Outcomes for Recurrent Mantle Cell Lymphoma Post-Ibrutinib Therapy: A Retrospective Cohort Study from a Japanese Administrative Database.
Treatment options in patients with mantle cell lymphoma (MCL) failing ibrutinib are limited, with no standard therapies defined. This study aimed to investigate real-world treatment patterns and outcomes for patients with MCL following ibrutinib. This study utilized a de-identified hospital-based claims database (Medical Data Vision) in Japan. Eligible patients were adults who were diagnosed with MCL and had received antitumor drugs between December 2010 and July 2020. Patients were followed from the first antitumor drug treatment until the end of available data up to July 2021. Time-to-event analyses utilized the Kaplan-Meier method. Factors for receiving post-ibrutinib therapy were explored with logistic regression analysis. Of the 1386 patients who started antitumor drug therapy, 247 patients received and discontinued ibrutinib at any line of therapy. Among them, 137 patients (55.5%) received subsequent therapy. The median age at the end of ibrutinib therapy was 77 (range 42-95), and 44 patients had a dependent activity of daily living (ADL). Factors negatively associated with receiving post-ibrutinib therapy after discontinuation of ibrutinib were age ≥ 75 years (odds ratio [95% CI] 0.46 [0.26-0.80]) and emergency hospital admissions (0.37 [0.17-0.84]). Immediate post-ibrutinib therapy regimens were highly diverse, with BR (bendamustine, rituximab) only prescribed in more than 10% of patients. The median duration of post-ibrutinib therapy was 1.5 months (95% CI 1.07-2.07). The median overall survival from the end of ibrutinib therapy in patients regardless of the receipt of post-ibrutinib therapy (n = 247), in those who did not receive post-ibrutinib therapy (n = 110), and in those who received post-ibrutinib therapy (n = 137) was 5.6 months (95% CI 3.8-8.7), 2.3 months (95% CI 1.2-3.9), and 8.7 months (95% CI 5.6-13.8), respectively. The most common adverse event during post-ibrutinib therapy was infection, with the use of anti-infectives (17%). Patients with MCL previously treated with ibrutinib have poor ability to carry out ADL and experience very poor outcomes. New safe, effective therapies are needed.


Neural networks for detection and classification of walking pattern changes due to ageing.
With age, gait functions reflected in the walking patterns degenerate and threaten the balance control mechanisms of the locomotor system. The aim of this paper is to explore applications of artificial neural networks for automated recognition of gait changes due to ageing from their respective gait-pattern characteristics. The ability of such discrimination has many advantages including the identification of at-risk or faulty gait. Various gait features (e.g., temporal-spatial, foot-ground reaction forces and lower limb joint angular data) were extracted from 12 young and 12 elderly participants during normal walking and these were utilized for training and testing on three neural network algorithms (Standard Backpropagation: Scaled Conjugate Gradient; and Backpropagation with Bayesian Regularization, BR). Receiver operating characteristics plots, sensitivity and specificity results as well as accuracy rates were used to evaluate performance of the three classifiers. Cross-validation test results indicate a maximum generalization performance of 83.3% in the recognition of the young and elderly gait patterns. Out of the three neural network algorithms, BR performed superiorly in the test results with best sensitivity, selectivity and detection rates. With the help of a feature selection technique, the maximum classification accuracy of the BR attained 100%, when trained with a small subset of selected gait features. The results of this study demonstrate the capability of neural networks in the detection of gait changes with ageing and their potentials for future applications as gait diagnostics.


Prevention--everybody's responsibility.
The importance of individual responsibility in many aspects of preventive medicine is emphasised in the introduction. A section on infectious disease as applied to Western society today follows with special mention of particular conditions such as turberculosis, influenza, rubella, gastro-intestinal diseases and Legionaire's Disease. The section on non-communicable disease is subdivided into coronary heart disease, malignant neoplasms and chronic bronchitis. It includes some discussion of screening. Short sections on prevention in the elderly, pregnancy and early life, dental health, accidents, alcoholism and drug misuse follow. In the conclusions the difficulty of determining priorities for different societies and the importance of establishing cost effectiveness of preventive measures are covered. The relative importance of societal, governmental and individual preventive measures are described and the authors emphasise that any expensive screening programme must adhere to established criteria.


Effect of limited ischemia time on the amount and function of mitochondria within human skeletal muscle cells.
The clinical success of total knee arthroplasty (TKA) depends substantially on the quadriceps muscle function. A frequently applied thigh tourniquet during TKA may induce ischemia related injuries to quadriceps muscle cells. Animal limb muscles subjected to 2-5 h ischemia revealed dysfunctional mitochondria, which in turn compromised the cellular bioenergetics and increased the level of reactive oxygen species. The hypothesis of the present study was that tourniquet application during TKA for 60 min (min) affects the amount and function of mitochondria within musculus vastus medialis cells. In a randomized clinical trial, 10 patients enrolled to undergo primary TKA. The patients were randomly assigned to the tourniquet (n = 5) or non-tourniquet group (n = 5) after obtaining a written informed consent. For each of the groups, the first muscle biopsy was harvested immediately after performing the surgical approach and the second biopsy exactly 60 min later. All biopsies (5 × 5 × 5 mm) 125 mm3 were harvested from musculus vastus medialis and snap-frozen in liquid nitrogen. The biochemical analysis of the prepared muscle tissues included the measurement of activities of mitochondrial respiratory chain enzyme complexes I-III and citrate synthase. Tourniquet-induced 60 min ischemia time did not significantly change the activities of the mitochondrial respiratory chain enzymes complexes I-III of the skeletal muscle cells. The citrate synthase activities found to be not significantly different between both groups. The use of tourniquet during TKA within a limited time period of 60 min remained without substantial effects on the amount and function of mitochondria within human skeletal muscle cells.


Efficient synthesis of highly functionalized indazoles and 2,3-dihydro-1,2-benzisoxazoles by reaction of stable Fischer dienyl carbenes and isocyanides.
A range of stable chromium and tungsten Fischer dienyl carbenes have been prepared by [3+2] cycloaddition of alkenylethynyl carbene complexes with nitrones or diazoalkanes. Treatment of these systems with isocyanides gives entry to highly functionalized 2,3-dihydro-1,2-benzisoxazoles and indazoles in a completely regioselective fashion, under mild conditions, and with high yields. This methodology can be also applied to the preparation of analogous naphthoisoxazoles starting from arylethynyl Fischer complexes. Reductive cleavage of the isoxazole moiety in the prepared heterocycles also enables the efficient synthesis of highly substituted p-aminophenols.


The emerging role of exosomes in Schizophrenia.
Schizophrenia (SCZ), a serious mental disorder, is one of the leading causes of disease burden worldwide. Exosomes, as a natural nanocarrier, are able to cross the blood-brain barrier (BBB) and play a key bridging role in central nervous system (CNS) communication, participating in important physiological processes such as neural regeneration, prominent plasticity, axonal support, and neuroinflammation. In recent years, exosomes have received widespread attention in the field of neurodegenerative diseases and mental disorders, especially Alzheimer's disease. However, there are few reviews on exosomes and SCZ. Therefore, we conducted a literature search in PubMed and Web of Science using the following search terms: "schizophrenia", "mental disorder", "central system", "exosome", "extracellular vesicles" to identify publications from January 2010 to December 2022. Our review summarized exosomes secreted by different cell types in the CNS and the double-edged role of exosomes in the development of SCZ, and discussed their future potential as biomarkers and therapeutic targets. In conclusion, this article provides an up-to-date overview of the current research on the involvement of exosomes in SCZ, while also highlighting the challenges that are currently faced in this field.


Estimating the cost of type 1 diabetes in Ireland.
Type 1 diabetes is a chronic disease, which given its existing and projected prevalence, is likely to pose a significant economic burden, both in terms of directs costs to the healthcare system and indirect costs to society. We aimed to estimate the economic burden of type 1 diabetes in Ireland, which at present, is unknown. A cost of illness study was undertaken to estimate the cost of type 1 diabetes in Ireland for 2018. Data for prevalence, morbidity, mortality, healthcare resource use, absenteeism, and unit costs were obtained from national, and where necessary, international sources. Direct healthcare costs were estimated for primary care, outpatient, emergency and inpatient care, for associated complications, structured education programmes, insulin and related care. Additionally, indirect costs from lost earnings due to premature death and employee absenteeism were estimated. Type 1 diabetes was estimated to cost €129 million in Ireland in 2018, with direct healthcare costs accounting for €81.5 million or 63% and indirect costs for €47.5 million or 37% of the total. On average, this amounted to €3994 per patient in direct healthcare costs and €2326 per patient in indirect costs. Type 1 diabetes is a leading public health problem. Our study is the first to assess the economic burden of type 1 diabetes in Ireland, and our results should be informative to policymakers tasked with prioritising healthcare and research funding resource allocation.


Classification of the terminal arterial vascularization of the appendix with a view to its use in reconstructive microsurgery.
The aim of this study was to examine the arterial vascularization of the appendix, in order to propose a classification of the different vascular types of the appendix for the realization of free transfer in reconstructive microsurgery. We achieved the removal as a monobloc of the cecum, of a part of the ileum, and the upper colon, then conducted the intra-arterial injection of a mixture composed of minium, and went on to the dissection of 25 specimens of appendix from West Africa. We analyzed the appendicular territory vascularized by the different discovered arteries. The average length of the appendix was 10.5 cm, ranging from 6.5 to 13.5 cm. The vascularization of the appendix was guaranteed by three arteries: the main appendicular artery, the ceco-appendicular artery and by one or several appendicular accessory arteries. We found five types of vascularization of the appendix according to the number and type of artery needed to guarantee the vascularization of the whole of the appendix including its base. It is evident from this study that a detailed analysis of the vascularization of the appendix is necessary before its removal for a reconstructive microsurgery, because in three cases out of four, the transplant must include at least two vessels in order to guarantee the whole of its vascularization.


Treatment of cerebrotendinous xanthomatosis in pregnancy: Patient and physician perspectives.
Cerebrotendinous xanthomatosis (CTX) is a rare, autosomal recessive disorder of bile acid synthesis that presents with varied and progressive symptomology. Early treatment with chenodeoxycholic acid (CDCA) improves symptoms and slows degeneration. Patients with CTX are commonly recommended to discontinue CDCA treatment during pregnancy because of theoretical risks to the fetus, but patient and clinician concerns about the risks of stopping treatment cause uncertainty. Herein, we report the experiences and perspectives of two women with CTX from the time of diagnosis through pregnancy, as well as decisions regarding CDCA treatment during pregnancy. Before becoming pregnant, both women were concerned about potential risks to their newborns if they continued or stopped CDCA treatment during pregnancy. Reassurance from their CTX specialist was the primary factor in their decision to continue treatment during pregnancy. After pregnancies complicated by preeclampsia, one gave birth to a healthy infant and the other gave birth to an infant later diagnosed with periventricular leukomalacia. Neither experienced CDCA-related complications.


Clinical outcomes and antibody transfer in a cohort of infants with in utero or perinatal exposure to SARS-CoV-2 (Coronascope Study).
We aimed to describe the outcomes, focusing on the hearing and neurological development, of infants born to mothers with COVID-19 during pregnancy and to evaluate the persistence of maternal antibodies in the first months of life. An observational, prospective study at a tertiary hospital in Madrid (Spain) on infants born to mothers with COVID-19 during pregnancy between March and September 2020 was conducted. A follow-up visit at 1-3 months of age with a physical and neurological examination, cranial ultrasound (cUS), SARS-CoV-2 RT-PCR on nasopharyngeal swab, and SARS-CoV-2 serology were performed. Hearing was evaluated at birth through the automated auditory brainstem response and at six months of age through the auditory steady-state response. A neurodevelopmental examination using the Bayley-III scale was performed at 12 months of age. Of 95 infants studied, neurological examination was normal in all of them at the follow-up visit, as was the cUS in 81/85 (95%) infants, with only mild abnormalities in four of them. Serology was positive in 47/95 (50%) infants, which was not associated with symptoms or severity of maternal infection. No hearing loss was detected, and neurodevelopment was normal in 96% of the infants (median Z score: 0). In this cohort, the majority of infants born to mothers with COVID-19 during pregnancy were healthy infants with a normal cUS, no hearing loss, and normal neurodevelopment in the first year of life. Only half of the infants had a positive serological result during the follow-up. • Hearing loss and neurodevelopmental delay in infants born to mothers with COVID-19 during pregnancy has been suggested, although data is inconsistent. Maternal antibody transfer seems to be high, with a rapid decrease during the first weeks of life. • Most infants born to mothers with COVID-19 during pregnancy had normal hearing screening, cranial ultrasound, and neurodevelopmental status at 12 months of life. Antibodies against SARS-CoV-2 were only detected in 50% of the infants at two months of life.


Platelet-derived growth factor and angiotensin II cause increases in cytosolic free calcium by different mechanisms in vascular smooth muscle cells.
Platelet-derived growth factor (PDGF) and angiotensin II (AII) are thought to mediate their biological effects in vascular smooth muscle cells (VSMCs) by causing alterations in cytosolic free calcium ([ Ca2+]i). In this study we examine the pathways by which PDGF and AII alter [Ca2+]i in VSMCs. Addition of PDGF resulted in a rapid, transient, concentration-dependent increase in [Ca2+]i; this rise in [Ca2+]i was blocked completely by preincubation of cells with ethylene glycol-bis (beta-aminoethyl ether) N,N,N',N'-tetraacetic acid (EGTA) or CoCl2, by the voltage-sensitive Ca2+-channel antagonists verapamil or nifedipine, by 12-O-tetradecanoylphorbol-13-acetate (TPA), or by pertussis toxin. AII also caused an increase in [Ca2+]i; however, AII-stimulated alterations in [Ca2+]i displayed different kinetics compared with those caused by PDGF. Pretreatment of cells with 8-(diethylamine)-octyl-3,4,5-trimethyoxybenzoate hydrochloride (TMB-8), almost totally inhibited AII-induced increases in [Ca2+]i. EGTA or CoCl2 only slightly diminished AII-stimulated increases in [Ca2+]i. Nifedipine, verapamil, TPA, and pertussis toxin pretreatment were without effect on AII-induced increases in [Ca2+]i. PDGF and AII both stimulated increases in total inositol phosphate accumulation, although the one-half maximal concentration (ED50) for alterations in [Ca2+]i and phosphoinisitide hydrolysis differed by a factor of 10 for PDGF (3 X 10(-10) M for Ca2+ vs. 2.5 X 10(-9) M for phosphoinositide hydrolysis), but they were essentially identical for AII (7.5 X 10(-9) M for Ca2+ vs. 5.0 X 10(-9) M for phosphoinositide hydrolysis). PDGF stimulated mitogenesis (as measured by [3H]-thymidine incorporation into DNA) in VSMCs with an ED50 similar to that for PDGF-induced alterations in phosphoinositide hydrolysis. PDGF-stimulated mitogenesis was blocked by pretreatment of cells with voltage-sensitive Ca2+ channel blockers, TPA, or pertussis toxin. These results suggest that PDGF and AII cause alterations in [Ca2+]i in VSMCs by at least quantitatively distinct mechanisms. PDGF binding activates a pertussis-toxin-sensitive Ca2+ influx into cells via voltage-sensitive Ca2+ channels (blocked by EGTA, verapamil, and nifedipine), as well as stimulating phosphoinositide hydrolysis leading to release of Ca2+ from intracellular stores. AII-induced alterations in [Ca2+]i are mainly the result of phosphoinositide hydrolysis and consequent entry of Ca2+ into the cytoplasm from intracellular stores. Our data also suggest that changes in [Ca2+]i caused by PDGF are required for PDGF-stimulated mitogenesis.


Pharmacokinetic and pharmacodynamic modeling of humanized anti-factor IX antibody (SB 249417) in humans.
SB 249417 is a humanized anti-factor IX/IXa antibody that, on administration to rats and monkeys, produces an immediate suppression of factor IX activity and prolongation of activated partial thromboplastin times (aPTT). Our objective was to establish the pharmacokinetics of SB 249417 and to explore its effects on factor IX activity levels and aPTT in humans. In this phase I, single-blind, randomized, placebo-controlled, parallel-group, single intravenous infusion study, individual and mean data from a total of 26 healthy volunteers at 5 dosing levels were analyzed. A 2-compartment pharmacokinetic model was used in the analysis of total SB 249417 concentration-time profiles. A modified indirect-response model was used, with the total concentration indirectly serving as the driving force for the suppression of free factor IX concentration (as assessed by factor IX activity). The aPTT was related to factor IX activity with a biexponential equation, and a population approach was used to generate posterior parameter estimates for the individual fittings. Mean parameter estimates from individual fittings are 0.092 L/kg for volume of distribution, 0.15 L/kg for steady-state volume of distribution, and 0.0021 L/kg per hour for systemic clearance. The model described well the factor IX activity and aPTT time course in response to SB 249417 at 5 dose levels. The estimated half-life of factor IX in blood was 21 hours. This model was stable and robust in fitting both mean and individual data. Endogenous factor IX baseline levels and dose were the major determinants of the decline in factor IX activity during the infusion period. Thereafter the recovery of factor IX activity was governed solely by the endogenous factor IX turnover rate.


Association of TNF-α (-308G/A) Gene Polymorphism with Changes in Circulating TNF-α Levels in Response to CPAP Treatment in Adults with Coronary Artery Disease and Obstructive Sleep Apnea.
We recently demonstrated that patients with coronary artery disease (CAD) and obstructive sleep apnea (OSA) carrying the tumor necrosis factor-alpha (TNF-α) A allele had increased circulating TNF-α levels compared with the ones carrying the TNF-α G allele. In the current study, we addressed the effect of TNF-α (-308G/A) gene polymorphism on circulating TNF-α levels following continuous positive airway pressure (CPAP) therapy. This study was a secondary analysis of the RICCADSA trial (NCT00519597) conducted in Sweden. CAD patients with OSA (apnea-hypopnea index) of ≥15 events/h and an Epworth Sleepiness Scale (ESS) score of <10 were randomized to CPAP or no-CPAP groups, and OSA patients with an ESS score of ≥10 were offered CPAP treatment. Blood samples were obtained at baseline and 12-month follow-up visits. TNF-α was measured by immunoassay (Luminex, R&D Systems). Genotyping of TNF-α-308G/A (single nucleotide polymorphism Rs1800629) was performed by polymerase chain reaction-restriction fragment length polymorphism. In all, 239 participants (206 men and 33 women; mean age 64.9 (SD 7.7) years) with polymorphism data and circulating levels of TNF-α at baseline and 1-year follow-up visits were included. The median circulating TNF-α values fell in both groups between baseline and 12 months with no significant within- or between-group differences. In a multivariate linear regression model, a significant change in circulating TNF-α levels from baseline across the genotypes from GA to GA and GA to AA (standardized β-coefficient -0.129, 95% confidence interval (CI) -1.82; -0.12; p = 0.025) was observed in the entire cohort. The association was more pronounced among the individuals who were using the device for at least 4 h/night (n = 86; standardized β-coefficient -2.979 (95% CI -6.11; -1.21); p = 0.004)), whereas no significant association was found among the patients who were non-adherent or randomized to no-CPAP. The participants carrying the TNF-α A allele were less responsive to CPAP treatment regarding the decline in circulating TNF-α despite CPAP adherence (standardized β-coefficient -0.212, (95% CI -5.66; -1.01); p = 0.005). Our results suggest that TNF-α (-308G/A) gene polymorphism is associated with changes in circulating TNF-α levels in response to CPAP treatment in adults with CAD and OSA.


Maternal SENP7 programs meiosis architecture and embryo survival in mouse.
Understanding the mechanisms underlying abnormal egg production and pregnancy loss is significant for human fertility. SENP7, a SUMO poly-chain editing enzyme, has been regarded as a mitotic regulator of heterochromatin integrity and DNA repair. Herein, we report the roles of SENP7 in mammalian reproductive scenario. Mouse oocytes deficient in SENP7 experienced meiotic arrest at prophase I and metaphase I stages, causing a substantial decrease of mature eggs. Hyperaceylation and hypomethylation of histone H3 and up-regulation of Cdc14B/C accompanied by down-regulation of CyclinB1 and CyclinB2 were further recognized as contributors to defective M-phase entry and spindle assembly in oocytes. The spindle assembly checkpoint activated by defective spindle morphogenesis, which was also caused by mislocalization and ubiquitylation-mediated proteasomal degradation of γ-tubulin, blocked oocytes at meiosis I stage. SENP7-depleted embryos exhibited severely defective maternal-zygotic transition and progressive degeneration, resulting in nearly no blastocyst production. The disrupted epigenetic landscape on histone H3 restricted Rad51C loading onto DNA lesions due to elevated HP1α euchromatic deposition, and reduced DNA 5hmC challenged the permissive status for zygotic DNA repair, which induce embryo death. Our study pinpoints SENP7 as a novel determinant in epigenetic programming and major pathways that govern oocyte and embryo development programs in mammals.


Phospho-STAT5 expression pattern with the MPL W515L mutation is similar to that seen in chronic myeloproliferative disorders with JAK2 V617F.
Abnormal nuclear megakaryocytic staining for phospho-STAT5 (pSTAT5) correlates with JAK2 V617F mutational status in non-chronic myelogenous leukemia chronic myeloproliferative disorders. However, a proportion of wild-type JAK2 non-chronic myelogenous leukemia chronic myeloproliferative disorders cases also demonstrate this abnormal pSTAT5 expression pattern. We report a patient with a JAK2 V617F-negative myeloproliferative/myelodysplastic syndrome who had abnormal megakaryocytic pSTAT5 expression and a MPL W515L mutation. The patient was a 71-year-old man with anemia and thrombocythemia on laboratory examination. His peripheral blood smear demonstrated occasional dysplastic neutrophils. Bone marrow biopsy revealed hypercellular marrow with features consistent with myeloproliferative/myelodysplastic syndrome. Immunohistochemistry for pSTAT5 showed abnormal nuclear megakaryocyte positivity. Cytogenetic analysis revealed a normal karyotype, fluorescence in situ hybridization for BCR-ABL was negative, and JAK2 genotyping demonstrated wild-type JAK2. However, MPL genotyping showed a MPL W515L mutation. Abnormal nuclear megakaryocytic staining for pSTAT5 expression, previously associated with the JAK2 V617F mutation, is also associated with MPL W515L, likely reflecting activation of the JAK-STAT signaling pathway.


Corrigendum: Diagnostic efficiency of metagenomic next-generation sequencing for suspected spinal tuberculosis in China: a multicenter prospective study.
[This corrects the article DOI: 10.3389/fmicb.2022.1018938.].


Skeletal Muscle Disorders: A Noncardiac Source of Cardiac Troponin T.
Cardiac troponin (cTn) T and cTnI are considered cardiac specific and equivalent in the diagnosis of acute myocardial infarction. Previous studies suggested rare skeletal myopathies as a noncardiac source of cTnT. We aimed to confirm the reliability/cardiac specificity of cTnT in patients with various skeletal muscle disorders (SMDs). We prospectively enrolled patients presenting with muscular complaints (≥2 weeks) for elective evaluation in 4 hospitals in 2 countries. After a cardiac workup, patients were adjudicated into 3 predefined cardiac disease categories. Concentrations of cTnT/I and resulting cTnT/I mismatches were assessed with high-sensitivity (hs-) cTnT (hs-cTnT-Elecsys) and 3 hs-cTnI assays (hs-cTnI-Architect, hs-cTnI-Access, hs-cTnI-Vista) and compared with those of control subjects without SMD presenting with adjudicated noncardiac chest pain to the emergency department (n=3508; mean age, 55 years; 37% female). In patients with available skeletal muscle biopsies, TNNT/I1-3 mRNA differential gene expression was compared with biopsies obtained in control subjects without SMD. Among 211 patients (mean age, 57 years; 42% female), 108 (51%) were adjudicated to having no cardiac disease, 44 (21%) to having mild disease, and 59 (28%) to having severe cardiac disease. hs-cTnT/I concentrations significantly increased from patients with no to those with mild and severe cardiac disease for all assays (all P<0.001). hs-cTnT-Elecsys concentrations were significantly higher in patients with SMD versus control subjects (median, 16 ng/L [interquartile range (IQR), 7-32.5 ng/L] versus 5 ng/L [IQR, 3-9 ng/L]; P<0.001), whereas hs-cTnI concentrations were mostly similar (hs-cTnI-Architect, 2.5 ng/L [IQR, 1.2-6.2 ng/L] versus 2.9 ng/L [IQR, 1.8-5.0 ng/L]; hs-cTnI-Access, 3.3 ng/L [IQR, 2.4-6.1 ng/L] versus 2.7 ng/L [IQR, 1.6-5.0 ng/L]; and hs-cTnI-Vista, 7.4 ng/L [IQR, 5.2-13.4 ng/L] versus 7.5 ng/L [IQR, 6-10 ng/L]). hs-cTnT-Elecsys concentrations were above the upper limit of normal in 55% of patients with SMD versus 13% of control subjects (P<0.01). mRNA analyses in skeletal muscle biopsies (n=33), mostly (n=24) from individuals with noninflammatory myopathy and myositis, showed 8-fold upregulation of TNNT2, encoding cTnT (but none for TNNI3, encoding cTnI) versus control subjects (n=16, PWald<0.001); the expression correlated with pathological disease activity (R=0.59, Pt-statistic<0.001) and circulating hs-cTnT concentrations (R=0.26, Pt-statistic=0.031). In patients with active chronic SMD, elevations in cTnT concentrations are common and not attributable to cardiac disease in the majority. This was not observed for cTnI and may be explained in part by re-expression of cTnT in skeletal muscle. URL: https://www. gov; Unique identifier: NCT03660969.


The infantile form of sialidosis type II associated with congenital adrenal hyperplasia: possible linkage between HLA and the neuraminidase deficiency gene.
The possible genetic linkage between HLA and neuraminidase deficiency was studied in a female patient with combined abnormalities of the infantile form of sialidosis type II and congenital adrenal hyperplasia caused by 21-hydroxylase deficiency, and six members of her family. Her parents were consanguineous. The patient has the homozygous HLA haplotypes, TS-1, Cw3, DRw9. Four of the tested family members, including a distant male relative with congenital adrenal hyperplasia, were heterozygous of this HLA complex, and the neuraminidase activities in their skin fibroblasts and/or lymphocytes showed values between those of the patient and controls (25-48%), suggesting a carrier state of sialidosis. This indicates that the neuraminidase deficiency gene, similar to the 21-hydroxylase deficiency gene, is closely linked to the HLA genotype and is located on chromosome 6.


Massive pulmonary embolism mimicking electrocardiographic pattern of Brugada syndrome.
Brugada syndrome is an inherited heart disease without structural abnormalities that is thought to arise as a result of accelerated inactivation of Na channels and predominance of transient outward K current to generate a voltage gradient in the right ventricular layers. Brugada syndrome occurs in patients with structurally normal heart and predisposes patients to malignant ventricular arrhythmias. Acute pulmonary embolism has been associated with a variety of electrocardiograms,and rarely, it may mimic electrocardiographic pattern of Brugada syndrome and this condition was defined as Brugada phenocopy.


The role of MOR and the CI operator sites on the genetic switch of the temperate bacteriophage TP901-1.
A genetic switch controls whether the temperate bacteriophage TP901-1 will enter a lytic or a lysogenic life cycle after infection of its host, Lactococcus lactis. We studied this bistable switch encoded in a small DNA fragment of 979 bp by fusing it to a reporter gene on a low-copy-number plasmid. The cloned DNA fragment contained the two divergently oriented promoters, P(R) and P(L), transcribing the lysogenic and lytic gene clusters; the two promoter-proximal genes, cI and mor; and the three CI operator sites, O(R), O(L) and O(D). We show that mor encodes a protein and that this protein in concert with CI is required for the bistability. Furthermore, interaction of CI at O(R) represses transcription from the lysogenic promoter, P(R). Thus, CI regulates its own transcription. Interaction of CI at O(L) represses transcription from the lytic promoter, P(L). The presence of only O(L) (absence of O(R) and O(D)) is enough to maintain a bistable system. The distantly located operator site, O(D), functions as a helper site by increasing binding of CI at O(R) and O(L). In the immune state, O(D) increases repression of the lytic promoter, P(L). Our results strongly support the model that a hexameric form of CI binds cooperatively to the three operator sites in the immune state forming a CI-DNA loop structure. Finally, we show that in the anti-immune state, repression of the lysogenic promoter is independent of the known CI operator sites but requires the presence of both CI and MOR.


Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis.
Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia with a concomitant expansion of CD4-CD8- double-negative (DN) αβ and Vδ2- γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES- phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients' T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients' total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αβ T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ-producing T cell subsets, thereby underlying TB.


When does methadone treatment reduce arrest and severity of arrest charges? An analysis of arrest records.
This is an analysis of the odds of arrest, severity of charges, and factors predicting these outcomes in the year after methadone treatment entry using arrest records of patients (N=289) participating in two opioid treatment programs (OTPs) in Baltimore, MD as part of a previously-reported study. Baseline Addiction Severity Index data were examined along with publicly-available dates of arrest and arrest charges from the year before and after OTP entry. Severity of charges was rated independently by three researchers using a 1-7 point scale. Data were analyzed using Generalized Estimating Equations and Multiple Regression. The majority of the patients had no arrests over both time periods (61.6% and 65.7%, respectively). Of those arrested, the majority of the sample were charged with non-severe crimes in the year before and after OTP entry (82.9% and 73.7%, respectively). There were no significant differences in the odds of arrest or severity of charges in the year before versus the year after OTP admission (both ps>0.05). Predictors of arrest following admission included an arrest in the year prior to admission (p<0.001), younger age (p<0.001), and more lifetime months of incarceration (p=0.045). Predictors of the higher severity of charges included younger age (p<0.001), African-American race (p=0.032), and more lifetime months of incarceration (p=0.018). While in this population, the odds of arrest and severity of charges did not decrease significantly in the year following OTP entry, we discuss the need to avoid generalizing findings without considering those factors that may influence the likelihood of post-OTP entry arrest.


Application of LC/MS and related techniques to high-throughput drug discovery.
The broad coordinated implementation of common platform technologies, such as LC/MS, can be a key factor in attaining increased throughput, sensitivity and data quality for pharmaceutical discovery. These platform technologies are the key tools that Medicinal Analytical Chemists rely upon to address the ever-changing needs of a drug discovery team. Despite the recent advances in key areas of sensitivity and speed for LC/MS, additional progress to address these never-ending analytical problems can be anticipated. This review will highlight current status and future advances for the applications of LC/MS and related techniques to high-throughput drug discovery.


Comparison of different labeling methods for the production of labeled target DNA for microarray hybridization.
Different labeling methods were studied to compare various approaches to the preparation of labeled target DNA for microarray experiments. The methods under investigation included a post-PCR labeling method using the Klenow fragment and a DecaLabel DNA labeling kit, the use of a Cy3-labeled forward primer in the PCR, generating either double-stranded or single-stranded PCR products, and the incorporation of Cy3-labeled dCTPs in the PCR. A microarray that had already been designed and used for the detection of microorganisms in compost was used in the study. PCR products from the organisms Burkholderia cepacia and Staphylococcus aureus were used in the comparison study, and the signals from the probes for these organisms analyzed. The highest signals were obtained when using the post-PCR labeling method, although with this method, more non-specific hybridizations were found. Single-stranded PCR products that had been labeled by the incorporation of a Cy3-labeled forward primer in the PCR were found to give the next highest signals upon hybridization for a majority of the tested probes, with less non-specific hybridizations. Hybridization with double-stranded PCR product labeled with a Cy3-labeled forward primer, or labeled by the incorporation of Cy3-labeled dCTPs resulted in acceptable signal to noise ratios for all probes except the UNIV 1389a and Burkholderia genus probes, both located toward the 3' end of the 16S rRNA gene. The comparison of the different DNA labeling methods revealed that labeling via the Cy3-forward primer approach is the most appropriate of the studied methods for the preparation of labeled target DNA for our purposes.


Heme oxygenase-derived endogenous carbon monoxide impairs flow-induced dilation in resistance vessels.
Vascular tissues normally express heat shock protein 32 (heme oxygenase [HO] 1), which degrades heme. A product of this reaction, carbon monoxide (CO), has been shown to promote relaxation of vascular smooth muscle, but it also inhibits NOS. Because flow-induced dilation is dependent upon the formation of endothelium-derived NO, we conducted the current study to determine if HO-mediated formation of CO impairs flow-induced dilation. In isolated pressurized first-order gracilis muscle arterioles, proximal and distal pressures were manipulated to generate intraluminal flows of 0 to 50 microL/min at a constant vascular midline pressure of 80 +/- 1 mmHg. Vehicle-treated vessels displayed flow-related vasodilation, which was abolished by a NOS inhibitor, Nomega-nitro-L-arginine methyl ester. Acute intraluminal pretreatment with an inhibitor of HO, chromium mesoporphyrin (CrMP), enhanced flow-induced responses in similarly prepared vessels. In contrast, a substrate for heme formation that drives CO generation, delta-aminolevulinic acid, abolished flow-induced dilation in a manner which could be fully prevented and reversed by CrMP. In addition, the HO product biliverdin had no effect on flow-induced dilation, whereas the responses were abolished by exogenous CO. Furthermore, spontaneous generation of CO was measured in isolated vascular segments to confirm that delta-aminolevulinic acid increased carbon formation by 29%, whereas CrMP reduced it by 43%. These data show flow-induced dilation can be impaired by a HO product, and that the impairment was not produced by biliverdin but is mimicked by CO. These results suggest that the HO-generated CO attenuates flow-induced dilation in the vasculature and, accordingly, may contribute to vascular dysfunction after injury.


The clinical significance of Mycobacterium triplex.
Mycobacterium triplex is a slow-growing nontuberculous mycobacteria (NTM) and is a rare cause of human disease. The pathogenicity, natural history and spectrum of disease is unknown. The aim of this study was to review the clinical features, outcomes and drug susceptibility testing (DST) of all M. triplex isolates in Queensland, Australia to guide management of this rare NTM infection in the future. This retrospective study included all patients who isolated M. triplex in Queensland, Australia from the 1st January 2000 to 31st December 2016. Clinical information was obtained from medical records to determine the clinical significance of isolates, natural history of disease and treatment outcomes. DST was performed on 15 isolates. Forty-three patients (21 male) had positive cultures for M. triplex. Thirty-nine patients had isolates from pulmonary specimens and 17 (43.6%) met the American Thoracic Society criteria for NTM lung disease. Six patients with pulmonary infection received antimicrobial therapy with 5 patients demonstrating treatment success. Four patients had localised extrapulmonary disease and were cured with surgical management ± antimicrobial therapy. DST suggests 93% of isolates are susceptible to macrolides. This is the largest case series of M. triplex isolates and confirms it is a rare human pathogen. Extrapulmonary disease responded well to surgical management. Treatment of M. triplex pulmonary disease is challenging, and the optimal antimicrobial regimen is unknown. However, the DST data suggests macrolide resistance is rare and macrolides should be included in treatment regimens.


Nucleic acid testing (NAT) for HCV RNA in Italian transfusion centres: an external quality assessment.
We conducted an external quality assessment of the results obtained in Italian transfusion centre laboratories employing nucleic acid testing (NAT) for detection of HCV RNA in donated blood. Of 110 transfusions centres in Italy, 101 voluntarily participated. Each laboratory received seven separate shipments of samples for HCV RNA testing by NAT. Each shipment contained 8 plasma samples for a total of 23 negative and 33 positive samples with viral loads ranging from 25 to 1000 IU/mL. Of the 2080 HCV RNA-negative samples, 14 (0.7%) were reported as positive. The highest percent of false-negative results (6.9%) was found on samples from the first shipment with viral loads from 75 to 100 IU/mL. In subsequent shipments, the highest false-negative percentage ranged from 0.6% for samples with viral loads of 170-1000 IU/mL to 3.4% for samples with viral loads of 35-50 IU/mL. A false-negative rate of 4.9% occurred in samples in the sixth shipment with the lowest viral load (25IU/mL). Five (4.9%) centres were identified as having laboratories with low-performance. There were no significant differences among genotypes 1b, 2c and 3a with respect to percent of false-negative results reported. Overall, the accuracy of NAT observed in this study of Italian transfusion centre laboratories was excellent for all HCV genotypes tested, even for samples with low HCV RNA titres.


Interactions between species and environments from incomplete information.
There are two contradictory aspects of the adaptive process in evolution. The first is that species must optimally increase their own fitness in a given environment. The second is that species must maintain their variation to be ready to respond to changing environments. In a strict sense, these two aspects might consider to be mutually exclusive. If species are optimally adapted, then the variation in the species that is suboptimal decreases and vice versa. To resolve this dilemma, species must find a balance between optimal adaptation and robust adaptation. Finding the balance between these processes requires both the local and global complete, static information. However, the balance between the processes must be dynamic. In this study, we propose a model that illustrates dynamic negotiation between the global and local information using lattice theory. The dynamic negotiation between these two levels results in an overestimate of fitness for each species. The overestimation of fitness in our model represents the multiplicity of fitness which is sometimes discussed as the exaptation. We show that species in our model demonstrate the power law of the lifespan distribution and 1/f fluctuation for the adaptive process. Our model allows for a balance between optimal adaptation and robust adaptation without any arbitrary parameters.


Dual-objective STORM reveals three-dimensional filament organization in the actin cytoskeleton.
By combining astigmatism imaging with a dual-objective scheme, we improved the image resolution of stochastic optical reconstruction microscopy (STORM) and obtained <10-nm lateral resolution and <20-nm axial resolution when imaging biological specimens. Using this approach, we resolved individual actin filaments in cells and revealed three-dimensional ultrastructure of the actin cytoskeleton. We observed two vertically separated layers of actin networks with distinct structural organizations in sheet-like cell protrusions.


Crucial ignored parameters on nanotoxicology: the importance of toxicity assay modifications and "cell vision".
Until now, the results of nanotoxicology research have shown that the interactions between nanoparticles (NPs) and cells are remarkably complex. In order to get a deep understanding of the NP-cell interactions, scientists have focused on the physicochemical effects. However, there are still considerable debates about the regulation of nanomaterials and the reported results are usually in contradictions. Here, we are going to introduce the potential key reasons for these conflicts. In this case, modification of conventional in vitro toxicity assays, is one of the crucial ignored matter in nanotoxicological sciences. More specifically, the conventional methods neglect important factors such as the sedimentation of NPs and absorption of proteins and other essential biomolecules onto the surface of NPs. Another ignored matter in nanotoxicological sciences is the effect of cell "vision" (i.e., cell type). In order to show the effects of these ignored subjects, we probed the effect of superparamagnetic iron oxide NPs (SPIONs), with various surface chemistries, on various cell lines. We found thatthe modification of conventional toxicity assays and the consideration of the "cell vision" concept are crucial matters to obtain reliable, and reproducible nanotoxicology data. These new concepts offer a suitable way to obtain a deep understanding on the cell-NP interactions. In addition, by consideration of these ignored factors, the conflict of future toxicological reports would be significantly decreased.


The N-acetylglucosamine-specific receptor of the thyroid. Binding characteristics, partial characterization, and potential role.
The binding characteristics of the GlcNAc binding protein present in thyroid membranes (Consiglio, E., Shifrin, S., Yavin, Z., Ambesi-Impiombato, F.S., Rall, J.E., Salvatore, G., and Kohn, L.D. (1981) J. Biol. Chem. 256, 10592-10599) were reinvestigated using neoglycoproteins as probes. Plasma membrane preparations from porcine thyroid specifically bound 125I-GlcNAc35-bovine serum albumin. Binding was dependent on the presence of calcium. Binding of ligand to receptor was minimal at neutral pH and maximal at pH 5.0. Equilibrium binding studies indicated positive cooperativity of binding and a site capacity of about 60 pmol/mg of protein. Competition studies were compatible with a specificity hierarchy of GlcNAc much greater than Gal; no recognition of mannose, fucose, or glucose moieties was noted. The receptor was detergent-solubilized from plasma membrane preparations and on the basis of the defined binding properties, purified by chromatography on a GlcNAc-Sepharose affinity column. The purified GlcNAc thyroid receptor has a subunit molecular size of about 45 kDa and appears to be an oligomer composed of three subunits. The receptor was identified as a component of thyrocytes by in situ cytochemical localization with fluorescent neoglycoproteins. In certain cases it was mainly present on, or near, the apical cell surface. It is suggested that this GlcNAc receptor functions in thyroglobulin metabolism, possibly involved in recycling of internalized thyroglobulin molecules back into the follicular lumen.


Mechanobiological based long bone growth model for the design of limb deformities correction devices.
A mechanobiological model of bone growth aimed for the design of medical devices for the treatment of limb deformities during childhood and adolescence was developed. Dimensional analysis was introduced as a tool for the systematic evaluation of the influence attributed to different factors that might modify the bone growth process. Simplifications were proposed, allowing the reduction of bone growth relevant parameters to four non-dimensional numbers, representing the chondrocyte sensitivity to stress, the epiphyseal plate geometry, the bone rigidity and the time. Benchmark situations considered for model validation were bone growth under normal conditions and an epiphyseal stapling treatment. A finite elements approach was used to analyze bone growth in the distal portion of the femur. Results are shown to be consistent with corresponding clinical data published in the literature, which indicates the potential of the here proposed method for the design of specific devices and treatments.


Salidroside inhibits endogenous hydrogen peroxide induced cytotoxicity of endothelial cells.
Salidroside, a phenylpropanoid glycoside isolated from Rhodiola rosea L., shows potent antioxidant property. Herein, we investigated the protective effects of salidroside against hydrogen peroxide (H2O2)-induced oxidative damage in human endothelial cells (EVC-304). EVC-304 cells were incubated in the presence or absence of low steady states of H2O2 (3-4 µM) generated by glucose oxidase (GOX) with or without salidroside. 3(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH) assays were performed, together with Hoechst 33258 staining and flow cytometric analysis using Annexin-V and propidium iodide (PI) label. The results indicated that salidroside pretreatment attenuated endogenous H2O2 induced apoptotic cell death in EVC-304 cells in a dose-dependent pattern. Furthermore, Western blot data revealed that salidroside inhibited activation of caspase-3, 9 and cleavage of poly(ADP-ribose) polymerase (PARP) induced by endogenous H2O2. It also decreased the expression of Bax and rescued the balance of pro- and anti-apoptotic proteins. All these results demonstrated that salidroside may present a potential therapy for oxidative stress in cardiovascular and cerebrovascular diseases.


Immunological consequence of renal transplantation and immunosuppression. I. Alterations in human natural killer-cell activity.
The role and activity of natural killer (NK) cells following renal transplantation remain unknown. To monitor NK activity, a 51Cr release of K-562 targets in prednisone- and azathioprine-treated patients receiving renal allografts was utilized. In 18 patients in whom NK activity was measured prior to and after transplantation, a significant diminution in NK activity within 3 weeks following transplantation was demonstrated compared to pretransplant values (34.71 vs 12.20%, respectively; P less than 0.001). In 11 subjects who had NK activity assayed at various intervals after transplantation but not prior to allografting, mean NK values were markedly lower (mean, 14.2%) than those of normal volunteers or patients maintained on hemodialysis (P less than 0.001). The latter two control groups demonstrated no difference (P = NS) in mean NK activity (39.46 vs 35.82%, respectively). In 5 of the 29 patients evaluated with good long-term graft function (mean, 2.7 years), restitution of normal NK activity was demonstrated. In two patients with bacterial infections, NK activity increased from 39.29 to 51.7% and from 13.54 to 20.00%. After infection, these values were 35.3% in the former and 3.39% in the latter. Viral infection did not appear to affect NK activity significantly. NK activity was increased in only one of seven patients with documented rejection episodes. In three of such patients, NK activity declined significantly following pulse methylprednisolone therapy.(ABSTRACT TRUNCATED AT 250 WORDS)


The cardiac protection of Baoyuan decoction via gut-heart axis metabolic pathway.
Gut-heart axis has emerged as a novel concept to provide new insights into the complex mechanisms of heart failure (HF) and offer new therapeutic targets. Cardiac hypertrophy (CH) is one of the etiological agents contributing to the development of HF. Baoyuan Decoction (BYD), a traditional Chinese medicine (TCM) formula, exhibits unambiguous effects on treating CH and preventing HF. Previously, we have reported that BYD-targeted endogenous metabolites are potentially linked to gut microbiota metabolism, but the contribution of gut microbiota and metabolic interaction to the cardioprotective efficacy of BYD remains to be elucidated. To investigate whether the gut microbiota plays a key role in anti-CH effects of BYD. A comprehensive strategy via incorporating pharmacodynamics, microbiomics, metabolomics, and microflora suppression model was adopted to investigate the links between the microbiota-host metabolic interaction and BYD efficacy in CH rats. Firstly, the efficacy evaluation of BYD in treating chronic isoproterenol (ISO)-induced CH rats was performed by using multiple pharmacodynamic approaches. Then, the fecal metabolomics and 16S rRNA sequencing techniques were used to obtain the microbial and metabolic features of BYD against CH. After that, the potential gut-heart axis-based mechanism of BYD against CH was predicted by bioinformatic network analysis and validated by multiple molecular biology approaches. Finally, the antibiotics (AB)-induced gut microbiota suppression was employed to investigate whether the anti-CH effects of BYD is associated with the gut microflora. The fecal microbial communities and metabolic compositions were significantly altered in ISO-induced CH rats, while BYD effectively ameliorated the CH-associated gut microbiota dysbiosis, especially of Firmicutes and Bacteroidetes, and time-dependently alleviated the disturbance of fecal metabolome and reversed the changes of key CH and gut microbiota-related metabolites, such as short/medium chain fatty acids, primary/secondary bile acids, and amino acids. The mechanism study showed that the anti-CH effect of BYD was related to inhibition of the derivatives of arginine and tryptophan and their downstream pro-hypertrophic, pro-inflammatory, and pro-oxidant signaling pathways. The following microflora suppression test showed that BYD-mediated myocardial protection was decreased either in pharmacodynamics or in metabolic modulation. This study demonstrates that the protection of BYD against CH is partially gut microbiota dependent, and the regulatory effects of gut metabolism-related tryptophan and arginine derivatives is an important cardioprotection mechanism of BYD.


Coronary artery bypass grafting and aortic valve replacement with cold cardioplegia in a patient with cold-induced urticaria.
Cold-induced urticaria is an uncommon but well described phenomenon in which a spectrum of responses may result from exposure to a cold stimulus. Patients with cold-induced urticaria who require cold cardiopulmonary bypass are at risk for hypotensive episodes. To describe the case of a 69-year-old man with documented cold-induced urticaria who required aortic valve replacement and coronary artery bypass surgery. After receiving a prophylactic anti-inflammatory regimen, the patient underwent cold cardiopulmonary bypass. After systemic cooling to 32 degrees C, cold blood cardioplegia was administered at 4 degrees C to obtain initial cardiac standstill. Thirty minutes before anticipated rewarming, anti-inflammatory medications were again administered. After rewarming to 37 degrees C for more than 33 minutes, he was successfully weaned from cardiopulmonary bypass without inotropic or pressor support and with normal pulmonary compliance. The prophylactic regimen was continued postoperatively. The patient was extubated 11 hours after surgery, and with the exception of a brief, self-limited episode of atrial fibrillation, his course was uneventful. He experienced no urticaria, angioedema, or hypotension and was discharged home on the fourth postoperative day. Although it is likely that the need for cold cardiopulmonary bypass surgery in patients with cold-induced urticaria is uncommon, it is encouraging that such a regimen may allow for the successful completion of the surgery.


Catastrophic thinking about pain increases discomfort during internal atrial cardioversion.
This study investigated whether pain catastrophizing is associated with distress and perceived disability in patients with atrial fibrillation, whether pain catastrophizing predicts pain and fear during a medical procedure of atrial cardioversion, and whether pain catastrophizing influences the effects of an opioid analgesic during internal cardioversion. A secondary analysis is performed upon data from a double-blind placebo-controlled trial during which the effect of intranasal butorphanol tartrate (INB) was evaluated in patients with atrial fibrillation using a step-up internal atrial cardioversion protocol. Before the procedure, patients completed measures of pain catastrophizing, mood, distress and perceived disability. After each shock, patients completed measures of pain and fear. We found that pain catastrophizing predicted the affective pain rating of the first shock, and the fear increase during subsequent shocks. There was no effect of INB. However, when controlling for the differences in pain catastrophizing, INB significantly reduced fear as compared to placebo. This suggests that the effects of INB during atrial cardioversion were overshadowed by the effects of pain catastrophizing. It is recommended that in future atrial cardioversion trials, stratification based on pain catastrophizing be performed. Reducing catastrophizing thinking about pain through cognitive-behavioral techniques are likely to reduce levels of fear during internal atrial cardioversion and may increase the effectiveness of concomitant analgesics.


SLC4A2, another gene involved in acid-base balancing machinery of osteoclasts, causes osteopetrosis.
SLC4A2 belongs to the Na+-independent solute carrier family 4 (SLC4) of anion exchangers, which regulate electroneutral exchange of Cl- for HCO3- and mediate intra- and extra-cellular pH, chloride concentration and cell volume. Slc4a2 also participates in gastric acid secretion, spermatogenesis and osteoclastogenesis. During osteoclast differentiation, Slc4a2 is exclusively expressed at the contra-lacunar membrane and is up-regulated with osteoclast maturation. Bi-allelic Slc4a2 loss-of-function mutations have been known to cause osteopetrosis in mice and cattle, but not in human. Recently, we have identified bi-allelic pathogenic variants in SLC4A2 in a patient affected by osteopetrosis with severe renal insufficiency, suggesting SLC4A2 deficiency causes a new type of autosomal recessive osteopetrosis (osteopetrosis, Ikegawa type). In this article, we review the advances in exploring the multiple functions of SLC4A2 with emphasis on its roles in osteoclast. Our review would contribute to understanding of the phenotypic spectrum and the pathomechanism of SLC4A2-associated osteopetrosis.


Central and peripheral regulation of gastric acid secretion by peptide YY.
Peptide YY (PYY) released postprandially from the ileum and colon displays a potent inhibition of cephalic and gastric phases of gastric acid secretion through both central and peripheral mechanisms. To modulate vagal regulation of gastric functions, circulating PYY enters the brain through the area postrema and the nucleus of the solitary tract, where it exerts a stimulatory action through PYY-preferring Y1-like receptors, and an inhibitory action through Y2 receptors. In the gastric mucosa, PYY binds to Y1 receptors in the enterochromaffin-like cells to inhibit gastrin-stimulated histamine release and calcium signaling via a pertussis toxin-sensitive pathway.


Combinations of three or four HIV virostatics applied in short sequences which differ from each other by drug rotation. Preliminary results of the viral loads and CD4 numbers.
This paper presents the evolution during its follow-up of a virostatic combination study of the type I-II trial conducted on ten AIDS-related complex (ARC) or acquired immunodeficiency syndrome (AIDS) patients [1, 9, respectively]. Its concept is based on the following original notions: a) it is not the number of the virostatics applied to each patient at any phase which determines their effect; it is the number of affected virus targets which determines the effect. Thus, the so called "tritherapies", imposed by the "AIDS Command" to thousands of patients selected at random, to be compared to the same number of subjects receiving only "bi" or "monotherapies", might be beginning to face failure because they attack only two targets: retro-transcriptase and HIV1 protease. Having discovered, owing to our experimental screening, original HIV1 virostatics, acriflavine (ACF) and several ellipticine analogues among which we have used methyl-hydroxy-ellipticine (MHE), we are able to attack two virus targets unaffected by classical virostatics: ACF attacks DNA, from its integrated double branched stage to the provirus one, and MHE inhibits topoisomerase II. We experimentally combined these two agents with AZT, which inhibits retro-transcriptase, thus we realized a combination affecting three targets. This three agent combination was able to eradicate Friend's virus from infected mice. Clinically, combinations of three drugs affecting four targets (as they are selected among the ten virostatics available today) give a stronger result than three drug combinations affecting only three targets, because they were selected from the five virostatics which were the only ones available at the beginning of the present study. Five patients out of five who received the combinations of four virostatics chosen among the ten currently available (thus affecting four targets) from the beginning of their treatment to the present have all reduced their viral load (VL) and maintained it below the detectable level (< 200 RNA copies/mL then 20 copies/mL); b) as the toxicities of virostatics and as HIV1 resistances may happen as soon as 12 weeks of treatment, the combinations have been, in our study, applied in shorter (3 week) sequences, differing from each other due to drug rotation; c) neither toxicity nor resistance occurred; d) curiously, the CD4 numbers, even when they increased rapidly, has never attained their normal count, and their curve may be a Gombertzian one. This CD4 restoration limitation can be due to persisting virus, as indicated in some patients by small peaks which may appear on some VL plateaus, though they disappear without treatment change.


Deposition of catechol-functionalized chitosan and silver nanoparticles on biomedical titanium surfaces for antibacterial application.
The titanium (Ti) and its alloys have been widely used for dental and orthopedic implants. However, the Ti-based implants may suffer from bacterial infection, which would result in insufficient healing, implant failure and repeated surgical intervention. It is of great interest to inhibit the bacterial adhesion and colonization on the Ti-based implants by introducing proper surface coatings. In this work, a simple method was employed to synthesize the water-soluble catechol-containing chitosan (CACS). The CACS coatings can be deposited onto various substrate surfaces and exhibit substrate-independent behavior. The CACS-coated Ti surfaces were further deposited with silver nanoparticles (Ag NPs) via in-situ reduction of Ag+ ions using catechol moieties as the reducing agents. The resulting AgNPs/CACS-coated Ti surfaces exhibit antibacterial properties and can prevent the surface adhesion of bacterial cells, as evidenced by the inhibition zone test, live/dead bacterial staining assay and spread plate method. In addition, they show negligible cytotoxicity to L929 mouse fibroblast cells.


Integration of molecular pathology with histopathology to accurately evaluate the biological behaviour of WHO grade 2 meningiomas and patient prognosis.
A molecular pathological grading method was tested in WHO grade 2 meningiomas to judge whether this molecular grading can more accurately evaluate meningioma biological behaviour. The medical records and paraffin-embedded tissues of surgically resected WHO grade 2 meningioma patients in our department from January 1, 2010, to December 31, 2020, were collected. The molecular pathological risk grading suggested by Sahm et al. was adopted and the patients were graded as low, intermediate and high risk. Progression-free survival (PFS), malignant progression-free survival (MPFS) and overall survival (OS) were analysed. Univariate and multivariate analysis were performed to determine the relationship between molecular risk grading and patient survival. Of the 98 patients, 13 (13.2%) were graded as low risk, 63 patients (64.3%) were graded as intermediate risk, and 22 patients (22.4%) were graded as high risk. With increasing molecular risk grade, the rates of tumour recurrence, malignant progression and mortality increased significantly (P < 0.05). Multivariate analysis showed that molecular risk grading was negatively associated with PFS (HR 0.018, 95% CI 0.003-0.092), MPFS (HR 0.040, 95% CI 0.006-0.266) and OS (HR 0.088, 95% CI 0.016-0.472) (P < 0.01), and gross total resection (Simpson grade I-III) significantly prolonged PFS (HR 5.882, 95% CI 2.538-13.699) and OS (HR 2.611, 95% CI 1.117-7.299) (P < 0.05). Sahm et al.'s molecular risk grading can further refine the classification of WHO grade 2 meningiomas and more accurately evaluate their biological behaviour and patient prognosis.


Dealing with menstrual cycle in sport: stop finding excuses to exclude women from research.
The current literature is mostly male-based, limiting evidence-based recommendations for training individualization for female athletes. Recently, studies have relied on recent findings showing a potential effect of the menstrual cycle to exclude female athletes from their samples. We highlight that the arguments usually put forward to this action are not acceptable. Our discussion aims to elucidate that female physiological parameter can be confounding variables in the same way than other parameters (temperature, nutrition, fatigue, etc.). Those are usually well handled in most studies. This is important to bridge the current sex data gap and promote research on female athletes. Specially, as we approach the next Olympic Games, were, for the first time, there will be full gender parity in terms of athlete numbers at the Olympic Games Paris 2024.


Distribution of distinct vacA, cagA and iceA alleles in Helicobacter pylori in Hong Kong.
There is a substantial genetic heterogeneity among Helicobacter pylori strains, and certain genotypes have been suggested to be associated with the virulence of this pathogen. The aim of this study was to investigate the distribution of H. pylori vacA, cagA and iceA genotypes and their association with duodenal ulcer disease in Hong Kong. Gastric biopsies of 72 H. pylori infected patients were analyzed by specific polymerase chain reactions. Of the 72 cases, 69 (95.8%) had vacA signal sequence s1c strains, and three (4.2%) had s1a strains. vacA middle region sequences, m1b and m2, were detected in 23 (31.9%) and 46 (63.9%), respectively. Six (8.3%) cases contained multiple vacA subtypes. vacA s2 allele was only observed in three (4.3%) cases, which were also infected with s1c subtype. cagA was present in 64 (88.9%) of 72 patients, and iceA1 subtype was detected in 46 (63.9%) cases. Neither cagA nor vacA and iceA were associated with duodenal ulcer disease. The distribution of vacA, cagA and iceA alleles in H. pylori strains in Hong Kong is similar to that in east Asia. There is a difference in the distribution of genotypes between strains in Hong Kong and those in mainland China, although strains in the two regions exhibit a very close relation. The association of these virulence genes and duodenal ulcer disease needs reappraisal, particularly under geographic considerations.


Excitotoxic increase of xanthine dehydrogenase and xanthine oxidase in the rat olfactory cortex.
Excitotoxic lesions induced by systemic injection of kainic acid, resulted in 2-3-fold increase of xanthine dehydrogenase and xanthine oxidase activities in the rat olfactory cortex 48-72 h after drug administration. A significant increase of the xanthine oxidase/dehydrogenase ratio was also observed at 4 and 48 h post-injection. No similar changes were noticed in the hippocampus. The enhancement of enzyme activity seems to be primarily a consequence of the altered cell composition in damaged area. Free radicals produced by the increased oxygen-dependent form of the enzyme could in turn aggravate the excitotoxic brain injury.


Retracted: Extracting Behavior Identification Features for Monitoring and Managing Speech-Dependent Smart Mental Illness Healthcare Systems.
[This retracts the article DOI: 10.1155/2022/8579640.].


Desferrioxamine B: reversible side effects of high daily doses.
16 patients with chronic liver or haematologic diseases were parenterally given various doses of Desferrioxamine B (DF). Each daily dose of DF (from 1 to 4 g) was given for a 7 days cycle. Liver, kidney and blood functions were investigated at the first and seventh day of each cycle, and 1 and 2 weeks after therapy was stopped. 1 g/day and 2 g/day had no side effects, with the exception of a fall of white blood cell (WBC) count in a single case on 2 g/day. 3 g/day (15 patients) were followed by rises of blood urea, creatinine, alkaline phosphatase and glutamyl-transpeptidase respectively in 4 cases, and by falls of WBC count in 3 cases. 4 g/day (9 patients) caused rises of creatinine, GPT and GOT (1 case) or LDH (1 case), while WBC count dropped in 4 cases. All changes were reversible within one-two weeks. These recorded changes were outside the range of pretreatment values as obtained over the previous four weeks.


[Effects of isoproteic and lipid rich diets on lipase, phospholipase A2, cholesterolesterase, trypsin and amylase activities in rat pancreatic juice and pancreas (author's transl)].
Isoproteic and lipid-rich diets containing about 15 or 20 % of sun flower triglyceride or soya phospholipids given to rats for 8 weeks were observed to increase lipase, phospholipase A2 and trypsin synthesis in the pancreas phospholipase A2 and trypsin synthesis in the pancreas and the activities of these enzymes in the pancreatic juice (Tables IV, V). Smaller effects are observed after 15 day administration of diets containing 40 % of triglycerids or phospholipids ; these diets decreased the ADN content of pancreas.


Stepwise developmental regression associated with novel CACNA1A mutation.
Mutations in CACNA1A were previously described in familial hemiplegic migraine, episodic ataxia type 2, and spinocerebellar ataxia type 6. We report on an 11-year-old girl with episodes of seizures, ataxia, headache, a decreased level of consciousness, and motor regression, with a background of mental retardation and mild cerebellar atrophy. Sequence analysis of the CACNA1A gene revealed a de novo Ile712Val sequence variant, which was not reported previously.


Amiodarone, Verapamil, or Diltiazem Use With Direct Oral Anticoagulants and the Risk of Hemorrhage in Older Adults.
Routinely used cardiac medications, based on pharmacokinetics, are hypothesized to increase drug levels of direct oral anticoagulants (DOACs), with the potential to increase the risk of hemorrhage. We set out to compare the risk for hemorrhage following initiation of amiodarone, verapamil, or diltiazem (moderate cytochrome P450 3A4 and/or P-glycoprotein activity) vs metoprolol or amlodipine (weak or no activity), among older adults prescribed DOACs. We conducted a population-based, retrospective cohort study of all adults (aged ≥ 66 years) on a DOAC (dabigatran, apixaban, rivaroxaban; n = 295,038) who were newly prescribed amiodarone (n = 4872), verapamil (n = 1284), or diltiazem (n = 14,638), compared with metoprolol or amlodipine, from Ontario, Canada (2009-2016). The outcome was hospital admission or emergency room visit with a major hemorrhage (upper or lower gastrointestinal tract, intracranial), examined using weighted models. A total of 1737 hemorrhage events occurred (amiodarone, 80 [1.6%] vs metoprolol 503 [2.3%]; verapamil, 32 [2.5%] vs amlodipine, 406 [1.6%]; diltiazem, 312 [2.1%] vs amlodipine, 404 [1.5%]). The weighted risk of major hemorrhage was not elevated with amiodarone, verapamil, or diltiazem initiation in DOAC users, compared to metoprolol or amlodipine, during the full follow-up period (hazard ratio [HR; 95% confidence interval]: amiodarone HR 0.77 [0.61-0.97]; verapamil HR 1.32 [0.88-1.98]; diltiazem HR 0.99 [0.85-1.15]). This finding was consistent with a broader definition of bleeding, adjusting for kidney function, by DOAC type or dosage. Hemorrhage risk with amiodarone, verapamil, and diltiazem was similar to that with comparators, among DOAC users aged > 66 years.


The provocative radiographic traction test for diagnosing craniocervical dissociation: a cadaveric biomechanical study and reappraisal of the pathogenesis of instability.
Craniocervical dissociation is a rare but serious condition, and missed injuries have been associated with poor neurologic outcomes and deterioration. A fluoroscopic traction test is employed to interrogate the craniocervical ligaments when clinical and imaging findings are equivocal. However, no specific protocol or known parameters with respect to traction or force applied have been established. This study sought to define the parameters of the radiographic traction test with sequential sectioning of the primary ligamentous restraints under controlled distraction of the craniocervical junction in a biomechanical model. This is a cadaveric biomechanical study. A custom loading apparatus applied traction forces in six specimens (O-C3) and the following ligaments were sectioned: alar, tectorial membrane, and occiput-C1 capsules to simulate varying degrees of craniocervical dissociation. Traction was applied 0 to 20 lb with fluoroscopy. Digital image analysis quantified the relative displacements of C0-C1, average craniocervical excursion, and under what load could a 2-mm craniocervical displacement be reproducibly recorded. A weight-distance table was produced and showed a marked loss of stability with sectioning of the ligaments and across all specimens in a similar pattern. Minimal translation was noted with sectioning of two of three ligaments in any order (<1-2 mm). All specimens exhibited a firm restraint to dissociation until the last of the three stabilizers was sectioned. Thus an "all-or-none" restraint to instability is present. All specimens failed at a weight of 5-10 lb (>2 mm). The current knowledge base of craniocervical injuries is very limited. This study shows that the key restraints to craniocervical instability are the alar ligaments, tectorial membrane, and the atlantooccipital joint capsules. Dissociation requires the complete incompetence of all three. The craniocervical traction test reliably demonstrates instability and requires no more than 5-10 lb of traction to perform.


Synthesis of Fe3O4 poly(styrene-glycidyl methacrylate) magnetic porous microspheres and application in the immobilization of Klebsiella sp. FD-3 to reduce Fe(III)EDTA in a NO(x) scrubbing solution.
Magnetic poly(styrene-glycidyl methacrylate) porous microspheres (MPPM) with high magnetic contents were prepared by surfactant reverse micelles and emulsion polymerization of monomers, in which the well-dispersed Fe(3)O(4) nanoparticles were modified by polyethylene glycol (PEG) and oleic acid (OA) respectively. The characterizations showed that both of the OA-MPPM and the PEG-MPPM were ferromagnetic, however, the OA-MPPM was used to immobilize the bacteria for more advantages. Therefore, the effects of monomer ratio, surfactant, crosslinker and amount of Fe(3)O(4) on the structure, morphology and magnetic contents of the OA-MPPM were investigated. Then, the OA-MPPM was utilized to immobilize Klebsiella sp. FD-3, an iron-reducing bacterium for Fe(III)EDTA reduction applied in NO(x) removal. Compared with free bacteria, the immobilized FD-3 showed a better tolerance to the unbeneficial pH and temperature conditions.


Purification and preliminary biochemical characterisation of the human and rat forms of the central nervous system-specific molecule, F3-87-8.
The F3-87-8 monoclonal antibody recognises a phylogenetically conserved antigenic determinant found exclusively in the mammalian CNS. We used this monoclonal antibody as the major purification step for obtaining pure. F3-87-8-bearing molecules from rat and human brains for biochemical analysis. In both rat and man, the F3-87-8 molecule is a heavily glycosylated protein, consisting of 47.6 and 47.0% carbohydrate by weight, respectively. In both species, it occurs as a doublet on polyacrylamide gel electrophoresis in sodium dodecyl sulphate, the Mr of the human form being 130,000 and 100,000. In the rat, the Mr of the doublet is slightly but consistently lower than in man, and the higher-Mr band is more pronounced. The amino acid composition of the rat and human forms is virtually identical, with a high content of serine and threonine. Significant differences are seen in carbohydrate composition, the rat form containing more sialic acid and neutral sugar and less hexosamine than the human form. beta-Elimination studies, in conjunction with carbohydrate analysis, suggest the presence of approximately 40 O-linked and 10-15 N-linked oligosaccharides per polypeptide chain of 500 amino acids, the N-linked chains predominantly of the high-mannose type. This makes it likely that the molecule adopts an extended rather than a coiled conformation on the membrane.


Protozoan myoglobin from Paramecium caudatum. Its unusual amino acid sequence.
A protozoan myoglobin (or monomeric hemoglobin) was isolated from Paramecium caudatum, and its complete amino acid sequence determined. It consists of 116 amino acid residues with a molecular mass of 12,565 daltons, this being much smaller than sperm whale myoglobin by 37 residues and even smaller than a bacterial hemoglobin from Vitreoscilla by 30 residues in terms of the monomer unit. A computer search showed no notable sequence homology with other hemoproteins. It contains two histidine residues at positions 68 and 84, but other lines of evidence seem to be needed to complete their final alignment. This is the first protozoan myoglobin to be sequenced. It may provide us with a new molecular basis for a further understanding of myoglobin-hemoglobin chemistry and their evolution.


Investigation of time-dependent alterations in adipokine levels and endoplasmic reticulum stress markers in obese patients with laparoscopic sleeve gastrectomy.
We aimed to investigate the time-dependent alterations of serum, adipose tissue WISP1, Nrg4, asprosin, SPX adipokines and serum ER stress markers GRP78, XBP1, ATF6, CHOP in obese patients who underwent laparoscopic sleeve gastrectomy (LSG). Morbidly obese patients (n = 19) and normal-weight individuals (n = 19) were compared. Preoperative (control, obese) and postoperative 1st, 3rd and 6th month (obese) follow-up measurements were obtained. Levels of adipokines, ER stress markers were measured with commercial kits. Body mass index (BMI), total fat, trunk fat mass, fat percentage of obese patients decreased after LSG. Postoperative serum glucose, insulin, HOMA-IR, triglyceride levels of obese patients decreased, HDL increased. In obese patients, preoperative LDL and total cholesterol, which were not different from control, were higher in the postoperative 6th month measurements. Omentum WISP1, subcutaneous adipose tissue WISP1 and SPX, and serum WISP1, asprosin, CHOP levels were higher, Nrg4 lower in obese patients. Serum Nrg4 was still lower in the postoperative 1st month measurements, while WISP1 was higher in the 3rd and asprosin in the 3rd, 6th months compared to control. 1st and 3rd month ATF6 and 3rd month CHOP concentrations were lower than preoperative values. Serum CHOP measured at the 6th month was significantly higher than control. Negative correlations were observed between serum Nrg4 and fat percentage, TG concentration. CHOP was negatively correlated with fat percentage. The correlations between changes in serum Nrg4, CHOP and fat percentage highlight the roles of Nrg4 and CHOP in the fat loss following LSG.


Surface-antigen expression profiling (SEP) in B-cell chronic lymphocytic leukemia (B-CLL): Identification of markers with prognostic relevance.
Studies of gene expression profiling (GEP) have been successfully used for the identification of molecules to be employed as potential prognosticators. With the aim of identifying the immunophenotypic profile of B-CLL subsets with different prognoses, we investigated by flow cytometry the expression of 36 surface antigens in 117 cases, 113 with survival data. In analogy with GEP, results were analyzed by applying unsupervised hierarchical algorithms (surface-antigen expression profiling, SEP). Distinct immunophenotypic groups (A, B1, B2 and C) were identified, group C (57/117) with longer survivals, as compared to groups A (23/117), B1 (16/117) and B2 (21/117). The immunophenotypic signatures of these groups were characterized by the coordinated and differential over-expression of: i) CD62L, CD54 and CD49c (group C); ii) CD38 and CD49d (group A); iii) none of the above markers (group B1 and B2). Other molecules were either not expressed, widely expressed by all samples, or were variably expressed within the observed B-CLL subgroups, although without a clearly distinguishable pattern. By employing an identical approach for investigating the reactivity of B-cell panel monoclonal antibodies (B-mAbs) in B-CLLs (29 cases) and in 19 B and non-B leukemia/lymphoma cell lines, we found mAbs (B012, B001, B006, B018, B019, B020, B017) mainly unreactive in all the samples, mAbs (B002, B010, B013, B014, B015) strongly reactive in B-CLLs and B-cell lines but not in non-B-cell lines, and mAbs recognizing antigens variably expressed in cell lines and B-CLLs. A hierarchical clustering focused on B-CLLs alone, combining reactivity values for B-mAbs with the expression of CD62L and CD38, these latter antigens identified as leader markers of B-CLL subsets with different prognosis, demonstrated a correlation between CD62L expression and the reactivity of B007, B003, B011 and B005 mAbs. These mAbs may represent potentially novel markers with prognostic relevance in B-CLLs.


The postweaning social isolation in C57BL/6 mice: preferential vulnerability in the male sex.
Social deprivation during early life can severely affect mental health later in adulthood, leading to the development of behavioural traits associated with several major psychiatric disorders including schizophrenia. This has led to the application of social isolation in laboratory animals to model the impact of environmental factors on the aetiopathology of schizophrenia. However, controversy exists over the precise behavioural profile and the robustness of some of the reported effects of social isolation rearing. Here, we evaluated the efficacy of postweaning social isolation to induce schizophrenia-related behavioural deficits in C57BL/6 mice of both sexes. The effects of social isolation clearly differed between sexes: isolated male but not female mice exhibited multiple habituation deficits and enhanced locomotor reaction to amphetamine. The preferential vulnerability in the male sex corresponds well with the earlier disease onset and poorer prognosis in male relative to female schizophrenic patients. In contrast, we observed no evidence for a disruption of sensorimotor gating in the prepulse inhibition paradigm despite the efficacy of social isolation to alter startle reactivity. With both success and failure in the induction of schizophrenia-related endophenotypes, the present study thus provides important characterizations and qualifications to the application of the social isolation model in mice. We conclude that social isolation in mice represents a valuable tool for the examination of candidate genes within the context of the "two-hit" hypothesis of the aetiological processes in schizophrenia.


Ultrasound-Based Assessment of Preperitoneal Fat as a Surrogate Marker of Cardiovascular Risk: Comparative Study Between People Living with HIV and Controls.
Optimal management of cardiovascular disease should start with the identification of subjects at subclinical stages. However, available tools are not always accurate or affordable. We assess the usefulness of ultrasound-guided measurement of abdominal fat layers as a surrogate marker of cardiovascular risk. We performed a cross-sectional, case-control, exploratory, pilot study in 10 people living with HIV (PLWH) and 10 HIV-uninfected subjects (control group) matched for age, sex, and body mass index. All participants were men 45-60 years of age, with no active disease or previous abdominal surgery; the PLWH group had been virologically suppressed for ≥2 years under stable antiretroviral therapy. The thickness of abdominal superficial and deep subcutaneous fat, preperitoneal fat, omental (periaortic) fat, and retroperitoneal (perirenal) fat was compared between both groups. Correlations between fat layers and traditional markers of cardiovascular risk were assessed. The thickness of most layers was always higher among PLWH. The differences were statistically significant for the preperitoneal fat layer (p = .04). The presence of atherosclerotic plaque was correlated with the preperitoneal fat layer in the PLWH group (odds ratio = 1.49, p = .02), and metabolic syndrome was correlated with superficial subcutaneous fat, although this was low (odds ratio = 0.54, p = .02). In the control group, several associations were found between carotid intima media thickness and abdominal fat layers. All abdominal fat layers were thicker in the PLWH group, especially preperitoneal fat, and several associations were found between specific fat layers and traditional cardiovascular risk markers. Our results suggest that the thickness of abdominal fat layers, assessed by ultrasound, could be a marker of cardiovascular risk. However, further studies with larger populations are required to confirm these findings.


Isolation and characterization of a stress-inducible Dunaliella salina Lcy-beta gene encoding a functional lycopene beta-cyclase.
The halotolerant green alga Dunaliella salina accumulates large amounts of beta-carotene when exposed to various stress conditions. Although several studies concerning accumulation and biotechnological production of beta-carotene have been published, the molecular basis and regulation of the genes involved in carotenoid biosynthesis in D. salina are still poorly known. In this paper, we report the isolation and regulation of the lycopene beta-cyclase (Lcy-beta) gene by abiotic stress. The function of this gene was determined by heterologous genetic complementation in E. coli. Gene expression and physiological analyses revealed that D. salina Lcy-beta steady-state transcript and carotenoid levels were up-regulated in response to all stress conditions tested (salt, light and nutrient depletion). The results presented here suggest that nutrient availability is a key factor influencing carotenogenesis as well as carotenoid biosynthesis-related gene expression in D. salina.


Clinical research: benefits of Bhattacharya modeling.
Bhattacharya modeling is a Gaussian method recommended by the Food and Agricultural Organization of the United Nations Guidelines for analyzing the eco-system. It is rarely used in clinical research. To investigate the performance of Bhattacharya modeling for clinical data analysis. Using as examples simulated vascular lab scores we assessed the performance of the Bhattacharya method. SPSS statistical software is used. 1. The Bhattacharya method better fitted the data from a single sample than did the usual Gaussian curve derived from the mean and standard deviation with 15 vs. 9 cuts. 2. Bhattacharya models demonstrated a significant difference at p < 0.0001 between the data from two parallel-groups, while the usual t-test and Mann-Whitney test were insignificant at p = 0.051 and 0.085. 3. Bhattacharya modeling of a histogram suggestive of certain subsets identified three Gaussian curves. We recommend that Bhattacharya modeling be more often considered in clinical research for the purpose of (1) unmasking normal values of diagnostic tests, (2) improving the p-values of data testing and (3) objectively searching subsets in the data.


Non-Epstein-Barr virus associated lymphoepithelioma-like carcinoma of the esophagogastric junction with microsatellite instability, K-ras wild type.
A 60-year-old male was admitted to our hospital for gastric cancer. Considering his general condition, total gastrectomy and dissection of regional lymph nodes were performed. Macroscopically, a 45 mm × 20 mm × 10 mm-sized, ulcero-infiltrative tumor located in the esophagogastric junction was described. Microscopically, the tumor consisted of a poorly differentiated adenocarcinoma intermingled with dense lymphoid infiltration predominantly composed of T-cell lymphocytes. The tumor cells infiltrated the submucosa, muscularis and subserosal layers of the stomach, respectively the esophageal adventitia. No metastases were noticed in the 58 regional lymph nodes. Based on the histopathological features, the diagnosis was lymphoepithelioma-like carcinoma, pT3N0 stage. In situ hybridization for Epstein-Barr virus showed no nuclear signal in tumor cells. The p53 expression was observed in fewer than 10% of the tumor cells. Real-time PCR analysis showed microsatellite instability without K-ras mutation in codon 12. No recurrences or metastases were reported 6 months after surgical intervention. No adjuvant therapy was performed.


Dendro-dendritic pentalaminar junctions in the Weaver mouse cerebellum.
The cerebellum of weaver mouse is characterized by an extensive reorganization of cell interaction secondary to the absence of mature granule cells. One yet undescribed modality of reorganization found in the hemispheres of 1-month-old animals consisted in the presence of dendro-dendritic pentalaminar junctions. The possible formation of these junctions by fusion of facing post-synaptic densities is discussed.


[Squamous cell epithelioma: retrospective analysis of a multidisciplinary approach with surgical treatment and periodontal treatment].
Retrospective analysis of a multidisciplinary approach between surgery treatment a periodontal treatment. In our experience the surgery treatment of the squamous cell carcinoma has been completed by periodontal treatment to eliminate the secondary consequences such as bleeding and salivating++ from the labial chyme.


Evidence for humoral immunodepression in NO2-exposed mice: influence of food restriction and stress.
The effects of food restriction or 20 ppm NO2 exposure on humoral immunity were investigated in normal and adrenalectomized C57Bl/6 mice. The thymic and splenic weights of sham-operated mice were similarly diminished after 4 days of NO2 exposure or 4 days of food depletion. The responses of corresponding adrenalectomized mice were less depressed. Undernutrition induced lymphoid organ involution and corticosteroids were partly involved. Plaque-forming cells (PFC) per spleen and per 10(6) cells were markedly depressed after 4 days of NO2 exposure, but less so after food deprivation. The same significant suppression of PFC was observed in adrenalectomized groups. Depression of humoral immunity was independent of stress-induced endogenous steroids. Moreover, NO2 had a specific effect on humoral immunodepression, food restriction being an associated factor.


Up-regulation of rat adipose tissue adiponectin gene expression by long-term but not by short-term food restriction.
Beneficial effects of food restriction as well as elevated circulating adiponectin concentration on the cardiovascular system, lipid metabolism and non-insulin dependent diabetes have been reported. The present article indicates that the reduction in rat body and adipose tissue weight after long-term (1 month) food restriction (either 75% or 50% of ad libitum food intake) was accompanied by the increase in serum adiponectin concentration. The increase in serum adiponectin concentration is the result of the significant increase in white adipose tissue adiponectin gene expression. In contrast to long-term food restriction, short-term (3 days) food restriction (either 75% or 50% of ad libitum food intake) did not influence body and fat mass as well as serum adiponectin concentration and white adipose tissue adiponectin mRNA level. The obtained results suggest that long-term food restriction is necessary to increase in serum adiponectin concentration that could be beneficial, to prevent some disorders associated with low serum adiponectin concentration like obesity and obesity-related diseases.


Effects of government spending on research workforce development: evidence from biomedical postdoctoral researchers.
We examine effects of government spending on postdoctoral researchers' (postdocs) productivity in biomedical sciences, the largest population of postdocs in the US. We analyze changes in the productivity of postdocs before and after the US government's 1997 decision to increase NIH funding. In the first round of analysis, we find that more government spending has resulted in longer postdoc careers. We see no significant changes in researchers' productivity in terms of publication and conference presentations. However, when the population is segmented by citizenship, we find that the effects are heterogeneous; US citizens stay longer in postdoc positions with no change in publications and, in contrast, international permanent residents (green card holders) produce more conference papers and publications without significant changes in postdoc duration. Possible explanations and policy implications of the analysis are discussed.


In vitro and in vivo DNA interaction with carbonyl-labeled (m)ethylnitrosoureas.
1. The carbonyl group of (m)ethyylnitrosoureas was found to interact with DNA both in vitro and in vivo. 2. (14C-carbonyl)radioactivity remained associated to DNA after a number of ethanolic precipitations as well as after RNase and protein digestion treatments, but was extremely labile to DNA enzymic and acid digestion. 3. Detectable amount of (14C-carbonyl)-radioactivity was still found in DNA of various rat tissues 18 days after i.p. administration of carbonyl-labeled methylnitrosourea.


Attention: Noisy Networks Are Tuned Out by the Claustrum.
The claustrum is one of the most well connected regions of the brain, yet its function has remained a mystery. A new study involving selective suppression of the activity of claustrum neurons has provided insight into the role of the claustrum in mediating attention.


Hemorrhoidal banding. A warning.
Band ligation of symptomatic internal hemorrhoids is a well-established and accepted outpatient procedure. The purpose of this paper is to alert the medical profession to potential complications and death following this procedure. Each of the four patients described in this report experienced pain and inability to urinate following banding. This report does not condemn banding but, rather, focuses on problems associated with a procedure perceived by many to be risk free.


Clinical value of ciliary assessment in bronchiectasis.
Although ciliary dysfunction and numerous ultrastructural defects have been described, and these could be etiologically important in the development of bronchiectasis, their correlation with relevant clinical parameters have not been systematically evaluated. We have prospectively evaluated the prevalence and clinical significance of ciliary beat frequency and ultrastructural defects of nasal respiratory mucosa obtained from 152 stable patients with idiopathic bronchiectasis (100F, 57.7 +/- 15.2 yrs) and 127 control subjects (58F, 56.0 +/- 24.2 yrs). Bronchiectasis patients had significantly slower ciliary beat frequency (p < 0.05), and a greater percent of patients had central and peripheral microtubular defects (OR 14.4, 95% CI 5.6-36.8), namely, extra peripheral microtubules, "9 + 1", "8 + 2", and compound cilia (p < 0.05), but not microtubular disarrangement, extra matrix or ciliary tail abnormalities (p > 0.05), than controls. Bronchiectasis patients also had a greater proportion of cilia with any ultrastructural microtubular defects, compound cilia, and ciliary tails than controls (p < 0.05). Ciliary beat frequency did not correlate with clinically relevant parameters (p > 0.05). However, the percent of cilia with central, but not peripheral, microtubular defects correlated with 24 h sputum volume (r = 0.40, p = 0.001, and r = -0.04, p = 0.70, respectively) and FEV1 (r = -0.24, p = 0.01, and r = 0.00, p = 0.99 respectively). Our results strongly suggest a pathogenic role for central microtubular defects in the development of idiopathic bronchiectasis.


Antiinflammatory triterpenoids from the fruiting bodies of Fomitopsis pinicola.
Twelve undescribed lanostane-type triterpenes, and twenty-two known triterpenes were isolated and identified from a medicinal bracket fungus Fomitopsis pinicola (Sw.) P. Karst. The structures of these compounds were determined by spectroscopic and spectrometric analyses. The antiinflammatory potential of thirty-two triterpene compounds was evaluated using neutrophils as an assay model, and pinicolasin J was the most potent inhibitor of superoxide anion generation and elastase release, with IC50 values of 1.81 ± 0.44 and 2.50 ± 0.64 μM, respectively. This study provides scientific insight into the nutritional supplement value and medicinal development of Fomitopsis pinicola.


Potential and limitations of drug targeting: an overview.
Potential and limitations of current efforts in drug targeting are discussed in terms of the criterion that targeting strategies must ultimately be gauged by their success in producing selectivity of pharmacological response thereby reducing or eliminating side effects which are not mechanism-related. A wide variety of approaches are considered, including: local drug administration, differential metabolism, carriers and vehicles, macromolecular recognition, site-specific activation and molecular specificity. Each approach is briefly assessed for its potential to be developed as a realistic candidate for human health care.