addition to intron-containing end-processed tRNA precursors is a limiting step in tRNA maturation when there is no Maf1 mediated RNA polymerase III (Pol III) repression. The correlation between CCA synthesis and Pol III regulation by Maf1 could be important in coordination of tRNA transcription, processing and regulation of translation.


Fulminant cerebellitis with radiological recurrence in an adult patient with Crohn's disease.
There are few reports of cerebellitis in adults and reports of recurrent cerebellitis are extremely rare. This report highlights both the fulminant course that may follow cerebellitis and a potentially important association with Crohn's disease. A 41-year-old man presented with headache and cerebellar dysfunction a month after ileo-colonic resection for Crohn's disease. MRI demonstrated T2-signal abnormalities, pial enhancement and cerebellar enlargement. His course was complicated by obstructive hydrocephalus, intraventricular hemorrhage associated with external ventricular drain placement and left transverse sinus venous thrombosis. Treatment with high-dose intravenous steroids and anti-coagulation resulted in improvement. Asymptomatic radiological worsening 13 months after initial presentation occurred during a relapse of Crohn's disease. He was treated with intravenous steroids and maintenance azathioprine for his Crohn's and suspected immune mediated cerebellitis. At last follow-up 4 years after initial presentation his clinical status remained unchanged and radiological changes had stabilized. Adult onset cerebellitis may be fulminant and recurrent. Early immunotherapy in acute relapsing cerebellitis may speed recovery and prevent recurrence. Onset and radiological relapse of cerebellitis during Crohn's disease flare-ups as in our case possibly suggests a shared autoimmune pathogenesis.


Systematic screening using FRAX® leads to increased use of, and adherence to, anti-osteoporosis medications: an analysis of the UK SCOOP trial.
In the large community-based SCOOP trial, systematic fracture risk screening using FRAX® led to greater use of AOM and greater adherence, in women at high fracture risk, compared with usual care. In the SCreening of Older wOmen for Prevention of fracture (SCOOP) trial, we investigated the effect of the screening intervention on subsequent long-term self-reported adherence to anti-osteoporosis medications (AOM). SCOOP was a primary care-based UK multicentre trial of screening for fracture risk. A total of 12,483 women (70-85 years) were randomised to either usual NHS care, or assessment using the FRAX® tool ± dual-energy X-ray absorptiometry (DXA), with medication recommended for those found to be at high risk of hip fracture. Self-reported AOM use was obtained by postal questionnaires at 6, 12, 24, 36, 48 and 60 months. Analysis was limited to those who initiated AOM during follow-up. Logistic regression was used to explore baseline determinants of adherence (good ≥ 80%; poor < 80%). The mean (SD) age of participants was 75.6 (4.2) years, with 6233 randomised to screening and 6250 to the control group. Of those participants identified at high fracture risk in the screening group, 38.2% of those on treatment at 6 months were still treated at 60 months, whereas the corresponding figure for the control group was 21.6%. Older age was associated with poorer adherence (OR per year increase in age 0.96 [95% CI 0.93, 0.99], p = 0.01), whereas history of parental hip fracture was associated with greater rate adherence (OR 1.67 [95% CI 1.23, 2.26], p < 0.01). Systematic fracture risk screening using FRAX® leads to greater use of AOM and greater adherence, in women at high fracture risk, compared with usual care.


Measuring emotional and cognitive empathy using dynamic, naturalistic, and spontaneous emotion displays.
Most measures of nonverbal receiving ability use posed expressions as stimuli. As empathy measures, such stimuli lack ecological validity, as the participant is not actually experiencing emotion. An alternative approach uses natural and dynamic displays of spontaneous expressions. The Communication of Affect Receiving Ability Test (CARAT) uses as stimuli spontaneous facial expressions and gestures filmed by an unobtrusive camera of solitary participants responding to emotional images. This article reports the development and initial validation of the CARAT-Spontaneous, Posed, Regulated (CARAT-SPR), which measures both abilities to detect emotion from spontaneous displays (emotion communication accuracy) and to differentiate spontaneous, posed, and regulated displays (expression categorization ability). Although spontaneous displays are natural responses to emotional images, posed displays involve asking the sender to display "as if" responding to a particular sort of image when no image is in fact present (simulation), while Regulated displays involve asking the sender to display "as if" responding to a particular sort of image when an image of opposite valence is in fact present (masking). Expression categorization ability involves judging deception-simulation and masking-and conceptually involves a kind of perspective-taking or cognitive empathy. Emotion communication using spontaneous clips achieved a high level of accuracy and was strongly correlated with ratings of sender expressivity. Expression categorization ability was not significantly correlated with expressivity ratings and was modestly negatively correlated with emotion communication accuracy. In a brief version of the CARAT-SPR, women showed evidence of greater emotion signal detection, whereas men reported greater confidence in expression categorization. (PsycINFO Database Record


Clearance of blood-borne pathogens mediated through bispecific monoclonal antibodies bound to the primate erythrocyte complement receptor.
The primate erythrocyte complement receptor facilitates both the immune adherence reaction and the immune complex clearance properties of primate erythrocytes. These phenomena have been studied for more than 40 years. However, it has only recently become apparent that these characteristics of primate erythrocytes may be useful in the generation of a therapy based on bispecific monoclonal antibodies. Our approach uses bispecific monoclonal antibody constructs (heteropolymers) that promote binding of specific target pathogens to primate erythrocytes via the complement receptor. Once bound to the erythrocytes, the pathogen-heteropolymer complex should be cleared from the circulation, phagocytosed and destroyed in the liver. Results with several prototype target pathogens in monkey models indicate it may be possible to use this technology to develop a robust and general therapy for the treatment of diseases associated with blood-borne pathogens.


Identification of mutations through dominant screening for obesity using C57BL/6 substrains.
The discovery of leptin substantiated the usefulness of a forward genetic approach in elucidating the molecular network regulating energy metabolism. However, no successful dominant screening for obesity has been reported, which may be due to the influence of quantitative trait loci between the screening and counter strains and the low fertility of obese mice. Here, we performed a dominant screening for obesity using C57BL/6 substrains, C57BL/6J and C57BL/6N, with the routine use of in vitro fertilization. The screening of more than 5000 mutagenized mice established two obese pedigrees in which single nucleotide substitutions in Mc4r and Sim1 genes were identified through whole-exome sequencing. The mutation in the Mc4r gene produces a premature stop codon, and the mutant SIM1 protein lacks transcriptional activity, showing that the haploinsufficiency of SIM1 and MC4R results in obesity. We further examined the hypothalamic neuropeptide expressions in the mutant pedigrees and mice with diet-induced obesity, which showed that each obesity mouse model has distinct neuropeptide expression profiles. This forward genetic screening scheme is useful and applicable to any research field in which mouse models work.


The diversification of the LIM superclass at the base of the metazoa increased subcellular complexity and promoted multicellular specialization.
Throughout evolution, the LIM domain has been deployed in many different domain configurations, which has led to the formation of a large and distinct group of proteins. LIM proteins are involved in relaying stimuli received at the cell surface to the nucleus in order to regulate cell structure, motility, and division. Despite their fundamental roles in cellular processes and human disease, little is known about the evolution of the LIM superclass. We have identified and characterized all known LIM domain-containing proteins in six metazoans and three non-metazoans. In addition, we performed a phylogenetic analysis on all LIM domains and, in the process, have identified a number of novel non-LIM domains and motifs in each of these proteins. Based on these results, we have formalized a classification system for LIM proteins, provided reasonable timing for class and family origin events; and identified lineage-specific loss events. Our analysis is the first detailed description of the full set of LIM proteins from the non-bilaterian species examined in this study. Six of the 14 LIM classes originated in the stem lineage of the Metazoa. The expansion of the LIM superclass at the base of the Metazoa undoubtedly contributed to the increase in subcellular complexity required for the transition from a unicellular to multicellular lifestyle and, as such, was a critically important event in the history of animal multicellularity.


Allograft inflammatory factor-1-like is not essential for age dependent weight gain or HFD-induced obesity and glucose insensitivity.
The allograft inflammatory factor (AIF) gene family consists of two identified paralogs - AIF1 and AIF1-like (AIF1L). The encoded proteins, AIF1 and AIF1L, are 80% similar in sequence and show conserved tertiary structure. While studies in human populations suggest links between AIF1 and metabolic diseases such as obesity and diabetes, such associations with AIF1L have not been reported. Drawing parallels based on structural similarity, we postulated that AIF1L might contribute to metabolic disorders, and studied it using mouse models. Here we report that AIF1L is expressed in major adipose depots and kidney but was not detectable in liver or skeletal muscle; in notable contrast to AIF1, AIF1L was also not found in spleen. Studies of AIF1L deficient mice showed no obvious postnatal developmental phenotype. In response to high fat diet (HFD) feeding for 6 or 18 weeks, WT and AIF1L deficient mice gained weight similarly, showed no differences in fat or lean mass accumulation, and displayed no changes in energy expenditure or systemic glucose handling. These findings indicate that AIF1L is not essential for the development of obesity or impaired glucose handling due to HFD, and advance understanding of this little-studied gene and its place in the AIF gene family.


Prospective medical assessment of adults surviving childhood cancer: study design, cohort characteristics, and feasibility of the St. Jude Lifetime Cohort study.
To facilitate prospective medical assessment of adults surviving pediatric malignancies and advance knowledge about long-term childhood cancer survivor health, St. Jude Children's Research Hospital (SJCRH) is establishing a lifetime cohort of survivors. Eligibility criteria for inclusion in the St. Jude Lifetime Cohort (SJLIFE) study include: (1) diagnosis of childhood malignancy treated at SJCRH; (2) survival ≥ 10 years from diagnosis; and (3) current age ≥ 18 years. Three levels of participation are offered: (1) comprehensive evaluation on SJCRH campus; (2) limited home evaluation; or (3) completion of health surveys only. A systematic recruitment structure based upon blocks of 50 patients initially focused on leukemia and lymphoma survivors and patients eligible for pilot studies. As of January 1, 2010, 1,625 (42%) of 3,900 eligible ≥ 10-year survivors have been contacted. Among the first 1,000 potentially eligible survivors selected for recruitment, 971 were subsequently confirmed to fulfill eligibility criteria. To date, 898/971 (92.5%) have been successfully contacted of whom 825 (91.8%) have agreed to participate. Among participants, 88.6% agreed to comprehensive medical evaluation, 0.4% limited local evaluation, and 11.0% survey only. Anticipated minimum overall participation rate for medical evaluation is 75.3% (731/971). Comparison of those contacted who agreed versus declined to participate revealed a greater proportion of males who declined participation (P = 0.001). Early results of the SJLIFE study support its feasibility to recruit aging childhood cancer survivors to research investigations evaluating late health outcomes by medical assessments.


An improvement to MBASIC algorithm for 3-D motion and depth estimation.
In model-based coding of facial images, the accuracy of motion and depth parameter estimates strongly affects the coding efficiency. MBASIC (model-based analysis-synthesis image coding) is a simple and effective iterative algorithm recently proposed by Aizawa et el. (see Signal Processing: Image Communication, no.1, p.139-52, 1989) for 3-D motion and depth estimation when the initial depth estimates are relatively accurate. In this correspondence, we analyze its performance in the presence of errors in the initial depth estimates and propose a modification to MBASIC algorithm that significantly improves its robustness to random errors with only a small increase in the computational load.


Tripartite conflicts of interest and high stakes patent extensions in the DSM-5.
The revision process for and recent publication of the DSM-5 initiated debates about the widening of diagnostic boundaries. The pharmaceutical industry had a major financial stake in the outcome of these debates. This study examines the three-part relationship among DSM panel members, principal investigators (PIs) of clinical trials for new DSM-5 diagnoses, and drug companies. Financial conflicts of interest (FCOI) of DSM panel members responsible for some new diagnoses in the DSM-5 and PIs of clinical trials for related drug treatments were identified. Trials were found by searching ClinicalTrials.gov. Patent and revenue information about these drugs was found using the US Food and Drug Administration's Orange Book and manufacturer Annual Reports. Thirteen trials met inclusion criteria (testing drugs for some new DSM disorders). Sixty-one percent of the DSM Task Force members and 27% of Work Group members reported FCOI to the trial drug manufacturers. In 5 of the 13 trials (38%), PIs reported ties other than research funding to the drug manufacturer. In 3 of the trials (23%), a PI had financial ties to the drug manufacturer and was also a DSM panel member who had decision-making authority over the revision process. These findings suggest that increased transparency (e.g., registration on ClinicalTrials.gov) and mandatory disclosure policies (e.g., the American Psychiatric Association's disclosure policy for DSM-5 panel members) alone may not be robust enough strategies to prevent the appearance of bias in both the DSM revision process as well as clinical decisions about appropriate interventions for DSM disorders.


Modelling the Interplay Between Neuron-Glia Cell Dysfunction and Glial Therapy in Autism Spectrum Disorder.
Autism spectrum disorder (ASD) is a complicated, interpersonally defined, static condition of the underdeveloped brain. Although the aetiology of autism remains unclear, disturbance of neuronglia interactions has lately been proposed as a significant event in the pathophysiology of ASD. In recent years, the contribution of glial cells to autism has been overlooked. In addition to neurons, glial cells play an essential role in mental activities, and a new strategy that emphasises neuron-glia interactions should be applied. Disturbance of neuron-glia connections has lately been proposed as a significant event in the pathophysiology of ASD because aberrant neuronal network formation and dysfunctional neurotransmission are fundamental to the pathology of the condition. In ASD, neuron and glial cell number changes cause brain circuits to malfunction and impact behaviour. A study revealed that reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Recent discoveries also suggest that dysfunction or changes in the ability of microglia to carry out physiological and defensive functions (such as failure in synaptic elimination or aberrant microglial activation) may be crucial for developing brain diseases, especially autism. The cerebellum, white matter, and cortical regions of autistic patients showed significant microglial activation. Reactive glial cells result in the loss of synaptic functioning and induce autism under inflammatory conditions. Replacement of defective glial cells (Cell-replacement treatment), glial progenitor cell-based therapy, and medication therapy (inhibition of microglia activation) are all utilised to treat glial dysfunction. This review discusses the role of glial cells in ASD and the various potential approaches to treating glial cell dysfunction.


Establishment of MUi030-A: A human induced pluripotent stem cell line carrying homozygous L444P mutation in the GBA1 gene to study type-3 Gaucher disease.
Gaucher disease (GD) is a common lysosomal storage disease resulting from mutations in the glucocerebrosidase (GBA1) gene. This genetic disorder manifests with symptoms affecting multiple organs, yet the underlying mechanisms leading to pathology remain elusive. In this study, we successfully generated the MUi030-A human induced pluripotent stem cell (hiPSC) line using a non-integration method from a male type-3 GD patient with a homozygous c.1448T>C (L444P) mutation. These hiPSCs displayed a normal karyotype and pluripotency markers and the remarkable ability to differentiate into cells representing all three germ layers. This resourceful model holds significant promise for illuminating GD's underlying pathogenesis.


Diffusion tensor MR imaging in chronic spinal cord injury.
Diffusion tensor MR imaging is emerging as an important tool for displaying anatomic changes in the brain after injury or disease but has been less widely applied to disorders of the spinal cord. The aim of this study was to characterize the diffusion properties of the entire human spinal cord in vivo during the chronic stages of spinal cord injury (SCI). These data provide insight into the structural changes that occur as a result of long-term recovery from spinal trauma. Thirteen neurologically intact subjects and 10 subjects with chronic SCI (>4 years postinjury) were enrolled in this study. A single-shot twice-refocused spin-echo diffusion-weighted echo-planar imaging pulse sequence was used to obtain axial images throughout the entire spinal cord (C1-L1) in <60 minutes. Despite heterogeneity in SCI lesion severity and location, diffusion characteristics of the chronic lesion were significantly elevated compared with those of uninjured controls. Fractional anisotropy was significantly lower at the chronic lesion and appeared dependent on the completeness of the injury. Conversely, mean diffusivity measurements in the upper cervical spinal cord in subjects with SCI were significantly lower than those in controls. These trends suggest that the entire neuraxis may be affected by long-term recovery from spinal trauma. These results suggest that diffusion tensor imaging may be useful in the assessment of SCI recovery.


Sterile endophthalmitis rates and particle size analyses of different formulations of triamcinolone acetonide.
To evaluate the rate of sterile endophthalmitis (SE) following intravitreal injection of three different formulations of triamcinolone acetonide (TA) in a single physician practice and also to assess the mean diameter and concentration of particles of the two TA formulations currently available commercially in the USA. It was hypothesized that TA formulations with smaller particles and/or greater concentrations would have a higher incidence of SE. Single-site, interventional case series in which the medical records of 392 consecutive eyes receiving intravitreal TA as Triesence(®), Kenalog(®)-40, or preservative-free TA between September 2008 and October 2013 were retrospectively reviewed for the incidence of SE. Particle sizing of TA formulations was conducted by an independent commercial laboratory. Five cases of SE were identified. The four cases of SE following Triesence(®) (4.6%) represented a rate significantly higher than the one case of SE following preservative-free TA (0.6%; P=0.049) and the 0% incidence rate of SE following Kenalog(®)-40 (P=0.0210). Triesence(®) had significantly smaller particles than Kenalog(®)-40 (P<0.0001). The rate of SE was the highest with the formulation of TA that had the smallest particle size and highest particle load (number of particles injected). The lowest rate of SE was seen with Kenalog(®)-40, the only TA formulation that contained a benzyl alcohol preservative. The data do not support a principal causative role of benzyl alcohol in the development of TA-induced SE. Instead, the data support the particle theory of TA-induced SE; however, larger-scale, multicenter studies are needed to confirm and expand on these findings.


Fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes: systematic review and meta-analysis of prospective studies.
The evidence on the association between fish consumption, dietary long-chain n-3 fatty acids, and risk of type 2 diabetes is inconsistent. We therefore performed a systematic review and meta-analysis of the available prospective evidence. Studies were identified by searching the PubMed and EMBASE databases through 15 December 2011 and by reviewing the reference lists of retrieved articles. Prospective studies were included if they reported relative risk (RR) estimates with 95% CIs for the association between fish consumption and/or dietary long-chain n-3 fatty acids and incidence of type 2 diabetes. A dose-response random-effects model was used to combine study-specific RRs. Potential sources of heterogeneity were explored by prespecified stratifications. Sixteen studies involving 527,441 participants and 24,082 diabetes cases were included. Considerable statistical heterogeneity in the overall summary estimates was partly explained by geographical differences. For each serving per week increment in fish consumption, the RRs (95% CIs) of type 2 diabetes were 1.05 (1.02-1.09), 1.03 (0.96-1.11), and 0.98 (0.97-1.00) combining U.S., European, and Asian/Australian studies, respectively. For each 0.30 g per day increment in long-chain n-3 fatty acids, the corresponding summary estimates were 1.17 (1.09-1.26), 0.98 (0.70-1.37), and 0.90 (0.82-0.98). Results from this meta-analysis indicate differences between geographical regions in observed associations of fish consumption and dietary intake of long-chain n-3 fatty acids with risk of type 2 diabetes. In consideration of the heterogeneous results, the relationship warrants further investigation. Meanwhile, current public health recommendations on fish consumption should be upheld unchanged.


Anorexia nervosa in the male: clinical features and follow-up of nine patients.
Nine male patients formed approximately 5% of patients presenting with anorexia nervosa from a population area. Their clinical and family features and outcome at a mean of 5 1/2 yr from onset were similar to those of female patients. All patients lost libido during the syndrome. In four patients at average weight at follow-up the level of libido and sexual activity was related to testosterone level, other hormonal investigations being normal in post pubertal patients. All patients had a history of increased attention to bodily appearance and/or diet before the onset of the illness (e.g. aberrant body size or appearance, close contact with an eating disorder patient).


Multivalent ligand-receptor binding on supported lipid bilayers.
Fluid supported lipid bilayers provide an excellent platform for studying multivalent protein-ligand interactions because the two-dimensional fluidity of the membrane allows for lateral rearrangement of ligands in order to optimize binding. Our laboratory has combined supported lipid bilayer-coated microfluidic platforms with total internal reflection fluorescence microscopy (TIRFM) to obtain equilibrium dissociation constant (K(D)) data for these systems. This high throughput, on-chip approach provides highly accurate thermodynamic information about multivalent binding events while requiring only very small sample volumes. Herein, we review some of the most salient findings from these studies. In particular, increasing ligand density on the membrane surface can provide a modest enhancement or attenuation of ligand-receptor binding depending upon whether the surface ligands interact strongly with each other. Such effects, however, lead to little more than one order of magnitude change in the apparent K(D) values. On the other hand, the lipophilicity and presentation of lipid bilayer-conjugated ligands can have a much greater impact. Indeed, changing the way a particular ligand is conjugated to the membrane can alter the apparent K(D) value by at least three orders of magnitude. Such a result speaks strongly to the role of ligand availability for multivalent ligand-receptor binding.


Crystal structure of YjeQ from Thermotoga maritima contains a circularly permuted GTPase domain.
We have determined the crystal structure of the GDP complex of the YjeQ protein from Thermotoga maritima (TmYjeQ), a member of the YjeQ GTPase subfamaily. TmYjeQ, a homologue of Escherichia coli YjeQ, which is known to bind to the ribosome, is composed of three domains: an N-terminal oligonucleotide/oligosaccharide-binding fold domain, a central GTPase domain, and a C-terminal zinc-finger domain. The crystal structure of TmYjeQ reveals two interesting domains: a circularly permutated GTPase domain and an unusual zinc-finger domain. The binding mode of GDP in the GTPase domain of TmYjeQ is similar to those of GDP or GTP analogs in ras proteins, a prototype GTPase. The N-terminal oligonucleotide/oligosaccharide-binding fold domain, together with the GTPase domain, forms the extended RNA-binding site. The C-terminal domain has an unusual zinc-finger motif composed of Cys-250, Cys-255, Cys-263, and His-257, with a remote structural similarity to a portion of a DNA-repair protein, rad51 fragment. The overall structural features of TmYjeQ make it a good candidate for an RNA-binding protein, which is consistent with the biochemical data of the YjeQ subfamily in binding to the ribosome.


Evaluation of the impact of the Canadian CT head rule on British practice.
The Canadian CT head rule has been developed to identify which adults with minor head injuries require computed tomography (CT). This is hoped will reduce the number of CT scans performed for minor head injury in North America. It was unclear whether applying the rule would reduce or even increase the number of CT scans requested in UK emergency departments. A retrospective evaluation was conducted of all adults who presented after minor head injuries to Addenbrooke's emergency department. Clinical information about patients with head injuries is collected on standardised forms. A dataset was constructed to predict how many patients would require head CT scans if the Canadian CT rule was applied. 1489 adults presented after minor head injury over a seven month period. Seventy four of these had CT scans for head injury, applying the Canadian CT head rule would have resulted in 132 CT scans being requested. This is significantly more (p>0.001). This would have resulted in a 68% increase in costs. The Canadian CT head rule would result in an increase in the number of CT scans requested for minor head injuries. This increased cost must be considered against the 488 skull radiographs that were requested during the study period.


Click-encoded rolling FISH for visualizing single-cell RNA polyadenylation and structures.
Spatially resolved visualization of RNA processing and structures is important for better studying single-cell RNA function and landscape. However, currently available RNA imaging methods are limited to sequence analysis, and not capable of identifying RNA processing events and structures. Here, we developed click-encoded rolling FISH (ClickerFISH) for visualizing RNA polyadenylation and structures in single cells. In ClickerFISH, RNA 3' polyadenylation tails, single-stranded and duplex regions are chemically labeled with different clickable DNA barcodes. These barcodes then initiate DNA rolling amplification, generating repetitive templates for FISH to image their subcellular distributions. Combined with single-molecule FISH, the proposed strategy can also obtain quantitative information of RNA of interest. Finally, we found that RNA poly(A) tailing and higher-order structures are spatially organized in a cell type-specific style with cell-to-cell heterogeneity. We also explored their spatiotemporal patterns during cell cycle stages, and revealed the highly dynamic organization especially in S phase. This method will help clarify the spatiotemporal architecture of RNA polyadenylation and structures.


Vestibular rehabilitation in multiple sclerosis: study protocol for a randomised controlled trial and cost-effectiveness analysis comparing customised with booklet based vestibular rehabilitation for vestibulopathy and a 12 month observational cohort study of the symptom reduction and recurrence rate following treatment for benign paroxysmal positional vertigo.
Symptoms arising from vestibular system dysfunction are observed in 49-59% of people with Multiple Sclerosis (MS). Symptoms may include vertigo, dizziness and/or imbalance. These impact on functional ability, contribute to falls and significant health and social care costs. In people with MS, vestibular dysfunction can be due to peripheral pathology that may include Benign Paroxysmal Positional Vertigo (BPPV), as well as central or combined pathology. Vestibular symptoms may be treated with vestibular rehabilitation (VR), and with repositioning manoeuvres in the case of BPPV. However, there is a paucity of evidence about the rate and degree of symptom recovery with VR for people with MS and vestibulopathy. In addition, given the multiplicity of symptoms and underpinning vestibular pathologies often seen in people with MS, a customised VR approach may be more clinically appropriate and cost effective than generic booklet-based approaches. Likewise, BPPV should be identified and treated appropriately. People with MS and symptoms of vertigo, dizziness and/or imbalance will be screened for central and/or peripheral vestibulopathy and/or BPPV. Following consent, people with BPPV will be treated with re-positioning manoeuvres over 1-3 sessions and followed up at 6 and 12 months to assess for any re-occurrence of BPPV. People with central and/or peripheral vestibulopathy will be entered into a randomised controlled trial (RCT). Trial participants will be randomly allocated (1:1) to either a 12-week generic booklet-based home programme with telephone support or a 12-week VR programme consisting of customised treatment including 12 face-to-face sessions and a home exercise programme. Customised or booklet-based interventions will start 2 weeks after randomisation and all trial participants will be followed up 14 and 26 weeks from randomisation. The primary clinical outcome is the Dizziness Handicap Inventory at 26 weeks and the primary economic endpoint is quality-adjusted life-years. A range of secondary outcomes associated with vestibular function will be used. If customised VR is demonstrated to be clinically and cost-effective compared to generic booklet-based VR this will inform practice guidelines and the development of training packages for therapists in the diagnosis and treatment of vestibulopathy in people with MS. ISRCTN Number: 27374299 Date of Registration 24/09/2018 Protocol Version 15 25/09/2019.


Association between hypoxia-inducible factor-1 alpha rs11549465 (1772 C>T) polymorphism and metabolic syndrome.
To find the association of single nucleotide polymorphism of hypoxia-inducible factor-1 alpha, rs11549465 (1772 Cytosine > Thymine) with metabolic syndrome, and to compare the anthropometric and biochemical variables in different genotypes of hypoxia-inducible factor-1 alpha. The cross-sectional comparative study was conducted at the University of Health Sciences, Lahore, Pakistan, from July 2016 to April 2019, and comprised patients of metabolic syndrome selected from the Sheikh Zayed Hospital, Lahore. Healthy controls were also enrolled. Fasting venous sample was taken for the determination of study parameters. The genetic variant of hypoxia-inducible factor-1 alpha was analysed by restriction fragment length polymorphism polymerase chain reaction. Data was analysed using SPSS 22. Out of 400 subjects, 200(50%) each were patients and controls. The frequency of CC genotype of hypoxia-inducible factor-1 alpha Cytosine > Thymine in patients was 166(83%) and in controls 147(73.5%); CT genotype was 34(17%) and 53(26.5%) respectively, while TT genotype was not observed. There was a significant association of the C allele and CC genotype (p=0.03) with the increased risk of metabolic syndrome (p=0.02). On comparison of study variables in the two genotypes, systolic blood pressure, anthropometric and lipid parameters were significantly higher in the wild CC genotype compared to CT in the control group (p<0.05), but there was no significant difference in the patients (p>0.05). Major allele C of hypoxia-inducible factor-1 alpha 1772 Cytosine > Thymine was found to be associated with increased risk of metabolic syndrome.


Derivatization methods for quantitative bioanalysis by LC-MS/MS.
LC with atmospheric pressure ionization MS is essential to a large number of quantitative bioanalyses for a variety of compounds, especially nonvolatile or highly polar compounds. However, in many instances, weak ionization, poor LC retention and instability of certain analytes hinder the development of the LC-MS/MS method. Chemical derivatization has been used for different classes of analytes to improve their ionization efficiency, chromatographic separation and chemical stability. This work presents an overview of chemical derivatization methods that have been applied to the quantitative LC-MS/MS analyses of nine classes of molecules, including aldehydes, amino acids, bisphosphonate drugs, carbohydrates, carboxylic acids, nucleosides and their associated analogs, steroids, thiol-containing compounds and vitamin D metabolites, in biological matrices.


Migraine is a neuronal disease.
Migraine is a common, paroxysmal, highly disabling primary headache disorder with a genetic background. The primary cause and the origin of migraine attacks are enigmatic. Numerous clinical and experimental results suggest that activation of the trigeminal system (TS) is crucial in its pathogenesis, but the primary cause of this activation is not fully understood. Since activation of the peripheral and central arms of the TS might be related to cortical spreading depression and to the activity of distinct brainstem nuclei (e.g. the periaqueductal grey), we conclude that migraine can be explained as an altered function of the neuronal elements of the TS, the brainstem, and the cortex, the centre of this process comprising activation of the TS. In light of our findings and the literature data, therefore, we can assume that migraine is mainly a neuronal disease.


Nerve injuries sustained during warfare: part I--Epidemiology.
We describe 261 peripheral nerve injuries sustained in war by 100 consecutive service men and women injured in Iraq and Afghanistan. Their mean age was 26.5 years (18.1 to 42.6), the median interval between injury and first review was 4.2 months (mean 8.4 months (0.36 to 48.49)) and median follow-up was 28.4 months (mean 20.5 months (1.3 to 64.2)). The nerve lesions were predominantly focal prolonged conduction block/neurapraxia in 116 (45%), axonotmesis in 92 (35%) and neurotmesis in 53 (20%) and were evenly distributed between the upper and the lower limbs. Explosions accounted for 164 (63%): 213 (82%) nerve injuries were associated with open wounds. Two or more main nerves were injured in 70 patients. The ulnar, common peroneal and tibial nerves were most commonly injured. In 69 patients there was a vascular injury, fracture, or both at the level of the nerve lesion. Major tissue loss was present in 50 patients: amputation of at least one limb was needed in 18. A total of 36 patients continued in severe neuropathic pain. This paper outlines the methods used in the assessment of these injuries and provides information about the depth and distribution of the nerve lesions, their associated injuries and neuropathic pain syndromes.


Predictions of future dangerousness in capital murder trials: is it time to "disinvent the wheel"?
Although recent U.S. Supreme Court decisions regarding the death penalty (e.g., Atkins v. Virginia, 2002) have renewed interest in mental health issues, one topic that has not received much attention recently is the ongoing use of expert testimony to support claims that defendants represent a "continuing threat to society." In this article, we (a) review prior research relevant to determining the accuracy of clinical predictions that capital defendants will commit future acts of criminal violence; (b) summarize new data from current and former death row inmates in Texas that bolster the claim that such predictions are gross overestimates of risk; and (c) review extant research addressing the potential utility of various risk assessment instruments that increasingly are being used to reinforce clinical predictions in capital trials. Despite significant recent advances in the field of risk assessment, clinical assertions that a defendant is likely to commit future violent acts appear to be highly inaccurate and ethically questionable at best. Moreover, available research offers little support for the claim that the accuracy of these predictions will be appreciably improved by relying on more structured risk assessment measures that have some demonstrated predictive validity in other contexts.


Microwave-assisted digestion and NaOH treatment of waste-activated sludge to recover phosphorus by crystallizing struvite.
A number of studies of waste-activated sludge (WAS) pretreatments, aimed at releasing phosphorus (P) from WAS and increasing the amount of P that can be recovered, have been performed. Here, a microwave-assisted digestion and NaOH treatment (MWs & NaOH) coupled crystallizing struvite, to promote the solubilization, transformation, and recovery of P from WAS, is proposed. Microwaves (MWs) can cause cavities to form in WAS, weakening the bonds between extracellular polymeric substances and the solid phase. Irradiating with MWs significantly increased the efficiency at which P was dissolved (i.e. transferred from the solid to the liquid phase) and the efficiency at which organic P was hydrolyzed and transformed into inorganic P when the NaOH treatment was performed. The P solubilization and transformation characteristic achieved in different treatments was examined by scanning electron microscopy and three-dimensional excitation emission matrix analysis. The MWs & NaOH method released 34.20-43.73% of total P from WAS, and 23.48-32.07% of the total P was recovered by crystallizing struvite at pH 9.5 and Mg:P ratio of 1.5:1. It would cost about USD 85-103 per ton of dry WAS to treat WAS using the MWs & NaOH method.


A Comparison of the Epidemiology, Clinical Features, and Treatment of Acute Osteomyelitis in Hospitalized Children in Latvia and Norway.
Background and objectives: Paediatric acute osteomyelitis (AO) may result in major life-threatening and limb-threatening complications if not recognized and treated early. The management of AO may depend on local microbial prevalence and virulence factors. This study compares the approach to paediatric AO in hospitals in two countries-Latvia and Norway. Materials and Methods: The study includes patients with AO hospitalized in the paediatric department in the Norwegian hospital Sørlandet Sykehus Kristiansand (SSK), in the period between the 1st of January 2012 and the 31st of December 2019. The results from SSK are compared to the results of a published study of AO in patients hospitalized at the Children's Clinical University Hospital (CCUH) in Riga, Latvia. Results: The most isolated pathogen from cultures in both hospitals was S. aureus (methicillin-sensitive). The lower extremity was the most affected body part (75% in CCUH, 95% in SSK), the main clinical symptom was pain (CCUH 92%, SSK 96.6%). Deep culture aspiration was most often taken intraoperatively in CCUH (76.6%) and percutaneously in SSK (44.8%). Oxacillin was the most applied antibiotic in CCUH (89.4%), and Cloxacillin in SSK (84.6%). Combined treatment with anti-Staphylococcal penicillins and Clindamycin was administered in 25.5% and 33.8% of CCUH and SSK patients, respectively. The median duration of the intravenous antibacterial treatment in CCUH and SSK was 15 and 10 days, respectively, and a switch to oral therapy was mainly made at discharge in both hospitals. The median total duration of antibiotic treatment was 25 days in CCUH and 35 days in SSK. 75% of CCUH and 10.3% of SSK patients were treated surgically. Complications were seen in 47% of patients in CCUH and in 38% in SSK. Conclusions: The transition to oral antibacterial treatment in both hospitals was delayed, which suggests a lack of criteria for discontinuation of intravenous therapy and could potentially contribute to longer hospitalization, higher cost of treatment and risk of complications. The use of more invasive techniques for deep culturing and significantly more common surgical interventions could possibly be linked to a higher complication rate in AO patients treated at the Latvian hospital.


Dual role of the leukocyte integrin αMβ2 in angiogenesis.
Polymorphonuclear neutrophils (PMNs) and macrophages are crucial contributors to neovascularization, serving as a source of chemokines, growth factors, and proteases. α(M)β(2)(CD11b/CD18) and α(L)β(2)(CD11a/CD18) are expressed prominently and have been implicated in various responses of these cell types. Thus, we investigated the role of these β2 integrins in angiogenesis. Angiogenesis was analyzed in wild-type (WT), α(M)-knockout (α(M)(-/-)), and α(L)-deficient (α(L)(-/-)) mice using B16F10 melanoma, RM1 prostate cancer, and Matrigel implants. In all models, vascular area was decreased by 50-70% in α(M)(-/-) mice, resulting in stunted tumor growth as compared with WT mice. In contrast, α(L) deficiency did not impair angiogenesis and tumor growth. The neovessels in α(M)(-/-) mice were leaky and immature because they lacked smooth muscle cell and pericytes. Defective angiogenesis in the α(M)(-/-) mice was associated with attenuated PMN and macrophage recruitment into tumors. In contrast to WT or the α(L)(-/-) leukocytes, the α(M)(-/-) myeloid cells showed impaired plasmin (Plm)-dependent extracellular matrix invasion, resulting from 50-75% decrease in plasminogen (Plg) binding and pericellular Plm activity. Surface plasmon resonance verified direct interaction of the α(M)I-domain, the major ligand binding site in the β(2) integrins, with Plg. However, the α(L)I-domain failed to bind Plg. In addition, endothelial cells failed to form tubes in the presence of conditioned medium collected from TNF-α-stimulated PMNs derived from the α(M)(-/-) mice because of severely impaired degranulation and secretion of VEGF. Thus, α(M)β(2) plays a dual role in angiogenesis, supporting not only Plm-dependent recruitment of myeloid cells to angiogenic niches, but also secretion of VEGF by these cells.


FoxP2 is a parvocellular-specific transcription factor in the visual thalamus of monkeys and ferrets.
Although the parallel visual pathways are a fundamental basis of visual processing, our knowledge of their molecular properties is still limited. Here, we uncovered a parvocellular-specific molecule in the dorsal lateral geniculate nucleus (dLGN) of higher mammals. We found that FoxP2 transcription factor was specifically expressed in X cells of the adult ferret dLGN. Interestingly, FoxP2 was also specifically expressed in parvocellular layers 3-6 of the dLGN of adult old world monkeys, providing new evidence for a homology between X cells in the ferret dLGN and parvocellular cells in the monkey dLGN. Furthermore, this expression pattern was established as early as gestation day 140 in the embryonic monkey dLGN, suggesting that parvocellular specification has already occurred when the cytoarchitectonic dLGN layers are formed. Our results should help in gaining a fundamental understanding of the development, evolution, and function of the parallel visual pathways, which are especially prominent in higher mammals.


Dielectron mass spectra from Au+Au collisions at √[s(NN)]=200 GeV.
We report the STAR measurements of dielectron (e(+)e(-)) production at midrapidity (|y(ee)|<1) in Au+Au collisions at √[s(NN)]=200 GeV. The measurements are evaluated in different invariant mass regions with a focus on 0.30-0.76 (ρ-like), 0.76-0.80 (ω-like), and 0.98-1.05 (ϕ-like) GeV/c(2). The spectrum in the ω-like and ϕ-like regions can be well described by the hadronic cocktail simulation. In the ρ-like region, however, the vacuum ρ spectral function cannot describe the shape of the dielectron excess. In this range, an enhancement of 1.77±0.11(stat)±0.24(syst)±0.33(cocktail) is determined with respect to the hadronic cocktail simulation that excludes the ρ meson. The excess yield in the ρ-like region increases with the number of collision participants faster than the ω and ϕ yields. Theoretical models with broadened ρ contributions through interactions with constituents in the hot QCD medium provide a consistent description of the dilepton mass spectra for the measurement presented here and the earlier data at the Super Proton Synchrotron energies.


Plant dependence on rhizobia for nitrogen influences induced plant defenses and herbivore performance.
Symbiotic rhizobia induce many changes in legumes that could affect aboveground interactions with herbivores. We explored how changing the intensity of Bradyrhizobium japonicum, as modulated by soil nitrogen (N) levels, influenced the interaction between soybean (Glycine max) and herbivores of different feeding guilds. When we employed a range of fertilizer applications to manipulate soil N, plants primarily dependent on rhizobia for N exhibited increased root nodulation and higher levels of foliar ureides than plants given N fertilizer; yet all treatments maintained similar total N levels. Soybean podworm (Helicoverpa zea) larvae grew best on plants with the highest levels of rhizobia but, somewhat surprisingly, preferred to feed on high-N-fertilized plants when given a choice. Induction of the defense signaling compound jasmonic acid (JA) by H. zea feeding damage was highest in plants primarily dependent on rhizobia. Differences in rhizobial dependency on soybean did not appear to affect interactions with the phloem-feeding soybean aphid (Aphis glycines). Overall, our results suggest that rhizobia association can affect plant nutritional quality and the induction of defense signaling pathways and that these effects may influence herbivore feeding preferences and performance-though such effects may vary considerably for different classes of herbivores.


Evaluation of Highest Level Pediatric Trauma Activation Criteria.
Despite the presence of a tiered in-hospital trauma triage system for the past decade, trauma centers still struggle with a definitive list of highest level activation criteria. In 2002, the American College of Surgeons (ACS) mandated 6 criteria for highest level activation. However, it is unknown if pediatric trauma centers follow these criteria. The purpose of this study is to identify and categorize the highest level pediatric trauma criteria used by pediatric trauma centers in the United States. In collaboration with the ACS, we reviewed activation criteria for highest level trauma activation for all ACS-verified level I pediatric trauma centers in the United States. Criteria were sorted by 2 reviewers into categories of indicators used for activation: patient demographic, physiologic, anatomic, intervention/resource usage, mechanism, and other. A total of 51 unique criteria for highest level trauma activation were identified from 54 (96%) of 56 level I pediatric trauma centers. Each center used between 1 and 29 criteria. A total of 42.6% of pediatric trauma centers followed all 6 criteria recommended by ACS. The most commonly omitted criterion was emergency physician discretion. The most common criteria not included in the ACS recommendations, but included in the highest level activation criteria, were amputation proximal to wrist or ankle (63%), and spinal cord injury/paralysis (63%). There is wide variation in the criteria used for highest level trauma activation among pediatric trauma centers. Further research investigating individual or grouped criteria to determine the most sensitive and specific criteria are necessary for appropriate triage and resource usage.


Providing Acute Care at Home: Community Paramedics Enhance an Advanced Illness Management Program-Preliminary Data.
Models addressing urgent clinical needs for older adults with multiple advanced chronic conditions are lacking. This observational study describes a Community Paramedicine (CP) model for treatment of acute medical conditions within an Advanced Illness Management (AIM) program, and compares its effect on emergency department (ED) use and subsequent hospitalization with that of traditional emergency medical services (EMS). Community paramedics were trained to evaluate and, with telemedicine-enhanced physician guidance, treat acute illnesses in individuals' homes. They were also able to transport to the ED if needed. The CP model was implemented between January 1, 2014, and April 30, 2015 in a suburban-urban AIM program. Participants included 1,602 individuals enrolled in the AIM program with high rates of dementia, decubitus ulcers, diabetes mellitus, congestive heart failure, and chronic obstructive pulmonary disease. Participants had a median age of 83 and an average of five activity of daily living dependencies (range 0-6). During the study period, there were 664 CP responses and 1,091 traditional EMS transports to the ED among 773 individuals. Only 22% of CP responses required transport; 78% were evaluated and treated in the home. Individuals that community paramedics transported to the ED had higher rates of hospitalization (82.2%) than those using traditional EMS (68.9%) (P < .001). Post-CP surveys showed that all respondents felt the program was of high quality. Results support the potential benefits of CP and invite further evaluation of this innovative care model.


In vitro characterization of the anticancer activity of membrane-active cationic peptides. I. Peptide-mediated cytotoxicity and peptide-enhanced cytotoxic activity of doxorubicin against wild-type and p-glycoprotein over-expressing tumor cell lines.
Cationic amphipathic peptides, such as the defensins and cecropins, induce cell death in prokaryotic and eukaryotic cells by increasing membrane permeability. Increased permeability may lead to cell lysis or, alternatively, may produce subtle changes in the membrane's barrier function that promote cell death. The in vitro cytotoxic and lytic activity of short mammalian-derived extended-helical cationic peptides and insect-derived alpha-helical peptides was measured in this study with the objective of establishing the anticancer potential of these agents. Two specific aims were addressed: (i) to assess the activity of peptides against non-malignant cells (sheep erythrocytes and human umbilical vein endothelial cells) versus tumor cells; and (ii) to characterize the cytotoxic activity using multidrug-resistant tumor cell lines in the presence and absence of the anthracycline doxorubicin. Cell lysis assays demonstrated that the lytic activity of the peptides tested was 2->50 times more cytotoxic to tumor cells than to non-malignant cells. Further, the cytotoxic activity of these peptides was equivalent when tested against sensitive and multidrug-resistant cell lines. In addition to their inherent cytotoxic activity, these membrane-active peptides can also augment the in vitro cytotoxic activity of doxorubicin against multidrug-resistant tumor cells.


Drought stress-responsive abscisic acid and salicylic acid crosstalk with the phenylpropanoid pathway in soybean seeds.
Crosstalk between hormones and secondary metabolites regulates the interactions between plants and stress. However, little is known about the effects of hormone crosstalk on the concentration of flavonoids in seeds. In this study, we identified abscisic acid (ABA) as a negative regulator of flavonoid accumulation in soybean seeds under drought-stress conditions. Alterations in flavonoid accumulation at several intensities of water stress, followed by a recovery period, were measured during the soybean seed-filling stage. Low soil moisture (SM 10%) significantly decreased the total flavonoid content in seeds. The decline in flavonoid content was proportional to the severity of drought stress and was dependent on the activities of phenylalanine ammonia-lyase (PAL) and chalcone synthase (CHS), two key phenylpropanoid pathway enzymes. The expression of phenylalanine ammonia-lyase 1 (GmPAL1), chalcone isomerase 1A (GmCHI1A), and chalcone synthase 8 (GmCHS8) was associated with phenolic and flavonoid accumulation in soybean seeds of plants subjected to drought stress. Interestingly, the expression levels of GmCHS8 were highly correlated with flavonoid levels under drought stress and water recovery conditions. Cinnamic acid, which is a biosynthesis precursor shared by both phenylpropanoid metabolism and salicylic acid (SA) biosynthesis, decreased under drought stress conditions. Notably, exogenous ABA suppressed the expression of GmPAL1, which encodes the first rate-limiting enzyme in the phenylpropanoid biosynthesis pathway and affects downstream products such as SA and flavonoids. In conclusion, drought stress altered the phenylpropanoid-derived compounds, at least with regard to flavonoid and SA accumulation in seeds, which was regulated by antagonistic interactions with ABA.


Predicting Ames Mutagenicity Using Conformal Prediction in the Ames/QSAR International Challenge Project.
Valid and predictive models for classifying Ames mutagenicity have been developed using conformal prediction. The models are Random Forest models using signature molecular descriptors. The investigation indicates, on excluding not-strongly mutagenic compounds (class B), that the validity for mutagenic compounds is increased for the predictions based on both public and the Division of Genetics and Mutagenesis, National Institute of Health Sciences of Japan (DGM/NIHS) data while less so when using only the latter data source. The former models only result in valid predictions for the majority, non-mutagenic, class whereas the latter models are valid for both classes, i.e. mutagenic and non-mutagenic compounds. These results demonstrate the importance of data consistency manifested through the superior predictive quality and validity of the models based only on DGM/NIHS generated data compared to a combination of this data with public data sources.


UDP-glucosamine as a substrate for dolichyl monophosphate glucosamine synthesis.
The sugar nucleotide analogue UDP-glucosamine was found to function as a sugar donor in microsomal preparations of both chick-embryo cells and rat liver, yielding dolichyl monophosphate glucosamine (Dol-P-GlcN). This was characterized by t.l.c. and retention by DEAE-cellulose. Glucosamine was the only water-soluble product released on mild acid hydrolysis. Dol-P-GlcN did not serve as substrate by transferring its glucosamine moiety to dolichol-linked oligosaccharide. Competition experiments between UDP-[3H]glucose and UDP-glucosamine showed Dol-P-[3H]glucose synthesis to be depressed by 56 or 73% in microsomes from chick-embryo cells and rat liver respectively. The concentrations of the UDP-sugars in this experiment were comparable with those occurring in galactosamine-metabolizing liver. These findings suggest that Dol-P-GlcN, formed as a metabolite of D-galactosamine, may interfere with Dol-P-dependent reactions.


Revisiting the initial steps of sexual development in the malaria parasite Plasmodium falciparum.
Human to vector transmission of malaria requires that some blood-stage parasites abandon asexual growth and convert into non-replicating sexual forms called gametocytes. The initial steps of gametocytogenesis remain largely uncharacterized. Here, we study this part of the malaria life cycle in Plasmodium falciparum using PfAP2-G, the master regulator of sexual conversion, as a marker of commitment. We demonstrate the existence of PfAP2-G-positive sexually committed parasite stages that precede the previously known committed schizont stage. We also found that sexual conversion can occur by two different routes: the previously described route in which PfAP2-G-expressing parasites complete a replicative cycle as committed forms before converting into gametocytes upon re-invasion, or a direct route with conversion within the same cycle as initial PfAP2-G expression. The latter route is linked to early PfAP2-G expression in ring stages. Reanalysis of published single-cell RNA-sequencing (RNA-seq) data confirmed the presence of both routes. Consistent with these results, using plaque assays we observed that, in contrast to the prevailing model, many schizonts produced mixed plaques containing both asexual parasites and gametocytes. Altogether, our results reveal unexpected features of the initial steps of sexual development and extend the current view of this part of the malaria life cycle.


[Eye manifestations as climacteric symptom].
The menopausal syndrome consists of a variety of psychic and physical signs of different intensity. At our outpatient department for problems in menopause and prevention of osteoporosis (1. Dept. of Gynaecol. and Obstetrics, Vienna) 1287 women who were consulting this department for the first time because of prevailing complaints or prophylactic reasons, were registered during the years 1988 and 1989. In the course of this work we paid particular attention to the symptom "eye complaint" as a sign of the beginning of the menopausal period. 98 out of 430 patients with eye complaints were examined ophthalmologically. Referring to our patient population we tried to analyse epidemiologically the frequency and the degree of severity of menopausal eye complaints as well as the therapeutical response to a hormone substitution therapy. To what extent an endocrinological explanation can be found and which facts lead us assume such a statement, we have tried to demonstrate in the discussion.


Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: absence of a temporal gradient.
The role of the basolateral amygdala (LA) in the acquisition and expression of Pavlovian fear conditioning was examined in 80 rats. Excitotoxic lesions were made in the BLA using N-methyl-D-aspartate 7 days before or 1, 14, or 28 days after Pavlovian fear conditioning. Conditioning consisted of three pairings of a tone with an aversive footshock in a novel chamber, and freezing behavior served as an index of conditional fear. BLA lesions abolished conditional freezing to both the contextual and acoustic conditional stimuli at all training-to-lesion intervals, and the magnitude of the impairment did not vary as a function of the training-to-lesion interval. Reacquisition training elevated levels of freezing in rats with BLA lesions but did not reduce the magnitude of their deficit in relation to that of controls. These results reveal that neurons in the BLA have an enduring role in the expression of conditional fear.


Anti-NuMA antibodies: clinical associations and significance in patients with primary Sjögren's syndrome or systemic lupus erythematosus.
To determine the clinical significance of anti-nuclear mitotic apparatus (NuMA) antibodies (AC-26 or AC-25) in patients with primary Sjögren's syndrome (pSS) and SLE. Between 2013 and 2018, clinical and immunological features of pSS and SLE patients with anti-NuMA antibodies were compared with anti-NuMA antibodies-negative pSS and SLE cohorts. Among 31 284 sera positive for antinuclear antibodies, 90 patients (0.29%) had anti-AC-26 (anti-NuMA1) and AC-25 (anti-HsEg5) antibodies (73.3% and 26.7%, respectively). Autoimmune diseases, mainly consisting in pSS (28.9%) and SLE (21.1%), were found in 67.8%. Anti-NuMA antibodies represented the unique ANA in 60% and 50% of patients with pSS and SLE patients, respectively. Compared with 137 anti-NuMA-negative pSS patients, 20 anti-NuMA-positive pSS presented with less frequent ocular sicca syndrome (70.0% vs 89.1%, P=0.031), dryness complications (15.0% vs 39.4%, P=0.045), or detectable anti-SSa and/or anti-SSb antibodies (40.0% vs 66.4%, P=0.027). Compared with 80 anti-NuMA-negative SLE patients, 14 anti-NuMA-positive SLE patients had no lupus nephritis (0.0% vs 28.8%, P=0.049), less frequent dsDNA antibodies (42.9% vs 75.0%, P=0.025) and complement consumption (21.4% vs 53.8%, P=0.040). Anti-NuMA-positive pSS and SLE patients less frequently required treatments compared with anti-NuMA-negative patients. Although rare, anti-NuMA antibodies are mainly associated with pSS and SLE and may be useful for diagnosis when other auto-antibodies are negative. PSS and SLE patients with anti-NuMA antibodies have less severe clinical and biological profiles, suggesting that anti-NuMA antibodies may constitute a good prognosis marker in both autoimmune diseases.


Nanocomposite therapy as a more efficacious and less inflammatory alternative to bone morphogenetic protein-2 in a rodent arthrodesis model.
The use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in spine fusion has led to concerns regarding a potential accompanying inflammatory response. This study evaluates a combination therapy (TrioMatrix®; Pioneer Surgical, Inc., Marquette, MI) comprised of a demineralized bone matrix (DBM), hydroxyapatite, and a nanofiber-based collagen scaffold in a rodent spine fusion model. Thirty-six athymic rats that underwent a posterolateral intertransverse spinal fusion were randomly assigned to 1 of 5 treatment groups: absorbable collagen sponge alone (ACS, negative control), 10 µg rhBMP-2 on ACS (positive control), TrioMatrix®, Grafton® (Osteotech, Inc., Eatontown, NJ), and DBX® (Synthes, Inc., West Chester, PA). Both TrioMatrix® and rhBMP-2-treated animals demonstrated 100% fusion rates as graded by manual palpation scores 8 weeks after implantation. This rate was significantly greater than those of the ACS, Grafton®, and DBX® groups. Notably, the use of TrioMatrix® as evaluated by microCT quantification led to a greater fusion mass volume when compared to all other groups, including the rhBMP-2 group. T2-weighted axial MRI images of the fusion bed demonstrated a significant host response associated with a large fluid collection with the use of rhBMP-2; this response was significantly reduced with the use of TrioMatrix®. Our results therefore demonstrate that a nanocomposite therapy represents a promising, cost-effective bone graft substitute that could be useful in spine fusions where BMP-2 is contraindicated.


Bullous pemphigoid in a patient treated with UVA-1 phototherapy for disseminated morphea.
Bullous pemphigoid is an autoimmune disease of the skin characterized by the production of antibodies directed at structures of the basement membrane zone (BMZ) leading to subepidermal blisters. Several causative triggers have been described in the literature, among them UV light. Here, we report on a 73-year-old Caucasian female with disseminated morphea who developed blisters on her extremities after receiving whole-body UVA-1 phototherapy. The initial differential diagnosis of a phototoxic versus photoallergic reaction was ruled out as the lesions continued to spread after discontinuation of phototherapy. Histological and direct immunofluorescence examination showing a subepidermal blister and linear IgG deposits along the BMZ along with detection of circulating anti-BMZ antibodies led to the diagnosis of bullous pemphigoid. Immunosuppressive therapy resulted in regression of all blisters. After ruling out other possible causes, such as neoplasias or drugs, we conclude that UVA-1 has to be regarded as the most likely trigger of the disease.


[Value of cytochemical tests in nephrology].
The activity of peripheral blood leukocyte enzymes (neutrophils and lymphocytes) was assessed by cytochemical methods in 166 patients with chronic glomerulonephritis, lupus nephritis and amyloidosis (primary, secondary, hereditary in periodical disease) to determine their importance for differential diagnosis and to assess the activity and prognosis of these nephropathies. Correlation of the nature of enzymatic shifts with nephropathy type, activity of inflammation and prognosis of nephritides was shown. The effectiveness of the use of cytochemical tests in examination of nephrological patients was substantiated.


Gasterophilosis in horses in Sardinia (Italy): effect of meteorological variables on adult egg-laying activity and presence of larvae in the digestive tract, and update of species.
Gasterophilus larvae are common obligate parasites of the digestive tract of the equids. Horses become infected with this parasite by ingesting the larvae hatched from eggs laid by the female flies. In this study carried out monthly, we (i) counted the Gasterophilus eggs deposited by female flies on the coat of 30 grazing horses, (ii) counted and identified the Gasterophilus larvae retrieved from the digestive tract of 128 slaughtered horses, and (iii) compared these results to meteorological data. Eggs were deposited on all monitored horses, and were present from October to January and from May to September, whereas they were absent from February to April. The number of laid eggs was significantly different between the months, body regions, genders, and age classes (p < 0.05). Larvae were recovered in 112 (87.5%) horses, and 6 species of Gasterophilus were identified. The prevailing species were Gasterophilus intestinalis (recovered in 110 horses; 85.9%) and Gasterophilus nasalis (69 horses; 53.9 %), recovered in all months. Gasterophilus inermis (5 horses; 3.9%), Gasterophilus pecorum (3 horses; 2.3%), Gasterophilus haemorrhoidalis (3 horses; 2.3%)¸ and Gasterophilus meridionalis (2 horses; 1.6%) larvae were also found. Significant differences were found among monthly larval burdens for both Gasterophilus spp. and G. intestinalis (p < 0.05), but not for G. nasalis (p > 0.05). Larval burdens and prevalences did not differed significantly between both genders and age classes (p > 0.05). Monthly eggs and larvae trends were not significantly correlated (p > 0.05). With regard to the meteorological variables, minimum air temperature was significantly correlated with the eggs trend (rho = 1.000; p < 0.001) and maximum air temperature with the Gasterophilus spp. (rho = 0.972; p < 0.001) and G. intestinalis (rho = 0.972; p < 0.001) larvae trends. In addition, the number of hours with a temperature below +10 °C was significantly correlated with G. intestinalis larvae trend (rho = 0.602; p < 0.05). Our findings confirmed that in Sardinia, Gasterophilosis is an important parasitosis in the horses, and it needs more attention and extensive and/or correct treatment to reduce its prevalence.


Formation of artificial chromosomes in Caenorhabditis elegans and analyses of their segregation in mitosis, DNA sequence composition and holocentromere organization.
To investigate how exogenous DNA concatemerizes to form episomal artificial chromosomes (ACs), acquire equal segregation ability and maintain stable holocentromeres, we injected DNA sequences with different features, including sequences that are repetitive or complex, and sequences with different AT-contents, into the gonad of Caenorhabditis elegans to form ACs in embryos, and monitored AC mitotic segregation. We demonstrated that AT-poor sequences (26% AT-content) delayed the acquisition of segregation competency of newly formed ACs. We also co-injected fragmented Saccharomyces cerevisiae genomic DNA, differentially expressed fluorescent markers and ubiquitously expressed selectable marker to construct a less repetitive, more complex AC. We sequenced the whole genome of a strain which propagates this AC through multiple generations, and de novo assembled the AC sequences. We discovered CENP-AHCP-3 domains/peaks are distributed along the AC, as in endogenous chromosomes, suggesting a holocentric architecture. We found that CENP-AHCP-3 binds to the unexpressed marker genes and many fragmented yeast sequences, but is excluded in the yeast extremely high-AT-content centromeric and mitochondrial DNA (> 83% AT-content) on the AC. We identified A-rich motifs in CENP-AHCP-3 domains/peaks on the AC and on endogenous chromosomes, which have some similarity with each other and similarity to some non-germline transcription factor binding sites.


Association between obesity and venous thromboembolism.
Obesity is associated with numerous pathological conditions, including venous thromboembolism (VTE). VTE is a multifactorial disease; more than half of the hospitalized patients are at risk for VTE.We aimed to assess the risk of VTE associated with obesity, taking into account the class of obesity (according to the body mass index), gender, age and the intervention of other acquired risk factors. A case-control study including 732 patients was designed. Collected data included: age, gender, body mass index, pregnancy/postpartum state, use of hormonal therapy, personal and family history of VTE, smoking, prolonged immobilization and the presence of comorbidities - acquired risk factors for VTE. The risk of VTE was expressed as odds ratio (OR) with 95% confidence interval. Multiple logistic regression analysis was used to detect the independent risk factors. P value <0.05 was considered significant statistic. Obesity was associated with a 6.2-fold increased risk for VTE. The risk of VTE associated with obesity was highest in patients aged >50 years and in cases included in classes II and III of obesity. The interaction between obesity and another acquired risk factor has almost doubled the risk of VTE. Multivariate logistic regression analysis showed obesity as an independent risk factor for VTE for both female and male patients. Obesity is an independent and moderate risk factor for VTE. The risk increases with body mass index, age and the presence of other acquired risk factors.


Protection of perfused lung from oxidant injury by inhibitors of anion exchange.
Hyperoxic lung injury is enhanced in isolated perfused lungs (IPL) in the presence of L-arginine. Reactive O2 species such as superoxide anion (O2-.) produced during hyperoxia are known to react with nitric oxide to form the strong oxidant species peroxynitrite. The appearance of O2-. in red blood cell membranes in vitro and in buffer-perfused lung preparations can be inhibited by the stilbene compound 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) DIDS also inhibits anion exchange across the cell membrane regulated by a family of anion exchange proteins (AE). In this study, we hypothesized that anion exchange inhibitors would prevent lung injury from hyperoxia and L-arginine (O2 + L-Arg) by decreasing O2-. flux into the vascular space of the IPL. We found that both DIDS and a structurally distinct anion transport blocker, dipyridamole, protected the rabbit IPL from pulmonary hypertension and edema produced by O2 + L-Arg. The protective effect was associated with increased nitrite concentrations in the perfusate. Protection also was conferred when sodium bicarbonate in the perfusion buffer was replaced with either sodium thiosulfate or N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES). In lungs perfused with thiosulfate or HEPES-containing buffer, protection from O2 and L-arginine was also associated with diminished detection of reducing activity consistent with O2-. in the vascular space. Western blot analysis of lung protein and immunocytochemical staining of lung sections using antibodies against rabbit red blood cell AE1 and mouse gastric AE2 peptide showed that lung contains membrane protein antigenically similar to gastric AE2. These data suggest the possibility that inhibition of AE or other anion transporters may play an important role in mediating oxidative lung injury.


Developments and Challenges of Miniature Piezoelectric Robots: A Review.
Miniature robots have been widely studied and applied in the fields of search and rescue, reconnaissance, micromanipulation, and even the interior of the human body benefiting from their highlight features of small size, light weight, and agile movement. With the development of new smart materials, many functional actuating elements have been proposed to construct miniature robots. Compared with other actuating elements, piezoelectric actuating elements have the advantages of compact structure, high power density, fast response, high resolution, and no electromagnetic interference, which make them greatly suitable for actuating miniature robots, and capture the attentions and favor of numerous scholars. In this paper, a comprehensive review of recent developments in miniature piezoelectric robots (MPRs) is provided. The MPRs are classified and summarized in detail from three aspects of operating environment, structure of piezoelectric actuating element, and working principle. In addition, new manufacturing methods and piezoelectric materials in MPRs, as well as the application situations, are sorted out and outlined. Finally, the challenges and future trends of MPRs are evaluated and discussed. It is hoped that this review will be of great assistance for determining appropriate designs and guiding future developments of MPRs, and provide a destination board to the researchers interested in MPRs.


Why overestimate or underestimate chronic kidney disease when correct estimation is possible?
There is no doubt that the introduction of the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines 14 years ago, and their subsequent updates, have substantially contributed to the early detection of different stages of chronic kidney disease (CKD). Several recent studies from different parts of the world mention a CKD prevalence of 8-13%. However, some editorials and reviews have begun to describe the weaknesses of a substantial number of studies. Maremar (maladies rénales chroniques au Maroc) is a recently published prevalence study of CKD, hypertension, diabetes and obesity in a randomized, representative and high response rate (85%) sample of the adult population of Morocco that strictly applied the KDIGO guidelines. When adjusted to the actual adult population of Morocco (2015), a rather low prevalence of CKD (2.9%) was found. Several reasons for this low prevalence were identified; the tagine-like population pyramid of the Maremar population was a factor, but even more important were the confirmation of proteinuria found at first screening and the proof of chronicity of decreased estimated glomerular filtration rate (eGFR), eliminating false positive results. In addition, it was found that when an arbitrary single threshold of eGFR (<60 mL/min/1.73 m2) was used to classify CKD stages 3, 4 and 5, it lead to substantial 'overdiagnosis' (false positives) in the elderly (>55 years of age), particularly in those without proteinuria, haematuria or hypertension. It also resulted in a significant 'underdiagnosis' (false negatives) in younger individuals with an eGFR >60 mL/min/1.73 m2 and below the third percentile of their age-/gender-category. The use of the third percentile eGFR level as a cut-off, based on age-gender-specific reference values of eGFR, allows the detection of these false positives and negatives. There is an urgent need for additional quality studies of the prevalence of CKD using the recent KDIGO guidelines in the correct way, to avoid overestimation of the true disease state of CKD by ≥50% with potentially dramatic consequences.


Hypoxia ameliorates intestinal inflammation through NLRP3/mTOR downregulation and autophagy activation.
Hypoxia regulates autophagy and nucleotide-binding oligomerization domain receptor, pyrin domain containing (NLRP)3, two innate immune mechanisms linked by mutual regulation and associated to IBD. Here we show that hypoxia ameliorates inflammation during the development of colitis by modulating autophagy and mammalian target of rapamycin (mTOR)/NLRP3 pathway. Hypoxia significantly reduces tumor necrosis factor α, interleukin (IL)-6 and NLRP3 expression, and increases the turnover of the autophagy protein p62 in colon biopsies of Crohn's disease patients, and in samples from dextran sulfate sodium-treated mice and Il-10 -/- mice. In vitro, NF-κB signaling and NLRP3 expression are reduced through hypoxia-induced autophagy. We also identify NLRP3 as a novel binding partner of mTOR. Dimethyloxalylglycine-mediated hydroxylase inhibition ameliorates colitis in mice, downregulates NLRP3 and promotes autophagy. We suggest that hypoxia counteracts inflammation through the downregulation of the binding of mTOR and NLRP3 and activation of autophagy.Hypoxia and HIF-1α activation are protective in mouse models of colitis, and the latter regulates autophagy. Here Cosin-Roger et al. show that hypoxia ameliorates intestinal inflammation in Crohn's patients and murine colitis models by inhibiting mTOR/NLRP3 pathway and promoting autophagy.


Anoplasty with skin tag flap for the treatment of chronic anal fissure.
to evaluate the long-term results of the correction of chronic anal fissures (CAF) in patients without anal hypertonia using the technique of anoplasty with skin tag flap. we conducted a prospective study of CAF patients refractory to conservative treatment without anal hypertonia, subjected to anoplasty with the use of anal plicoma to cover the bloody area. We confirmed the absence of anal hypertonia through rectal exam and electromanometry. We applied a visual pain questionnaire and the Cleveland Clinic fecal incontinence score before and after surgery. we followed 15 patients with chronic anal fissure for a mean period of 29 months (12-56). The mean age was 41 years (29-69) and the duration of symptoms ranged from six months to five years. Healing occurred between three and six weeks for 13 patients (86.7%). The other two patients underwent debridement and new anoplasty successfully. No plicoma necrosis or anal stenosis occurred in any patient. The anal incontinence score did not change after the procedure, and all patients reported reduced pain. After 12 months of follow-up, none of the patients presented recurrence or anal incontinence, and 93.3% (14/15) of the patients were very satisfied. fissurectomy and anoplasty with the use of sentinel plie is a safe technique that results in improvement in pain without change of fecal continence and with high satisfaction rates.


THE GUILLAIN-BARRE DISEASE COMPLEX-An Analysis of the Disease with Therapeutic Suggestions and Report of 26 Cases.
The Guillain-Barré disease complex may result from a number of causes and have a wide variety of effects. The basic mechanism seems to be an immunizing or allergic reaction to many pathogens or their products, causing edema of the nerve roots in the spine, specifically about the meningeal covering. Resulting pressure on the axon causes nerve damage proportional to the severity and duration of pressure. Results in the 26 cases here reported and in other reports indicate that corticosteroids are the treatment of choice, the purpose being to reduce edema as promptly as possible. As might be expected, this therapy is of little value in the post-inflammatory stage of the disease, although prophylactic administration should continue for several months. Nerve and muscle rehabilitation are the chief aims of later treatment.


IL-1-induced post-transcriptional mechanisms target overlapping translational silencing and destabilizing elements in IκBζ mRNA.
The inflammatory cytokine IL-1 induces profound changes in gene expression. This is contributed in part by activating translation of a distinct set of mRNAs, including IκBζ, as indicated by genome-wide analysis of changes in ribosomal occupancy in IL-1α-treated HeLa cells. Polysome profiling of IκBζ mRNA and reporter mRNAs carrying its 3' UTR indicated poor translation in unstimulated cells. 3' UTR-mediated translational silencing was confirmed by suppression of luciferase activity. Translational silencing was unaffected by replacing the poly(A) tail with a histone stem-loop, but lost under conditions of cap-independent internal initiation. IL-1 treatment of the cells caused profound shifts of endogenous and reporter mRNAs to polysome fractions and relieved suppression of luciferase activity. IL-1 also inhibited rapid mRNA degradation. Both translational activation and mRNA stabilization involved IRAK1 and -2 but occurred independently of the p38 MAPK pathway, which is known to target certain other post-transcriptional mechanisms. The translational silencing RNA element contains the destabilizing element but requires additional 5' sequences and is impaired by mutations that leave destabilization unaffected. These differences in function are associated with differential changes in protein binding in vitro. Thus, rapid degradation occurs independently of the translational silencing effect. The results provide evidence for a novel mode of post-transcriptional control by IL-1, which impinges on the time course and pattern of IL-1-induced gene expression.


Point-of-care testing for hepatitis C virus infection at an Italian dental clinic: portrait of the pilot study population.
The dental clinic is an appropriate place to promote the prevention of hepatitis C virus (HCV) infection and fast access for care of HCV-positive subjects with new-generation anti-HCV drugs. This study aimed to determine the socio-demographic profile of subjects screened for HCV virus in a dental clinic to acquire useful information for future campaigns of prevention. An easy, free-of-charge, screen salivary test was offered to patients referred to the dental clinic of San Raffaele Scientific Research Hospital in Milan, Italy for dental procedures. These patients were also asked to complete an anonymous questionnaire on demographics and risk behaviours. A total of 1388 of 2097 (66.19%) questionnaires were evaluable. The demographics of the population responding to this initiative was primarily Italians citizen (96.47%), homogeneous gender distribution (55.55%), age over 50 (609 subjects; 43.88%), with high-level education and stable professional positions. 905 subjects (65.20%) were never tested for HCV before. The test showed positive reactivity in 22 cases (1.05%); of these, 21 subjects were known to be HCV-positive, and the test confirmed their status. One subject was newly diagnosed as HCV-positive. The percentage of subjects who were never tested for HCV infection appears too high (905 subjects, i.e., 65.20%), especially among subjects with high level of education and professions, and among adults over 40 or young people (18-25). The easy screening test in dental clinic can help raise awareness, promote early diagnosis and prevention, and provide a fast link to care for HCV infection.