The role of spatial frequency information in the decoding of facial expressions of pain: a novel hybrid task.
Spatial frequency (SF) information contributes to the recognition of facial expressions, including pain. Low-SF encodes facial configuration and structure and often dominates over high-SF information, which encodes fine details in facial features. This low-SF preference has not been investigated within the context of pain. In this study, we investigated whether perpetual preference differences exist for low-SF and high-SF pain information. A novel hybrid expression paradigm was used in which 2 different expressions, one containing low-SF information and the other high-SF information, were combined in a facial hybrid. Participants are instructed to identify the core expression contained within the hybrid, allowing for the measurement of SF information preference. Three experiments were conducted (46 participants in each) that varied the expressions within the hybrid faces: respectively pain-neutral, pain-fear, and pain-happiness. In order to measure the temporal aspects of image processing, each hybrid image was presented for 33, 67, 150, and 300 ms. As expected, identification of pain and other expressions was dominated by low-SF information across the 3 experiments. The low-SF preference was largest when the presentation of hybrid faces was brief and reduced as the presentation duration increased. A sex difference was also found in experiment 1. For women, the low-SF preference was dampened by high-SF pain information, when viewing low-SF neutral expressions. These results not only confirm the role that SF information has in the recognition of pain in facial expressions but suggests that in some situations, there may be sex differences in how pain is communicated.


Peplomycin. DNA breakage and in vivo inhibition of DNA polymerases and ligase from human normal and leukemic cells.
Peplomycin, a bleomycin-related cytostatic agent, was tested on DNA polymerases and DNA ligase. These enzymes were purified from normal human immunocompetent cells (thymocytes and lymphocytes) and from peripheral blast cells from different kinds of acute lymphoblastic and acute non-lymphoblastic leukemia. At low concentration ranges (1-25 microM) this compound was found to strongly inhibit polymerase alpha and ligase from leukemic cells while being less effective on the enzyme activity from normal thymocytes and lymphocytes. At the DNA level, low concentrations of peplomycin resulted in the induction of dose-dependent single-stranded breaks. The incubation of peplomycin (5 microM) with plasmid DNA resulted in its degradation as observed by agarose gel electrophoresis. Lowering the peplomycin concentration showed that ligase inhibition takes place prior to this phenomenon. The decreased formation of the ligase--adenylate complex under the effect of peplomycin is consistent with a direct interaction between the drug and the enzyme. These results are discussed in terms of possible selective cytostatic effects of peplomycin on leukemic cells.


Human-like mouse models for testing the efficacy and safety of anti-beta2-microglobulin monoclonal antibodies to treat myeloma.
We showed recently that anti-beta2-microglobulin (beta2M) monoclonal antibodies (mAb) have remarkably strong apoptotic effects on myeloma cells in vitro and in SCID-hu mice. However, whether the mAbs will be therapeutic and safe in the treatment of myeloma patients, in whom every tissue expresses low densities of MHC class I molecules and elevated levels of soluble beta2M are present, remains to be determined. In this study, human-like myeloma mouse models (HLA-A2-transgenic NOD/SCID mice) were developed, which express mature and functional human MHC class I (HLA-A2 and human beta2M) on murine organs and present high levels of circulating human beta2M derived from human myeloma cells. Myeloma-bearing mice were treated intraperitoneally with anti-beta2M mAbs, and the distribution and effects of the mAbs on normal organs and established tumors were examined. Our results show that anti-beta2M mAbs were effective in suppressing myeloma growth in treated mice. The therapeutic efficacy of the mAbs in these mice are comparable with those observed in myeloma-bearing nontransgenic NOD/SCID mice in which no human MHC class I is expressed on murine organs. Furthermore, although the mAbs can be detected on different organs, no tissue damage or cell apoptosis was observed in the mice. Based on the antimyeloma efficacy and low toxicity in the mice, our study suggests that anti-beta2M mAbs may be safe and the tissue-expressing and soluble beta2M may not compromise their therapeutic effects in myeloma patients. This study provides further support for the future application of the mAbs as therapeutic agents for multiple myeloma.


Improved methods for separation of human cytokeratins.
The cytokeratins from human bladder and esophageal epithelia were separated using chromatographic techniques. The cytokeratins were first extracted from fresh autopsy tissue using high and low salt buffers. Urea, 8.0-9.5 M, was used to solubilize the resulting cytokeratin pellet. Imidazole was found to increase the solubility of the pellet but reducing agents such as 2-mercaptoethanol were not beneficial. DEAE ion exchange chromatography produced three fractions which were analyzed by using one and two-dimensional electrophoresis. The third fraction was shown to contain the acidic cytokeratins and was further fractionated on a moderately polar reverse phase HPLC column using an acetonitrile elution gradient. Tetramethylammonium tetrafluoroborate was added to the mobile phase to react with any unreacted silanol groups on the stationary phase, and trifluoroacetic acid was added to ion pair with the protein. HPLC fractions of the acidic proteins from human esophagus revealed seven reproducible peaks. All seven peaks were shown by Western blotting to contain an epitope found on cytokeratin 13. The results suggest that the isolation and separation procedures have produced a series of peptide products which all retain a similar epitope but which vary significantly in their hydrophobic characteristics.


Peripheral Fragile X messenger ribonucleoprotein is required for the timely closure of a critical period for neuronal susceptibility in the ventral cochlear nucleus.
Alterations in neuronal plasticity and critical periods are common across neurodevelopmental diseases, including Fragile X syndrome (FXS), the leading single-gene cause of autism. Characterized with sensory dysfunction, FXS is the result of gene silencing of Fragile X messenger ribonucleoprotein 1 (FMR1) and loss of its product, Fragile X messenger ribonucleoprotein (FMRP). The mechanisms underlying altered critical period and sensory dysfunction in FXS are obscure. Here, we performed genetic and surgical deprivation of peripheral auditory inputs in wildtype and Fmr1 knockout (KO) mice across ages and investigated the effects of global FMRP loss on deafferentation-induced neuronal changes in the ventral cochlear nucleus (VCN) and auditory brainstem responses. The degree of neuronal cell loss during the critical period was unchanged in Fmr1 KO mice. However, the closure of the critical period was delayed. Importantly, this delay was temporally coincidental with reduced hearing sensitivity, implying an association with sensory inputs. Functional analyses further identified early-onset and long-lasting alterations in signal transmission from the spiral ganglion to the VCN, suggesting a peripheral site of FMRP action. Finally, we generated conditional Fmr1 KO (cKO) mice with selective deletion of FMRP in spiral ganglion but not VCN neurons. cKO mice recapitulated the delay in the VCN critical period closure in Fmr1 KO mice, confirming an involvement of cochlear FMRP in shaping the temporal features of neuronal critical periods in the brain. Together, these results identify a novel peripheral mechanism of neurodevelopmental pathogenesis.


Consensus recommendations for the standardized histopathological evaluation and reporting after radical oesophago-gastrectomy (HERO consensus).
Variation in the approach, radicality, and quality of gastroesophageal surgery impacts patient outcomes. Pathological outcomes such as lymph node yield are routinely used as surrogate markers of surgical quality, but are subject to significant variations in histopathological evaluation and reporting. A multi-society consensus group was convened to develop evidence-based recommendations for the standardized assessment of gastroesophageal cancer specimens. A consensus group comprised of surgeons, pathologists, and oncologists was convened on behalf of the Association of Upper Gastrointestinal Surgery of Great Britain & Ireland. Literature was reviewed for 17 key questions. Draft recommendations were voted upon via an anonymous Delphi process. Consensus was considered achieved where >70% of participants were in agreement. Consensus was achieved on 18 statements for all 17 questions. Twelve strong recommendations regarding preparation and assessment of lymph nodes, margins, and reporting methods were made. Importantly, there was 100% agreement that the all specimens should be reported using the Royal College of Pathologists Guidelines as the minimum acceptable dataset. In addition, two weak recommendations regarding method and duration of specimen fixation were made. Four topics lacked sufficient evidence and no recommendation was made. These consensus recommendations provide explicit guidance for gastroesophageal cancer specimen preparation and assessment, to provide maximum benefit for patient care and standardize reporting to allow benchmarking and improvement of surgical quality.


Re-examining the size/charge paradigm: differing in vivo characteristics of size- and charge-matched mesoporous silica nanoparticles.
The combination of nanoparticle (NP) size, charge, and surface chemistry (e.g., extent of modification with polyethylene glycol (PEG)) is accepted as a key determinant of NP/cellular interactions. However, the influence of spatial arrangement and accessibility of the charged molecules on the NP surface vis-à-vis the average surface charge (zeta (ζ) potential) is incompletely understood. Here we demonstrate that two types of mesoporous silica nanoparticles (MSNP) that are matched in terms of primary and hydrodynamic particle size, shape, pore structure, colloidal stability, and ζ potential, but differ in surface chemistry, viz. the spatial arrangement and relative exposure of surface amines, have profoundly different interactions with cells and tissues when evaluated in vitro and in vivo. While both particles are ∼50 nm in diameter, PEGylated, and positively charged (ζ = +40 mV), PEG-PEI (MSNPs modified with exposed polyamines), but not PEG-NMe3(+) (MSNP modified with distributed, obstructed amines) rapidly bind serum proteins, diverse cells types in vitro, and endothelial and white blood cells in vivo (ex ovo chick embryo model). This finding helps elucidate the relative role of surface exposure of charged molecules vs ζ potential in otherwise physicochemically matched MSNP and highlights protein corona neutrality as an important design consideration when synthesizing cationic NPs for biological applications.


Reduced Lean Body Mass and Cardiometabolic Diseases in Adult Males with Overweight and Obesity: A Pilot Study.
Little is known about the reduction in lean body mass (LBM) and its health consequences in overweight and in obesity, especially in males. Therefore, we aimed to assess the prevalence of low LBM in treatment-seeking adult males with overweight and obesity and the association with cardiometabolic diseases, i.e., type 2 diabetes, cardiovascular diseases and dyslipidemia. A body composition assessment was conducted by a bio-impedance analyzer (InBody 170) among a total of 110 males, of whom 72 were overweight and obese and were referred to the Outpatient Clinic in the Department of Nutrition and Dietetics at Beirut Arab University (BAU) in Lebanon, and 38 were normal-weight participants of similar ages. The participants with overweight and obesity were then categorized as being with or without low LBM. Of the sample of 72 participants, 50 (69.4%) met the criteria for reduced LBM and displayed a significantly higher prevalence of cardiometabolic diseases (i.e., type 2 diabetes, cardiovascular diseases and dyslipidemia) than those with normal LBM (36.0% vs. 9.1%; p = 0.019). Logistic regression analysis showed that low LBM increases the odds of having cardiometabolic diseases by nearly 550% (odds ratio (OR) = 5.46, 95% confidence interval (CI) = 1.31⁻26.39, p < 0.05) after adjusting for total fat and central adiposity. Treatment-seeking adult males with overweight and obesity displayed a great prevalence of reduced LBM, which seems to be strongly associated with cardiovascular and metabolic diseases.


The function neutralizing anti-TrkA antibody MNAC13 reduces inflammatory and neuropathic pain.
Nerve growth factor (NGF) is involved in pain transduction mechanisms and plays a key role in many persistent pain states, notably those associated with inflammation. On this basis, both the NGF ligand and its receptor TrkA (tyrosine kinase A) represent an eligible target for pain therapy. Although the direct involvement of NGF in pain modulation is well established, the effect of a direct functional block of the TrkA receptor is still unknown. In this study, we have demonstrated that MNAC13, the only anti-TrkA monoclonal antibody for which function neutralizing properties have been clearly shown both in vitro and in vivo, induces analgesia in both inflammatory and neuropathic pain models, with a surprisingly long-lasting effect in the latter. The formalin-evoked pain licking responses are significantly reduced by the MNAC13 antibody in CD1 mice. Remarkably, treatment with the anti-TrkA antibody also produces a significant antiallodynic effect on neuropathic pain: repeated i.p. injections of MNAC13 induce significant functional recovery in mice subjected to sciatic nerve ligation, with effects persisting after administration. Furthermore, a clear synergistic effect is observed when MNAC13 is administered in combination with opioids, at doses that are not efficacious per se. This study represents a direct demonstration that neutralizing antibodies directed against the TrkA receptor may display potent analgesic effects in inflammatory and chronic pain.


Successful Left-Heart Decompression during Extracorporeal Membrane Oxygenation in an Adult Patient by Percutaneous Transaortic Catheter Venting.
Venoarterial extracorporeal membrane oxygenation (VA ECMO) is widely used in patients with cardiogenic shock. Insufficient decompression of the left ventricle (LV) is considered a major factor preventing adequate LV recovery. A 40-year-old male was diagnosed with acute myocardial infarction, and revascularization was performed using percutaneous stenting. However, cardiogenic shock occurred, and VA ECMO was initiated. Severe LV failure developed, and percutaneous transaortic catheter venting (TACV) was incorporated into the venous circuit of VA ECMO under transthoracic echocardiography guidance. The patient was successfully weaned from VA ECMO. Percutaneous TACV is an effective, relatively noninvasive, and rapid method of LV decompression in patients undergoing VA ECMO.


[Tetracyclic derivatives of diltiazem from aurones and thioaurones].
Tetracyclic derivatives of diltiazem from aurones and thioaurones Heating the aurones 1a, b and the thioaurones 1c, d with 2-aminothiophenol in polyphosphoric acid (PPA) under nitrogen yields the 6,12-dihydrobenzofuro[2,3-c][1,5]benzothiazepines 3a,b and the sulfur analogues 3c, d, respectively. Reaction of the annulated benzofuranes 3a,b with 2-chloroethyl-N,N-dimethylammonium chloride and potassium carbonate leads to S-alkylation and ring opening forming the 3-imino-aurones 5. The tetracycles 3 react with sodium hydride in DMF under ring contraction to afford the benzofuro- and benzothieno[3,2-b]quinolines 6. The stability of the partially saturated tetracycles 3 is investigated by anodic oxidation using the rotating platinum electrode by means of differential pulse voltammetry. The measured half wave potentials of the 1,4-dihydropyridine partial structure in compounds 3 are compared with that of nifedipine.


[Thinking about health once again: programs and territories].
This article, of a conceptual nature, uses critical theory to discuss the programmatic logic within the sociosanitary field as a technical answer without any questions, provided to territories or spaces with questions awaiting translation. The purpose is to put programmatic logic, which is the legacy of public health planning and an expression of instrumental reason, into discussion, and in this way examine the temporal-spatial conception as an axis for thinking and acting within the complexity of the social world, recognizing other knowledge and practices. The questions, answers, knowledge and actions in the sociosanitary field constitute the focus of a reflection rooted in concepts that seek to deconstruct the ideological project represented by health programs through an analysis of their scientific basis (the epistemological component of the technical), which is antagonistic to any emancipatory project.


Decomposition of leaf litter in the Brazilian savanna on limestone and sandstone Neosols.
Litter decomposition in the soil is an important stage of the nutrient cycling process that interferes with functioning of terrestrial ecosystems. Soil fertility and litter nutritional quality are fundamental factors that affect decomposition efficiency of plant residues. We evaluated decomposition in two areas of 'cerrado sensu stricto', each with a type of Neosol - limestone (eutrophic) and sandstone (dystrophic). In a rural area located in the municipality of Ituiutaba (MG, Brazil), 10 plots were randomly selected to install litter bags with 10 g of mixture of dry leaves that were used to estimate rate and time of leaf-litter decomposition from October/2015 to January/2016. Decomposition rate in the limestone cerrado was significantly higher than in the sandstone cerrado. This difference mustn't be explained by the edaphic texture between areas, since it was similar between them. But may be explained through aluminum absence and higher soil fertility in the limestone cerrado, especially phosphorus that is highly limiting in dystrophic cerrados like the sandstone cerrados, in which decay of decomposing leaf-litter was directly proportional to the levels of phosphorus. Limestone presence reduces aluminum toxicity and circumvent phosphorus limitation in the cerrado, favoring decomposition. Such influence is probably an important feature for limestone cerrados.


Multiregional Radiogenomic Assessment of Prostate Microenvironments with Multiparametric MR Imaging and DNA Whole-Exome Sequencing of Prostate Glands with Adenocarcinoma.
Purpose To assess the underlying genomic variation of prostate gland microenvironments of patients with prostate adenocarcinoma in the context of colocalized multiparametric magnetic resonance (MR) imaging and histopathologic assessment of normal and abnormal regions by using whole-exome sequencing. Materials and Methods Six patients with prostate adenocarcinoma who underwent robotic prostatectomy with whole-mount preservation of the prostate were identified, which enabled spatial mapping between preoperative multiparametric MR imaging and the gland. Four regions of interest were identified within each gland, including regions found to be normal and abnormal via histopathologic analysis. Whole-exome DNA sequencing (>50 times coverage) was performed on each of these spatially targeted regions. Radiogenomic analysis of imaging and mutation data were performed with hierarchical clustering, phylogenetic analysis, and principal component analysis. Results Radiogenomic multiparametric MR imaging and whole-exome spatial characterization in six patients with prostate adenocarcinoma (three patients, Gleason score of 3 + 4; and three patients, Gleason score of 4 + 5) was performed across 23 spatially distinct regions. Hierarchical clustering separated histopathologic analysis-proven high-grade lesions from the normal regions, and this reflected concordance between multiparametric MR imaging and resultant histopathologic analysis in all patients. Seventy-seven mutations involving 29 cancer-associated genes across the 23 spatially distinct prostate samples were identified. There was no significant difference in mutation load in cancer-associated genes between regions that were proven to be normal via histopathologic analysis (34 mutations per sample ± 19), mildly suspicious via multiparametric MR imaging (37 mutations per sample ± 21), intermediately suspicious via multiparametric MR imaging (31 mutations per sample ± 15), and high-grade cancer (33 mutations per sample ± 18) (P = .30). Principal component analysis resolved samples from different patients and further classified samples (regardless of histopathologic status) from prostate glands with Gleason score 3 + 4 versus 4 + 5 samples. Conclusion Multiregion spatial multiparametric MR imaging and whole-exome radiogenomic analysis of prostate glands with adenocarcinoma shows a continuum of mutations across regions that were found via histologic analysis to be high grade and normal. © RSNA, 2017 Online supplemental material is available for this article.


Bronchopulmonary dysplasia: its effects upon the heart and lungs.
Bronchopulmonary dysplasia (BPD) is one of the most significant sequelae of prematurity, affecting the pulmonary and cardiovascular structures especially. From the first weeks of life, there exists a close anatomical and functional relationship between these two systems. Changes in intrathoracic pressure or pulmonary vascular resistance greatly impact both the left and right sides of the heart. In turn, increasing afterload and decreasing preload affect blood flow through the lung, as well as the state of oxygenation and ventilation. BPD affects the function, growth, and development of the heart and lung, due to the hypoxia, acidosis, hyperoxia, and fibrosis associated with the fibroproliferative repair process. Significance of clinical findings and the role of the bedside caregiver are also discussed.


Cochlear implants for mumps deafness: two paediatric cases.
Good outcomes have been reported regarding the use of cochlear implants for mumps deafness. The mumps virus induces meningitis and/or encephalitis, which can cause central nervous system damage resulting in retrolabyrinthine hearing loss, for which a cochlear implant would be less effective. We installed a cochlear implant in two patients with bilateral mumps deafness; one achieved a good result with the cochlear implant, but the other did not. We discuss two possible reasons for the different outcomes. Case 1 was a three-year-old girl with bilateral parotid swelling, vomiting and walking disorder. One year after cochlear implant insertion, speech perception did not develop despite of good pure tone thresholds. Case 2 was an eight-year-old girl with bilateral parotid swelling. A cochlear implant enabled her to improve hearing perception. Although cochlear implants have been reported to be helpful for mumps deafness, cases that involve central nervous system damage may not achieve good results.


Prevalence of Hearing Loss by Severity in the United States.
To estimate the age- and severity-specific prevalence of hearing impairment in the United States. We conducted cross-sectional analyses of 2001 through 2010 data from the National Health and Nutrition Examination Survey on 9648 individuals aged 12 years or older. Hearing loss was defined as mild (> 25 dB through 40 dB), moderate (> 40 dB through 60 dB), severe (> 60 dB through 80 dB), or profound (> 80 dB). An estimated 25.4 million, 10.7 million, 1.8 million, and 0.4 million US residents aged 12 years or older, respectively, have mild, moderate, severe, and profound better-ear hearing loss. Older individuals displayed a higher prevalence of hearing loss and more severe levels of loss. Across most ages, the prevalence was higher among Hispanic and non-Hispanic Whites than among non-Hispanic Blacks and was higher among men than women. Hearing loss directly affects 23% of Americans aged 12 years or older. The majority of these individuals have mild hearing loss; however, moderate loss is more prevalent than mild loss among individuals aged 80 years or older. Our estimates can inform national public health initiatives on hearing loss and help guide policy recommendations currently being discussed at the Institute of Medicine and the White House.


Risk and Protective Factors for Cigarette Use in Young Adolescents in a School Setting: What Could Be Done Better?
Smoking among Malaysian adolescents remains a public health concern despite concerted efforts in tobacco control. The aims of this study were to examine the prevalence and determinants of current-smoking status in young adolescents. This cross sectional study used the first round of the Malaysian Health and Adolescents Research Team's prospective cohort study. It was conducted in three States of the Central and Northern regions of Peninsular Malaysia between March and May 2012. The study used the multistage stratified sampling design. A total of 1,342 adolescents of both sexes, aged 12-13 years, were sampled from randomly selected urban and rural national schools. Information on current smoking status and associated factors were collected by a self-administered, pre-tested, validated, structured questionnaire. Seven percent of the samples were current-smokers; the majority (62%) of them started smoking at the age of 11 years or below. The prevalence of current smoking was significantly higher in males (odds ratio [OR] = 2.37; 95% CI: 1.46, 3.84), those who were influenced by smoker friends (OR = 8.35; 95% CI: 4.90, 14.25), who were unaware of the health risks of smoking (OR =1.85; 95% CI: 1.02, 3.36) and who reported a lack of satisfaction about their overall life (OR =3.26; 95% CI: 1.73, 6.12). The study findings provide valuable information to strengthen the existing school-based smoking prevention program through integration of social competence and social influence curricula. The program should empower the young adolescents to refuse tobacco offers, to overcome social influences and to resist peer pressure to avoid starting smoking. Particular focuses to include mental health service to prevent both emotional and behavioural problems are needed.


Risk of falls and major bleeds in patients on oral anticoagulation therapy.
The risk of falls is the most commonly cited reason for not providing oral anticoagulation, although the risk of bleeding associated with falls on oral anticoagulants is still debated. We aimed to evaluate whether patients on oral anticoagulation with high falls risk have an increased risk of major bleeding. We prospectively studied consecutive adult medical patients who were discharged on oral anticoagulants. The outcome was the time to a first major bleed within a 12-month follow-up period adjusted for age, sex, alcohol abuse, number of drugs, concomitant treatment with antiplatelet agents, and history of stroke or transient ischemic attack. Among the 515 enrolled patients, 35 patients had a first major bleed during follow-up (incidence rate: 7.5 per 100 patient-years). Overall, 308 patients (59.8%) were at high risk of falls, and these patients had a nonsignificantly higher crude incidence rate of major bleeding than patients at low risk of falls (8.0 vs 6.8 per 100 patient-years, P=.64). In multivariate analysis, a high falls risk was not statistically significantly associated with the risk of a major bleed (hazard ratio 1.09; 95% confidence interval, 0.54-2.21). Overall, only 3 major bleeds occurred directly after a fall (incidence rate: 0.6 per 100 patient-years). In this prospective cohort, patients on oral anticoagulants at high risk of falls did not have a significantly increased risk of major bleeds. These findings suggest that being at risk of falls is not a valid reason to avoid oral anticoagulants in medical patients.


Physical and other non-pharmacological interventions for fibromyalgia.
There is little empirical evidence for the effectiveness of physical and other non-pharmacological approaches to the management of fibromyalgia. Although a number of studies have been conducted into such approaches, many of these are uncontrolled, and relatively few randomized controlled trials of appropriate size and methodological rigour have been carried out. This chapter provides an overview of the evidence available under the following headings: exercise, EMG biofeedback training, electrotherapy and acupuncture, patient education and self-management programmes, multimodal treatment approaches, and other interventions. It is hard to reach firm conclusions from the literature, owing to the variety of interventions that have been evaluated and the varying methodological quality of the studies concerned. Nonetheless, in terms of specific interventions, exercise therapy has received a moderate degree of support from the literature, and has been subjected to more randomized studies than any other intervention. In contrast, there is little or no evidence available for most types of electrotherapy. In terms of overall management strategies, a multimodal programme of management, including physical, psychological and educational components and delivered in a multidisciplinary setting, has gained some support from descriptive and experimental studies, and accords with current understanding of the aetiology and clinical features of fibromyalgia. There is a clear need for further systematic evaluation of the effectiveness of non-pharmacological treatment approaches in fibromyalgia.


Synergistic inhibition of enterovirus 71 replication by interferon and rupintrivir.
Enterovirus 71 (EV71) can cause severe diseases and even lead to death in children. There is no vaccine or specific antiviral therapy to prevent or cure EV71 infection. Although interferon (IFN)-α has been used in the treatment of several viral infections, we found that IFN-α alone was ineffective in restricting EV71 replication in Vero cells. Through a bioinformatics analysis, several cellular proteins in the IFN response pathway were identified as susceptible substrates that might be degraded by the EV71-encoded 3C protease (3C(pro)). Indeed, IRF9 was shown to be vulnerable to 3C(pro) cleavage, as revealed by enzyme-based and cell-based assays. Thus, the IFN-mediated antiviral mechanism compromised by the viral 3C(pro) in EV71-infected cells may be accountable, at least partially, for that IFN-α cannot inhibit EV71 replication. Because rupintrivir (AG7088) is known to be an effective EV71 inhibitor, we investigated the effects of the combination of rupintrivir and IFN-α on EV71 replication and found that they strongly synergized with each other in inhibiting EV71 replication. Because rupintrivir was shown to be generally tolerable in earlier clinical investigations, it is worth evaluating whether a combination of rupintrivir and IFN-α could be an effective treatment for EV71.


Is efficiency of suppressor tRNAs controlled at the level of ribosomal proofreading in vivo?
Ribosomal rpsD mutations did not stimulate nonsense suppressor tRNAs in a general manner according to their increased ribosomal ambiguity and decreased proofreading efficiency. Streptomycin, which stimulates error production by blocking proofreading in vitro, did not increase efficiency of suppressor tRNAs in strains with normal or streptomycin-resistant (rpsL) ribosomes. It did so only in combination with one rpsL mutation which is associated with streptomycin pseudodependence.


Brain changes associated with postural training in patients with cerebellar degeneration: a voxel-based morphometry study.
Recent research indicates that physiotherapy can improve motor performance of patients with cerebellar degeneration. Given the known contributions of the cerebellum to motor learning, it remains unclear whether such observable changes in performance are mediated by the cerebellum or cerebral brain areas involved in motor control and learning. The current study addressed this question by assessing the increase in gray matter volume due to sensorimotor training in cerebellar patients using voxel-based morphometry. Nineteen human subjects with pure cerebellar degeneration and matched healthy controls were trained for 2 weeks on a balance task. Postural and clinical assessments along with structural magnetic resonance imaging were performed pretraining and post-training. The main findings were as follows. First, training enhanced balance performance in cerebellar patients. Second, in contrast to controls patients revealed significantly more post-training gray matter volume in the dorsal premotor cortex. Third, training-related increase in gray matter volume was observed within the cerebellum and was more pronounced in controls than in patients. However, statistically cerebellar changes were at the trend level and thus require additional, independent confirmation. We conclude that sensorimotor training of patients with cerebellar neurodegeneration induces gray matter changes primarily within nonaffected neocortical regions of the cerebellar-cortical loop. Residual function of the cerebellum appears to be exploited suggesting either a recovery from degeneration or intact processes of cerebellar plasticity in the remaining healthy tissue.


Advances in Oncologic Shoulder Girdle Resection and Reconstruction.
The bony shoulder girdle consists of the clavicle, humerus, and scapula, which work synergistically to form a complex articulation that is essential for use of the upper extremity. The shoulder girdle is the most common location for primary and secondary bone tumors in the upper extremity, and following resection of these tumors, reconstruction of the upper extremity is challenging. Compared with those in the lower extremity, reconstructive techniques in the upper extremity have historically been unreliable and fraught with complications and poor functional outcomes. Newer reconstructive techniques using reverse total shoulder arthroplasty and functional muscle flaps have shown promise to improve outcomes while reducing complications for proximal humerus reconstructions. Despite these advancements, reconstruction following scapulectomy remains challenging and is still associated with more frequent complications and compromised function.


The trauma team--a system of initial trauma care.
Trauma remains the leading cause of death under the age of 35 years. England and Wales lost 252,000 working years from accidental deaths, including poison, in 1992. In this country, preventable deaths from trauma are inappropriately high. In many hospitals there are not enough personnel; in the majority, there are no recognisable trauma care systems, which can reduce preventable deaths to a minimum. The appropriateness of trauma centres for this country is being assessed in Stoke-on-Trent, and a report is due out later this year. Even if the recommendation is made to establish such centres, it is unlikely that many will be set up. Consequently most hospitals will have to rely on their own resources to set up and run a trauma team. This type of trauma care system is the subject of this article.


[Activity of main enzymes of ammonium assimilation in Bradyrhizobium japonicum under the influence of plant flavonoid inductors].
The activity of key enzymes of ammonium assimilation in cell-free extracts of soybean rhizobia characterized with different effectiveness in symbiosis, has been researched. It has been found out that at highly efficient strain Bradyrhizobium japonicum UKM B-6035 the most active links in the system of ammonium assimilation reactions are glutamate synthase (glutamate-oxoglutarate-aminotransferase, GOGAT) and glutamate dehydrogenase (GDH). Whereas the most active links at the ineffective strain B. japonicum 21110 are glutamine synthetase (GS) and GDH. Under the influence of specific for soybean-rhizobia symbiosis flavonoid genistein (0.01 nm) GS-activity of the highly efficient strain has considerably increased (60.9 times), and this activity has exceeded the one of the ineffective strain more than twice. GDH has been activated in the presence of genistein in both researched strains. The nonspecific flavonoid naringenin has not stimulated GS-activity of the highly efficient rhizobia, but has stimulated the activity of GDH-way.


Cooling for newborns with hypoxic ischaemic encephalopathy.
Newborn animal and human pilot studies suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae, without adverse effects. To determine whether therapeutic hypothermia in encephalopathic asphyxiated newborn infants reduces mortality and long-term neurodevelopmental disability, without clinically important side effects. The standard search strategy of the Neonatal Review Group as outlined in the Cochrane Library (Issue 2, 2003) was used. Randomised controlled trials evaluating therapeutic hypothermia in term newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue Issue 2, 2003), MEDLINE (1966 to July 2003), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal hand searching. Randomised controlled trials comparing the use of therapeutic hypothermia with normothermia in encephalopathic newborn infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies were included. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome. Three reviewers independently selected, assessed the quality of and extracted data from the included studies. Authors were contacted for further information. Meta-analyses were performed using relative risk and risk difference for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals. Two randomised controlled trials were included in this review, comprising 50 term infants with moderate/ severe encephalopathy and evidence of intrapartum asphyxia. There was no significant effect of therapeutic hypothermia on the combined outcome of death or major neurodevelopmental disability in survivors followed. No adverse effects of hypothermia on short term medical outcomes or on some 'early' indicators of neurodevelopmental outcome were detected. Although two small randomised controlled trials demonstrated neither evidence of benefit or harm, current evidence is inadequate to assess either safety or efficacy of therapeutic hypothermia in newborn infants with hypoxic ischaemic encephalopathy. Therapeutic hypothermia for encephalopathic asphyxiated newborn infants should be further evaluated in well designed randomised controlled trials.


Preventing Type 2 diabetes and the dysmetabolic syndrome in the real world: a realistic view.
The last two decades have seen an explosive increase in the number of people with diabetes globally. There is now an urgent need for strategies to prevent the emerging global epidemic. Several recent successful intervention studies, both lifestyle and pharmacological, targeting subjects with impaired glucose tolerance (IGT) have stimulated enthusiasm for prevention of Type 2 diabetes. Lifestyle interventions reduced the incidence of diabetes by over 50% in the Finnish Diabetes Prevention Study and the Diabetes Prevention Program. Can the findings of these two studies be applied globally? Underpinning the enthusiasm, there needs to be a realistic approach to interventions in both developed and developing nations, and in ethnic groups where a better understanding of the socio-economic, cultural and demographic issues and perceptions surrounding chronic diseases such as diabetes is required. Whether the strategies used in these two studies can be translated into a 'real world' scenario is doubtful. In practice, it is more than likely that a number of strategies will be needed to compliment the lifestyle approach. These will include pharmacological approaches with metformin, acarbose and other agents used to treat diabetes and its complications, currently under investigation. Longer-term follow-up studies will also clarify whether both lifestyle and pharmacological interventions actually prevent Type 2 diabetes, or merely delay its onset.


Factors related to attrition from VA healthcare use: findings from the National Survey of Women Veterans.
While prior research characterizes women Veterans' barriers to accessing and using Veterans Health Administration (VA) care, there has been little attention to women who access VA and use services, but then discontinue use. Recent data suggest that among women Veterans, there is a 30 % attrition rate within 3 years of initial VA use. To compare individual characteristics and perceptions about VA care between women Veteran VA attriters (those who discontinue use) and non-attriters (those who continue use), and to compare recent versus remote attriters. Cross-sectional, population-based 2008-2009 national telephone survey. Six hundred twenty-six attriters and 2,065 non-attriters who responded to the National Survey of Women Veterans. Population weighted demographic, military and health characteristics; perceptions about VA healthcare; length of time since last VA use; among attriters, reasons for no longer using VA care. Fifty-four percent of the weighted VA ever user population reported that they no longer use VA. Forty-five percent of attrition was within the past ten years. Attriters had better overall health (p = 0.007), higher income (p < 0.001), and were more likely to have health insurance (p < 0.001) compared with non-attriters. Attriters had less positive perceptions of VA than non-attriters, with attriters having lower ratings of VA quality and of gender-specific features of VA care (p < 0.001). Women Veterans who discontinued VA use since 2001 did not differ from those with more remote VA use on most measures of VA perceptions. Overall, among attriters, distance to VA sites of care and having alternate insurance coverage were the most common reasons for discontinuing VA use. We found high VA attrition despite recent advances in VA care for women Veterans. Women's attrition from VA could reduce the critical mass of women Veterans in VA and affect current system-wide efforts to provide high-quality care for women Veterans. An understanding of reasons for attrition can inform organizational efforts to re-engage women who have attrited, to retain current users, and potentially to attract new VA patients.


In a study of a population cohort in South Africa, HIV patients on antiretrovirals had nearly full recovery of employment.
Antiretroviral therapy for HIV may have important economic benefits for patients and their households. We quantified the impact of HIV treatment on employment status among HIV patients in rural South Africa who were enrolled in a public-sector HIV treatment program supported by the President's Emergency Plan for AIDS Relief. We linked clinical data from more than 2,000 patients in the treatment program with ten years of longitudinal socioeconomic data from a complete community-based population cohort of more than 30,000 adults residing in the clinical catchment area. We estimated the employment effects of HIV treatment in fixed-effects regressions. Four years after the initiation of antiretroviral therapy, employment among HIV patients had recovered to about 90 percent of baseline rates observed in the same patients three to five years before they started treatment. Many patients initiated treatment early enough that they were able to avoid any loss of employment due to HIV. These results represent the first estimates of employment recovery among HIV patients in a general population, relative to the employment levels that these patients had prior to job-threatening HIV illness and the decision to seek care. There are large economic benefits to HIV treatment. For some patients, further gains could be obtained from initiating antiretroviral therapy earlier, prior to HIV-related job loss.


A population-based dietary inflammatory index predicts levels of C-reactive protein in the Seasonal Variation of Blood Cholesterol Study (SEASONS).
To perform construct validation of the population-based Dietary Inflammatory Index (DII) using dietary data from two different dietary assessments and serum high-sensitivity C-reactive protein (hs-CRP) as the construct validator. Using data derived from (i) three 24 h dietary recalls (24HR) at baseline and at the end of each subsequent quarter (i.e. up to fifteen over a year) and (ii) a 7 d dietary recall (7DDR) measured at baseline and then quarterly, regression analyses were conducted to test the effect of the DII score on serum hs-CRP as dichotomous (≤3 mg/l, >3 mg/l), while controlling for important potential confounders. Existing data from the Seasonal Variation of Blood Cholesterol Study (SEASONS), a longitudinal observational study of healthy participants recruited in Worcester, MA, USA and participants were followed for 1 year. Participants who had at least one hs-CRP measurement over her/his 1-year participation (n 495 for 24HR, n 559 for 7DDR). Higher DII scores were associated with values of hs-CRP >3 mg/l (OR = 1·08; 95 % CI 1·01, 1·16, P = 0·035 for the 24HR; and OR = 1·10; 95 % CI 1·02, 1·19, P = 0·015 for the 7DDR). The population-based DII was associated with interval changes in hs-CRP using both the 24HR and 7DDR. The success of this first-of-a-kind attempt at relating individuals' intakes of inflammation-modulating foods using this refined DII, and the finding that there is virtually no drop-off in predictive capability using a structured questionnaire in comparison to the 24HR standard, sets the stage for use of the DII in a wide variety of other epidemiological and clinical studies.


Developmental origin of polycystic ovary syndrome - a hypothesis.
Polycystic ovary syndrome (PCOS) is a common but complex endocrine disorder and is a major cause of anovulation and consequent subfertility. It is also associated with a metabolic disturbance, characterized by hyperinsulinaemia and insulin resistance that carries an increased risk of type 2 diabetes in later life. Despite its prevalence little is known about its aetiology, but there is increasing evidence for an important genetic involvement. On the basis of experimental observations in the prenatally androgenized sheep and rhesus monkey, and supported by data from human studies, we propose that the clinical and biochemical features of PCOS can arise as a consequence of genetically determined hypersecretion of androgens by the ovary during, or very likely long before, puberty. The resulting hyperandrogenism results in 'programming' of the hypothalamic-pituitary unit to favour excess LH secretion, and encourages preferential abdominal adiposity that predisposes to insulin resistance. The severity of hyperinsulinaemia and insulin resistance (which has a profound influence on the phenotype of PCOS) is further influenced by both genetic factors (such as polymorphism in the insulin gene regulatory region) and environmental factors, notably obesity. This hypothesis therefore suggests a unifying, 'linear' model to explain the aetiology of the heterogeneous phenotype.


Hypoxic mitochondria: accomplices in resistance.
Mitochondria originated from a distant ancestor: the α-proteobacteria. They evolved over millions of years in a symbiotic relationship in eukaryotic cells by favoring consumption of oxygen by the electron transport chain with production of ATP. Contemporary mitochondria still play a crucial role in providing energy but also in apoptosis. Because of this symbiotic relationship and their pivotal function, mitochondria undoubtedly participate in tumorigenesis. Genetic defects in mitochondrial DNA, blockade of oxidative phosphorylation and mitophagy in tumor cells modify the production of damaging reactive oxygen species and restrain apoptosis. As the environment of tumor cells becomes more and more hypoxic, the hypoxia-inducible factor (HIF) is stabilized and participates in the reprogramming of cell metabolism. Recently, we became interested in asking whether HIF and hypoxia affect mitochondrial function. In this review, we show that hypoxia induces enlargement of mitochondria, due to abnormal fusion, which results in resistance to apoptosis and thus in survival. The role of hypoxia-induced BNIP3 and BNIP3L, proteins recently described as pro-survival proteins, in survival is also discussed.


Urinary polyamines for evaluating the course of disease for patients with small cell carcinoma of the lung.
Clinical correlates with urinary excretion of polyamines were evaluated for 29 newly diagnosed and 35 previously treated patients with small cell carcinoma of the lung (SCC). The frequencies of pretreatment abnormalities were 12 (41%) for putrescine, 18 (62%) for spermidine, and 20 (69%) for spermine. In assessing disease parameters, the combined use of the abnormalities of spermidine and spermine as a discriminant was more effective than that of all three polyamines; it correlated significantly with extent of limited and extensive disease (P less than 0.001), and also resulted in significant separation of survival curves, the median survival of 11 months for both elevated compared to 19 months for neither or only one elevated (P = 0.062). No significant difference was seen in the abnormalities between no metastasis and one metastasis, whereas the frequencies of the abnormalities was highly increased in two or more metastases. The distribution of polyamines determined at regular treatment intervals showed distinctively more elevated patterns in progressive disease than in stable disease or partial and complete responses (P less than 0.01). In order to evaluate therapeutic effects on the relationship between polyamine excretion and tumor regression, correlations between urinary putrescine and spermidine were determined. The values of the ratio of spermidine to putrescine were significantly smaller in responders than in nonresponders (P less than 0.01); and these may be related to smaller tumor mass and higher tumor proliferative activity in responders, and larger tumor mass and lower tumor proliferative activity in nonresponders.


New strategies for paying retiree health care costs.
Adequately funding the costs of retiree health care--both by individuals and employers--is essential to the nation's financial stability. But health reform bills, including the one proposed by the Clinton Administration, would fund these costs out of current revenue, creating an enormous future taxpayer liability. No matter what reform plan Congress passes, lawmakers should offer savings plans that encourage Americans to fund these benefits while they're working.


Procedures for RIA I-125 waste disposal.
I-125 can be effectively removed from coated tubes and plastic beads used as solid-phase separators by a 50% household bleach solution. This technique enables the user to dispose of these separators into common trash.


Specification of cell fate in the developing eye of Drosophila.
Determination of cell fate in the developing eye of Drosophila depends on cellular interactions. In the eye imaginal disc, an initially unpatterned epithelial sheath of cells, single cells are specified in regular intervals to become the R8 photoreceptor cells. Genes such as Notch and scabrous participate in this process suggesting that specification of ommatidial founder cells and the formation of bristles in the adult epidermis involve a similar mechanism known as lateral inhibition. The subsequent steps of ommatidial assembly involve a different mechanism: undetermined cells read their position based on the contacts they make with neighbors that have already begun to differentiate. The development of the R7 photoreceptor cell is best understood. The key role seems to be played by sevenless, a receptor tyrosine kinase on the surface of the R7 precursor. It transmits the positional information--most likely encoded by boss on the neighboring R8 cell membrane--into the cell via its tyrosine kinase that activates a signal transduction cascade. Two components of this cascade--Sos and sina--have been identified genetically. sina encodes a nuclear protein whose expression is not limited to R7. Constitutive activation of the sevenless kinase by overexpression results in the diversion of other ommatidial cells into the R7 pathway, suggesting that activation of the sevenless signalling pathway is sufficient to specify R7 development.


Deoxyhypusine synthase activity is essential for cell viability in the yeast Saccharomyces cerevisiae.
Deoxyhypusine synthase catalyzes the first step in the posttranslational synthesis of an unusual amino acid, hypusine (N epsilon-(4-amino-2-hydroxybutyl)lysine), in the eukaryotic translation initiation factor 5A (eIF-5A) precursor protein. The null mutation in the single copy gene, yDHS, encoding deoxyhypusine synthase results in the loss of viability in the yeast Saccharomyces cerevisiae. Upon depletion of deoxyhypusine synthase, and consequently of eIF-5A, cessation of growth was accompanied by a marked enlargement of cells, suggesting a defect in cell cycle progression or in cell division. Two residues of the yeast enzyme, Lys308 and Lys350, corresponding to Lys287 and Lys329, respectively, known to be critical for the activity of the human enzyme, were targeted for site-directed mutagenesis. The chromosomal ydhs null mutation was complemented by the plasmid-borne yDHS wild-type gene, but not by mutated genes encoding inactive proteins, including that with Lys350-->Arg substitution or with substitutions at both Lys308 and Lys350. The mutated gene ydhs (K308R) encoding a protein with diminished activities (< 1% of wild type) could support growth but only to a very limited extent. These findings provide strong evidence that the hypusine modification is indeed essential for the survival of S. cerevisiae and imply a vital function for eIF-5A in all eukaryotes.


The glabra1 mutation affects cuticle formation and plant responses to microbes.
Systemic acquired resistance (SAR) is a form of defense that provides resistance against a broad spectrum of pathogens in plants. Previous work indicates a role for plastidial glycerolipid biosynthesis in SAR. Specifically, mutations in FATTY ACID DESATURASE7 (FAD7), which lead to reduced trienoic fatty acid levels and compromised plastidial lipid biosynthesis, have been associated with defective SAR. We show that the defective SAR in Arabidopsis (Arabidopsis thaliana) fad7-1 plants is not associated with a mutation in FAD7 but rather with a second-site mutation in GLABRA1 (GL1), a gene well known for its role in trichome formation. The compromised SAR in gl1 plants is associated with impairment in their cuticles. Furthermore, mutations in two other components of trichome development, GL3 and TRANSPARENT TESTA GLABRA1, also impaired cuticle development and SAR. This suggests an overlap in the biochemical pathways leading to cuticle and trichome development. Interestingly, exogenous application of gibberellic acid (GA) not only enhanced SAR in wild-type plants but also restored SAR in gl1 plants. In contrast to GA, the defense phytohoromes salicylic acid and jasmonic acid were unable to restore SAR in gl1 plants. GA application increased levels of cuticular components but not trichome formation on gl1 plants, thus implicating cuticle, but not trichomes, as an important component of SAR. Our findings question the prudence of using mutant backgrounds for genetic screens and underscore a need to reevaluate phenotypes previously studied in the gl1 background.


Endoscopic retrieval of an accidentally ingested bur during a dental procedure: a case report.
Accidental ingestion of a dental bur during the dental procedure is a rare, but a potentially serious complication. Early recognition and foreign body retrieval is essential to prevent adverse patient outcomes. A 76-year old male patient, presented to the department with a chief complaint of sensitivity in his upper right back tooth due to attrition. After assessing the pulp status, root canal therapy was planned for the tooth. During the procedure, it was noticed that the dental bur slipped out of the hand piece and the patient had accidentally ingested it. The patient was conscious and had no trouble while breathing at the time of ingestion of the bur although he had mild cough which lasted for a short duration. The dental procedure was aborted immediately and the patient was taken to the hospital for emergency care. The presence and location of the dental bur was confirmed using chest and abdominal x-rays and it was subsequently retrieved by esophagogastroduodenoscopy (EGD) procedure under general anaesthesia on the same day as a part of the emergency procedure. The analysis of this case reaffirms the importance of the use of physical barriers such as rubber dams and gauze screens as precautionary measures to prevent such incidents from occurring. Ingestion of instruments are uncertain and hazardous complications to encounter during a dental procedure. The need for physical barrier like rubber dam is mandatory for all dental procedures. However, the dentist should be well trained to handle such medical emergencies and reassure the patient by taking them into confidence. Each incident encountered should be thoroughly documented to supply adequate guidance for treatment aspects. This would fulfil the professional responsibilities of the dentist/ clinician and may help avoid possible legal and ethical issues. This case report emphasizes on the need for the usage of physical barriers during dental procedures in order to avoid medical emergencies.


Ventilation in patients with intra-abdominal hypertension: what every critical care physician needs to know.
The incidence of intra-abdominal hypertension (IAH) is high and still underappreciated by critical care physicians throughout the world. One in four to one in three patients will have IAH on admission, while one out of two will develop IAH within the first week of Intensive Care Unit stay. IAH is associated with high morbidity and mortality. Although considerable progress has been made over the past decades, some important questions remain regarding the optimal ventilation management in patients with IAH. An important first step is to measure intra-abdominal pressure (IAP). If IAH (IAP > 12 mmHg) is present, medical therapies should be initiated to reduce IAP as small reductions in intra-abdominal volume can significantly reduce IAP and airway pressures. Protective lung ventilation with low tidal volumes in patients with respiratory failure and IAH is important. Abdominal-thoracic pressure transmission is around 50%. In patients with IAH, higher positive end-expiratory pressure (PEEP) levels are often required to avoid alveolar collapse but the optimal PEEP in these patients is still unknown. During recruitment manoeuvres, higher opening pressures may be required while closely monitoring oxygenation and the haemodynamic response. During lung-protective ventilation, whilst keeping driving pressures within safe limits, higher plateau pressures than normally considered might be acceptable. Monitoring of the respiratory function and adapting the ventilatory settings during anaesthesia and critical care are of great importance. This review will focus on how to deal with the respiratory derangements in critically ill patients with IAH.


CFTR Cl- channel function in native human colon correlates with the genotype and phenotype in cystic fibrosis.
Cystic fibrosis (CF) is caused by over 1000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and presents with a widely variable phenotype. Genotype-phenotype studies identified CFTR mutations that were associated with pancreatic sufficiency (PS). Residual Cl- channel function was shown for selected PS mutations in heterologous cells. However, the functional consequences of most CFTR mutations in native epithelia are not well established. To elucidate the relationships between epithelial CFTR function, CFTR genotype, and patient phenotype, we measured cyclic adenosine monophosphate (cAMP)-mediated Cl- secretion in rectal biopsy specimens from 45 CF patients who had at least 1 non-DeltaF508 mutation carrying a wide spectrum of CFTR mutations. We compared CFTR genotypes and clinical manifestations of CF patients who expressed residual CFTR-mediated Cl- secretion with patients in whom Cl- secretion was absent. Residual anion secretion was detected in 40% of CF patients, and was associated with later disease onset (P < 0.0001), higher frequency of PS (P < 0.0001), and less severe lung disease (P < 0.05). Clinical outcomes correlated with the magnitude of residual CFTR activity, which was in the range of approximately 12%-54% of controls. Specific CFTR mutations confer residual CFTR function to rectal epithelia, which is related closely to a mild disease phenotype. Quantification of rectal CFTR-mediated Cl- secretion may be a sensitive test to predict the prognosis of CF disease and identify CF patients who would benefit from therapeutic strategies that would increase residual CFTR activity.


Arterial stiffness and arteriovenous fistula failure of maturation.
Increased arterial stiffness is a common finding in patients with end-stage renal disease. Following creation of an arteriovenous fistula (AVF), appropriate dilation of the feeding artery must occur to facilitate AVF maturation. Arterial stiffness may impair the arterial dilation required to facilitate AVF development and contribute to subsequent failure to mature (FTM). The aim of this pilot study was to investigate the association between measurements of central and peripheral arterial stiffness, and AVF FTM. Patients undergoing AVF creation in a single centre (Belfast City Hospital, UK) between January and December 2015 were invited to have their carotid-femoral pulse wave velocity (PWV), brachial-radial PWV and augmentation index (AI) measured prior to AVF creation. Subsequent AVF outcomes were identified. Fifty-nine patients who had an AVF procedure were included in the final analysis (mean age 62 years); 50.8% had diabetes mellitus. The mean pre-operative arterial diameter for all AVFs was 3.9 mm. Average values for carotid-femoral PWV were 9.5 m/s, brachial-radial PWV 7.7 m/s and AI 25.6%. Using logistic regression, these arterial stiffness parameters did not predict AVF FTM: carotid-femoral PWV (P = 0.20), brachial-radial PWV (P = 0.13), AI (P = 0.50). This is the largest study to date exploring the association between arterial stiffness and AVF FTM. The measured central and peripheral arterial stiffness parameters were not associated with AVF FTM. Further research is needed to define if non-invasive arterial physiological measurements would be clinically useful in the prediction of AVF FTM.


The Geomycology of Elemental Cycling and Transformations in the Environment.
Geomicrobiology addresses the roles of microorganisms in geological and geochemical processes, and geomycology is a part of this topic focusing on the fungi. Geoactive roles of fungi include organic and inorganic transformations important in nutrient and element cycling, rock and mineral bioweathering, mycogenic biomineral formation, and metal-fungal interactions. Lichens and mycorrhizas are significant geoactive agents. Organic matter decomposition is important for cycling of major biomass-associated elements, e.g., C, H, N, O, P, and S, as well as all other elements found in lower concentrations. Transformations of metals and minerals are central to geomicrobiology, and fungi affect changes in metal speciation, as well as mediate mineral formation or dissolution. Such mechanisms are components of biogeochemical cycles for metals as well as associated elements in biomass, soil, rocks, and minerals, e.g., S, P, and metalloids. Fungi may have the greatest geochemical influence within the terrestrial environment. However, they are also important in the aquatic environment and are significant components of the deep subsurface, extreme environments, and habitats polluted by xenobiotics, metals, and radionuclides. Applications of geomycology include metal and radionuclide bioleaching, biorecovery, detoxification, bioremediation, and the production of biominerals or metal(loid) elements with catalytic or other properties. Adverse effects include biodeterioration of natural and synthetic materials, rock and mineral-based building materials (e.g., concrete), cultural heritage, metals, alloys, and related substances and adverse effects on radionuclide mobility and containment. The ubiquity and importance of fungi in the biosphere underline the importance of geomycology as a conceptual framework encompassing the environmental activities of fungi.


Utilizing a Digital Multi-Language Patient Questionnaire for Diagnostic Imaging Examinations.
In diagnostic imaging (DI) practice, patient questionnaires allow clinical staff to gather medical history information directly from patients. However, language barriers can prevent patients from completing the questionnaires and may endanger patient safety if the patient fails to indicate critical medical information. Interpreters are commonly employed to help patients convey important medical details; however, there are limits to their practical utilization. Thus, the purpose of this study was to evaluate the feasibility and practicality of a digital multi-language questionnaire designed to help overcome the language barriers between patients and clinical staff. The standard English-language questionnaire for bone mineral density (BMD) examinations was used in this study. It was translated into several languages and presented in an electronic form to patients in a language most suitable for them. The completed questionnaires, along with the patient responses, were automatically converted into English, allowing them to be reviewed by DI staff through a radiological information system (RIS) and picture archiving and communication system (PACS). Patients and clinical staff commented on the comfort of using the translated questionnaires. The modified Wald method was used to establish the confidence interval. The results showed that all patients and clinical staff were comfortable using the translated questionnaires. Ultimately, in this study we have developed a digital multi-language questionnaire for BMD examinations which can be converted into different languages and be stored in RIS and PACS. To the best of our knowledge, this approach had not been applied or tested elsewhere.


Linking Genetic Kinship and Demographic Analyses to Characterize Dispersal: Methods and Application to Blanding's Turtle.
Characterizing how frequently, and at what life stages and spatial scales, dispersal occurs can be difficult, especially for species with cryptic juvenile periods and long reproductive life spans. Using a combination of mark-recapture information, microsatellite genetic data, and demographic simulations, we characterize natal and breeding dispersal patterns in the long-lived, slow-maturing, and endangered Blanding's turtle (Emydoidea blandingii), focusing on nesting females. We captured and genotyped 310 individual Blanding's turtles (including 220 nesting females) in a central Wisconsin population from 2010 to 2013, with additional information on movements among 3 focal nesting areas within this population available from carapace-marking conducted from 2001 to 2009. Mark-recapture analyses indicated that dispersal among the 3 focal nesting areas was infrequent (<0.03 annual probability). Dyads of females with inferred first-order relationships were more likely to be found within the same nesting area than split between areas, and the proportion of related dyads declined with increasing distance among nesting areas. The observed distribution of related dyads for nesting females was consistent with a probability of natal dispersal at first breeding between nearby nesting areas of approximately 0.1 based on demographic simulations. Our simulation-based estimates of infrequent female dispersal were corroborated by significant spatial genetic autocorrelation among nesting females at scales of <500 m. Nevertheless, a lack of spatial genetic autocorrelation among non-nesting turtles (males and females) suggested extensive local connectivity, possibly mediated by male movements or long-distance movements made by females between terrestrial nesting areas and aquatic habitats. We show here that coupling genetic and demographic information with simulations of individual-based population models can be an effective approach for untangling the contributions of natal and breeding dispersal to spatial ecology.


Storage of Fruits and Vegetables in Refrigerator Increases their Phenolic Acids but Decreases the Total Phenolics, Anthocyanins and Vitamin C with Subsequent Loss of their Antioxidant Capacity.
It is of paramount importance for consumers, scientists and industrialists to understand how low-temperature storage of food items affects their bioactive compounds and properties. This study evaluated the effects of cold storage on total phenolics (TP), phenolic acids profile (PA), total anthocyanins (TA), total ascorbic acid (Vit. C) and antioxidant activity (AA) of 19 fruits and vegetables, collected from local Indian markets and stored in refrigerator (4 °C) during 15 days. Content of TP was highest in dill and amaranth and decreased (up to 29.67%) with storage. Leafy vegetables (amaranth, dill, onion, fenugreek and spinach) contained higher amounts of the 12 PA revealed by UPLC-UV; ellagic, gallic, sinapic and vanillic acids levels were the highest; chlorogenic acid (ρ = 0.423), syringic acid (ρ = 0.403) and sinapic acid (ρ = 0.452) mostly correlated with TP; and the PA increased during storage. Highest contents of Vit C estimated by AOAC, DCPIP and DNP methods were found in amaranth, dill and pomegranate, and decreased with storage. Pomegranate showed highest TA levels and low-temperature storage did not significantly increase TA, which was the largest contributor of TP in fruits and vegetables (ρ = 0.661). Storage induced a drastic decrease of AA, which mostly correlated with TP (ρ = 0.808, 0.690 and 0.458 for DPPH, ABTS and FRAP assays, respectively). Spearman's correlation confirmed by principal component analysis demonstrated that dill, pomegranate and amaranth had the highest overall antioxidant capacity, whereas orange juice and carrot showed the lowest. The results provide support for a key-role of TP, followed by Vit. C and TA in antioxidant capacity of fruits and vegetables, which could be interesting dietary sources of natural antioxidants for prevention of diseases caused by oxidative stress.


Determination methods for the anticancer drug dicycloplatin, a supramolecule assembled through hydrogen bonding.
Dicycloplatin is a new generation supramolecular platinum-containing anti-cancer drug. Due to its structure, it is difficult to differentiate dicycloplatin from physical mixtures of carboplatin and cyclobutane dicarboxylate, and confounding results may arise during drug characterization. To solve this problem, this study aims to provide a reliable and reproducible standard for the determination of dicycloplatin. A simple method for dicycloplatin quality control has been developed using X-ray powder diffraction (XRPD) and high performance liquid chromatography (HPLC). XRPD allowed the control of impurities and dissociation of the dicycloplatin active ingredient to less than 1%, and HPLC allowed the monitoring and control of the relative molar ratio of carboplatin and cyclobutane dicarboxylate within the purity range. The study proved for the first time that the dicycloplatin supramolecule is substantially different from a physical mixture of carboplatin and cyclobutane dicarboxylate.


[New simplified regimen for Helicobacter pylori eradication achieves high effectiveness. Prospective study in a private clinic in Lima, Peru].
To determine the effectiveness of two new therapeutic regimes for Helicobacter pylori versus triple therapy that includes a proton pump inhibitor, amoxicillin and clarithromycin. prospective study, non-randomized, in a private Hospital in Lima, Peru. Patients with biopsy and/or rapid ureasa test proven Helicobacter pylori infection received one of the three therapeutic regimens and were followed with a urea breath test 1 to 6 months upon completion of therapy. Triple therapy achieved eradication in 49/68 of cases (71.2%); quadruple therapy (doxycycline + metronidazole + bismuth + esomeprazole) in 52/62 (83.9%), and the simplified regimen with doxycycline + furazolidone + bismuth, obtained success in 79/83 of cases (95.2%). Statistically significant difference with p<0.005 and p<0.05 respectively. Triple therapy against Hp does not achieve acceptable effectiveness in our institution. This highlights the need to look for new therapeutic options, being the simplified regime (doxycycline, furazolidone and bismuth) used in the current study a good option, requiring further studies for validation.


[Duplications of the wing-hinge structures in the Pth mutants of drosophila melanogaster].
The Pth mutation of Drosophila melanogaster, a unique dominant mutation obtained by us, causes the notum duplications that are followed by the duplications of ventral and dorsal wing-hinge structures. The duplications of the wing hinge have a strictly coordinated structure, can be ranged in a continuous series, and are divided into four distinct types, none of which overlaps with the other. The order of the emergence of the ventral wing-hinge structures was determined in duplication forms, and the shape, size, and location of these structures were compared with normal parameters. The growth of the presumptive wing-hinge region was shown to have a vectorial mode; the directions of the main vectors and their center were determined. A geometrical model is proposed, which adequately explains the strict specificity in the structure of duplications as well as the agreement between the duplication forms to one another in each of the four types.


Association of Interleukin-31 gene polymorphisms with risk of cryptorchidism in a Chinese population.
This study aims to investigate the possible association between Interleukin-31 (IL-31) gene polymorphisms and cryptorchidism risk.Two single nucleotide polymorphisms of IL-31, rs7977932 (C/G) and rs4758680 (C/A), were selected to be investigated in this study. Polymerase chain reaction-restriction fragment length polymorphism methods were used to discriminate the selected single nucleotide polymorphisms of IL-31 gene. A hospital-based case-control study of 112 cryptorchidism patients and 425 healthy controls was conducted.The frequencies of the C allele of rs4758680 in the patients with cryptorchidism were significantly higher compared with those in controls (89% vs 83%, P = .02, OR = 0.58, 95% CI = 0. 37-0.92). Compared with CC genotype in dominant model, notable decreased frequencies of A carriers (CA/AA genotypes) were observed in cryptorchidism patients (P = . 03, OR = 0.58, 95% CI = 0.35-0.96).Results demonstrated that IL-31 gene polymorphisms were associated with the genetic susceptibility to cryptorchidism in a Chinese population. Compared with CC genotype, the A carriers (CA/AA genotypes) of rs4758680 were protect factors in cryptorchidism susceptibility.


Pseudomyxoma peritonei of 92 Chinese patients: clinical characteristics, pathological classification and prognostic factors.
To assess the clinicopathologic features and its relationship with prognosis of pseudomyxoma peritonei (PMP) in Chinese patients. The clinicopathologic features and follow-up data of 92 patients with PMP were reviewed and retrospectively analyzed. The cases were categorized into three groups: disseminated peritoneal adenomucinosis (DPAM), peritoneal mucinous carcinomatosis (PMCA), and peritoneal mucinous carcinomatosis with intermediate or discordant features (PMCA-I/D). The log-rank test was used to analyze survival for each group and various clinicopathological parameters. Multivariate Cox proportional-hazard models were constructed to determine the important factors associated with survival. The median age at diagnosis was 51.9 years (range: 22-76 years). The median follow up was 124 mo. The 3-, 5- and 10-year survival rates were 74.0%, 67.4% and 49.1%, respectively. There were 49 (53.2%) patients with DPAM, 26 (28.3%) with PMCA-I and 17 (18.5%) with PMCA. Patients with DPAM, PMCA-I/D and PMCA exhibited statistically significant difference in survival (P = 0.001). The 3 year survival for DPAM, PMCAI/D and PMCA was 97.0%, 80.0% and 67.0%, respectively; the 5 year survival was 80.0%, 67.0% and 50.0%, respectively; and the 10 year survival was 65.0%, 28.0% and 14.0%, respectively. Survival rate was significantly lowest in patients < 40 age years of age (P = 0.011). Appendiceal tumor and extra-ovarian parenchymal organ involvement were significantly related to overall survival. Patients with appendiceal mucinous adenocarcinoma (MACA) showed the significantly poorer prognosis (P = 0.011). Multivariate analysis showed that pathological classification, age, appendiceal tumor were significant related to overall survival. The clinical process "PMP" should be pathologically classified into DPAM, PMCA and PMCA-I/D. Pathological classification, age, appendiceal MACA are survival independent predictors in Chinese patients with PMP.


Acute graft-versus-host disease: are we close to bringing the bench to the bedside?
Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (AHSCT) associated with significant morbidity and mortality. This review focuses on the pathophysiology, prevention, and treatment of acute GVHD. Specifically, we explain how new discoveries in immunology have expanded our understanding of GVHD, in which tissue damage from chemotherapy or radiation results in cytokine release, activating T cells, resulting in proliferation and differentiation, trafficking to target organs, and tissue destruction and inflammation. Insights into the mechanisms of this disease relate directly to the development of preventive strategies and therapies, such as immunosuppression, calcineurin inhibitors, T-cell depletion, CCR5 antagonists, gut decontamination, extracorporeal photopheresis, and more. Understanding the immunobiology of GVHD and developing effective preventions and treatments are critical to the continuing success of AHSCT.


Effects of exposure to multiple trace metals on biochemical, histological and ultrastructural features of gills of a freshwater fish, Channa punctata Bloch.
The trace metals are frequently encountered as mixtures of essential and non-essential elements. Therefore, evaluation of their toxic effects individually does not offer a realistic estimate of their impact on biological processes. We studied effects of a mixture of four essential and toxic metals (Cu, Cd, Fe and Ni) on biochemical and morphological characteristics of the gills of a biomarker freshwater fish Channa punctata (Bloch) using environmentally relevant concentrations. Fish were exposed to metal mixture through tank water for 7, 15 and 30 days. Biochemical studies as well as light microscopy (LM) and scanning electron microscopy (SEM) revealed significant metal exposure-induced alterations in gills. Besides ultastructural changes, activities of antioxidant enzymes such catalase (CAT), glutathione S-transferase (GST) and superoxide dismutase (SOD) were significantly altered in the gills of exposed fish. The reduced glutathione (GSH) was significantly (p<0.001) decreased, while lipid peroxidation (LPO) was significantly (p<0.001) increased. The main alterations in general morphology of fish gills included spiking and fusion of secondary lamellae, formation of club-shaped filaments, and vacuolization and necrosis of filament epithelium in the interlamellar regions. SEM studies showed gradual increase of the density and apical surface area of the chloride cells and transformation of the surface structure of the pavement cells. The results of this study indicate adaptive as well a toxic responses in fish gills exposed to mixture of trace metals. Low concentrations of trace metal appear to compromise the antioxidant defense of gills. Lesions in the gill morphology caused by the effect of low concentrations of trace metals could lead to functional alterations and interference with fundamental processes such as maintenance of osmoregulation, gas exchange and xenobiotic metabolism in the exposed fish populations.


Structural Chemistry of Zeolitic Imidazolate Frameworks.
Zeolitic imidazolate frameworks (ZIFs) are a subclass of reticular structures based on tetrahedral four-connected networks of zeolites and minerals. They are composed of transition-metal ions and imidazolate-type linkers, and their pore size and shape, surface area, and functionality can be precisely controlled. Despite their potential, two questions remain unanswered: how to synthesize more diverse ZIF structures and how ZIFs differentiate from other crystalline solids. In other words, how can we use our understanding of their unique structures to better design and synthesize ZIFs? In this Review, we first summarize the methods for synthesizing a wide range of ZIFs. We then review the crystal structure of ZIFs and describe the relationship between their structure and properties using an in-depth analysis. We also discuss several important and intrinsic features that make ZIFs stand out from MOFs and discrete molecular cages. Finally, we outline the future direction for this class of porous crystals.


Epinephrine-primed murine bone marrow-derived dendritic cells facilitate production of IL-17A and IL-4 but not IFN-γ by CD4+ T cells.
Sympathetic activation leading to the release of epinephrine and norepinephrine, is known as an important regulatory circuit related to immune-mediated diseases. However, questions still remain on the behavior of antigen presenting cells (APC) dictated by stress-induced sympathetic neurotransmitters. The purpose of this study was to examine the fate of bone marrow-derived dendritic cell (BMDC)-associated influences on resting CD4(+) T cell activation. We hypothesize that pre-exposure of dendritic cells (DCs) can modify the intensity of cytokine production, leading to preference in resting CD4(+) T cell activation. BMDCs were pre-treated with epinephrine for 2h followed by subsequent treatment of lipopolysaccharide (LPS). Subsequently, BMDCs were cocultured with purified CD4(+) T cells from mouse spleen in the absence or presence of anti-CD3 stimulation in epinephrine-free media. Epinephrine pre-treatment enhanced surface expression of MHCII, CD80 and CD86. Quantitative RT-PCR showed that epinephrine pre-treatment induced a significant transcriptional decrease of IL-12p40 and a significant increase of IL-12p35 and IL-23p19. In addition, β2-adrenergic-blockade was shown to reverse these effects. Epinephrine pre-treatment also induced a significant decrease of IL-12p70 and a significant increase of IL-23 and IL-10 cytokine production. Importantly, these changes corresponded with increased IL-4 and IL-17A, but not IFN-g cytokine production by CD4(+) T cells in a b2-adrenergic receptor-dependent manner. These results suggest that exposure to stress-derived epinephrine dictates dendritic cells to generate a dominant Th2/Th17 phenotype in the context of subsequent exposure to a pathogenic stimulus.


Reproductive conflict delays the recovery of an endangered social species.
1. Evolutionary theory predicts that individuals, in order to increase their relative fitness, can evolve behaviours that are detrimental for the group or population. This mismatch is particularly visible in social organisms. Despite its potential to affect the population dynamics of social animals, this principle has not yet been applied to real-life conservation. 2. Social group structure has been argued to stabilize population dynamics due to the buffering effects of nonreproducing subordinates. However, competition for breeding positions in such species can also interfere with the reproduction of breeding pairs. 3. Seychelles magpie robins, Copsychus sechellarum, live in social groups where subordinate individuals do not breed. Analysis of long-term individual-based data and short-term behavioural observations show that subordinates increase the territorial takeover frequency of established breeders. Such takeovers delay offspring production and decrease territory productivity. 4. Individual-based simulations of the Seychelles magpie robin population parameterized with the long-term data show that this process has significantly postponed the recovery of the species from the Critically Endangered status. 5. Social conflict thus can extend the period of high extinction risk, which we show to have population consequences that should be taken into account in management programmes. This is the first quantitative assessment of the effects of social conflict on conservation.


[Modulating effect of glutamate transporter inhibitors on accumulation and release of the neuromediator by the brain nerve terminals in rats].
L-[14C]glutamate uptake and release processes in nerve terminals has been investigated using the nontransportable and transportable competitive inhibitors of glutamate transport as tools. The effects of DL-threo-beta-benzyloxyaspartate (DL-TBOA) and DL-threo-beta-hydroxyaspartate (DL-THA) on the accumulation of L-[14C]glutamate have been evaluated after the exposure of rats to centrifuge-induced hypergravity. Both analogs potently inhibited the L-[14C]glutamate uptake in a dose-dependent manner (100 microM glutamate, 30 s incubation period). The IC50 values for DL-TBOA calculated on the basis of curves of non-linear regression kinetic analysis was 18 +/- 2 microM and 11 +/- 2 microM (p < or = 0.05) before and after the exposure to artificial gravity, respectively. L-THA, transportable analog, exhibited similar inhibitory characteristics (18 +/- 2 and 12 +/- 2 microM, respectively). We have also demonstrated that DL-TBOA exerted slighter effect on depolarization-evoked carrier-mediated L-[14C]glutamate release in control rats in comparison with gravity-loaded ones. Thus, DL-TBOA had complex effect on glutamatergic transmission, inhibited uptake and release of L-glutamate, and perhaps, became more potent under centrifuge-induced hypergravity.


Urinary concentrations of di(2-ethylhexyl) phthalate metabolites and serum reproductive hormones: pooled analysis of fertile and infertile men.
Urinary concentrations of metabolites of the anti-androgenic xenobiotic di-(2-ethylhexyl) phthalate (DEHP) were previously shown to be weakly associated with serum levels of several hormones in 2 disparate US populations: partners of pregnant women participating in the Study for Future Families and partners in infertile couples from Massachusetts General Hospital infertility clinic. The observed associations between phthalate metabolites and reproductive hormones were robust and insensitive to the characteristics of the subpopulation or the laboratory in which the hormones were measured, despite the fact that these 2 populations span a range of fertility, urinary phthalate metabolites, and reproductive hormone levels. We therefore examined associations between urinary metabolites of DEHP and reproductive hormones-follicle-stimulating hormone, luteinizing hormone, testosterone (T), inhibin B, and estradiol (E(2))-and sex hormone-binding globulin (SHBG) in the pooled population. The magnitude of the associations seen were similar to those reported for each population separately, but effect estimates were more precise because of the increased sample size and the greater range of phthalate metabolite concentrations and hormone levels. Urinary concentrations of 3 metabolites of DEHP [mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP)] were inversely associated with the free androgen index (FAI = T/SHBG) and calculated free testosterone. Urinary concentrations of MEHHP and MEOHP were positively associated with SHBG, and MEHP was inversely associated with E(2). No other phthalate metabolites were associated with serum hormones, consistent with results in each population. Our results in this diverse population suggest that DEHP exposure is robustly associated with some male sex steroid hormones.


Broadly neutralizing and protective nanobodies against SARS-CoV-2 Omicron subvariants BA.1, BA.2, and BA.4/5 and diverse sarbecoviruses.
As SARS-CoV-2 Omicron and other variants of concern (VOCs) continue spreading worldwide, development of antibodies and vaccines to confer broad and protective activity is a global priority. Here, we report on the identification of a special group of nanobodies from immunized alpaca with potency against diverse VOCs including Omicron subvariants BA.1, BA.2 and BA.4/5, SARS-CoV-1, and major sarbecoviruses. Crystal structure analysis of one representative nanobody, 3-2A2-4, discovers a highly conserved epitope located between the cryptic and the outer face of the receptor binding domain (RBD), distinctive from the receptor ACE2 binding site. Cryo-EM and biochemical evaluation reveal that 3-2A2-4 interferes structural alteration of RBD required for ACE2 binding. Passive delivery of 3-2A2-4 protects K18-hACE2 mice from infection of authentic SARS-CoV-2 Delta and Omicron. Identification of these unique nanobodies will inform the development of next generation antibody therapies and design of pan-sarbecovirus vaccines.


Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies.
The design of a human immunodeficiency virus-1 (HIV-1) immunogen that can induce broadly reactive neutralizing antibodies is a major goal of HIV-1 vaccine development. Although rare human monoclonal antibodies (mAbs) exist that broadly neutralize HIV-1, HIV-1 envelope immunogens do not induce these antibody specificities. Here we demonstrate that the two most broadly reactive HIV-1 envelope gp41 human mAbs, 2F5 and 4E10, are polyspecific autoantibodies reactive with the phospholipid cardiolipin. Thus, current HIV-1 vaccines may not induce these types of antibodies because of autoantigen mimicry of the conserved membrane-proximal epitopes of the virus. These results may have important implications for generating effective neutralizing antibody responses by using HIV-1 vaccines.


Neurological complications of cervical spine manipulation.
To obtain preliminary data on neurological complications of spinal manipulation in the UK all members of the Association of British Neurologists were asked to report cases referred to them of neurological complications occurring within 24 hours of cervical spine manipulation over a 12-month period. The response rate was 74%. 24 respondents reported at least one case each, contributing to a total of about 35 cases. These included 7 cases of stroke in brainstem territory (4 with confirmation of vertebral artery dissection), 2 cases of stroke in carotid territory and 1 case of acute subdural haematoma. There were 3 cases of myelopathy and 3 of cervical radiculopathy. Concern about neurological complications following cervical spine manipulation appears to be justified. A large long-term prospective study is required to determine the scale of the hazard.


Molecular characterization of Kita-Kyushu lung cancer antigen (KK-LC-1) expressing carcinomas.
Cancer/testis antigens (CTAs) are strongly expressed in some solid tumors but minimally expressed in normal tissue, making them appealing therapeutic targets. KK-LC-1 (CXorf61) has cytoplasmic expression in gastric, breast, and lung cancer. We characterized the molecular subtypes of non-small cell lung cancer (NSCLC) expressing KK-LC-1 to inform rational clinical trials of T-cell receptor therapy (TCR-T) targeting KK-LC-1. 9790 NSCLC tumors that underwent whole transcriptome sequencing (Illumina NovaSeq) and NextGen DNA sequencing (NextSeq, 592 Genes and NovaSEQ, WES) at Caris Life Sciences (Phoenix, AZ) were analyzed. Tumors were split into quartiles based on KK-LC-1 expression and pathological and molecular differences were investigated. Adenocarcinoma had significantly higher KK-LC-1 expression than squamous cell carcinoma (median, 3.25 vs. 1.17 transcripts per million (TPM), p < 0.0001). Tumors with the highest quartile of KK-LC-1 expression had a greater proportion of tumors with high tumor mutation burden (TMB) (≥10 mutations per megabase; 44% vs. 28% in Q1, p < 0.001). Increased KK-LC-1 expression was associated with increased M1 macrophage abundance. Higher levels of KK-LC-1 expression were seen in pan-wild type and KRAS mutated tumors and associated with high TMB. TCR-T therapy directed against KK-LC-1 should be considered in patients whose clinical features reflect these characteristics.


Sonographically guided deep plantar fascia injections: where does the injectate go?
To determine the distribution of sonographically guided deep plantar fascia injections in an unembalmed cadaveric model. A single experienced operator completed 10 sonographically guided deep plantar fascia injections in 10 unembalmed cadaveric specimens (5 right and 5 left) obtained from 6 donors (2 male and 4 female) aged 49 to 95 years (mean, 77.5 years) with a mean body mass index of 23.2 kg/m(2) (range, 18.4-26.3 kg/m(2)). A 12-3-MHz linear array transducer was used to direct a 22-gauge, 38-mm stainless steel needle deep to the plantar fascia at the anterior aspect of the calcaneus using an in-plane, medial-to-lateral approach. In each case, 1.5 mL of 50% diluted colored latex was injected deep to the plantar fascia. After a minimum of 72 hours, study coinvestigators dissected each specimen to assess injectate placement. All 10 injections accurately placed latex adjacent to the deep side of the plantar fascia at the anterior calcaneus. However, the flexor digitorum brevis (FDB) origin from the plantar fascia variably limited direct latex contact with the plantar fascia, and small amounts of latex interdigitated with the FDB origin in 90% (9 of 10). In all 10 specimens, latex also covered the traversing first branch of the lateral plantar nerve (FBLPN, ie, Baxter nerve) between the FDB and quadratus plantae muscles. No latex was found in the plantar fat pad or plantar fascia in any specimen. Sonographically guided deep plantar fascia injections reliably deliver latex deep to the plantar fascia while avoiding intrafascial injection. However, the extent of direct plantar fascia contact is variable due to the intervening FDB. On the contrary, the traversing FBLPN is reliably covered by the injection. Deep plantar fascia injections may have a role in the management of refractory plantar fasciitis, particularly following failed superficial perifascial or intrafascial injections, in cases of preferential deep plantar fascia involvement, or when entrapment/irritation of the distal FBLPN is suspected.


Surface code quantum communication.
Quantum communication typically involves a linear chain of repeater stations, each capable of reliable local quantum computation and connected to their nearest neighbors by unreliable communication links. The communication rate of existing protocols is low as two-way classical communication is used. By using a surface code across the repeater chain and generating Bell pairs between neighboring stations with probability of heralded success greater than 0.65 and fidelity greater than 0.96, we show that two-way communication can be avoided and quantum information can be sent over arbitrary distances with arbitrarily low error at a rate limited only by the local gate speed. This is achieved by using the unreliable Bell pairs to measure nonlocal stabilizers and feeding heralded failure information into post-transmission error correction. Our scheme also applies when the probability of heralded success is arbitrarily low.


Structure-composition trends in multicomponent borosilicate-based glasses deduced from molecular dynamics simulations with improved B-O and P-O force fields.
We present a comprehensive molecular dynamics (MD) simulation study of composition-structure trends in a set of 25 glasses of widely spanning compositions from the following four systems of increasing complexity: Na2O-B2O3, Na2O-B2O3-SiO2, Na2O-CaO-SiO2-P2O5, and Na2O-CaO-B2O3-SiO2-P2O5. The simulations involved new B-O and P-O potential parameters developed within the polarizable shell-model framework, thereby combining the beneficial features of an overall high accuracy and excellent transferability among different glass systems and compositions: this was confirmed by the good accordance with experimental data on the relative BO3/BO4 populations in borate and boro(phospho)silicate networks, as well as with the orthophosphate fractions in bioactive (boro)phosphosilicate glasses, which is believed to strongly influence their bone-bonding properties. The bearing of the simulated melt-cooling rate on the borate/phosphate speciations is discussed. Each local {BO3, BO4, SiO4, PO4} coordination environment remained independent of the precise set of co-existing network formers, while all trends observed in bond-lengths/angles mainly reflected the glass-network polymerization, i.e., the relative amounts of bridging oxygen (BO) and non-bridging oxygen (NBO) species. The structural roles of the Na+/Ca2+ cations were also probed, targeting their local coordination environments and their relative preferences to associate with the various borate, silicate, and phosphate moieties. We evaluate and discuss the common classification of alkali/alkaline-earth metal ions as charge-compensators of either BO4 tetrahedra or NBO anions in borosilicate glasses, also encompassing the less explored NBO-rich regime: the Na+/Ca2+ cations mainly associate with BO/NBO species of SiO4/BO3 groups, with significant relative Na-BO4 contacts only observed in B-rich glass networks devoid of NBO species, whereas NBO-rich glass networks also reveal substantial amounts of NBO-bearing BO4 tetrahedra.