Treatment of primary glioblastoma multiforme with cetuximab, radiotherapy and temozolomide (GERT)--phase I/II trial: study protocol.
The implementation of combined radiochemotherapy (RCHT) with temozolomide (TMZ) has lead to a significant increase in overall survival times in patients with Glioblastoma multiforme (GBM), however, outcome still remains unsatisfactory. The majority of GBMs show an overexpression and/or amplification of the epidermal growth factor receptor (EGFR). Therefore, addition of EGFR-inhibition with cetuximab to the current standard treatment approach with radiotherapy and TMZ seems promising. GERT is a one-armed single-center phase I/II trial. In a first step, dose-escalation of TMZ from 50 mg/m2 to 75 mg/m2 together with radiotherapy and cetuximab will be performed. Should safety be proven, the phase II trial will be initiated with the standard dose of 75 mg/m2 of TMZ. Cetuximab will be applied in the standard application dose of 400 mg/m2 in week 1, thereafter at a dose of 250 mg/m2 weekly. A total of 46 patients will be included into this phase I/II trial. Primary endpoints are feasibility and toxicity, secondary endpoints are overall and progression-free survival. An interim analysis will be performed after inclusion of 15 patients into the main study. Patients' enrollment will be performed over a period of 2 years. The observation time will end 2 years after inclusion of the last patient. The goal of this study is to evaluate the safety and efficacy of combined RCHT-immunotherapy with TMZ and cetuximab as first-line treatment for patients with primary GBM.


Selective recovery of RNAs from bacterial pathogens after their internalization by human host cells.
Selective RNA extractions are required when studying bacterial gene expression within complex mixtures of pathogens and human cells, during adhesion, internalization and survival within the host. New technologies should be developed and implemented to enrich the amount of bacterial RNAs since the majority of RNAs are from the eukaryotic host cells, requiring high read depth coverage to capture the bacterial transcriptomes in dual-RNAseq studies. This will improve our understanding about bacterial adaptation to the host cell defenses, and about how they will adapt to an intracellular life. Here we present an RNA extraction protocol to selectively enrich the lowest bacterial RNA fraction from a mixture of human and bacterial cells, using zirconium beads, with minimal RNA degradation. Zirconium beads have higher capacity to extract bacterial RNAs than glass beads after pathogen internalization. We optimized the beads size and composition for an optimal bacterial lysis and RNA extraction. The protocol was validated on two human cell lines, differentiated macrophages and osteoblasts, with either Gram-positive (Staphylococcus aureus) or -negative (Salmonella typhimurium) bacteria. Relative to other published protocols, yield of total RNA recovery was significantly improved, while host cell infection was performed with a lower bacterial inoculum. Within the host, bacterial RNA recovery yields were about six-fold lower than an RNA extraction from pure bacteria, but the quality of the RNA recovered was essentially similar. Bacterial RNA recovery was more efficient for S. aureus than for S. typhimurium, probably due to their higher protection by the Gram-positive cell walls during the early step of eukaryotic cell lysis. These purified bacterial RNAs allow subsequent genes expression studies in the course of host cell-bacteria interactions.


Synergistic activation of PtdIns 3-kinase by tyrosine-phosphorylated peptide and beta gamma-subunits of GTP-binding proteins.
Stimulation of differentiated THP-1 cells by insulin led to rapid accumulation of PtdIns(3,4,5)P3, a product of PtdIns 3-kinase. Stimulation of the GTP-binding-protein-linked receptor by N-formylmethionyl-leucyl-phenylalanine (fMLP) also induced the accumulation of PtdIns(3,4,5)P3 in the cells. The effect of insulin was, while that of fMLP was not, accompanied by increased PtdIns 3-kinase activity in the anti-phosphotyrosine immuno-precipitate. The combination of insulin and fMLP induced more PtdIns(3,4,5)P3 production than the sum of the individual effects. The insulin-induced recruitment of PtdIns 3-kinase activity in the anti-phosphotyrosine immunoprecipitate was unaffected by the combined treatment with fMLP. To investigate the mechanism underlying the synergistic accumulation of PtdIns(3,4,5)P3, we separated the cytosolic proteins of THP-1 cells on a Mono Q column. PtdIns 3-kinase activities were eluted in two peaks, and one of the peaks markedly increased on the addition of beta gamma-subunits of GTP-binding proteins (G beta gamma). The other peak was affected only slightly by G beta gamma, but was synergistically increased by G beta gamma and a tyrosine-phosphorylated peptide which was synthesized accordingly to the amino acid sequence of insulin receptor substrate-1. The activity in the latter fraction was completely immunoprecipitated by an antibody against the regulatory subunit of PtdIns 3-kinase (p85). These results suggest that the conventional PtdIns 3-kinase (p85/p110), which has been implicated in insulin-induced cellular events, or a closely related isoenzyme is controlled by a combination of a tyrosine-phosphorylated protein and a GTP-binding protein in intact cells.


Multivariate analysis of morphological variation in accessions of Aegilops crassa from Iran.
Principal component and cluster analyses were used to evaluate the pattern of morphological variation in 122 accessions of Aegilops crassa for 14 quantitative characters. With the principal component analysis, the first five principal components with eigenvalues more than 1 contributed 69.5% of the variability amongst accessions, whereas PC6 to PC14 were less than unity. Plant height, stem diameter, spike length and number of spikelets per spike were the most important characters in the first principal component. The germplasm was grouped into five clusters using cluster analysis. Although each cluster had some specific characteristics of its own, but clusters were not clearly separated when plotted by the first two principal components. Mahalanobis distances (D2) determined that plant height, stem diameter, spike length, number of spikelets per spike, node width, seed length, seed width and flowering date characters as the most important characters in differentiating the accessions. The morphological variation of Aegilops crassa accessions obtained in this study provides useful information for the future collection and makes these genetic resources more accessible to breeders.


Structural insight into activation mechanism of Toxoplasma gondii nucleoside triphosphate diphosphohydrolases by disulfide reduction.
The intracellular parasite Toxoplasma gondii produces two nucleoside triphosphate diphosphohydrolases (NTPDase1 and -3). These tetrameric, cysteine-rich enzymes require activation by reductive cleavage of a hitherto unknown disulfide bond. Despite a 97% sequence identity, both isozymes differ largely in their ability to hydrolyze ATP and ADP. Here, we present crystal structures of inactive NTPDase3 as an apo form and in complex with the product AMP to resolutions of 2.0 and 2.2 Å, respectively. We find that the enzyme is present in an open conformation that precludes productive substrate binding and catalysis. The cysteine bridge 258-268 is identified to be responsible for locking of activity. Crystal structures of constitutively active variants of NTPDase1 and -3 generated by mutation of Cys(258)-Cys(268) show that opening of the regulatory cysteine bridge induces a pronounced contraction of the whole tetramer. This is accompanied by a 12° domain closure motion resulting in the correct arrangement of all active site residues. A complex structure of activated NTPDase3 with a non-hydrolyzable ATP analog and the cofactor Mg(2+) to a resolution of 2.85 Å indicates that catalytic differences between the NTPDases are primarily dictated by differences in positioning of the adenine base caused by substitution of Arg(492) and Glu(493) in NTPDase1 by glycines in NTPDase3.


In situ bioreduction of uranium (VI) to submicromolar levels and reoxidation by dissolved oxygen.
Groundwater within Area 3 of the U.S. Department of Energy (DOE) Environmental Remediation Sciences Program (ERSP) Field Research Center at Oak Ridge, TN (ORFRC) contains up to 135 microM uranium as U(VI). Through a series of experiments at a pilot scale test facility, we explored the lower limits of groundwater U(VI) that can be achieved by in-situ biostimulation and the effects of dissolved oxygen on immobilized uranium. Weekly 2 day additions of ethanol over a 2-year period stimulated growth of denitrifying, Fe(III)-reducing, and sulfate-reducing bacteria, and immobilization of uranium as U(IV), with dissolved uranium concentrations decreasing to low levels. Following sulfite addition to remove dissolved oxygen, aqueous U(VI) concentrations fell below the U.S. Environmental Protection Agengy maximum contaminant limit (MCL) for drinking water (< 30/microg L(-1) or 0.126 microM). Under anaerobic conditions, these low concentrations were stable, even in the absence of added ethanol. However, when sulfite additions stopped, and dissolved oxygen (4.0-5.5 mg L(-1)) entered the injection well, spatially variable changes in aqueous U(VI) occurred over a 60 day period, with concentrations increasing rapidly from < 0.13 to 2.0 microM at a multilevel sampling (MLS) well located close to the injection well, but changing little at an MLS well located further away. Resumption of ethanol addition restored reduction of Fe(III), sulfate, and U(VI) within 36 h. After 2 years of ethanol addition, X-ray absorption near-edge structure spectroscopy (XANES) analyses indicated that U(IV) comprised 60-80% of the total uranium in sediment samples. Atthe completion of the project (day 1260), U concentrations in MLS wells were less than 0.1 microM. The microbial community at MLS wells with low U(VI) contained bacteria that are known to reduce uranium, including Desulfovibrio spp. and Geobacter spp., in both sediment and groundwater. The dominant Fe(III)-reducing species were Geothrix spp.


A summary of cryptosporidiosis outbreaks reported in France and overseas departments, 2017-2020.
Cryptosporidium is a known foodborne pathogen, ranked fifth out of 24 among foodborne parasites in terms of importance and a cause of many cryptosporidiosis outbreaks worldwide. In France, very few outbreaks were reported before 2017, and data recently obtained by the Expert Laboratory of the Cryptosporidiosis National Reference Center (CNR-LE-Cryptosporidiosis) have shown that outbreaks are in fact common and frequently underreported. In this work, we aim to report the characteristics of outbreaks detected in France during the period 2017-2020 and present a summary of investigations carried out by the CNR-LE-Cryptosporidiosis. During the study period, there were eleven cryptosporidiosis outbreaks, including three with no identified origin. Among the eight identified outbreaks: six were due to water contamination (five tap water and one recreational water), one was due to direct contact with infected calves, and one was due to consumption of contaminated curd cheese. Among these outbreaks, five of them exceeded one hundred cases. Recent results obtained by the CNR-LE-Cryptosporidiosis revealed the multiannual occurrence of Cryptosporidium outbreaks in France. Waterborne outbreaks were more frequently detected, while foodborne outbreaks which are more difficult to detect were likely underreported.


NMR solution structure of type II human cellular retinoic acid binding protein: implications for ligand binding.
The structure of human apo-cellular retinoic acid binding protein II (apo-CRABPII) in solution at pH 7.3 has been determined by NMR spectroscopy. The sequential assignments of the 1H, 13C, and 15N resonances of apo-CRABPII were established by multinuclear, multidimensional NMR spectroscopy. The solution structure of apo-CRABPII was derived from 2382 experimental NMR restraints using a hybrid distance geometry-simulated annealing protocol. The root-mean-square deviation of the ensemble of 25 refined conformers that represent the structure from the mean coordinate set derived from them was 0.54 +/- 0.18 and 0.92 +/- 0.20 A for the backbone atoms and all heavy atoms, respectively, of all residues except Ala32-Pro39 and Thr57-Glu62, which are in disordered regions. The solution structure of apo-CRABPII is similar to the crystal structure of holo-CRABPII [Kleywegt, G. J., Bergfors, T., Senn, H., Le Motte, P., Gsell, B., Shudo, K., and Jones, T. A. (1994) Structure 2, 1241-1258] except the ligand entrance, which is sufficiently enlarged in the apoprotein to be readily accessible to retinoic acid. The enlargement of the ligand entrance of apo-CRABPII relative to that of holo-CRABPII is due mainly to a concerted conformational change in three structural elements, namely, the second helix, the betaC-betaD loop, and the betaE-betaF loop. Furthermore, the ligand-binding pocket of apo-CRABPII showed evidence of dynamic disorder; among the 21 residues that constitute this pocket, 16 residues had weak or no detectable cross-peaks in the two-dimensional 1H-15N HSQC spectrum recorded under conditions of minimal water saturation or dephasing. Apo-CRABPII is largely monomeric in solution, with no evidence for the dimeric structure shown in the crystal structure of apo-CRABPI which was suggested to be a prerequisite for ligand entry [Thompson, J. R., Bratt, J. M., and Banaszak, L. J. (1995) J. Mol. Biol. 252, 433-446]. Thus, the widening of the ligand entrance required for entry of retinoic acid appears to be a property of monomeric apo-CRABPII.


DNA alkylation repair limits spontaneous base substitution mutations in Escherichia coli.
The Escherichia coli Ada and Ogt DNA methyltransferases (MTases) are known to transfer simple alkyl groups from O6-alkylguanine and O4-alkylthymine, directly restoring these alkylated DNA lesions to guanine and thymine. In addition to being exquisitely sensitive to the mutagenic effects of methylating agents, E. coli ada ogt null mutants display a higher spontaneous mutation rate than the wild type. Here, we determined which base substitution mutations are elevated in the MTase-deficient cells by monitoring the reversion of six mutated lacZ alleles that revert via each of the six possible base substitution mutations. During exponential growth, the spontaneous rate of G:C to A:T transitions and G:C to C:G transversions was elevated about fourfold in ada ogt double mutant versus wild-type E. coli. Furthermore, compared with the wild type, stationary populations of the MTase-deficient E. coli (under lactose selection) displayed increased G:C to A:T and A:T to G:C transitions (10- and 3-fold, respectively) and increased G:C to C:G, A:T to C:G, and A:T to T:A transversions (10-, 2.5-, and 1.7-fold, respectively). ada and ogt single mutants did not suffer elevated spontaneous mutation rates for any base substitution event, and the cloned ada and ogt genes each restored wild-type spontaneous mutation rates to the ada ogt MTase-deficient strains. We infer that both the Ada MTase and the Ogt MTase can repair the endogenously produced DNA lesions responsible for each of the five base substitution events that are elevated in MTase-deficient cells. Simple methylating and ethylating agents induced G:C to A:T and A:T to G:C transitions in these strains but did not significantly induce G:C to C:G, A:T to C:G, and A:T to T:A transversions. We deduce that S-adenosylmethionine (known to e a weak methylating agent) is not the only metabolite responsible for endogenous DNA alkylation and that at least some of the endogenous metabolites that cause O-alkyl DNA damage in E. coli are not simple methylating or ethylating agents.


Research progress on the treatment of perimenopausal insomnia with Chaihu Jia Longgu Muli decoction based on brain-intestine-bacteria axis: A review.
With the progress and rapid societal development, women are confronted with multifaceted pressures in their lives, encompassing familial and other domains. Furthermore, during the perimenopausal phase, endocrine equilibrium is disrupted, leading to the emergence of psychological and physiological health challenges. Insomnia is a prevalent symptom among perimenopausal individuals. The brain-gut-bacteria axis assumes a pivotal role in the prevention, diagnosis, and management of perimenopausal insomnia. Chaihu Jia Longgu Muli decoction is a commonly prescribed remedy for addressing perimenopopausal insomnia. Consequently, this paper aims to investigate the interplay between the brain-gut-bacteria axis, intestinal microbiota, and the pathogenesis of perimenopausal insomnia. The study focuses on examining the regulatory effects of Chaihu Jia Longgu Muli decoction on the nervous system, intestinal microbiota, and the hypothalamus-pituitary-adrenal axis. Additionally, it explores the mechanisms underlying Hujia Longgu Muli decoction in mitigating perimenopausal insomnia.


RIFM fragrance ingredient safety assessment, hydroxycitronellal dimethyl acetal, CAS Registry Number 141-92-4.
Hydroxycitronellal dimethyl acetal was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog hydroxycitronellal diethyl acetal (CAS # 7779-94-4) show that hydroxycitronellal dimethyl acetal is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material and the exposure to hydroxycitronellal dimethyl acetal is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from hydroxycitronellal dimethyl acetal and from read-across material hydroxycitronellal diethyl acetal (CAS # 7779-94-4) show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; hydroxycitronellal dimethyl acetal is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; hydroxycitronellal dimethyl acetal was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.


A two-pronged strategy to suppress host protein synthesis by SARS coronavirus Nsp1 protein.
Severe acute respiratory syndrome coronavirus nsp1 protein suppresses host gene expression, including type I interferon production, by promoting host mRNA degradation and inhibiting host translation, in infected cells. We present evidence that nsp1 uses a novel, two-pronged strategy to inhibit host translation and gene expression. Nsp1 bound to the 40S ribosomal subunit and inactivated the translational activity of the 40S subunits. Furthermore, the nsp1-40S ribosome complex induced the modification of the 5' region of capped mRNA template and rendered the template RNA translationally incompetent. Nsp1 also induced RNA cleavage in templates carrying the internal ribosome entry site (IRES) from encephalomyocarditis virus, but not in those carrying IRES elements from hepatitis C or cricket paralysis viruses, demonstrating that the nsp1-induced RNA modification was template-dependent. We speculate that the mRNAs that underwent the nsp1-mediated modification are marked for rapid turnover by the host RNA degradation machinery.


Significance tests for R2 of out-of-sample prediction using polygenic scores.
The coefficient of determination (R2) is a well-established measure to indicate the predictive ability of polygenic scores (PGSs). However, the sampling variance of R2 is rarely considered so that 95% confidence intervals (CI) are not usually reported. Moreover, when comparisons are made between PGSs based on different discovery samples, the sampling covariance of R2 is required to test the difference between them. Here, we show how to estimate the variance and covariance of R2 values to assess the 95% CI and p value of the R2 difference. We apply this approach to real data calculating PGSs in 28,880 European participants derived from UK Biobank (UKBB) and Biobank Japan (BBJ) GWAS summary statistics for cholesterol and BMI. We quantify the significantly higher predictive ability of UKBB PGSs compared to BBJ PGSs (p value 7.6e-31 for cholesterol and 1.4e-50 for BMI). A joint model of UKBB and BBJ PGSs significantly improves the predictive ability, compared to a model of UKBB PGS only (p value 3.5e-05 for cholesterol and 1.3e-28 for BMI). We also show that the predictive ability of regulatory SNPs is significantly enriched over non-regulatory SNPs for cholesterol (p value 8.9e-26 for UKBB and 3.8e-17 for BBJ). We suggest that the proposed approach (available in R package r2redux) should be used to test the statistical significance of difference between pairs of PGSs, which may help to draw a correct conclusion about the comparative predictive ability of PGSs.


[Macrophage disappearance reaction in mice during an infection caused by Coxsackie B3 virus].
Intraperitoneal inoculation of 2 1/2-3-month-old male BALB/c mice with Coxsackie B3 virus in a dose of 10(7.2) TCD50 was demonstrated to be accompanied by inhibition of the starch-induced exudation of leukocytes into the peritoneal cavity. A decrease in the number of macrophages was observed in 3-day exudates induced at 4 and 21 days but not at 0, 7, and 14 days of infection. The macrophage disappearance reaction showed that the intraperitoneal inoculation of the challenge virus dose (10(7.2) TCD50) was not accompanied at 4-5 hours by changes in the absolute number of macrophages in the pre-existing exudates, but an increase in the absolute number of lymphocytes was observed in the exudates induced at 0, 4, 7, and 14 days of infection, and of polymorphonuclear leukocytes in exudates induced at all the intervals studied. It is assumed that these changes, depending on the period of infection, may be determined by immunological and non-immunological mechanisms.


Cabp2-Gene Therapy Restores Inner Hair Cell Calcium Currents and Improves Hearing in a DFNB93 Mouse Model.
Clinical management of auditory synaptopathies like other genetic hearing disorders is currently limited to the use of hearing aids or cochlear implants. However, future gene therapy promises restoration of hearing in selected forms of monogenic hearing impairment, in which cochlear morphology is preserved over a time window that enables intervention. This includes non-syndromic autosomal recessive hearing impairment DFNB93, caused by defects in the CABP2 gene. Calcium-binding protein 2 (CaBP2) is a potent modulator of inner hair cell (IHC) voltage-gated calcium channels CaV1.3. Based on disease modeling in Cabp2-/- mice, DFNB93 hearing impairment has been ascribed to enhanced steady-state inactivation of IHC CaV1.3 channels, effectively limiting their availability to trigger synaptic transmission. This, however, does not seem to interfere with cochlear development and does not cause early degeneration of hair cells or their synapses. Here, we studied the potential of a gene therapeutic approach for the treatment of DFNB93. We used AAV2/1 and AAV-PHP.eB viral vectors to deliver the Cabp2 coding sequence into IHCs of early postnatal Cabp2-/- mice and assessed the level of restoration of hair cell function and hearing. Combining in vitro and in vivo approaches, we observed high transduction efficiency, and restoration of IHC CaV1.3 function resulting in improved hearing of Cabp2-/- mice. These preclinical results prove the feasibility of DFNB93 gene therapy.


Emergency department visits for nontraumatic dental conditions: a systematic literature review.
To summarize the literature on factors associated with emergency department (ED) use for nontraumatic dental conditions (NTDCs). Following a database search, empirical studies were included if they examined factors associated with ED visits for NTDCs. The factors identified in these studies were further categorized using the Andersen Behavioral Model. Where appropriate, odds ratios (ORs) predicting the likelihood of NTDC ED visits were extracted to obtain summary estimates using random effects models. Sixty-three articles were included. Nontraumatic dental ED visits made up about 2.2 percent of all ED visits. Having public health insurance coverage such as Medicaid [OR = 2.17, 95 percent confidence interval (CI) = 1.79-2.64], and being uninsured (OR = 2.80, 95 percent CI = 2.39-3.39) were predictive of ED visits for NTDCs. Adults were more likely to use the ED for NTDCs compared to children and older adults. Rural adults had increased odds of ED use for NTDCs compared to urban adults (OR = 1.31, 95 percent CI = 1.12-1.52). Among younger children, regular dental care without sealant placement was associated with increased ED use for NTDCs. In the United States, both expansion and restriction of Medicaid dental coverage for adults were associated with increased ED visits for NTDCs. Policy makers and health care providers should address modifiable factors such as accessible dental care for the uninsured, and comprehensive dental coverage for those with public dental benefits. Targeted interventions should focus on young adults, children with special needs, and subpopulations with low socioeconomic status and chronic health conditions.


Deletion of internal sequences results in tobacco mosaic virus defective RNAs that accumulate to high levels without interfering with replication of the helper virus.
Deletion of certain internal sequences of the tobacco mosaic tobamovirus (TMV) genome was required to create replication-defective RNAs (dRNA) that were replicated in trans by TMV. All dRNAs that accumulated to detectable levels were missing nucleotides 3420-4902, which appeared to constitute a core region that inhibited replication in trans. Deletion of additional sequences resulted in dRNAs that varied tremendously in ability to be replicated from none to levels exceeding that of the helper viral RNA. Accumulation of dRNA negative- and positive-stranded RNAs of each dRNA paralleled those of the helper virus. Negative-stranded RNA accumulation of both helper and dRNA ceased at the same early time in the infection while synthesis of both positive-stranded RNAs continued, suggesting that both dRNAs and helper virus RNAs were synthesized from the same pool of replicase complexes. Positive- to negative-stranded RNA ratios for the dRNAs were similar to, or slightly greater than the wild-type helper virus. Full-length dRNAs were not supported in trans by a replication-competent helper virus. Even though some of the artificially constructed dRNAs accumulated to levels exceeding the level of the helper virus, none appreciably affected the replication of the helper virus, suggesting that the dRNAs are produced from "excess" replicase capacity.


Antidiuresis and natriuresis induced by gastric distension in water-loaded rats.
Antidiuretic and natriuretic responses were observed following gastric distension in anesthetized, water-loaded rats. An increase of intragastric pressure to 25, 30, 35, and 40 cm H2O of 2-minute duration respectively elicited 11, 35, 45, and 55% inhibition of water diuresis with concomitant, graded increase of sodium excretion by the kidney. These antidiuretic and natriuretic responses to gastric distension persisted and sustained the same intensity after acute bilateral cervical vagotomy, indicating that the sensory input conveyed from the gastric mechanoreceptors to central nervous system during gastric distension should involve afferent fibers other than vagus nerve. Rats with diabetes insipidus (D1) produced by hypothalamic lesions were also tested, but neither antidiuresis nor natriuresis in response to gastric distension was observed in these D1 rats whose neurohypophysis contained little antidiuretic hormone (ADH). In conclusion, gastric distension may induce liberation of ADH and probably other neurohypophysial hormone which affects renal handling of sodium and water in anesthetized, water-loaded rats.


Efficient induction of point mutations allowing recovery of specific locus mutations in zebrafish.
A technique is described that greatly increases the efficiency of recovering specific locus point mutations in zebrafish (Danio rerio). Founder individuals that were mosaic for point mutations were produced by mutagenizing postmeiotic gametes with the alkylating agent N-ethyl-N-nitrosourea. Under optimal conditions, each founder carried an average of 10 mutations affecting genes required for embryogenesis. Moreover, approximately 2% of these founders transmitted new mutations at any prespecified pigmentation locus. Analyses of new pigmentation mutations confirmed that most were likely to be point mutations. Thus, mutagenesis of postmeiotic gametes with N-ethyl-N-nitrosourea yielded frequencies of point mutations at specific loci that were 10- to 15-fold higher than previously achieved in zebrafish. Our procedure should, therefore, greatly facilitate recovery of multiple mutant alleles at any locus of interest.


Safety, correlative markers, and clinical results of adjuvant nivolumab in combination with vaccine in resected high-risk metastatic melanoma.
The anti-programmed death-1 (PD-1) antibody nivolumab (BMS-936558) has clinical activity in patients with metastatic melanoma. Nivolumab plus vaccine was investigated as adjuvant therapy in resected stage IIIC and IV melanoma patients. HLA-A*0201 positive patients with HMB-45, NY-ESO-1, and/or MART-1 positive resected tumors received nivolumab (1 mg/kg, 3 mg/kg, or 10 mg/kg i.v.) with a multi-peptide vaccine (gp100, MART-1, and NY-ESO-1 with Montanide ISA 51 VG) every 2 weeks for 12 doses followed by nivolumab maintenance every 12 weeks for 8 doses. Primary objective was safety and determination of a maximum tolerated dose (MTD). Secondary objectives included relapse-free survival (RFS), overall survival (OS), and immunologic correlative studies. Thirty-three patients were enrolled. Median age was 47 years; 55% were male. Two patients had stage IIIC disease; 31 patients had stage IV disease. Median follow-up was 32.1 months. MTD was not reached. Most common related adverse events (>40%) were vaccine injection site reaction, fatigue, rash, pruritus, nausea, and arthralgias. Five related grade 3 adverse events [hypokalemia (1), rash (1), enteritis (1), and colitis (2)] were observed. Ten of 33 patients relapsed. Estimated median RFS was 47.1 months; median OS was not reached. Increases in CTLA-4(+)/CD4(+), CD25(+)Treg/CD4(+), and tetramer specific CD8(+) T-cell populations were observed with treatment (P < 0.05). Trends for lower baseline myeloid-derived suppressor cell and CD25(+)Treg/CD4(+) populations were seen in nonrelapsing patients; PD-L1 tumor status was not significantly associated with RFS. Nivolumab with vaccine is well tolerated as adjuvant therapy and demonstrates immunologic activity with promising survival in high-risk resected melanoma, justifying further study.


Serine racemase suppresses chondrogenic differentiation in cartilage in a Sox9-dependent manner.
Serine racemase (SR) is responsible for the biosynthesis of D-serine (D-Ser), an endogenous co-agonist for N-methyl-D-aspartate (NMDA) receptors, from L-serine (L-Ser) in the central nervous system. In the present study, we investigated the role of SR in the regulation of chondrogenic differentiation in cartilage. On in situ hybridization analysis of tibia from neonatal rats, SR mRNA was ubiquitously expressed in all cell layers of proliferating to hypertrophic chondrocytes. In the pre-chondrogenic cell line ATDC5 cells, mRNA expression was seen with SR irrespective of the cellular maturity, with no mRNA expression of the NR1 subunit essential for the heteromeric assembly of functional NMDA receptor channels. In ATDC5 cells stably overexpressing SR, significant inhibition was found with the maturation-dependent temporal increases in Alcian blue staining, alkaline phosphatase (ALP) activity and mRNA expression of type II and type X collagens. Stable overexpression of SR significantly impaired the sry-type HMG box 9 (Sox9) transcriptinal activity in ATDC5 cells, while Sox9 transcriptional activity was significantly inhibited in COS7 cells with co-introduction of SR and Sox9. However, no significant inhibition was seen with Sox9 transcriptional activity in COS7 cells co-introduced of either SR(K56G) defective of D-Ser formation ability or 3-phosphoglycerate dehydrogenase essential for D-Ser biosynthesis. The co-introduction of SR with Sox9 significantly decreased the Sox9 protein level with that of Sox9 mRNA being unchanged. These results suggest that SR may negatively regulate cellular differentiation through the inhibition of Sox9 transcriptional activity in chondrocytes.


Cognitive function, physical performance, health, and disease: norms from the georgia centenarian study.
This study provides, for the first time, normative data on cognitive functioning and physical performance, health and health behaviors, and diseases from a population-based sample of 244 centenarians and near-centenarians (M age = 100.5 years, range 98-108, 84.8% women, 21.3% African American) from the Georgia Centenarian Study. Data are presented by the four key dimensions of gender, race, residence, and educational attainment. Results illustrate the profound range of functioning in this age group and indicate considerable differences as a function of each dimension. Bivariate models generally suggest that cognitive functioning and physical performance is higher for men than women; whites than African Americans; community than facility residents; and those with more than high school education than those with less than high school education. Multivariate models elaborate that differences in educational attainment generally account for the largest proportion of variance in cognitive functioning and residential status generally accounts for the largest proportion of variance in physical performance measures. Addition of health variables seldom increases variance accounted for in each domain beyond these four dimensions.


Three-dimensional imaging on a chip using optofluidics light-sheet fluorescence microscopy.
Volumetric, sub-micron to micron level resolution imaging is necessary to assay phenotypes or characteristics at the sub-cellular/organelle scale. However, three-dimensional fluorescence imaging of cells is typically low throughput or compromises on the achievable resolution in space and time. Here, we capitalise on the flow control capabilities of microfluidics and combine it with microoptics to integrate light-sheet based imaging directly into a microfluidic chip. Our optofluidic system flows suspended cells through a sub-micrometer thick light-sheet formed using micro-optical components that are cast directly in polydimethylsiloxane (PDMS). This design ensures accurate alignment, drift-free operation, and easy integration with conventional microfluidics, while providing sufficient spatial resolution, optical sectioning and volumetric data acquisition. We demonstrate imaging rates of 120 ms per cell at sub-μm resolution, that allow extraction of complex cellular phenotypes, exemplified by imaging of cell clusters, receptor distribution, and the analysis of endosomal size changes.


The hepatitis C self-management programme: a randomized controlled trial.
Chronic hepatitis C (HCV) infection afflicts millions of people worldwide. While antiviral treatments are effective for some patients, many either cannot or choose not to receive antiviral treatment. Education about behavioural changes like alcohol avoidance and symptom management, in contrast, is universally recommended, particularly in HCV-infected persons from disadvantaged groups where liver risk factors are most prevalent. Self-management interventions are one option for fostering improved HCV knowledge and health-related quality of life (HRQOL). One hundred and thirty-two patients with VA with HCV (mean age of 54.6, 95% men, 41% ethnic minority, 83% unmarried, 72% unemployed/disabled, 48% homeless in last 5 years) were randomized to either a 6-week self-management workshop or an information-only intervention. The weekly 2-h self-management sessions were based on cognitive-behavioural principles and were adapted from an existing self-management programme that has been efficacious with other chronic diseases. HCV-specific modules were added. Outcomes including HRQOL, HCV knowledge, self-efficacy, depression, energy and health distress were measured at baseline and 6 weeks later. Data were analysed using ANOVA. When compared to the information-only group, participants attending the self-management workshop improved more on HCV knowledge (P < 0.001), HCV self-efficacy (P = 0.011), and SF-36 energy/vitality (P = 0.040). Similar trends were found for SF-36 physical functioning (P = 0.055) and health distress (P = 0.055). Attending the self-management programme improved disease knowledge and HRQOL 6 weeks later in this disadvantaged population. The intervention can improve the health of people with hepatitis C, independent of antiviral therapy. Future research will study longer-term outcomes, effects on antiviral treatment and costs.


Ca2+-independent protein kinase C isoforms may modulate parietal cell HCl secretion.
Although activation of adenosine 3',5'-cyclic monophosphate by histamine and of Ca2+-dependent signaling pathways by cholinergic agonists is a generally recognized mechanism for increasing parietal cell HCl secretion, the role of protein kinase C (PKC) in this process is controversial. In this study, acid-secretory responses of gastric glands from rabbits [measured as accumulation of aminopyrine (AP)] were found to be relatively resistant to the PKC inhibitors calphostin C, chelerythrine chloride, staurosporine, and the bisindolylmaleimide-like inhibitors Ro 31-8220, Gö 6976, and bisindolylmaleimide I hydrochloride. Western analyses of the PKC isozyme profile in highly enriched parietal cells (98% purity) indicated that this cell type expresses abundant levels of the novel isoforms PKC-epsilon and PKC-mu and abundant levels of the atypical isoforms PKC-iota, PKC-lambda, and PKC-zeta. In contrast, there appeared to be low to undetectable expression of the classical isoforms PKC-alpha and PKC-beta1/beta2, respectively. Relatively high concentrations of Ro 31-8220 potentiated both carbachol- and histamine-stimulated AP accumulation (IC50 857 +/- 100 and 910 +/- 98 nM, respectively). There was a similar dose dependence for Ro 31-8220 inhibition of in situ phosphorylation of a parietal cell phosphoprotein, pp66 (IC50 750 +/- 120 nM). Similar concentrations of Ro 31-8220 also inhibited phosphorylation of the cytoskeletal, actin membrane cross-linking phosphoprotein ezrin, but not other phosphoproteins. Ezrin phosphorylation was increased by carbachol and 12-O-tetradecanoylphorbol 13-acetate (TPA). Because carbachol and TPA stimulate pp66 phosphorylation in a Ca2+-independent manner, our results suggest that one or more novel PKC isoforms may be involved in negative regulation of HCl secretion. In related experiments, PKC-epsilon, but not PKC-mu, was immunolocalized by confocal microscopy to a parietal cell compartment that bore a striking resemblance to that containing filamentous actin. Moreover, pp66 was enriched in a Triton X-100-insoluble parietal cell fraction, suggesting a potential cytoskeletal localization for this unknown protein. Given their location and sensitivity to Ro 31-8220, it is possible that pp66 and ezrin interact in a PKC-dependent manner to regulate the well-known morphological changes that occur in concert with agonist-dependent activation of parietal cell HCl secretion.


Experiences and difficulties for primary caretakers of children with celiac disease - A qualitative study.
The purpose of this study was to understand the experiences of primary caretakers (PCTs) with a child diagnosed with celiac disease (CeD). There is paucity of research in understanding the experiences of PCTs of children with CeD in India. Purposive sampling was used to select PCTs of CeD-affected children from a tertiary hospital in New Delhi. Ten PCTs took part in the investigation. To gather the data, semi-structured interviews were held with participants. Hindi was used to administer the interviews. The current study focused on the difficulties and worries PCTs experience in managing CeD. The main themes and sub-themes that emerged from the data were diagnosis of CeD (misdiagnosis of CeD, late diagnosis of CeD, feelings at the time of diagnosis, help from a doctor/nutritionist at the time of diagnosis); characteristics of CeD (CeD as a new disease, CeD as an allergy); attitude towards wheat (wheat as a poison, ignorance regarding negative effect of wheat); influence of significant others (making fun of the child, queries from others are a source of worry, non-acceptance of celiac disease by others and pressure to give gluten to the child); issues in following gluten-free diet (GFD) (fear of cross-contamination, distrust on GFD available outside home, GFD is expensive, making GFD is difficult, joint family, non-adherence to GFD, making non-GFD along with GFD); effect of CeD (financial effect of CeD, effect on physical and mental health of the child and PCT, effect on social life, change in family dynamics, eating restrictions); management of CeD (GFD for the whole family to manage CeD, family support to manage CeD, adhering to GFD, early diagnosis); and concerns (future marital concern for the child, cure of CeD, proper physical growth). The current study gave an understanding of how PCTs dealt with a child's CeD. The difficulties and worries of caretakers should be taken into consideration and appropriate recommendations made to lessen the strain of managing the child's CeD and the daily obstacles associated with it.


A developmental perspective of self-construals and sex differences: comment on Cross and Madson (1997)
S. E. Cross and L. Madson (1997) proposed that women and men differ in self-construals, with women as interdependent and men as independent, and that these construals are seen to underlie many sex differences in social behavior. In this article, the authors address the issues of sex differences in self-construals, the stability of self-construals, and the centrality of interdependence-independence to sex differences. They examine the proposal next from a developmental perspective, suggesting that development of the self does not precede children's gender-related behavior. Evidence regarding the socialization processes that may contribute to sex differences in self-construals is largely inconclusive, especially regarding the differential treatment of boys and girls by parents. Their developmental perspective provides insights into ways that Cross and Madson's approach can be elaborated to explain sex differences in social behavior.


Distribution of AGG interruption patterns within nine world populations.
The CGG trinucleotide repeat within the FMR1 gene is associated with multiple clinical disorders, including fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X syndrome. Differences in the distribution and prevalence of CGG repeat length and of AGG interruption patterns have been reported among different populations and ethnicities. In this study we characterized the AGG interruption patterns within 3,065 normal CGG repeat alleles from nine world populations including Australia, Chile, United Arab Emirates, Guatemala, Indonesia, Italy, Mexico, Spain, and United States. Additionally, we compared these populations with those previously reported, and summarized the similarities and differences. We observed significant differences in AGG interruption patterns. Frequencies of longer alleles, longer uninterrupted CGG repeat segments and alleles with greater than 2 AGG interruptions varied between cohorts. The prevalence of fragile X syndrome and FMR1 associated disorders in various populations is thought to be affected by the total length of the CGG repeat and may also be influenced by the AGG distribution pattern. Thus, the results of this study may be important in considering the risk of fragile X-related conditions in various populations.


Reservoir engineering to accelerate the dissolution of CO2 stored in aquifers.
It is possible to accelerate the dissolution of CO2 injected into deep aquifers by pumping brine from regions where it is undersaturated into regions occupied by CO2. For a horizontally confined reservoir geometry, we find that it is possible to dissolve most of the injected CO2 within a few hundred years at an energy cost that is less than 20% of the cost of compressing the CO2 to reservoir conditions. We anticipate that use of reservoir engineering to accelerate dissolution can reduce the risks of CO2 storage by reducing the duration over which buoyant free-phase CO2 is present underground. Such techniques could simplify risk assessment by reducing uncertainty about the long-term fate of injected CO2, and could expand the range of reservoirs which are acceptable for storage.


Pilonidal sinus (Nadi vrana): A case study.
Pilonidal sinus (PNS) occurs in the cleavage between the buttocks (natal cleft) and can cause discomfort, embarrassment and absence from work for thousands of young people (mostly men) annually. The incidence of the disease is calculated to be 26 per 100,000 people. It occurs 2.2 times more often in men than in women. Age at presentation is 21 years for men and 19 years for women this case report describes a 22-year-old man with pilonidal sinus who was treated with ksharasutra.


Synovial Tissue Heterogeneity in Japanese Patients With Rheumatoid Arthritis Elucidated Using a Cell-Type Deconvolution Approach.
Recent advances in single-cell RNA sequencing technology have improved our understanding of the immunological landscape of rheumatoid arthritis (RA). We aimed to stratify the synovium from East Asian patients with RA by immune cell compositions and gain insight into the inflammatory drivers of each synovial phenotype. Synovial tissues were obtained from East Asian patients in Japan with RA (n = 41) undergoing articular surgery. The cellular composition was quantified by a deconvolution approach using a public single-cell-based reference. Inflammatory pathway activity was calculated by gene set variation analysis, and chromatin accessibility was evaluated using assay of transposase accessible chromatin-sequencing. We stratified RA synovium into three distinct subtypes based on the hierarchical clustering of cellular composition data. One subtype was characterized by abundant HLA-DRAhigh synovial fibroblasts, autoimmune-associated B cells, GZMK+ GZMB+ CD8+ T cells, interleukin (IL)1-β+ monocytes, and plasmablasts. In addition, tumor necrosis factor (TNF)-α, interferons (IFNs), and IL-6 signaling were highly activated in this subtype, and the expression of various chemokines was significantly enhanced. Moreover, we found an open chromatin region overlapping with RA risk locus rs9405192 near the IRF4 gene, suggesting the genetic background influences the development of this inflammatory synovial state. The other two subtypes were characterized by increased IFNs and IL-6 signaling, and expression of molecules associated with degeneration, respectively. This study adds insights into the synovial heterogeneity in East Asian patients and shows a promising link with predominant inflammatory signals. Evaluating the site of inflammation has the potential to lead to appropriate drug selection that matches the individual pathology.


Real-Time Vehicle Roll Angle Estimation Based on Neural Networks in IoT Low-Cost Devices.
The high rate of vehicle-crash victims has a fatal economic and social impact in today's societies. In particular, road crashes where heavy vehicles are involved cause more severe damage because they are prone to rollover. For this reason, many researches are focused on developing RSC Roll Stability Control (RSC) systems. Concerning the design of RSC systems with an adequate performance, it is mandatory to know the dynamics of the vehicle. The main problem arises from the lack of ability to directly capture several required dynamic vehicle variables, such as roll angle, from low-cost sensors. Previous studies demonstrate that low-cost sensors can provide data in real-time with the required precision and reliability. Even more, other research works indicate that neural networks are efficient mechanisms to estimate roll angle. Nevertheless, it is necessary to assess that the fusion of data coming from low-cost devices and estimations provided by neural networks can fulfill hard real-time processing constraints, achieving high level of accuracy during circulation of a vehicle in real situations. In order to address this issue, this study has two main goals: (1) Design and develop an IoT based architecture, integrating ANN in low cost kits with different hardware architectures in order to estimate under real-time constraints the vehicle roll angle. This architecture is able to work under high dynamic conditions, by following specific best practices and considerations during its design; (2) assess that the IoT architecture deployed in low-cost experimental kits achieve the hard real-time performance constraints estimating the roll angle with the required calculation accuracy. To fulfil these objectives, an experimental environment was set up, composed of a van with two set of low-cost kits, one including a Raspberry Pi 3 Model Band the other having an Intel Edison System on Chip linked to a SparkFun 9 Degrees of Freedom module. This experimental environment be tested in different maneuvers for comparison purposes. Neural networks embedded in low-cost sensor kits provide roll angle estimations highly approximated to real values. Even more, Intel Edison and Raspberry Pi 3 Model B have enough computing capabilities to successfully run roll angle estimation based on neural networks to determine rollover risk situations, fulfilling real-time operation restrictions stated for this problem.


Solitary fibrous tumor of the pleura.
Solitary fibrous tumor of the pleura (SFTP) is a rare tumor of mesenchymal origin which can grow to a large size and present with symptoms of cough and pleuritic chest pain. No specific etiological factors for SFTPs are known and they may grow undetected for several years. These tumors are usually benign and may mimic a variety of malignancies. SFTPs are often detected as peripheral opacities on chest X-ray. Unfortunately, fine needle aspiration rarely provides adequate information for a definitive diagnosis. Imaging with computed tomography provides details about the size and extent of any invasion into adjacent tissues. Surgical resection is the mainstay of treatment, and immunohistochemistry of the resected tumor often provides confirmation of the diagnosis. Some SFTPs have been observed to be malignant, and surgical intervention is often lifesaving. There is no adequate data to support the usage of radiotherapy and chemotherapy in the treatment of SFTPs. This tumor exemplifies malignancies which require surgical resection to preempt worse outcomes. Awareness of their presentation and clinical course may help the clinician provide a prompt referral to the thoracic surgeon for resection.


Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4- and 1/4-length fragments.
The 72-kDa gelatinase/type IV collagenase (MMP-2) is a member of the matrix metalloproteinase (MMP) family of enzymes. This enzyme is known to cleave type IV collagen as well as degrade denatured collagens. However, native interstitial collagens are reportedly resistant to MMP-2 and are thought to be susceptible only to the interstitial collagenases MMP-1 and MMP-8. In this study we report that both human and chicken MMP-2, free of tissue inhibitors of metalloproteinases (TIMPs) are capable of cleaving soluble, triple helical type I collagen generating the 3/4- and 1/4-length collagen fragments characteristic of vertebrate interstitial collagenases. MMP-2 cleaves at the same Gly-Ile/Leu bond in the collagen alpha chains as interstitial collagenases with kcat and Km values similar to that of MMP-1. MMP-2 also is capable of degrading reconstituted type I collagen fibrils. The closely related 92-kDa gelatinase/type IV collagenase (MMP-9) is unable to cleave soluble or fibrillar collagen under identical conditions indicating that the specific collagenolytic activity of MMP-2 is not a general property of gelatinases. That MMP-2, a potent gelatinase, also can cleave fibrillar collagen provides an alternative to the proposal that two enzymes, an interstitial collagenase and a gelatinase, are required for the complete dissolution of stromal collagen during cellular invasion.


Bovine cysticercosis and taeniosis: The effect of an alternative post-mortem detection method on prevalence and economic impact.
In Europe, bovine cysticercosis (BCC) is detected by routine meat inspection (MI) at the slaughterhouse. The prevalence of BCC in Belgium based on MI is estimated at 0.23%. MI has a known low sensitivity for animals with localised infections and alternative detection techniques should be considered. A mathematical scenario-analysis model was built to determine the current prevalence of BCC in Belgium based on MI results combined with results of dissection of the predilection sites (PS) and the B158/B60 Ag-ELISA on serum of 614 carcasses found negative on MI. Additionally, the impact of the introduction of the B158/B60 Ag-ELISA at slaughter on the prevalence of BCC and taeniosis and on the economic impact related to Taenia saginata was estimated for Belgium. Data for estimating the economic impact were gathered from multiple sources within the meat and human health sectors and included value loss for infected carcasses, inspection costs, carcass destruction costs, cattle insurance costs and costs related to taeniosis (consultation physician, drugs and laboratory test). The model estimated the current prevalence of BCC to be 42.5% (95% CI: 32.4-60.7%) and the sensitivity of the MI for viable and degenerated cysticerci at only 0.54% (95% CI: 0.37-0.71%). A total of 213,344 viable cysticerci (95% CI: 122,962-386.249) were estimated to be present in the infected carcasses in one year and only 408 (95% CI: 356-464) of these were present in the carcasses detected at current MI. The annual number of human taeniosis cases is estimated at 11,000 by using the sale numbers of niclosamide in Belgium. Implementation of the Ag-ELISA at slaughter (Se = 36.37%; Sp = 99.36%) would greatly reduce the prevalence of BCC to 0.6% and the number of taeniosis cases to 89 in year 10. Unfortunately, the accompanying resulting increase in costs for the animal owners, slaughterhouses and the insurance company, would be extremely high in the first years. Cattle owners would suffer losses of up to €21 million in the first year after implementation of the Ag-ELISA (compared to an annual loss of €3.5 million in the current situation), slaughterhouses of €10 million (compared to €200,000 currently) and the insurance company of almost €6 million (compared to €2.3 million profit currently). Therefore, implementation of the Ag-ELISA might not be feasible and other options for controlling T. saginata should be investigated.


[Role of Mg2+-dependent alkaline endodnaase of blood serum in tumorigenesis in A/smail mice].
An enzymoassay of levels of Mg2+-dependent alkaline endoDNAase of protein spectrum of blood serum of noninbred albino mice by SDS-electrophoresis in 10% PAAG established a fairly high heterogeneity of the enzyme. The variety of alkaline endoDNAases must be due to the limited proteolysis of their high-molecular precursor by specific proteases as described in the literature. No alkaline endoDNAase activity was identified by analysis of 10-150 kDa protein spectrum in A/smail line mice without ascites hepatoma. It was detected (pH 8.3) in the 25-45 kDa range on day 10 after tumor transplantation. Considering the gravity of disease (pre-lethal stage), on day 10, it was suggested that the level be accounted for by decay of diseased cells. The lack or extremely low level of endoDNAase activity in original blood serum expressed a mechanism of enhancing sensitivity to tumor cell effects. In mice bearing ascites hepatoma, the enzyme levels (pH 8.3) were much higher on day 10. DNAase activity (pH 7.5) was not induced in response to the heterogenous DNA. Our data point to possible defects in the induction of Mg2+-dependent alkaline endoDNAases (pH 8.3) and DNAses (pH 7.5) as well as their role in raising sensitivity to transplantable ascites hepatoma.


Digital subtraction angiography in patients with cerebral ischaemic attacks and normal continuous wave Doppler studies.
The cervico-cranial arteries were studied using digital subtraction angiography in 50 patients with reversible cerebral ischaemic attacks and normal continuous wave Doppler examination. Digital subtraction angiography was able to visualise the arteries satisfactorily in 45 patients (90%), and revealed minor arterial abnormalities in 12 patients (24%). However, neither occlusions nor stenoses greater than 50% of the diameter of the vessel lumen were found. Although digital subtraction angiography is more accurate than continuous wave Doppler examination in detecting arterial lesions, it did not provide alternative therapeutic choices in any of these patients.


[Prenatal ultrasound diagnosis of adrenal neuroblastoma].
Neuroblastoma is the most frequent solid malignant tumor in the neonatal period; however, its diagnosis is very difficult in the prenatal one. This kind of tumor has a high morbidity and mortality rate due to the metastatic risk. Its prognosis depends on the affected area, on the extension of the tumor, and on the associated abnormalities. The antenatal ultrasound diagnosis is possible by finding a mixed mass in the adrenal gland. We report a case of a bilateral adrenal neuroblastoma diagnosed by antenatal ultrasonography at the 29th week of gestation. We describe the principal findings and show the contribution of the tridimensional ultrasound on the relationship of the tumor with the nearby structures.


Domestic violence: a cross-sectional study in an Iranian city.
To determine the prevalence of domestic physical violence against women and its associated factors in Sanandaj city, Islamic Republic of Iran, a random sample of 1000 married women completed a questionnaire. Of the respondents, 15% had been assaulted by their husbands at least once in the previous year and 38% at some time during the marriage. Economic problems were the most frequent cause of domestic quarrels. There was a significant association between husbands' educational level and violence against wives. Physical violence against housewives was significantly more frequent than against employed women. Husband's job was also significantly associated with violence. The existence of a child or daughter in the family was associated with less domestic physical violence against women.


[Structure and function of erythrocytes in lymphomas].
Significant changes have been recorded in the concentration of sulfhydryl groups, histidine, lipoproteins, catalase activity, saponin resistance, and kinetics of chemiluminescent responses of red blood cells in lymphoma patients. Lymphosarcoma is characterized by changes in the structure and function of red blood cells at the early stage of the process, whereas in lymphogranulomatosis changes are observed with the disease progressing, when pronounced signs of tumor intoxication are noted and anemia is present. In lymphosarcoma patients an increase of peripheral blood mononuclears is recorded which expresses the erythroid differentiating antigens with the use of monoclonal antibodies against glycophorin A (ZAE-3) and human erythroblast antigen AG-EB (HAE-9). In lymphogranulomatosis patients it was not detected.


Consumption of Alcohol, Cannabis, and Tobacco in a Cohort of Adolescents before and during COVID-19 Confinement.
The aim of this study was to identify changes in the hazardous consumption of alcohol, tobacco, and cannabis, due to the COVID-19 lockdown in 2020 in a cohort of schooled adolescents from Central Catalonia. We also analyzed the effect of the individual and social factors on risky consumption during confinement. This longitudinal study involved a subsample of 303 adolescents aged 14-18 years, who were attending 4th year of compulsory secondary education (ESO), 2nd year of college preparation (baccalaureate), or Vocational and Educational Training (VET). We collected data before COVID-19 lockdown (October 2019-February 2020) and 2 months after the lockdown ended. We estimated the prevalence of risky substance use in the sample at baseline for each independent variable. We used Poisson regression models with robust variance to compute the Cumulative Incidence (CI) and Relative Risk (RR), with their respective 95% confidence interval. We found that VET students had a significantly (p < 0.05) higher risk of substance use: binge drinking (RR = 3.21 (95%CI: 1.00-10.34)); hazardous drinking of alcohol (RR = 3.75 (95%CI: 1.12-12.54)), hazardous consumption of cannabis (RR = 3.75 (95%CI: 0.65-21.59)) and daily smoking of tobacco (RR = 4.82 (95%CI: 1.74-13.39)). The results showed a general trend of reduction of consumption during COVID-19 confinement period. This study suggests that VET students were more likely to engage in hazardous drinking of alcohol and daily smoking of tobacco. No statistically significant differences were found for the other age groups and variables.


Discrete metastasis of solid tumors to extraocular muscles.
We report five cases of discrete solid tumor metastasis to extraocular muscles. Computed tomography confirmed that orbital involvement in all cases was confined to the extraocular muscles; there was no tumor in the bony orbit or in the adjacent paranasal sinuses or intracranial space. In two of our five cases, ophthalmic signs were the first evidence of metastatic disease; in the three other cases, there was a known history of cancer prior to orbital involvement. Pain, diplopia, and proptosis were the most common presenting manifestations. Neuroimaging demonstrated bilateral focal, nodular enlargement of multiple extraocular muscles in three cases. Diffuse enlargement of a single muscle occurred in the two other cases, inclusive of the tendinous insertion in one instance. Fine-needle aspiration biopsy provided a diagnosis of undifferentiated malignancy in all four cases in which it was performed.


Self-Administration of Cotinine in Wistar Rats: Comparisons to Nicotine.
Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs). Nicotine supports self-administration in rodents. However, it remains undetermined whether cotinine can be self-administered. This study aimed to characterize cotinine self-administration in rats, to compare effects of cotinine to those of nicotine, and to determine potential involvement of nAChRs in cotinine's effects. Adult Wistar rats were trained to self-administer cotinine or nicotine (0.0075, 0.015, 0.03, or 0.06 mg/kg per infusion) under fixed-ratio (FR) and progressive-ratio (PR) schedules. Blood nicotine and cotinine levels were determined after the last FR session. Effects of mecamylamine, a nonselective nAChR antagonist, and varenicline, a partial agonist for α4β2* nAChRs, on cotinine and nicotine self-administration were determined. Rats readily acquired cotinine self-administration, responded more on active lever, and increased motivation to self-administer cotinine when the reinforcement requirement increased. Blood cotinine levels ranged from 77 to 792 ng/ml. Nicotine induced more infusions at lower doses during FR schedules and greater breakpoints at higher doses during the PR schedule than cotinine. There was no difference in cotinine self-administration between male and female rats. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results indicate that cotinine was self-administered by rats. These effects of cotinine were less robust than nicotine and exhibited no sex difference. nAChRs appeared to be differentially involved in self-administration of nicotine and cotinine. These results suggest cotinine may play a role in the development of nicotine use and misuse. SIGNIFICANCE STATEMENT: Nicotine addiction is a serious public health problem. Cotinine is the major metabolite of nicotine, but its involvement in nicotine reinforcement remains elusive. Our findings indicate that cotinine, at doses producing clinically relevant blood cotinine levels, supported intravenous self-administration in rats. Cotinine self-administration was less robust than nicotine. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results suggest cotinine may play a role in the development of nicotine use and misuse.


Evaluation of resting traps to examine the behaviour and ecology of mosquito vectors in an area of rapidly changing land use in Sabah, Malaysian Borneo.
Widespread deforestation occurring in the tropics is hypothesized to impact the transmission of vector-borne diseases (VBD). Predicting how environmental changes will impact VBD transmission is dependent on understanding the ecology and behaviour of potential vector species outside of domestic settings. However there are few reliable sampling tools for measuring the habitat preference and host choice of mosquito vectors; with almost none suitable for sampling recently blood-fed, resting mosquitoes. This study evaluated the use of two mosquito traps: the resting bucket (RB) and sticky resting bucket (SRB) traps relative to CDC backpack aspiration (CDC) for sampling mosquitoes resting in a range of habitats representing a gradient of deforestation. Eight habitats were selected for sampling around two villages in Kudat District, Malaysian Borneo, to reflect the range of habitats available to mosquitoes in and around human dwellings, and nearby forest habitats where reservoir hosts are present: secondary forest (edge, interior and canopy); plantations (palm and rubber); and human settlements (inside, under and around houses). Over 31 days, 2243 mosquitoes were collected in 5748 discrete collections. Nine mosquito genera were sampled with Aedes and Culex species being present in all habitats and most abundant. RB and CDC backpack aspiration were most efficient for sampling Culex whereas CDC backpack aspiration and SRB were most efficient for Aedes. Most Aedes identified to species level were Ae. albopictus (91%), with their abundance being highest in forest edge habitats. In contrast, Culex were most abundant under houses. Most blood-fed mosquitoes (76%) were found in human settlements; with humans and chickens being the only blood source. RB and SRB traps proved capable of sampling mosquitoes resting in all sampled habitats. However, sampling efficiency was generally low (c.0.1 per trap per day), necessitating traps to be deployed in high numbers for mosquito detection. None of the traps were effective for sampling zoonotic malaria vectors; however, SRB collected relatively higher numbers of the dengue vector Ae. albopictus. The higher abundance of mosquitoes in forest edge habitats indicates the potential value of these traps for investigating sylvatic dengue transmission. This study has demonstrated the merits in application of simple resting traps for characterising mosquito vector resting behaviour outside of the home.


A Soil-free System for Assaying Nematicidal Activity of Chemicals.
A biological assay system for studying the nematicidal activity of chemicals has been devised using a model consisting of cucumber (Cucumis sativus L. cv. Long Marketer) seedlings growing in the diSPo(R) growth-pouch apparatus. Meloidogyne incognita was used as the test organism. The response was quantified in terms of the numbers of galls produced. Statistical procedures were applied to estimate the ED(50) values of currently available nematicides. This system permits accurate quantification of galling and requires much less space and effort than the currently used methods.


Suppression of auditory nerve responses. II. Suppression threshold and growth, iso-suppression contours.
Two-tone "synchrony suppression" was studied in responses of single auditory nerve fibers recorded from anesthetized cats. Suppression thresholds for suppressor tones set to a fiber's characteristic frequency (CF) were approximately equal to discharge rate thresholds for CF tones. Suppression thresholds above and below CF were usually lower than the corresponding discharge rate thresholds. However, at all frequencies studied (including CF), suppression thresholds were higher than the corresponding thresholds for discharge synchronization. Across fibers, rates of suppression growth for suppressors at CF were greatest in low-CF fibers and least in high-CF fibers, and there was a systematic decrease in suppression growth rate at CF as CF increased. Within fibers, rates of suppression growth above CF were typically less than at CF, and slopes were monotonically decreasing functions of frequency. Within-fiber rates of suppression growth below CF were variable, but they usually were greater than rates of growth at CF. Iso-suppression contours (frequencies and intensities producing criterion amounts of suppression) indicated that tones near CF are the most potent suppressors at near-threshold intensities, and that the frequency producing the most suppression usually shifts downward as the amount of suppression increases. These data support the notion that synchrony suppression arises primarily as a passive consequence of hair cell activation.


Surface Penetration without Enrichment: Simulations Show Ion Surface Propensities Consistent with Both Elevated Surface Tension and Surface Sensitive Spectroscopy.
Molecular dynamics was used to investigate ion surface propensities in NaCl, KBr, and CsI solutions with an MP2-based force field. Although NaCl is found to be strongly repelled from the liquid-vapor interface, softer ions, such as I-, penetrate closely to the interface. Despite the surface penetration, the concentration of CsI near the interface is still lower than that in the bulk, thus leading to no surface enrichment. The salt concentration is found to affect relative surface propensities of the ions. More significant surface penetration is observed at higher salt concentrations. Softer ions at higher concentrations form a complex multilayer arrangement that can not be characterized as a simple surface bilayer. The simulated ion distributions explain the spectroscopic evidence of surface perturbation by soft ions with a negative surface excess consistent with an increased surface tension of salt solutions.


A 10 year follow-up of semi-annual screening for early detection of lung cancer in the Erfurt County, GDR.
A prospective and controlled study for early detection of lung cancer in the county of Erfurt with a follow-up of 10 years is presented. A collective of 41,532 males born between 1907 and 1932 was screened by chest fluorography at 6 month intervals and compared with a control group consisting of 102,348 males of the same age, who were screened at intervals of about 18 months. No significant reduction of overall mortality and of lung cancer mortality was achieved. Semi-annual screening brought about a higher detection rate (9%/6.5%), an increase in the resection rate (28%/19%) and higher 5 and 10 year survival rates (52%; 27%/39%; 19%) of resected patients than screening in 18 month intervals. Among those patients who refused resection or were surgically untreatable, the difference in survival rates between the two investigation groups lasted only up to the 12 months barrier. This is regarded as the effect of the lead-time bias. Fluorographic screening is effective only in patients with peripheral cancers. Patients resected for central lung cancers did not show differences in the survival rates. In both investigation groups considered together surgical therapy was possible mainly in those patients who had been detected by screening (resection rate: 48%; 5 yr survival rate: 26.9%). The resection rate of all the others amounted to 9%, the 5 yr survival rate to 1.4%. Therefore we consider fluorography to time as the only chance for lung cancer control of high risk groups in spite of the absence of reduction of lung cancer mortality.


Novel fractal feature-based multiclass glaucoma detection and progression prediction.
We investigate the use of fractal analysis (FA) as the basis of a system for multiclass prediction of the progression of glaucoma. FA is applied to pseudo two-dimensional images converted from one-dimensional retinal nerve fiber layer (RNFL) data obtained from the eyes of normal subjects, and from subjects with progressive and non-progressive glaucoma. FA features are obtained using a box-counting method and a multi-fractional Brownian motion method that incorporates texture and multiresolution analyses. Both features are used for Gaussian kernel-based multiclass classification. Sensitivity, specificity, and area under receiver operating characteristic curve (AUROC) are computed for the FA features and for metrics obtained using wavelet-Fourier analysis (WFA) and fast-Fourier analysis (FFA). The AUROCs that predict progressors from non-progressors based on classifiers trained using a dataset comprised of non-progressors and ocular normal subjects are 0.70, 0.71 and 0.82 for WFA, FFA, and FA, respectively. The correct multiclass classification rates among progressors, non-progressors, and ocular normal subjects are 0.82, 0.86 and 0.88 for WFA, FFA, and FA, respectively. Simultaneous multiclass classification among progressors, non-progressors, and ocular normal subjects has not been previously described. The novel FA-based features achieve better performance with fewer features and less computational complexity than WFA and FFA.


Surgical Management of Obstructive Sleep Apnea.
Surgical management of snoring and obstructive sleep apnea is indicated when a surgically correctable abnormality is believed to be the source of the problem. Many patients opt for surgical treatment after noninvasive forms of treatment have been proven ineffective or difficult to tolerate. With increasing frequency, functional rhinoplasty, septoplasty, turbinoplasty, palatal surgery, and orthognathic surgery are being used in the management of snoring and obstructive sleep apnea. Plastic surgeons' experience with aesthetic nasal surgery, nasal reconstruction, palatal surgery, and craniofacial surgery puts them at the forefront of performing surgery for snoring and sleep apnea. The role of functional septorhinoplasty, turbinoplasty, palatal surgery, genioglossal advancement, and orthognathic surgery is indispensable in the surgical management of obstructive sleep apnea. Multidisciplinary management of these patients is critical, and plastic surgeons are encouraged to work collaboratively with sleep medicine clinicians and centers.


Hydrogen Bond Strength-Mediated Self-Assembly of Supramolecular Nanogels for Selective and Effective Cancer Treatment.
This study provides a significant contribution to the development of multiple hydrogen-bonded supramolecular nanocarrier systems by demonstrating that controlling the hydrogen bond strength within supramolecular polymers represents a crucial factor to tailor the drug delivery performance and enhance the effectiveness of cancer therapy. Herein, we successfully developed two kinds of poly(ethylene glycol)-based telechelic polymers Cy-PEG and UrCy-PEG having self-constituted double and quadruple hydrogen-bonding cytosine (Cy) and ureido-cytosine (UrCy) end-capped groups, respectively, which directly assemble into spherical nanogels with a number of interesting physical characteristics in aqueous solutions. The UrCy-PEG nanogels containing quadruple hydrogen-bonded UrCy dimers exhibited excellent long-term structural stability in a serum-containing biological medium, whereas the double hydrogen-bonded Cy moieties could not maintain the structural integrity of the Cy-PEG nanogels. More importantly, after the drug encapsulation process, a series of in vitro experiments clearly confirmed that drug-loaded UrCy-PEG nanogels induced selective apoptotic cell death in cancer cells without causing significant cytotoxicity to healthy cells, while drug-loaded Cy-PEG nanogels exerted nonselective cytotoxicity toward both cancer and normal cells, indicating that increasing the strength of hydrogen bonds in nanogels plays a key role in enhancing the selective cellular uptake and cytotoxicity of drugs and the subsequent induction of apoptosis in cancer cells.


Role of biphasic changes in splenic dendritic cell activity in a mouse model of multiple organ dysfunction syndrome.
To analyze the changes in splenic dendritic cell (DC) activity and serum cytokine levels during the progression of multiple organ dysfunction syndrome (MODS). A C57BL/6 mouse model of MODS was established by intraperitoneal injection of zymosan. Immunohistochemistry and flow cytometry were used to detect expression of I-A(b) (MHC-II molecules of mice) as well as co-stimulatory and co-inhibitory molecules in spleen and DC surface. The levels of various cytokines in serum and spleen tissue were analyzed 6 h, 12 h, 24 h, 48 h, 5 d and 12 d after injury. Death occurred at 24-48 h and 10-12 d after injury. The expression of I-A(b) and CD86 in spleen tissue and on DCs increased 6-12 h after injury, followed by gradual reduction and at 12 d. The inhibitory molecule, PD-L1, was expressed on normal DCs, but expression of PD-1 was undetectable. PD-L1 and PD-1 expression increased and remained high at 5 d and 12 d after injury. In addition, TNF and IL-1 levels increased 6-12 h after injury; HMGB1 and IL-10 levels increased 24 h and 5 d after injury, respectively. In contrast, IL-2 and IL-12 decreased with disease progression. At 12 d after injury, proinflammatory and anti-inflammatory cytokine levels remained high, while IL-2 and IL-12 were significantly reduced. IL-10 and IL-12 changes in spleen were consistent with those in serum. MODS progression was characterized by changes in splenic DC activity as well as altered serum pro-inflammatory and anti-inflammatory cytokine levels, suggesting early immune activation and predominant immune tolerance at the late stage.


Surgical treatment of inflammatory bowel diseases in northwestern Italy: a multicentric study by the G.S.M.I.I. (Inflammatory Bowel Disease Study Group).
Improved medical therapy and bowel sparing and sphincter saving techniques have changed surgery for UC and CD. Collaboration between gastroenterologists and surgeons is necessary to uniform the indications for surgical treatment reducing emergency operations. GISMII multicentric study aimed to show indications, timing and impact of surgery, through retrospective analysis of cases observed between 1992 to 1996. Data were obtained by 16 departments of General Surgery. 102 UC and 376 CD patients were analyzed. In UC patients surgery was performed for failure of medical therapy in 54%, complications in 28.4%, cancer or dysplasia in 10% of cases, 83.3% elective procedures. 30.4% ileo-anal pouch, 30.4% total procto-colectomies with definitive ileostomies, 32.4% total colectomies with ileo-rectal anastomosis, 6.8% segmental resections, were performed. In CD patients surgery was performed in 21% for medical therapy failure, in 79% for complications. 53.4% of patients were submitted to 1 operation, 84% elective procedures. Reoperations were performed in 46.6% of patients, 70.3% elective procedures. In the first operation bowel resection was performed in 79.1%, stricturoplasty in 14.3%; in the subsequent operations bowel resection 62.8%, stricturoplasty 21.7%, increasing number of temporary or definitive ileo-stomies. Collaboration between gastroenterologists and surgeons is necessary to obtain optimal results, reducing the incidence of emergency surgery, and complications. The short period observed between diagnosis and operation (21.4 months) is due to the increasing tendency of gastroenterologists to anticipate a surgical procedure when young patients with a chronic disease need a prolonged medical therapy.


Sudden infant death syndrome.
Sudden infant death syndrome (SIDS) continues to be the most common cause of postneonatal infant death. SIDS is a complex, multifactorial disorder, the cause of which is still not fully understood. However, much is known now about environmental risk factors, some of which are modifiable. These include maternal and antenatal risk factors such as smoking during pregnancy, as well as infant-related risk factors such as non-supine sleeping position and soft bedding. Emerging evidence also substantiates an expanding number of genetic risk factors. Interactions between environmental and genetic risk factors may be of critical importance in determining an infant's actual risk of SIDS. Although no practical way exists to identify which infants will die of SIDS, nor is there a safe and proven prevention strategy even if identification were feasible, reducing exposure to modifiable risk factors has helped to lower the incidence of SIDS. Current challenges include wider dissemination of guidelines to all people who care for infants, dissemination of guidelines in culturally appropriate ways, and surveillance of SIDS trends and other outcomes associated with implementation of these guidelines.


A novel small molecule ameliorates ocular neovascularisation and synergises with anti-VEGF therapy.
Ocular neovascularisation underlies blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. These diseases cause irreversible vision loss, and provide a significant health and economic burden. Biologics targeting vascular endothelial growth factor (VEGF) are the major approach for treatment. However, up to 30% of patients are non-responsive to these drugs and they are associated with ocular and systemic side effects. Therefore, there is a need for small molecule ocular angiogenesis inhibitors to complement existing therapies. We examined the safety and therapeutic potential of SH-11037, a synthetic derivative of the antiangiogenic homoisoflavonoid cremastranone, in models of ocular neovascularisation. SH-11037 dose-dependently suppressed angiogenesis in the choroidal sprouting assay ex vivo and inhibited ocular developmental angiogenesis in zebrafish larvae. Additionally, intravitreal SH-11037 (1 μM) significantly reduced choroidal neovascularisation (CNV) lesion volume in the laser-induced CNV mouse model, comparable to an anti-VEGF antibody. Moreover, SH-11037 synergised with anti-VEGF treatments in vitro and in vivo. Up to 100 μM SH-11037 was not associated with signs of ocular toxicity and did not interfere with retinal function or pre-existing retinal vasculature. SH-11037 is thus a safe and effective treatment for murine ocular neovascularisation, worthy of further mechanistic and pharmacokinetic evaluation.


Unilateral psoriasis in a woman with ipsilateral post-mastectomy lymphedema.
Psoriasis is a multi-factorial disease with various clinical manifestations. We present a case of unilateral psoriasis associated with ipsilateral lymphedema that developed after mastectomy for breast cancer. A 42-year-old Korean woman was referred to our clinic with a 1-month history of multiple erythematous scaly patches on the right arm, back, and breast and was diagnosed with psoriasis by a skin biopsy. Three years previously, she had been diagnosed with breast cancer (T1N2), underwent a right quadrantectomy and axillary lymph node dissection, and completed adjuvant chemotherapy followed by high-dose adjuvant radiotherapy. She had started rehabilitation therapy on the right arm for secondary lymphedema 30 months previously. Because of the long interval between radiation and psoriasis, we speculated that changes in the local milieu caused by the lymphedema might be a causative factor. We hereby report a rare case of unilateral psoriasis following post-mastectomy lymphedema.


A Retrospective Interventional Cohort Study to Assess the Safety and Efficacy of Sandostatin LAR for Treatment of Recurrent and/or Refractory Meningiomas.
Background: Meningiomas are the most common adult primary intracranial tumors in the United States. Despite high recurrence rate of atypical and malignant subtypes, there is no approved drug indicated specifically for meningioma. Since the majority of meningiomas exhibit high density of somatostatin receptors subtypes, somatostatin analogs have been under close investigation. The aim of this study was to evaluate efficacy and safety of Sandostatin LAR (octreotide) in patients with progressive, and/or recurrent meningioma, and identify subset of patients who were more likely to benefit from this treatment. Methods: A total of 43 patients ≥ 18 years old were included in the retrospective chart review. The patients underwent treatment with Sandostatin LAR (octreotide) from 01.01.2010 to 06.01.2017 at the University of California, Irvine after confirmation of the diagnosis. Six months progression free survival (PFS6) was defined as a primary endpoint, and the overall survival (OS), safety, and toxicity were identified as secondary endpoints. Results: The OS for 6 months, 1, and 3 years for all WHO grades was 94.8, 88.1, and 67.0%, respectively. The PFS6 for WHO I, II, III, and all was 89.4, 89, 33.3, and 80% respectively. For patients with no prior surgeries, chemotherapy or radiation, the PFS6 was 88.9, 84.8, and 94.8%, respectively. Interestingly, the PFS6 was 90.5% for skull-based and 80% for 3-6 cm tumors. Patients with tumors in parasagittal location had PFS6 of 83.3% compared to PFS6 of 50.0% for patients with convexity tumors. Evaluation of PFS6 based on the effect of estrogen and progesterone on meningioma identified that ER-PR+ tumors had PFS6 of 87.8% while patients with ER-PR- meningiomas had PFS6 of 62.5%. Median TTP for WHO grade I, II, and III was 3.1, 2.40, and 0.26 years, respectively. Subgroup analysis showed that median TTP was 3.1 years for <3 cm tumors, 3.22 years for skull-based tumors, 2.37 years for patients with prior surgeries and 3.10 years for patients with no history of chemotherapy. History of radiation had no effect on median TTP. Sandostatin LAR (octreotide) was well-tolerated. Conclusions:This is one of the largest retrospective analysis of meningioma patients treated with Sandostatin LAR (octreotide) suggesting that this treatment has minimal to no adverse events and could prolong overall survival, and progression free survival especially for patients with ER-PR+ tumors who underwent surgeries for small skull-based tumors.


Reaching the unreached: treatment as prevention as a workable strategy to mitigate HIV and its consequences in high-risk groups.
While there have been significant advances in curbing the HIV disease epidemic worldwide, there continues to be significant number of incident cases with 2.3 million new infections in the year 2012 alone. Treatment as prevention (TasP), which involves the use of antiretroviral drugs to decrease the likelihood of HIV illness, death and transmission from infected individuals to their noninfected sexual and /or drug paraphernalia-sharing injecting partners, must be incorporated into any HIV prevention strategy that is going to be successful on a large scale. Especially in resource-limited settings, the focus of the prevention approach should be on high-risk groups who contribute disproportionately to community HIV transmission, including people who inject drugs (PWID), men who have sex with men (MSM) and sex workers. Innovative strategies including integrated care services adapted to different patient care settings have to and can be employed to reach these at-risk populations.


Identifying how GPs spend their time and the obstacles they face: a mixed-methods study.
Although problems that impair task completion - known as operational failures - are an important focus of concern in primary care, they have remained little studied. To quantify the time GPs spend on different activities during clinical sessions; to identify the number of operational failures they encounter; and to characterise the nature of operational failures and their impact for GPs. Mixed-method triangulation study with 61 GPs in 28 NHS general practices in England from December 2018 to December 2019. Time-motion methods, ethnographic observations, and interviews were used. Time-motion data on 7679 GP tasks during 238 hours of practice in 61 clinical sessions suggested that operational failures were responsible for around 5.0% (95% confidence interval [CI] = 4.5% to 5.4%) of all tasks undertaken by GPs and accounted for 3.9% (95% CI = 3.2% to 4.5%) of clinical time. However, qualitative data showed that time-motion methods, which depend on pre-programmed categories, substantially underestimated operational failures. Qualitative data also enabled further characterisation of operational failures, extending beyond those measured directly in the time-motion data (for example, interruptions, deficits in equipment/supplies, and technology) to include problems linked to GPs' coordination role and weaknesses in work systems and processes. The impacts of operational failures were highly consequential for GPs' experiences of work. GPs experience frequent operational failures, disrupting patient care, impairing experiences of work, and imposing burden in an already pressurised system. This better understanding of the nature and impact of operational failures allows for identification of targets for improvement and indicates the need for coordinated action to support GPs.


ThermoLabAnimal - A high-throughput analysis software for non-invasive thermal assessment of laboratory mice.
Body temperature changes in laboratory mice are often assessed by invasive and stressful methods, which may confound the measurement. Infrared thermography is a possible non-invasive alternative, but the cost of standard thermal cameras, lack of dedicated software for biomedical purposes, and labour-intensiveness of thermal image analysis have limited their use. An additional limitation lies on the scarcity of research on the causing factors of differences between body surface and core body temperature. We propose a method for automatic assessment of mean body surface temperature in freely-moving mice, using dedicated software for thermal image analysis. While skin surface temperature may not necessarily be linearly correlated with core body temperature (in itself an imprecise concept), under standardized environmental conditions, such as those in which laboratory animals are kept, mean body surface temperature can provide useful information on their thermal status (i.e. deviations from normothermia, namely hypo- and hyperthermia). We developed a publicly available software that includes an imaging analysis workflow/algorithm for automatic segmentation of the pixels associated with the animal from the pixels associated with the background, removing the need for manually defining the area of analysis. A batch analysis mode is also available, for automatic and high-throughput analysis of all image files located in a folder. The software is compatible with the most widespread thermal camera manufacturer, 'FLIR Systems', as well as with the low-cost 'Thermal Expert TE-Q1' miniaturized high-resolution thermal camera used for this study. Furthermore, the software has been validated in a mouse model expressing non-transient hypothermia, where the thermal analysis results were compared with readings from implanted thermo-sensitive passive integrated transponders tags. Thermography allows for thermal assessment of laboratory animals without the effect of handling stress on their physiology or behaviour. Our automatic image analysis software also removes observer errors and bias, while speeding up the data processing.


Contrasting effect of alpha/beta- and gamma-interferons on expression of macrophage Ia antigens.
IFN-gamma is known to induce the expression of Ia antigens on macrophages. We found that murine IFN-alpha and -beta blocked the effects of IFN-gamma in a dose-dependent manner. The antagonistic effect of IFN-alpha and -beta was observed even when macrophages were prestimulated with IFN-gamma. These inhibitory effects of IFN-alpha or -beta were blocked by their respective antibodies. The block exerted by IFN-alpha/beta was similar whether Ia levels were monitored by immunofluorescence with anti-Ia mAb, or by stimulation of freshly sensitized, alloreactive T lymphoblasts. Adherent macrophage-rich populations from newborn mice were incapable of expressing Ia antigens following stimulation with IFN-gamma, and would inhibit the response of adult macrophages to this lymphokine. Addition of anti-IFN-beta mAb, but not anti-IFN-alpha allowed newborns' macrophages to express Ia in response to IFN-gamma, and ablated the suppressive activity toward adult cells. These results indicate that IFN-alpha and -beta, which can be produced in the course of self-defense responses and during ontogeny, may contribute to the down-regulation of macrophage Ia expression.


Crack cocaine: a five-year follow-up study of treated patients.
To follow-up a group of 131 crack cocaine users and examine drug use, treatment experience, employment status, involvement in crime and mortality at 2 and 5 years. Consecutive crack-dependent patients who were admitted to a detoxification unit in São Paulo between 1992 and 1994 were re-interviewed on two occasions: 1995-1996 and 1998-1999. 5 years after treatment information was obtained on 124 (95%) of the original cohort. 39.7% (n = 52) of the patients reported having been abstinent from cocaine for at least the last year, and 21.4% (n = 28) had used the drug. Of those subjects not using cocaine at 2 years, 19 (62%) were still abstinent at 5 years. Twenty-three (17.6%) patients had died by the 5-year follow-up with homicide, due to firearms or other weapons, being the commonest cause (n = 13). The annual adjusted mortality rate for the sample was 24.92 deaths/1,000 individuals, the excess mortality rate was of 21.64 deaths/1,000 individuals, and the standardized mortality ratio was 7.60. A history of injecting drug use, unemployment at the time of the index admission and administrative discharge at the index admission were factors that contributed to the risk of dying over the next 5 years. There was a progressive movement towards abstinence over the follow-up period, and there was evidence that once abstinence had been achieved it was maintained. On the other hand, the mortality rate was extremely high and was higher among those who were still using crack at 2 years.


Mechanisms of neuro-robotic prosthesis operation in leg amputees.
Above-knee amputees suffer the lack of sensory information, even while using most advanced prostheses. Restoring intraneural sensory feedback results in functional and cognitive benefits. It is unknown how this artificial feedback, restored through a neuro-robotic leg, influences users' sensorimotor strategies and its implications for future wearable robotics. To unveil these mechanisms, we measured gait markers of a sensorized neuroprosthesis in two leg amputees during motor tasks of different difficulty. Novel sensorimotor strategies were intuitively promoted, allowing for a higher walking speed in both tasks. We objectively quantified the augmented prosthesis' confidence and observed the reshaping of the legs' kinematics toward a more physiological gait. In a possible scenario of a leg amputee driving a conventional car, we showed a finer pressure estimation from the prosthesis. Users exploited different features of the neural stimulation during tasks, suggesting that a simple prosthesis sensorization could be effective for future neuro-robotic prostheses.


A Neonate With Vertical Transmission of COVID-19 and Acute Respiratory Failure: A Case Report.
This case describes a case of vertical transmission of COVID-19 from a mother to her neonate. The neonate subsequently developed acute respiratory failure consistent with adult symptoms of COVID-19. This preterm neonate was born at 33 4/7 weeks' gestational age to a COVID-19-positive mother and admitted to the neonatal intensive care unit (NICU) for prematurity and respiratory distress. The neonate developed acute respiratory failure with severe persistent pulmonary hypertension of newborn (PPHN) and required intubation and maximum respiratory and cardiovascular support. The neonate subsequently tested positive for COVID-19 at 24 hours of life. Acute respiratory failure related to COVID-19 infection. The neonate was admitted to the NICU on CPAP. At 11 hours of life, the neonate began to exhibit signs of worsening respiratory distress requiring intubation, mechanical, and high frequency ventilation. An echocardiogram revealed severe PPHN. The neonate required dopamine to manage hypotension and was treated with steroids to decrease inflammation associated with airway edema noted during intubation. Pharmaceutically induced paralysis, analgesia, and sedation was used to manage persistent hypoxia. The neonate fully recovered from acute respiratory failure and was discharged home with the mother. Newborns born to mothers who are positive for COVID-19 are at risk for vertical transmission of COVID-19 and should be monitored closely for acute respiratory failure. Respiratory medical management should include supportive care. Staff should also encourage parents to consider receiving the COVID-19 vaccine to protect their newborn from the possibility of developing acute respiratory failure.