[Clinical, immunological and psychiatric characteristics of tuberculosis infection initial period in adolescents].
Variability of tuberculin reactions in adolescents may be represented by changes of a negative tuberculin test to a positive or false one, then to a positive test. Adolescents primarily infected with tuberculosis have predisposing factors: inadequate immunoprophylaxis contact with tuberculosis patients, discord in physical development, hyperergic sensitivity to tuberculin, which can determine a further course of tuberculosis infection. The variability of tuberculin reactions in adolescents is characterized by changed immunological responsiveness as higher immunospecific parameters and lower nonspecific responsiveness parameters, as well as decreased attention; there is a trend for frequent development of primary infection in persons having character accentuation. The aforesaid allows the variability of tuberculin reactions to be regarded as "minor disease".


[Immune response in the surgical patient: effect of anesthesia and blood transfusion].
Anesthesiology has progressed spectacularly over the last two decades, largely parallel to developments in basic and clinically applied sciences such as immunology. The anesthesiologist's involvement now extends to all matters involved in perioperative care. Surgery, anesthetic procedures themselves, and other associated techniques such as blood transfusion all alter the patient's immune response and all fall within the range of procedures monitored by the anesthesiologist. The repercussions on the patient are important, given that alterations suppose increased risk of postoperative infection and increased recurrence of neoplastic disease. The present article reviews available knowledge on how and to what extent the patient's immune status is affected in the perioperative period. Generally, surgery and anesthesia induce immune system depression. It is possible to demonstrate a decrease in the number and activity of circulating immune cells and alterations of various types in interleukins and in protein synthesis during acute phase response. Research in this field is complex given that the individual effect of each factor involved is difficult to measure and experimental or clinical designs usually yield only biased views. Replacement of lost red blood cells is another factor leading to immunological changes. New anesthetic techniques, the optimization of methods already in use, and the development of modern, less immunodepressant drugs and of alternatives to homologous blood transfusion are all solutions that have been proposed. This is an exciting field of study in which today, perhaps more than ever, the anesthesiologist has a critical role to play.


Male erectile dysfunction: its prevalence in Western australia and associated sociodemographic factors.
This is a report of a population-based cross-sectional observational study in Western Australia (WA) on male erectile dysfunction (ED). To assess the prevalence of ED in WA and to examine its associated sociodemographic factors. Postal questionnaires were sent to randomly selected age-stratified male population samples obtained from the WA Electoral Roll. In addition to items covering sociodemographic and clinical information, the Australian Standard Classification of Occupations (ASCO), the Socioeconomic Index for Area (SEIFA), and the 5-item International Index of Erectile Function (IIEF-5) were used. One thousand seven hundred seventy (41.9%) of 4,228 questionnaires were returned. One thousand five hundred eighty (89.3%) were completed questionnaires from men aged 20.1 to 99.6 years (mean 57.9, median 59.1, standard deviation 18.5). The prevalences of any ED and of severe ED among adult males in WA, adjusted for age distribution, were 25.1 and 8.5%, respectively. Standardized to World Health Organization (WHO) World Standard Population, the corresponding prevalences were 23.4 and 7.4%. Prevalence, as well as severity, of ED increased with age. Thirty-eight percent of the participants who were married or had partners experienced ED (severe ED 19.1%). The prevalence of ED was not significantly different between "white-collar" and "blue-collar" workers. Despite the great majority of the affected participants having experienced ED for >1 year, only 14.1% reported having ever received any treatment for ED. The study has provided population-based epidemiological data on ED in Western Australian men covering a wide range of ages. The finding that ED is age related, highly prevalent, and grossly underdiagnosed and undertreated is pertinent to global population aging and a rapidly aging Australian population. To facilitate comparisons across populations with different age distributions, all future population-based studies on ED should be standardized to WHO World Standard Population.


Hsp70 molecular chaperones: emerging roles in human disease and identification of small molecule modulators.
Molecular chaperones are best known for their ability to aid in the solubilization of mis-folded proteins, and as a result play essential roles in protein folding, degradation, and transport. However, many molecular chaperones also play essential roles in signal transduction cascades. For example, Hsp70 molecular chaperones are a highly conserved, abundant class of chaperones that are found in every species and in nearly every cellular compartment in eukaryotes. In addition to their well-established roles in facilitating protein folding and in the targeting of proteins to organelles and to proteolytic machines, Hsp70s are anti-apoptotic and inhibition of Hsp70 function in some cases is sufficient to induce tumor cell death. Hsp70 function is also vital for the replication of viruses. Based on these data, small molecule Hsp70 modulators might, in principle, be used for the treatment of specific cancers, infections, and protein conformational diseases. In this review, we summarize the structural and functional characteristics of Hsp70 chaperones, and then discuss their roles in cellular physiology. Finally, we will review the recent discovery of small molecules that alter Hsp70 expression and function.


Recommendations of the ISBT Working Party on Granulocyte Immunobiology for leucocyte antibody screening in the investigation and prevention of antibody-mediated transfusion-related acute lung injury.
Transfusion-related acute lung injury (TRALI) is currently one of the most common causes of transfusion-related major morbidity and death. Among the many TRALI mediators, leucocyte antibodies have been identified as important triggers of severe TRALI. These recommendations were compiled by experts of the ISBT Working Party on Granulocyte Immunobiology, based on the results obtained in eight international granulocyte immunology workshops, their personal experiences and on published study results. Leucocyte antibody screening has to include the detection of human leucocyte antigen (HLA) class I, class II and human neutrophil alloantigen antibodies using established and validated techniques. HLA class I antibody detection should be restricted to antibodies clinically relevant for TRALI. To avoid unnecessary workload, TRALI diagnosis should be assessed by consultation with the reporting clinician and thorough exclusion of transfusion-associated circulatory overload/cardiac insufficiency. In patients diagnosed with TRALI having donors with detectable leucocyte antibodies, evidence of leucocyte incompatibility should be provided by either cross-matching or typing of patient for cognate antigen. Leucocyte antibody screening for the immunological clarification of TRALI cases as well as for identification of potentially alloimmunized blood donors is feasible and can be performed in a reasonable and quality assured manner. This practice can contribute to the prevention of antibody-mediated TRALI.


Non-aflatoxigenicity of commercial Aspergillus oryzae strains due to genetic defects compared to aflatoxigenic Aspergillus flavus.
Aspergillus oryzae is generally recognized as safe, but it is closely related to A. flavus in morphology and genetic characteristics. In this study, we tested the aflatoxigenicity and genetic analysis of nine commercial A. oryzae strains that were used in Korean soybean fermented products. Cultural and HPLC analyses showed that none of the commercial strains produced detectable amount of aflatoxins. According to the molecular analysis of 17 genes in the aflatoxin (AF) biosynthetic pathway, the commercial strains could be classified into three groups. The group I strains contained all the 17 AF biosynthetic genes tested in this study; the group II strains deleted nine AF biosynthetic genes and possessed eight genes, including aflG, aflI, aflK, aflL, aflM, aflO, aflP, and aflQ; the group III strains only had six AF biosynthetic genes, including aflG, aflI, aflK, aflO, aflP, and aflQ. With the reverse transcription polymerase chain reaction, the group I A. oryzae strains showed no expression of aflG, aflQ and/or aflM genes, which resulted in the lack of AF-producing ability. Group II and group III strains could not produce AF owing to the deletion of more than half of the AF biosynthetic genes. In addition, the sequence data of polyketide synthase A (pksA) of group I strains of A. oryzae showed that there were three point mutations (two silent mutations and one missense mutation) compared with aflatoxigenic A. flavus used as the positive control in this study.


Spectral monitoring of surfactant clearance during alveolar epithelial type II cell differentiation.
In this study, we report on the noninvasive identification of spectral markers of alveolar type II (ATII) cell differentiation in vitro using Raman microspectroscopy. ATII cells are progenitor cells for alveolar type I (ATI) cells in vivo, and spontaneously differentiate toward an ATI-like phenotype in culture. We analyzed undifferentiated and differentiated primary human ATII cells, and correlated Raman spectral changes to cellular changes in morphology and marker protein synthesis (surfactant protein C, alkaline phosphatase, caveolin-1). Undifferentiated ATII cells demonstrated spectra with strong phospholipid vibrations, arising from alveolar surfactant stored within cytoplasmic lamellar bodies (Lbs). Differentiated ATI-like cells yielded spectra with significantly less lipid content. Factor analysis revealed a phospholipid-dominated spectral component as the main discriminator between the ATII and ATI-like phenotypes. Spectral modeling of the data revealed a significant decrease in the spectral contribution of cellular lipids-specifically phosphatidyl choline, the main constituent of surfactant, as ATII cells differentiate. These observations were consistent with the clearance of surfactant from Lbs as ATII cells differentiate, and were further supported by cytochemical staining for Lbs. These results demonstrate the first spectral characterization of primary human ATII cells, and provide insight into the biochemical properties of alveolar surfactant in its unperturbed cellular environment.


AAV vectors displaying bispecific DARPins enable dual-control targeted gene delivery.
Precise delivery of genes to therapy-relevant cells is crucial for in vivo gene therapy. Receptor-targeting as prime strategy for this purpose is limited to cell types defined by a single cell-surface marker. Many target cells are characterized by combinations of more than one marker, such as the HIV reservoir cells. Here, we explored the tropism of adeno-associated viral vectors (AAV2) displaying designed ankyrin repeat proteins (DARPins) mono- and bispecific for CD4 and CD32a. Cryo-electron tomography revealed an unaltered capsid structure in the presence of DARPins. Surprisingly, bispecific AAVs transduced CD4/CD32a double-positive cells at much higher efficiencies than single-positive cells, even if present in low amounts in cell mixtures or human blood. This preference was confirmed when vector particles were systemically administered into mice. Cell trafficking studies revealed an increased cell entry rate for bispecific over monospecific AAVs. When equipped with an HIV genome-targeting CRISPR/Cas cassette, the vectors prevented HIV replication in T cell cultures. The data provide proof-of-concept for high-precision gene delivery through tandem-binding regions on AAV. Reminiscent of biological products following Boolean logic AND gating, the data suggest a new option for receptor-targeted vectors to improve the specificity and safety of in vivo gene therapy.


Concanavalin A and alloxan interactions on glucose-induced insulin secretion and biosynthesis from islets of Langerhans.
The pretreatment of isolated islets of Langerhans with concanavalin A (Con A) completely blocks alloxan from suppressing the insulin release response to glucose. The lectin itself inhibits insulin secretion. This effect is dose dependent and reversible. Con A, however, has no protective action against the inhibition of glucose-induced insulin biosynthesis in islets exposed to alloxan. The protective action of Con A on alloxan toxicity is likely to be at the beta-cell surface at a membrane recognition site for glucose as a stimulus for secretion. The insulin biosynthetic effect of glucose appears to be mediated through a separate mechanism.


The Invisible Burden: Diagnosing and Combatting Typhoid Fever in Asia and Africa.
Measuring the burden of typhoid fever and developing effective strategies to reduce it require a surveillance infrastructure that is currently lacking in many endemic countries. Recent efforts and partnerships between local and international researchers have helped to provide new data on the incidence and control of typhoid in parts of Asia and Africa. Here, we highlight examples from India, Nepal, Vietnam, Fiji, Sierra Leone, and Malawi that summarize past and present experiences with the diagnosis, treatment, and prevention of typhoid fever in different locations with endemic disease. While there is no validated road map for the elimination of typhoid, the lessons learned in studying the epidemiology and control of typhoid in these settings can provide insights to guide future disease control efforts.


Safety and efficacy of a feed additive consisting of Bacillus velezensis PTA-6507, B. velezensis NRRL B-50013 and B. velezensis NRRL B-50104 (Enviva® PRO 202 GT) for turkeys for fattening (Danisco Animal Nutrition).
Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of the additive consisting of Bacillus amyloliquefaciens PTA-6507, B. amyloliquefaciens NRRL B-50013 and B. amyloliquefaciens NRRL B-50104 (trade name: Enviva® PRO 202 GT) for turkeys for fattening. The product under assessment is based on viable spores of three strains originally identified as B. amyloliquefaciens which, in the course of the current assessment, were reclassified as Bacillus velezensis. The bacterial species B. velezensis is considered suitable for the qualified presumption of safety (QPS) approach to safety assessment. The identity of the active agents was established. The active agents do not harbour acquired antimicrobial resistance genes and lack toxigenic potential and the capacity to produce aminoglycosides. Following the QPS approach, the three bacterial strains are presumed safe for the target species, consumers and the environment. Since no concerns are expected from the other components of the additive, Enviva® PRO 202 GT is also considered safe for the target species, consumers and the environment. Enviva® PRO 202 GT is non-irritant to skin and eyes and is not a dermal sensitiser. Due to the proteinaceous nature of the active agents, the additive should be considered a respiratory sensitiser. In a previous opinion, it was concluded that Enviva® PRO 202 GT has a potential to be efficacious as a zootechnical additive in chickens for fattening at the recommended level of 7.5 × 107 CFU/kg complete feed. It is considered that conclusions on efficacy of Enviva® PRO 202 GT in chickens for fattening can be extrapolated to turkeys for fattening. Therefore, the FEEDAP Panel concludes that Enviva® PRO 202 GT has the potential to be efficacious in turkeys for fattening at 7.5 × 107 CFU/kg complete feed.


Demonstration of W chromosome-specific repetitive DNA sequences in the domestic fowl, Gallus g. domesticus.
Evidence is presented to demonstrate the presence of W chromosome-specific repetitive DNA sequences in the female White Leghorn chicken, Gallus g. domesticus, based on two different experimental approaches. First, 3H-labelled, female chicken DNA was hybridized with excess, unlabelled, mercurated, male DNA, and unhybridized single-stranded 3H-DNA (3H-SHU-DNA) was recovered by SH-Sepharose and hydroxyapatite column chromatography. Approximately 24% of the hybridizable 3H-SHU-DNA was female-specific and localized on the W chromosome. The second approach was to examine female-specific DNA fragments among the digests of chicken DNA with various restriction endonucleases. Among them, we found that digestion with XhoI produced two prominent female-specific brands of 0.60 kb (= kilobase pairs) and 1.1 kb. The 0.60 kb fragment was isolated and 3H-labelled by nick-translation. Female-specificity of the 3H-XhoI--0.60 kb DNA was judged to be at least 95% under the conditions of hybridization with membrane filter-bound DNA. Presence of amplified XhoI--0.60 kb DNA on the W chromosome seems to be limited to different lines of G.g. domesticus and no such repeat was detected in three species belonging to other genera in the order Galliformes and in three species belonging to other avian orders.


Social Virtual Reality (VR) Involvement Affects Depression When Social Connectedness and Self-Esteem Are Low: A Moderated Mediation on Well-Being.
While social interaction and play in a VR environment are becoming ever more popular, little is known about how social VR games affect users. The purpose of this study was to elucidate the role of several contingent factors in social VR games by modeling the relationships between involvement, well-being, depression, self-esteem, and social connectedness. A conditional process-moderated mediation model of the measured variables was analyzed with 220 pieces of collected data. The result showed that: (1) the direct effect of involvement on well-being was significant, and (2) the index of moderated mediation involving depression, self-esteem, and social connectedness was significant. We conclude that high levels of involvement in social VR games by socially isolated users with low self-esteem can negatively affect their well-being. The findings of this study contribute in several ways to our understanding of the effect of social VR games upon users and provide important practical implications.


Research progress on occurrence characteristics and source analysis of microfibers in the marine environment.
Synthetic microfiber pollution is a growing concern in the marine environment. However, critical issues associated with microfiber origins in marine environments have not been resolved. Herein, the potential sources of marine microfibers are systematically reviewed. The obtained results indicate that surface runoffs are primary contributors that transport land-based microfibers to oceans, and the breakdown of larger fiber plastic waste due to weathering processes is also a notable secondary source of marine microfibers. Additionally, there are three main approaches for marine microplastic source apportionment, namely, anthropogenic source classification, statistical analysis, and numerical simulations based on the Lagrangian particle tracking method. These methods establish the connections between characteristics, transport pathways and sources of microplastics, which provides new insights to further conduct microfiber source apportionment. This study helps to better understand sources analysis and transport pathways of microfibers into oceans and presents a scientific basis to further control microfiber pollution in marine environments.


FXIII deficiency due to base exchange Thr 449 (ACT) --> Ile (ATT) in exon 11 of the factor 13A gene. A cause of bleeding?
A 17-year old man was sent to us for coagulation testing because he suffered from acute bleeding which started immediately after making an incision in the skin for a urological surgery. The patient had a history of mild bleeding symptoms (nose bleeds during the childhood, gingival bleeds). Results of laboratory investigations: Blood group 0, closure times (PFA 100):132 s (ADP/collagen) and 300 s (epinephrine/collagen), VWF antigen 57%, VWF activity 50%, factor VIII activity 66%, factor XIII activity 59%. The results were confirmed by further investigations. Additionally, two relevant genetic findings were obtained: first a heterozygous base exchange in exon 11 of the factor 13A gene -Thr 449 (ACT)>Ile (ATT)-, not described before the completion of the study, and second the homozygous state of the 807 C-allele within the integrin alpha2 gene. The patient inherited the base exchange in the factor 13A gene from his mother. Homozygosity of the 807 C allele in the integrin alpha2 gene is associated with a very low expression of the platelet collagen receptor. Individuals with low VWF due to blood group 0 and low platelet collagen receptor density often exhibit a bleeding tendency, e.g. bleedings from mucosal membranes or menorrhagia in females. In our opinion the light factor XIII deficiency in our patient is coincidental and not the sole cause of bleeding.


Glaucoma-Associated CDR1 Peptide Promotes RGC Survival in Retinal Explants through Molecular Interaction with Acidic Leucine Rich Nuclear Phosphoprotein 32A (ANP32A).
Glaucoma is a complex, multifactorial optic neuropathy mainly characterized by the progressive loss of retinal ganglion cells (RGCs) and their axons, resulting in a decline of visual function. The pathogenic molecular mechanism of glaucoma is still not well understood, and therapeutic strategies specifically addressing the neurodegenerative component of this ocular disease are urgently needed. Novel immunotherapeutics might overcome this problem by targeting specific molecular structures in the retina and providing direct neuroprotection via different modes of action. Within the scope of this research, the present study showed for the first time beneficial effects of the synthetic CDR1 peptide SCTGTSSDVGGYNYVSWYQ on the viability of RGCs ex vivo in a concentration-dependent manner compared to untreated control explants (CTRL, 50 µg/mL: p < 0.05 and 100 µg/mL: p < 0.001). Thereby, this specific peptide was identified first as a potential biomarker candidate in the serum of glaucoma patients and was significantly lower expressed in systemic IgG molecules compared to healthy control subjects. Furthermore, MS-based co-immunoprecipitation experiments confirmed the specific interaction of synthetic CDR1 with retinal acidic leucine-rich nuclear phosphoprotein 32A (ANP32A; p < 0.001 and log2 fold change > 3), which is a highly expressed protein in neurological tissues with multifactorial biological functions. In silico binding prediction analysis revealed the N-terminal leucine-rich repeat (LRR) domain of ANP32A as a significant binding site for synthetic CDR1, which was previously reported as an important docking site for protein-protein interactions (PPI). In accordance with these findings, quantitative proteomic analysis of the retinae ± CDR1 treatment resulted in the identification of 25 protein markers, which were significantly differentially distributed between both experimental groups (CTRL and CDR1, p < 0.05). Particularly, acetyl-CoA biosynthesis I-related enzymes (e.g., DLAT and PDHA1), as well as cytoskeleton-regulating proteins (e.g., MSN), were highly expressed by synthetic CDR1 treatment in the retina; on the contrary, direct ANP32A-interacting proteins (e.g., NME1 and PPP2R4), as well as neurodegenerative-related markers (e.g., CEND1), were identified with significant lower abundancy in the CDR1-treated retinae compared to CTRL. Furthermore, retinal protein phosphorylation and histone acetylation were also affected by synthetic CDR1, which are both partially controlled by ANP32A. In conclusion, the synthetic CDR1 peptide provides a great translational potential for the treatment of glaucoma in the future by eliciting its neuroprotective mechanism via specific interaction with ANP32A's N terminal LRR domain.


Mortality and Morbidity of Heart Failure Hospitalization in Adult Patients With Congenital Heart Disease.
Little is known about outcomes following heart failure (HF) hospitalization among adults with congenital heart disease (CHD) in the United States. We aim to compare the outcomes of HF versus non-HF hospitalizations in adults with CHD. Using a national deidentified administrative claims data set, patients with adult congenital heart disease (ACHD) hospitalized with and without HF (ACHDHF+, ACHDHF-) were characterized to determine the predictors of 90-day and 1-year mortality and quantify the risk of mortality, major adverse cardiac and cerebrovascular events, and health resource use. Cox proportional hazard regression was used to compare ACHDHF+ versus ACHDHF- for risk of events and health resource use. Of 26 454 unique ACHD admissions between January 1, 2010 and December 31, 2020, 5826 (22%) were ACHDHF+ and 20 628 (78%) were ACHDHF-. The ACHD HF+ hospitalizations increased from 6.6% to 14.0% (P<0.0001). Over a mean follow-up period of 2.23 ± 2.19 years, patients with ACHDHF+ had a higher risk of mortality (hazard ratio [HR], 1.86 [95% CI, 1.67-2.07], P<0.001), major adverse cardiac and cerebrovascular events (HR, 1.73 [95% CI, 1.63-1.83], P<0.001) and health resource use including rehospitalization (HR, 1.09 [95% CI, 1.05-1.14], P<0.001) and increased postacute care service use (HR, 1.56 [95% CI, 1.32-1.85], P<0.001). Cardiology clinic visits within 30 days of hospital admission were associated with lower 90-day and 1-year all-cause mortality (odds ratio [OR], 0.62 [95% CI, 0.49-0.78], P<0.001; OR, 0.69 [95% CI, 0.58-0.83], P<0.001, respectively). HF hospitalization is associated with increased risk of mortality and morbidity with high health resource use in patients with ACHD. Recent cardiology clinic attendance appears to mitigate these risks.


Late antibody-mediated rejection in renal allografts: outcome after conventional and novel therapies.
Although several strategies for treating early antibody-mediated rejection (AMR) in kidney transplants have been investigated, evidence on treatment of late AMR manifesting after 6 months is sparse. In this single-center series, we present data on 23 consecutive patients treated for late AMR. Late AMR was diagnosed using Banff 2007 criteria along with presence of donor-specific antibodies (DSA) and acute rise in serum creatinine (SCr). Response to therapy was assessed by improvement in SCr, histologic improvement, and decline in DSA strength. Overall, 17% (4/23) had documented nonadherence while 69% (16/23) had physician-recommended reduction in immunosuppression before AMR. Eighteen patients (78%) were treated with plasmapheresis or low-dose IVIg+rituximab; 11 (49%) with refractory AMR also received one to three cycles of bortezomib. While there was an improvement (P=0.02) in mean SCr (2.4 mg/dL) at the end of therapy compared with SCr at the time of diagnosis (2.9 mg/dL), this improvement was not sustained at most recent follow-up. Eleven (48%) patients had no histologic resolution on follow-up biopsy. Lack of histologic response was associated with older patients (odds ratio [OR]=3.17; P=0.04), presence of cytotoxic DSA at time of diagnosis (OR=200; P=0.04), and severe chronic vasculopathy (cv≥2) on index biopsy (OR=50; P=0.06). A major setting in which late AMR occurred in our cohort was reduction or change in immunosuppression. Our data demonstrate an inadequate response of late AMR to current and novel (bortezomib) therapies. The benefits of therapy need to be counterweighed with potential adverse effects especially in older patients, large antibody loads, and chronic allograft vasculopathy.


WIPPER: an accurate and efficient field phenotyping platform for large-scale applications.
More accurate, rapid, and easy phenotyping tools are required to match the recent advances in high-throughput genotyping for accelerating breeding and genetic analysis. The conventional data recording in field notebooks and then inputting data to computers for further analysis is inefficient, time-consuming, laborious, and prone to human error. Here, we report WIPPER (for Wireless Plant Phenotyper), a new phenotyping platform that combines field phenotyping and data recording with the aid of Bluetooth communication, thus saving time and labor not only for field data recoding but also for inputting data to computers. Additionally, it eliminates the risk of human error associated with phenotyping and inputting data. We applied WIPPER to 100 individuals of a rice recombinant inbred line (RIL) for measuring leaf width and relative chlorophyll content (SPAD value), and were able to record an accurate data in a significantly reduced time compared with the conventional method of data collection. We are currently using WIPPER for routine management of rice germplasm including recording and documenting information on phenotypic data, seeds, and DNA for their accelerated utilization in crop breeding.


Glucocorticoid-related changes in body mass index among children and adolescents with rheumatic diseases.
To examine the temporal and dose-related effects of glucocorticoids (GCs) on body mass index (BMI) in children with rheumatic diseases. Children initiating GCs for a rheumatic disease (n = 130) were assessed every 3 months for 18 months. BMI, weight, and height Z score trajectories were described according to GC starting dosage in prednisone equivalents: high (≥1.0 mg/kg/day), low (<0.2 mg/kg/day to a maximum of 7.5 mg/day), and moderate (between high and low) dosage. The impact of GC dosing, underlying diagnosis, pubertal status, physical activity, and disease activity on BMI Z scores and on percent body fat was assessed with longitudinal mixed-effects growth curve models. The GC starting dose was high in 59% and moderate in 39% of patients. The peak BMI Z score was +1.29 at 4 months with high-dose GCs and +0.69 at 4.2 months with moderate-dose GCs (P < 0.001). Overall, 50% (95% confidence interval 41-59%) of the children returned to within +0.25 SD of their baseline BMI Z score. Oral GC dose over the preceding 3 months was the most significant determinant of BMI Z score and percent body fat. The proportion of days in receipt of GCs, disease activity, and a diagnosis of systemic-onset juvenile idiopathic arthritis were also associated with BMI Z scores. The correlation between changes in BMI and changes in percent body fat was 0.09. In children with rheumatic diseases starting moderate and high doses of GCs, BMI Z scores peaked at 4 months, and only half returned to within +0.25 SD of their baseline BMI Z score after 18 months.


The G389R mutation in the MAPT gene presenting as sporadic corticobasal syndrome.
A few patients with mutations in the microtubule-associated protein tau gene (MAPT), affected by frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T), may clinically present with a corticobasal syndrome (CBS). We report a case of apparently sporadic CBS bearing a mutation in the MAPT gene so far associated with frontotemporal dementia (FTD) phenotype. The patient is a 41-year-old man with progressive asymmetric signs of cortical and basal ganglia involvement consistent with CBS. Magnetic resonance imaging showed asymmetric cortical atrophy and unusual corticospinal tract hyperintensity in T2-weighted images. Genetic testing revealed a heterozygous G to C mutation at the first base of codon 389 of the MAPT gene, changing glycine to arginine (G389R), in the patient and his unaffected elderly father. In conclusion, the MAPT G389R mutation shows phenotypic variability resulting in both FTD and CBS. The mutation also demonstrates incomplete penetrance. Corticospinal tract degeneration is an exceptional finding.


Biologically plausible and evidence-based risk intervals in immunization safety research.
In immunization safety research, individuals are considered at risk for the development of certain adverse events following immunization (AEFI) within a specific period of time referred to as the risk interval. These intervals should ideally be determined based on biologic plausibility considering features of the AEFI, presumed or known pathologic mechanism, and the vaccine. Misspecification of the length and timing of these intervals may result in introducing bias in epidemiologic and clinical studies of immunization safety. To date, little work has been done to formally assess and determine biologically plausible and evidence-based risk intervals in immunization safety research. In this report, we present a systematic process to define biologically plausible and evidence-based risk interval estimates for two specific AEFIs, febrile seizures and acute disseminated encephalomyelitis. In addition, we review methodologic issues related to the determination of risk intervals for consideration in future studies of immunization safety.


Structural aspects of denitrifying enzymes.
The reduction of nitrate to nitrogen gas via nitrite, nitric oxide and nitrous oxide is the metabolic pathway usually known as denitrification, a key step in the nitrogen cycle. As observed for other elemental cycles, a battery of enzymes are utilized, namely the reductases for nitrate, nitrite, nitric oxide and nitrous oxide, as well as multiple electron donors that interact with these enzymes, in order to carry out the stepwise reactions that involve key intermediates. Because of the importance of this pathway (of parallel importance to the nitrogen-fixation pathway), efforts are underway to understand the structures of the participating enzymes and to uncover mechanistic aspects. Three-dimensional structures have been solved for the majority of these enzymes in the past few years, revealing the architecture of the active metal sites as well as global structural aspects, and possible mechanistic aspects. In addition, the recognition of specific electron-transfer partners raises important questions regarding specific electron-transfer pathways, partner recognition and control of metabolism.


Chromatin "prepattern" and histone modifiers in a fate choice for liver and pancreas.
Transcriptionally silent genes can be marked by histone modifications and regulatory proteins that indicate the genes' potential to be activated. Such marks have been identified in pluripotent cells, but it is unknown how such marks occur in descendant, multipotent embryonic cells that have restricted cell fate choices. We isolated mouse embryonic endoderm cells and assessed histone modifications at regulatory elements of silent genes that are activated upon liver or pancreas fate choices. We found that the liver and pancreas elements have distinct chromatin patterns. Furthermore, the histone acetyltransferase P300, recruited via bone morphogenetic protein signaling, and the histone methyltransferase Ezh2 have modulatory roles in the fate choice. These studies reveal a functional "prepattern" of chromatin states within multipotent progenitors and potential targets to modulate cell fate induction.


Comparative Analysis of Gammaherpesvirus Circular RNA Repertoires: Conserved and Unique Viral Circular RNAs.
Recent studies have identified circular RNAs (circRNAs) expressed from the Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV) human DNA tumor viruses. To gain initial insights into the potential relevance of EBV circRNAs in virus biology and disease, we assessed the circRNAome of the interspecies homologue rhesus macaque lymphocryptovirus (rLCV) in a naturally occurring lymphoma from a simian immunodeficiency virus (SIV)-infected rhesus macaque. This analysis revealed rLCV orthologues of the latency-associated EBV circular RNAs circRPMS1_E4_E3a and circEBNA_U. Also identified in two samples displaying unusually high lytic gene expression was a novel rLCV circRNA that contains both conserved and rLCV-specific RPMS1 exons and whose backsplice junctions flank an rLCV lytic origin of replication (OriLyt). Analysis of a lytic infection model for the murid herpesvirus 68 (MHV68) rhadinovirus identified a cluster of circRNAs near an MHV68 lytic origin of replication, with the most abundant of these, circM11_ORF69, spanning the OriLyt. Lastly, analysis of KSHV latency and reactivation models revealed the latency associated circRNA originating from the vIRF4 gene as the predominant viral circRNA. Together, the results of this study broaden our appreciation for circRNA repertoires in the Lymphocryptovirus and Rhadinovirus genera of gammaherpesviruses and provide evolutionary support for viral circRNA functions in latency and viral replication.IMPORTANCE Infection with oncogenic gammaherpesviruses leads to long-term viral persistence through a dynamic interplay between the virus and the host immune system. Critical for remodeling of the host cell environment after the immune responses are viral noncoding RNAs that modulate host signaling pathways without attracting adaptive immune recognition. Despite the importance of noncoding RNAs in persistent infection, the circRNA class of noncoding RNAs has only recently been identified in gammaherpesviruses. Accordingly, their roles in virus infection and associated oncogenesis are unknown. Here we report evolutionary conservation of EBV-encoded circRNAs determined by assessing the circRNAome in rLCV-infected lymphomas from an SIV-infected rhesus macaque, and we report latent and lytic circRNAs from KSHV and MHV68. These experiments demonstrate utilization of the circular RNA class of RNAs across 4 members of the gammaherpesvirus subfamily, and they identify orthologues and potential homoplastic circRNAs, implying conserved circRNA functions in virus biology and associated malignancies.


Excitatory amino acid receptor activation in the raphe pallidus area mediates prostaglandin-evoked thermogenesis.
To investigate the role of excitatory amino acid neurotransmission within the rostral raphe pallidus area (RPa) in thermogenic and cardiovascular responses, changes in sympathetic nerve activity to brown adipose tissue (BAT), BAT temperature, expired CO(2), arterial pressure, and heart rate were recorded after microinjection of excitatory amino acid (EAA) receptor agonists into the RPa in urethan-chloralose-anesthetized, ventilated rats. To determine whether EAA neurotransmission within the RPa is necessary for the responses evoked by disinhibition of the RPa or by prostaglandin E(2) acting within the medial preoptic area, BAT sympathetic nerve activity, BAT temperature, expired CO(2), arterial pressure, and heart rate were measured during these treatments both before and after blockade of EAA receptors within the RPa. Microinjection of EAA receptor agonists into the RPa resulted in significant increases in all measured variables; these increases were attenuated by prior microinjection of the respective EAA receptor antagonists into the RPa. Microinjection of prostaglandin E(2) into the medial preoptic area or microinjection of bicuculline into the RPa resulted in respective significant increases in BAT sympathetic nerve activity (+approximately 190% and +approximately 235% of resting levels), in BAT temperature (approximately 1.8 degrees C and approximately 2 degrees C), in expired CO(2) (approximately 1.1% and approximately 1.1%), and in heart rate (approximately 97 beats per minute (bpm) and approximately 100 bpm). Blockade of ionotropic EAA receptors within the RPa by microinjection of kynurenate completely reversed the prostaglandin E(2) or bicuculline-evoked increases in all of the measured variables. Blockade of either N-methyl-D-aspartate (NMDA) receptors or non-NMDA receptors alone resulted in marked attenuations of the prostaglandin E(2)-evoked effects on all of the measured variables. These data demonstrate that activation of an EAA input to the RPa is necessary for the BAT thermogenic and the cardiovascular effects resulting from the actions of prostaglandin E(2) within the medial preoptic area or from the disinhibition of local neurons in the RPa.


Sexual risk reduction among Zambian couples.
Zambia has over 1 million HIV infections nationwide and an urban prevalence rate of 23%. This study compared the impact of male involvement in multiple and single session risk reduction interventions among inconsistent condom users in Zambia and the role of serostatus among HIV-seropositive and serodiscordant couples. Couples (N=392) were randomised into intervention arms. Among inconsistent condom users at baseline (N=83), condom use increased in both conditions and this increase was maintained over a 12- month period. At 12 months, seronegative men in the multiple session condition increased sexual barrier (male and female condoms) use in comparison with those in the single session condition (F=16.13, =0.001) while seropositive individuals increased sexual barrier use regardless of condition. Results illustrate the importance of both single and multiple session risk reduction counseling among seronegative men in serodiscordant couples in Zambia, and highlight the differing perception of risk between seropositive and serodiscordant persons.


Quantitative detection of human spermatogonia for optimization of spermatogonial stem cell culture.
Can human spermatogonia be detected in long-term primary testicular cell cultures using validated, germ cell-specific markers of spermatogonia? Germ cell-specific markers of spermatogonia/spermatogonial stem cells (SSCs) are detected in early (1-2 weeks) but not late (> 6 weeks) primary testicular cell cultures; somatic cell markers are detected in late primary testicular cell cultures. The development of conditions for human SSC culture is critically dependent on the ability to define cell types unequivocally and to quantify spermatogonia/SSCs. Growth by somatic cells presents a major challenge in the establishment of SSC cultures and therefore markers that define spermatogonia/SSCs, but are not also expressed by testicular somatic cells, are essential for accurate characterization of SSC cultures. Testicular tissue from eight organ donors with normal spermatogenesis was used for assay validation and establishing primary testicular cell cultures. Immunofluorescence analysis of normal human testicular tissue was used to validate antibodies (UTF1, SALL4, DAZL and VIM) and then the antibodies were used to demonstrate that primary testicular cells cultured in vitro for 1-2 weeks were composed of somatic cells and rare germ cells. Primary testicular cell cultures were further characterized by comparing to testicular somatic cell cultures using quantitative reverse transcriptase PCR (UTF1, FGFR3, ZBTB16, GPR125, DAZL, GATA4 and VIM) and flow cytometry (CD9 and SSEA4). UTF1, FGFR3, DAZL and ZBTB16 qRT-PCR and SSEA4 flow cytometry were validated for the sensitive, quantitative and specific detection of germ cells. In contrast, GPR125 mRNA and CD9 were found to be not specific to germ cells because they were also expressed in testicular somatic cell cultures. While the germ cell-specific markers were detected in early primary testicular cell cultures (1-2 weeks), their expression steadily declined over time in vitro. After 6 weeks in culture only somatic cells were detected. Different groups attempting SSC culture have utilized different sources of human testes and minor differences in the preparation and maintenance of the testicular cell cultures. Differences in outcome may be explained by genetic background of the source tissue or technical differences. The ability to propagate human SSCs in vitro is a prerequisite for proposed autologous transplantation therapy aimed at restoring fertility to men who have been treated for childhood cancer. By applying the assays validated here it will be possible to quantitatively compare human SSC culture conditions. The eventual development of conditions for long-term propagation of human SSCs in vitro will greatly facilitate learning about the basic biology of these cells and in turn the ability to use human SSCs in therapy. The experiments presented in this manuscript were funded by a Project Development Team within the ICTSI NIH/NCRR Grant Number TR000006. The authors declare no competing interests. Not applicable.


[Status of the bronchi in patients with pulmonary tuberculosis and different haptoglobin phenotype].
External respiration function test and bronchologic examination were conducted in 206 pulmonary tuberculosis patients with different haptoglobin (Hp) phenotypes. It was found that obstructive changes in peripheral portions of the bronchial tree were most common and marked among the revealed disorders of pulmonary ventilation function. These changes promote a decrease in the ventilation reserve to a great extent. As compared to Hp 2-1 carriers, specific endobronchitis and bronchial obstruction symptoms were significantly more frequent in patients with Hp 2-2. Bronchial obstruction symptoms alone were twice as frequent as in patients with Hp 1-1 than in Hp 2-1 carriers. The findings indicate that there is a close relationship between the status of the bronchi in pulmonary tuberculosis patients and the genetically determined Hp phenotype.


Ore improver additions alter livestock manure compost ecosystem C:N:P stoichiometry.
Deciphering the pivotal components of nutrient metabolism in compost is of paramount importance. To this end, ecoenzymatic stoichiometry, enzyme vector modeling, and statistical analysis were employed to explore the impact of exogenous ore improver on nutrient changes throughout the livestock composting process. The total phosphorus increased from 12.86 to 18.72 g kg-1, accompanied by a marked neutralized pH with ore improver, resulting in the Carbon-, nitrogen-, and phosphorus-related enzyme activities decreases. However, the potential C:P and N:P acquisition activities represented by ln(βG + CB): ln(ALP) and ln(NAG): ln(ALP), were increased with ore improver addition. Based on the ecoenzymatic stoiometry theory, these changes reflect a decreasing trend in the relative P/N limitation, with pH and total phosphorus as the decisive factors. Our study showed that the practical employment of eco stoichiometry could benefit the manure composting process. Moreover, we should also consider the ecological effects from pH for the waste material utilization in sustainable agriculture.


A field test of electret ion chambers for environmental remediation verification.
In 1999, the State of Idaho INEEL Oversight Program performed a field test to determine if electret ion chambers could be used as a replacement to soil sampling in field survey releases at a remediated radioactively contaminated site. This study compared exposure rates measured using electret ion chambers with gamma spectroscopic analysis results of soil samples collected at the remediated site. Exposure rate measurements were made in 1999 using electret ion chambers at the same locations that INEEL Oversight Program sampled soil in 1998 following MARSSIM protocol. The waste site was divided into nine survey units based upon site history including previous site surveys and physical boundaries. Exposure rate measurements at the remediation site compared well with exposure rate measurements made at reference background locations used for routine environmental monitoring by the State of Idaho indicating that the remedial action met cleanup criteria. A poor correlation between exposure rate measurements and 137Cs concentrations and other discrepancies were observed during this study with respect to measurements made during the 1998 final site survey.


Cognitive Functioning in Euthymic Bipolar Patients on Monotherapy with Novel Antipsychotics or Mood Stabilizers.
Bipolar disorder is associated with cognitive dysfunction in several domains. Medication effect is a potential confounder that can only be statistically controlled in many studies. The cognitive profile in bipolar disorder during remission on maintenance antipsychotics or mood stabilizers medication has not been compared before. We compared the cognitive profile of bipolar disorder patients euthymic for 2 month or more on monotherapy with novel antipsychotics (AP) (n=16), lithium carbonate (Li) (n=25) or valproic acid (VPA; n=26). Forty-two individuals were assessed as controls. The cognitive battery included Wechsler Adult Intelligence Scale-Revised (WAIS-R) subtests, the Wechsler Memory Scale (WMS), and Wisconsin Card Sorting Test (WCST). All three patient groups compared to controls performed poorly on the working memory and verbal memory tasks (F=3.59, df=3, p=0.02 for WAIS-R Arithmetic and F=123.64, df=3, p<0.01 for WMS Logical Memory). The differences remained significant after controlling for age. Across patients, the only significant difference was between the Li and AP groups in terms of working memory. The Li group performed better (F=3.59, df=2, p=0.02) and the difference survived correction for age and clinical features. The findings of this study suggest that working memory impairment in bipolar patients on monotherapy with atypical AP, whereas verbal memory impairment might be related to bipolar disorder itself. Working memory might be a state marker, whereas verbal memory could be a trait marker of bipolar disorder. Atypical AP might have an adverse effect on cognition in bipolar disorder. These findings cannot be generalized to all bipolar patients, particularly the poor responders to monotherapy.


Selective extraction of maleic hydrazide in foods using magnetic molecularly imprinted polymers and colorimetric detection via smartphone.
Maleic hydrazide (MH) is a plant growth regulator, herbicide, and sprout inhibitor used to improve the growth and quality of certain vegetables and fruits, unfortunately, MH has genotoxic and carcinogenic effects; thus, MH residues in food need to be analyzed. Herein, magnetic molecularly imprinted polymers (MagMIP) were synthesized by radical polymerization in just 30 min using a microwave for rapid and selective extraction of MH. The colorimetric detection of MH using the immobilized Folin Ciocalteau's reagent (FCR) on 96-well microplate via smartphone sensor exhibits useful sensitivity for MH with a limit of detection (LOD = 0.6 ppm) which is far lower than the maximum residue limits (higher than 5 ppm). The immobilized FCR was stored dry at two different storage conditions at +4 °C and room temperature without losing its performance over six months. The coupling MagMIP-extraction/clean-up and smartphone determination were tested towards food samples (i.e., potatoes, and carrots), obtaining good recovery (79-96 %), high repeatability (RSD 4.5 %; n = 10), and high selectivity for MH determination.


An autoethnography of pregnancy and birth during Covid times: Transcending the illusio of overwork in academia?
Under the pressure of always increasing demands of publication, excessive working hours are widespread in academia. Based on an autoethnography of myself as a pregnant woman under Covid, I explore the extent of my being caught by the illusio-"being taken in and by the game" (Bourdieu & Wacquant, 1992), that prompted me to remain absorbed by the publishing game and to overwork until the very last day before giving birth to my son. I also explore how the forced deceleration induced by the maternity leave as well as the Covid confinement contributed to increased awareness and reflection thus helping me to transcend the illusio that prompted me to overwork. I also reflect to the extent of this conversion being reversible given the continued pressures of the academic context.


Reduced-Order Filters-Based Adaptive Backstepping Control for Perturbed Nonlinear Systems.
In this article, a robust adaptive output-feedback control approach is presented for a class of nonlinear output-feedback systems with parameter uncertainties and time-varying bounded disturbances. A reduced-order filter driven by control input is proposed to reconstruct unmeasured states. The state estimation error is shown to be bounded by dynamic signals driven by system output. The bound estimation technique is employed to estimate the unknown disturbance bound. Based on the backstepping design with three sets of tuning functions, an adaptive output-feedback control scheme with the flat-zone modification is proposed. It is shown that all the signals in the resulting closed-loop adaptive control systems are bounded, and the output tracking error converges to a prespecified small neighborhood of the origin. Two simulation examples are provided to illustrate the effectiveness and validity of the proposed approach.


Pharmacokinetics and pharmacodynamics of posaconazole for invasive pulmonary aspergillosis: clinical implications for antifungal therapy.
Posaconazole is a triazole with anti-Aspergillus activity. However, little is known about the utility of posaconazole as primary therapy for invasive pulmonary aspergillosis. An in vitro model of the human alveolus was used to study the impact of minimum inhibitory concentrations (MIC) on exposure-response relationships. The pharmacokinetic-pharmacodynamic relationships of posaconazole were examined in an inhalational murine model of invasive pulmonary aspergillosis. A mathematical model was fitted to the entire data set. This model was then used to describe the relationship between drug exposure, quantified in terms of the area under the concentration time curve to MIC (AUC:MIC) and the observed antifungal effect. The posaconazole MIC was an important determinant of exposure-response relationships and accounted for a portion of the observed variance. Murine pharmacokinetics were linear for dosages 1-20 mg/kg/day. There was a dose-dependent decline in serum galactomannan concentrations, with near-maximal suppression following 20 mg/kg/day. The murine pharmacokinetic-pharmacodynamic data were well described by the mathematical model. An AUC:MIC ratio of 167 was associated with half-maximal antifungal effect. These results provide the experimental foundation for the selection of candidate posaconazole regimens for the primary treatment of invasive pulmonary aspergillosis in profoundly neutropenic hosts.


Generalised linear model of periodic limb movements.
During sleep, the lower extremities exhibit periodic repetitive movements which are referred to as Period Limb Movement (PLM). Polysomnography (PSG) is the gold standard for diagnosing periodic limb movement disorder. The frequency of PLM episodes per hour of sleep (PLMI) determines the severity of the condition. PLM are generated by a dynamic process, however PLMI measures only the average PLM rate and does not capture the dynamic properties of PLM. Here, we characterise PLM dynamics using a generalised dynamic model as a function of sleep stage, timing of past PLM events and adjacent sleep disordered-breathing events. We analysed PSG recordings of 237 men and 222 women enrolled in the Multi-ethnic Study of Atherosclerosis (MESA) dataset to model dynamic PLM features. We statistically analysed whether these dynamics are associated with sex, age, and BMI. Modelling suggests instantaneous PLM rates are greater in men than women and higher in N1 and N2 non-rapid eye movement sleep than N3 and rapid eye movement sleep. The generalised model constitutes statistically robust approach towards the characterisation of periodic limb movement.Clinical Relevance- The generalised model may enable differentiated diagnostics of periodic limb movement disorder.


[Skin necrosis: report of eleven cases].
Skin necrosis must be considered as a syndrome, because it is a clinical manifestation of different diseases. An early diagnosis is very important to choose the appropriate treatment. Therefore, its causes should be suspected and confirmed quickly. We report eleven patients with skin necrosis seen at our Department, caused by different etiologies: Warfarin-induced skin necrosis, loxoscelism, diabetic microangiopathy, ecthyma gangrenosum, disseminated intravascular coagulation, necrotizing vasculitis, paraneoplastic extensive necrotizing vasculitis, livedoid vasculopathy, necrotizing fasciitis, necrosis secondary to the use of vasoactive drugs and necrosis secondary to the use of cocaine. We also report the results of our literature review on the subject.


Cauda Equina Syndrome: A Review of 15 Patients Who Underwent Percutaneous Transforaminal Endoscopic Lumbar Discectomy (PTELD) Under Local Anaesthesia.
To analyse the results of Cauda Equina Syndrome (CES) operated by Percutaneous Transforaminal Endoscopic Lumbar Discectomy (PTELD). The study is a retrospective series of 15 patients operated by PTELD. Bladder dysfunction was classified as incomplete CES (CESI) and complete CES retention (CESR). Bladder / motor recovery rate and its timing, Oswestry Disability Index (ODI), Visual Analogue Score (VAS), patient satisfaction index, and sexual dysfunction were used to measure the outcome objectively. Additionally, in CESR patients, post-void residual (PVR) urine was measured by sonography. Complications and technical problems were noted. There were ten patients of CESI and five patients of CESR. The average follow-up was 20.33(12.05) months. Bladder symptoms recovery was 100%, and motor recovery was 80%. VAS for back pain recovered to 0.53(0.52) from 8(2.39). VAS for leg pain recovered to 0.13(0.35) from 9.20(1.32). ODI improved to 6.07(2.85) from 77.52(13.20). The time to the recovery of bladder function was 1.47(1.55) days. All CESR patient's abnormal PVR urine was normalised at five weeks post-operative. No complications were reported. However, five technical executional problems occurred. PTELD can be considered for CES treatment due to its substantial and quick recovery advantages. However, more evidence support is needed to make it a practice recommendation.


Neurotrophin roles in retinal ganglion cell survival: lessons from rat glaucoma models.
The neurotrophin (NT) hypothesis proposes that the obstruction of retrograde transport at the optic nerve head results in the deprivation of neurotrophic support to retinal ganglion cells (RGC) leading to apoptotic cell death in glaucoma. An important corollary to this concept is the implication that appropriate enhancement of neurotrophic support will prolong the survival of injured RGC indefinitely. This hypothesis is, perhaps, the most widely recognized theory to explain RGC loss resulting from exposure of the eye to elevated intraocular pressure (IOP). Recent studies of NT signaling using rat glaucoma models, have examined the endogenous responses of the retina to pressure exposure as well as studies designed to augment NT signaling in order to rescue RGC from apoptosis following pressure-induced injury. The examination of these studies in this review reveals a number of consistent observations and provides direction for further investigations of this hypothesis.


Peaceful use of disastrous neurotoxicants.
The increasing exposure to environmental neurotoxicants in the last decades caused serious health problems in the world population. Some of the neurotoxic agents are being used in agriculture and household such as insecticides and rodenticides and others are of natural origin like snake and scorpion venoms. Additional group of harmful substances is the chemical warfare agents including nerve and blistering agents that are known for their disastrous effects on neuronal tissues. The present paper presents a combination of epidemiological/clinical and molecular approaches for investigating the effect of certain groups of neurotoxicants on a variety of pathologies. The work of Finkelstein and coworkers describes epidemiological and clinical studies on acute and chronic organophosphate (OP)-induced neurotoxicity in certain populations in Israel. They mainly investigated the neurotoxic effects of low-level long-term exposure to OP in agricultural areas but also dealt with acute exposures as well. A molecular approach to OP mechanism of neuronal injury was described by Milatovic and coworkers. They demonstrated OP-induced oxidative injury in pyramidal neurons in the CA1 hippocampal area and its suppression by antioxidants. Lecht and coworkers described the novel snake venom angioneurins as important mediators of the physiological cross-talk between the cardiovascular and nervous systems. They also showed that under certain conditions these angioneurins may induce pathologies such as tumor development or disruption of the vascular barrier function during envenomation. Additional mechanistic/therapeutic approach was presented by Brodsky, Rosengarten, Proscura, Shapira and Wormser. They developed a novel anti-inflammatory peptide that reduced skin irritation induced by heat and sulfur mustard (SM) stimuli. Since SM causes neuropsychiatric symptoms and alterations in neurological functions this peptide may serve as a potential treatment of neuronal injuries caused by environmental neurotoxicants. These reviews highlight different aspects of neurotoxicity, addressing epidemiology and mechanisms of toxicity; and identifying novel potential therapies.


Activation and routing of membrane-tethered prohormone convertases 1 and 2.
Many peptide hormones and neuropeptides are processed by members of the subtilisin-like family of prohormone convertases (PCs), which are either soluble or integral membrane proteins. PC1 and PC2 are soluble PCs that are primarily localized to large dense core vesicles in neurons and endocrine cells. We examined whether PC1 and PC2 were active when expressed as membrane-tethered proteins, and how tethering to membranes alters the biosynthesis, enzymatic activity, and intracellular routing of these PCs. PC1 and PC2 chimeras were constructed using the transmembrane domain and cytoplasmic domain of the amidating enzyme, peptidylglycine alpha-amidating monooxygenase (PAM). The membrane-tethered PCs were rerouted from large dense core vesicles to the Golgi region. In addition, the chimeras were transiently expressed at the cell surface and rapidly internalized to the Golgi region in a fashion similar to PAM. Membrane-tethered PC1 and PC2 exhibited changes in pro-domain maturation rates, N-glycosylation, and in the pH and calcium optima required for maximal enzymatic activity against a fluorogenic substrate. In addition, the PC chimeras efficiently cleaved endogenous pro-opiomelanocortin to the correct bioactive peptides. The PAM transmembrane domain/cytoplasmic domain also prevented stimulated secretion of pro-opiomelanocortin products in AtT-20 cells.


VA Geriatric Scholars Program's impact on prescribing potentially inappropriate medications.
The Veterans Affairs (VA) Geriatric Scholars Program (GSP) is a workforce development program to enhance skills and competencies among VA clinicians who provide healthcare for older veterans in VA primary care clinics. An intensive geriatrics didactics (IGD) course is a core element of this professional development program. The objective of this study was to evaluate the impact of completing the IGD course on providers' rates of prescribing definite potentially inappropriate medications (DPIMs) based on Beers Criteria from 2008 to 2016. We applied a longitudinal interrupted time series design to examine changes in DPIM prescribing rates for GSP participants before and after completing the IGD course. The time series was divided into two 12-month periods, representing the preintervention period (ie, 12 months prior to completing the IGD course) and the postintervention period (ie, 12 months after completing the IGD course), and populated with pharmacy dispensing data from the VA's Corporate Data Warehouse. An adjusted slope impact model was developed to estimate the postintervention change in the proportion of the dispensed medications identified as DPIMs. After adjusting for case mix, we observed a statistically significant reduction in the proportion of DPIMs dispensed post IGD (slope change, 0.994; 95% CI, 0.991-0.997). This change in slope reflects a total decrease of 7971 DPIM dispensings during the postintervention period. This equates to an estimated 24 fewer DPIM dispensings per provider during the postintervention period. Although the size of the effect was modest, we found that participation in the GSP IGD course reduced prescribing of DPIMs for older veterans.


The complete mitogenome of the Murray Cod, Maccullochella peelii (Mitchell, 1838) (Teleostei: Percichthyidae).
The complete mitochondrial genome of the iconic Australian freshwater fish, the Murray Cod, Maccullochella peelii, was recovered from partial genome sequencing data using the HiSeq platform (Illumina, San Diego, CA). The mitogenome consists of 16,442 bp (58% A + T content) containing 13 protein-coding genes, 2 ribosomal subunit genes, 22 transfer RNAs, and a 768 bp non-coding AT-rich region. This is the first mitogenome sequence for the genus Maccullochella, and the fourth for the family Percichthyidae.


Ethical issues in medical research in the developing world: a report on a meeting organised by Fondation Mérieux.
This paper reports on a multidisciplinary meeting held to discuss ethical issues in medical research in the developing world. Many studies, including clinical trials, are conducted in developing countries with a high burden of disease. Conditions under which this research is conducted vary because of differences in culture, public health, political, legal and social contexts specific to these countries. Research practices, including standards of care for participants, may vary as a result. It is therefore not surprising that ethical issues emerge. This meeting sought to identify and discuss these issues from the perspectives of the many actors in such research, including community representatives, with a view to finding ethical and pragmatic solutions to these issues. Dialogue between these actors was also promoted, with a view to identifying the need to develop such dialogue in future. Drawing from the experiences of the speakers, the colloquium attempted to outline some answers to several key questions characterising the field today. Experiences related to epidemiologic research, vaccine trials, drug trials, diagnostic tests and to some fundamental ethical issues in health research. Speakers were from different countries, disciplines and professions. The meeting provided a forum for consultation and debate between different ethics actors. Both encouraging findings and challenges emerged.


Load-sharing characteristics of stenting and post-dilation in heavily calcified coronary artery.
In this work, stenting in non-calcified and heavily calcified coronary arteries was quantified in terms of diameter-pressure relationships and load transfer from the balloon to the artery. The efficacy of post-dilation in non-calcified and heavily calcified coronary arteries was also characterized in terms of load sharing and the changes in tissue mechanics. Our results have shown that stent expansion exhibits a cylindrical shape in non-calcified lesions, while it exhibits a dog bone shape in heavily calcified lesions. Load-sharing analysis has shown that only a small portion of the pressure load (1.4 N, 0.8% of total pressure load) was transferred to the non-calcified lesion, while a large amount of the pressure load (19 N, 12%) was transferred to the heavily calcified lesion. In addition, the increasing inflation pressure (from 10 to 20 atm) can effectively increase the minimal lumen diameter (from 1.48 mm to 2.82 mm) of the heavily calcified lesion, the stress (from 1.5 MPa to 8.4 MPa) the strain energy in the calcification (1.77 mJ to 26.5 mJ), which associated with the potential of calcification fracture. Results indicated that increasing inflation pressure can be an effective way to improve the stent expansion if a dog bone shape of the stenting profile is observed. Considering the risk of a balloon burst, our results support the design and application of the high-pressure balloon for post-dilation.


Piezoelectric polymers.
Polymers with piezoelectric and pyroelectric properties that make them useful for biomedical applications and devices are considered. The characteristics of such polymers are examined, and transducers made from them are discussed. Laboratory developments of devices using piezoelectric polymers are briefly reviewed, and the slowness of product development in this area is commented on.


An automated rapid detection system using the quenching probe method for detecting interleukin 28B and inosine triphosphatase single nucleotide polymorphisms in chronic hepatitis C.
Single nucleotide polymorphisms (SNPs) in the interleukin 28B gene (IL28B) are good pretreatment predictors of anti-hepatitis C virus (HCV) therapy with interferon. SNPs of the inosine triphosphatase (ITPA) gene are associated with reduced haemoglobin levels during treatment with ribavirin. The i-densy™ (Arkray, Inc.), which is based on the quenching probe (QP) method, automatically detects target genes in blood samples by fluorescence quenching within 100 min. Using a QP and primer set, a gene amplification response is generated that can quickly and easily detect a specific gene's arrangement by fluorometry. The present study was conducted to compare the utility of i-densy (QP method) with that of conventional direct sequencing (DS) for detecting SNPs in the IL28B and ITPA genes in chronic hepatitis C patients. Between June 2011 and January 2012, 73 consecutive patients underwent genotyping of IL28B, and 54 patients underwent genotyping of ITPA. All of the patients were seropositive for HCV-RNA. The IL28B and ITPA genotypes were tested for bi-allelic polymorphisms in rs8099917 (T/T, T/G and G/G; minor allele, G) and rs1127354 (C/C, C/A and A/A; minor allele, A), respectively. The results obtained with the QP method were identical to those obtained with the conventional DS method. The frequency of the IL28B genotypes TT, GT and GG were 74%, 24.7% and 1.4%, respectively, and those of the ITPA genotypes CC, AC and AA were 68.5%, 29.6% and 1.9%, respectively. These results indicate that the i-densy using the QP method can automatically, quickly and easily identify genotypes of IL28B and ITPA.


Innovative Methods and Applications in Mucoadhesion Research.
The present review is aimed at elucidating relatively new aspects of mucoadhesion/mucus interaction and related phenomena that emerged from a Mucoadhesion workshop held in Munster on 2-3 September 2015 as a satellite event of the ICCC 13th-EUCHIS 12th. After a brief outline of the new issues, the focus is on mucus description, purification, and mucus/mucin characterization, all steps that are pivotal to the understanding of mucus related phenomena and the choice of the correct mucosal model for in vitro and ex vivo experiments, alternative bio/mucomimetic materials are also presented. Then a selection of preparative techniques and testing methods are described (at molecular as well as micro and macroscale) that may support the pharmaceutical development of mucus interactive systems and assist formulators in the scale-up and industrialization steps. Recent applications of mucoadhesive systems (including medical devices) intended for different routes of administration (oral, gastrointestinal, vaginal, nasal, ocular, and intravesical) and for the treatment of difficult to treat pathologies or the alleviation of symptoms are described.


The ARID1B phenotype: what we have learned so far.
Evidence is now accumulating from a number of sequencing studies that ARID1B not only appears to be one of the most frequently mutated intellectual disability (ID) genes, but that the range of phenotypes caused by ARID1B mutations seems to be extremely wide. Thus, it is one of the most interesting ID genes identified so far in the exome sequencing era. In this article, we review the literature surrounding ARID1B and attempt to delineate the ARID1B phenotype. The vast majority of published ARID1B patients have been ascertained through studies of Coffin-Siris syndrome (CSS), which leads to bias when documenting the frequencies of phenotypic features. Additional observations of those individuals ascertained through exome sequencing studies helps in delineation of the broader clinical phenotype. We are currently establishing an ARID1B consortium, aimed at collecting ARID1B patients identified through genome-wide sequencing strategies. We hope that this endeavor will eventually lead to a more comprehensive view of the ARID1B phenotype.


Dimerized Drosophila myosin VIIa: a processive motor.
The molecular mechanism of processive movement of single myosin molecules from classes V and VI along their actin tracks has recently attracted extraordinary attention. Another member of the myosin superfamily, myosin VII, plays vital roles in the sensory function of Drosophila and mammals. We studied the molecular mechanism of Drosophila myosin VIIa, using transient kinetics and single-molecule motility assays. Myosin VIIa moves along actin filaments as a processive, double-headed single molecule when dimerized by the inclusion of a leucine zipper at the C terminus of the coiled-coil domain. Its motility is approximately 8-10 times slower than that of myosin V, and its step size is 30 nm, which is consistent with the presence of five IQ motifs in its neck region. The kinetic basis for the processive motility of myosin VIIa is the relative magnitude of the release rate constants of phosphate (fast) and ADP (slow) as in myosins V and VI. The ATPase pathway is rate-limited by a reversible interconversion between two distinct ADP-bound actomyosin states, which results in high steady-state occupancy of a strongly actin-bound myosin species. The distinctive features of myosin VIIa (long run lengths, slow motility) will be very useful in video-based single-molecule applications. In cells, this kinetic behavior would allow myosin VIIa to exert and hold tension on actin filaments and, if dimerized, to function as a processive cargo transporter.


Monitoring Anti-Pythium insidiosum IgG Antibodies and (1→3)-β-d-Glucan in Vascular Pythiosis.
Despite aggressive treatment, vascular pythiosis has a mortality rate of 40%. This is due to delays in diagnosis and a lack of effective monitoring tools. To overcome this drawback, serum beta-d-glucan (BG) and P. insidiosum-specific antibody (Pi-Ab) were examined as potential monitoring markers in vascular pythiosis. A prospective cohort study of vascular pythiosis patients was carried out from January 2010 to July 2016. Clinical information and blood samples were collected and evaluated by the BG and Pi-Ab assays. Linear mixed-effect models were used to compare BG and Pi-Ab levels. The in vitro susceptibility test was performed with all P. insidiosum isolates from culture-positive cases. A total of 50 patients were enrolled: 45 survived and 5 died during follow-up. The survivors had a significantly shorter time to medical care (P < 0.0001) and a significantly shorter waiting time to the first surgery (P < 0.0001). There were no differences in BG levels among the groups at diagnosis (P = 0.33); however, BG levels among survivors were significantly lower than those of the deceased group at 0.5 months (P < 0.0001) and became undetectable after 3 months. Survivors were able to maintain an enzyme-linked immunosorbent assay (ELISA) value (EV) of Pi-Ab above 8, whereas the EV among deceased patients was less than 4. In vitro susceptibility results revealed no synergistic effects between itraconazole and terbinafine. This study showed that BG and Pi-Ab are potentially valuable markers to monitor the disease after treatment initiation. An unchanged BG level at 2 weeks after surgery should prompt an evaluation for residual disease.


Exercise capacity predicts health status in alpha(1)-antitrypsin deficiency.
Resting lung function is only weakly related to health status in chronic obstructive pulmonary disease, reflecting the multifactorial causes of impairment and the heterogeneous nature of the condition. The current study examined whether density mask analysis of high-resolution computed tomography (HRCT) or exercise capacity were better surrogates for health status in a well-defined, homogeneous group of patients with alpha(1)-antitrypsin deficiency (PiZ). Twenty-nine patients with predominantly lower zone emphysema on HRCT were studied. Exercise was assessed by incremental treadmill (V O(2) peak) and shuttle walking tests (ISWT) and health status by the St. George's Respiratory Questionnaire (SGRQ) and SF-36. Although lower zone expiratory HRCT was related to exercise capacity (rho = -0.64 and -0.63 for V O(2) peak and ISWT, respectively, p < 0.001), multiple regression analysis suggested that FEV(1) was a marginally better predictor (rho = -0.64 and -0.65, p < 0.001). HRCT also related significantly to health status (rho = -0.37 for SGRQ activity, p < 0.05), although again FEV(1) showed a stronger relationship (rho = -0.43, p = 0.01). However, exercise capacity was the best predictor of health status with the ISWT accounting for up to 55% of the variability seen in SGRQ total and up to 53% of the SF-36 domain scores (physical functioning). Although both HRCT and lung function relate to health status, exercise capacity is the best predictor of patients disability in these patients with predominantly lower zone emphysema.


Parent-Reported Clinical Utility of Pediatric Genomic Sequencing.
Genomic sequencing (GS) is increasingly used for diagnostic evaluation, yet follow-up care is not well understood. We assessed clinicians' recommendations after GS, parent-reported follow-up, and actions parents initiated in response to learning their child's GS results. We surveyed parents of children who received GS through the Clinical Sequencing Evidence Generating Research consortium ∼5 to 7 months after return of results. We compared the proportion of parents who reported discussing their child's result with a clinician, clinicians' recommendations, and parents' follow-up actions by GS result type using χ2 tests. A total of 1188 respondents completed survey measures on recommended medical actions (n = 1187) and/or parent-initiated actions (n = 913). Most parents who completed recommended medical actions questions (n = 833, 70.3%) reported having discussed their child's GS results with clinicians. Clinicians made recommendations to change current care for patients with positive GS results (n = 79, 39.1%) more frequently than for those with inconclusive (n = 31, 12.4%) or negative results (n = 44, 11.9%; P < .001). Many parents discussed (n = 152 completed, n = 135 planned) implications of GS results for future pregnancies with a clinician. Aside from clinical recommendations, 13.0% (n = 119) of parents initiated changes to their child's health or lifestyle. In diverse pediatric clinical contexts, GS results can lead to recommendations for follow-up care, but they likely do not prompt large increases in the quantity of care received.


RNA splice site selection: evidence for a 5' leads to 3' scanning model.
Human G gamma-globin genes containing tandem duplications of the donor (5') or acceptor (3') RNA splice sites of the second intervening sequence were constructed in order to ascertain the directionality of RNA splice site selection. These genes were introduced into cultured monkey cells, and their transcripts were analyzed. Transcripts of these duplication variants were spliced only at the proximal copy of the duplicated splice sites. These data are consistent with a 5' leads to 3' model of splice site selection.


[Peritoneal dialysis in the treatment of chronic renal failure].
Fifty-four patients were treated with peritoneal dialysis for terminal chronic renal failure. Clinical-laboratory indices were assessed in patients on chronic peritoneal dialysis. Advantages of continuous ambulatory peritoneal dialysis over hemodialysis are analysed in terms of social rehabilitation of the patients. Complications of chronic peritoneal dialysis as a method and algorithms of their treatment are outlined. The role of peritoneal dialysis as a preparatory stage before transplantation of the kidney is assessed.


Smoking Cessation Support for Pregnant Women Provided by English Stop Smoking Services and National Health Service Trusts: A Survey.
Reducing smoking rates in pregnancy continues to be a public health priority. Given a recent UK government policy change resulting in The National Health Service (NHS) making a significant new contribution to cessation support in pregnancy in England, in addition to that of Local Authorities (LA), an up-to-date assessment of national support offered to pregnant women is needed. LA Stop Smoking Service (SSS) managers and representatives from maternity services in NHS Trusts were invited to participate in an online survey in autumn 2020. Topics included service configuration, staffing, practitioner consultations and treatments offered. The survey response rate was 66% (99/151) of LAs and 68% (95/140) of Trusts. Most LAs provided smoking support for pregnant smokers (78%), whereas under half (43%) of NHS Trusts did. Combination nicotine replacement therapy, i.e., a combination of a patch and short-acting product, was offered by LAs (92%) and Trusts (95%) and most commonly for 12 weeks duration, at 53% and 50%, respectively. Similar national online training was undertaken by those supporting women, with the majority undertaking the specialist pregnancy-specific module: LAs 60% and Trusts 79%. However, clinicians were reported to deliver specialist stop smoking support in over 50% of Trusts, whereas this was reported in only 16% of LAs. In England, both LA and NHS Trusts are currently delivering similar stop smoking support to pregnant women. Having nationally recognised treatment programmes and training allows for the delivery of consistent, evidence-based smoking cessation to pregnant women in different healthcare settings.


Induction of specific tolerance to allografts in rats by therapy with non-mitogenic, non-depleting anti-CD3 monoclonal antibody: association with TH2 cytokines not anergy.
Anti-CD3 monoclonal antibodies (mAb) are potent immunosuppressives in transplantation but most do not induce tolerance. They induce anergy in Th1 cells but, if they bind to Fc receptors on antigen presenting cells, they activate T cells to release cytokines. This study examined the mechanisms of transplant tolerance induction to PVG fully allogeneic grafts in dark agouti rats by G4.18, a mouse immunoglobulinG3 anti-rat CD3 mAb that does not bind rat Fc receptors. Evidence of T cell activation was assayed by flow cytometry, reverse transcription (RT)-polymerase chain reaction (PCR) for cytokine mRNA, and responsiveness in mixed lymphocyte culture. G4.18 treatment modulated T cell receptor/CD3 and CD2 and depleted T cells by <20% but did not induce activation surface markers. mRNA for interleukin (IL)-2, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and IL-4 in the lymph node, spleen, and thymus was not increased, and IFN-gamma mRNA was reduced. G4.18-treated and naive rat cells had similar proliferation and expression of IL-2, IFN-gamma, and IL-4 in vitro. G4.18-treated allograft recipients had no induction of mRNA for IL-2, IFN-gamma, TNF-alpha, TNF-beta, IL-4, IL-5, IL-10, perforin, and granzyme A & B in the spleen or grafts, with levels similar to those in isografts. The IL-4 and IL-5 mRNA levels in the spleen but not the graft of G4.18-treated recipients were higher than in rejecting and naive animals. Cells from G4.18-treated graft recipients proliferated more rapidly to the donor than to the third party and had increased IL-4 expression. G4.18 induced transplant tolerance by a combination of modulation and blocking of the TCR/CD3, associated with increased Th2 cytokines, without depletion, induction of anergy, or nonspecific activation of T cells.


Statistical Models for the Analysis of Isobaric Tags Multiplexed Quantitative Proteomics.
Mass spectrometry is being used to identify protein biomarkers that can facilitate development of drug treatment. Mass spectrometry-based labeling proteomic experiments result in complex proteomic data that is hierarchical in nature often with small sample size studies. The generalized linear model (GLM) is the most popular approach in proteomics to compare protein abundances between groups. However, GLM does not address all the complexities of proteomics data such as repeated measures and variance heterogeneity. Linear models for microarray data (LIMMA) and mixed models are two approaches that can address some of these data complexities to provide better statistical estimates. We compared these three statistical models (GLM, LIMMA, and mixed models) under two different normalization approaches (quantile normalization and median sweeping) to demonstrate when each approach is the best for tagged proteins. We evaluated these methods using a spiked-in data set of known protein abundances, a systemic lupus erythematosus (SLE) data set, and simulated data from multiplexed labeling experiments that use tandem mass tags (TMT). Data are available via ProteomeXchange with identifier PXD005486. We found median sweeping to be a preferred approach of data normalization, and with this normalization approach there was overlap with findings across all methods with GLM being a subset of mixed models. The conclusion is that the mixed model had the best type I error with median sweeping, whereas LIMMA had the better overall statistical properties regardless of normalization approaches.


[Prevalence of Cyclospora sp., Cryptosporidium sp, microsporidia and fecal coliform determination in fresh fruit and vegetables consumed in Costa Rica].
The presence of Cyclospora sp., Cryptosporidium sp. and microsporidia and the levels of fecal coliforms were determined in lettuce, parsley, cilantro, strawberries and blackberries acquired in local agricultural markets of the Central Valley of Costa Rica, in order to establish the possible transmission risk of these microorganisms and other pathogens from the consumption of these raw products. During the second semester of 2001 and the first of 2002, 50 different samples of each product, 25 taken in the dry season and 25 in the rainy season and coming from five different local agricultural markets were evaluated. The fecal coliforms count was done according to the technique recommended by Vanderzant & Splittstoesser. The parasite determination was done using Zielh Nielsen and Weber staining techniques from a sediment obtained through the rinse of the mentioned products, using sterile peptonated water 0.1% and centrifuging at 900 G for 15 min. One hundred per cent of vegetable samples had fecal coliforms and the greatest prevalence was obtained during the rainy season. Although all vegetables presented fecal coliforms in high concentrations, lettuce and cilantro presented statistical difference between rainy and dry season, being greater during the rainy season. Fecal coliforms were not detected in strawberries and blackberries probablydue to its low pH. All products evaluated presented, at least once, Cryptosporidium sp., Cyclospora sp. and microsporidia, showing the risk they represent to Public Health. Cryptosporidium was present in all products but strawberries. Microsporidia was present in all products except blackberries and Cyclospora was only isolated from lettuce during the dry season. These results show the importance of introducing in the country Good Agricultural Practices, especially due to the resistance of Cryptosporidium and Cyclospora to disinfecting agents.


Women's choice between indigenous and Western contraception in urban Mozambique.
Research on women's reproductive behavior and family planning in developing countries is usually focused on western contraceptive methods and rarely addresses indigenous contraception, such as herbs, amulets, and charms that are believed to prevent pregnancy. However, the available data demonstrate that indigenous contraception is widely known, and its prevalence often rivals that of western methods. Based on qualitative data collected in Greater Maputo, Mozambique, in 1993, this study explores and analyzes women's choice between western methods-mainly oral contraceptives, intra-uterine devices and injectables-available from state-run family planning clinics, and indigenous contraception, a combination of herbal and magical medicine, provided by traditional healers. The study demonstrates that women's choice between the two types of methods is determined by their sociodemographic characteristics and cultural background, access to these methods, perceptions of the effectiveness and undesirable side-effects of these methods, and by restrictions imposed by the providers. Although indigenous methods may not compete with western contraception in the long run, their present-day persistence warrants the attention of scholars and policymakers who intend to integrate women's concerns and constraints in the design of family planning systems.


Science and the universities.
The university system in Canada, as well as its method of funding, was built on the expectation of growth. It is now necessary to consider what effect the expected decline in enrollment may have on the ability of the university system to serve national needs. Neither the government nor the universities have had any experience that would fit them for carrying out effectively, humanly, and economically the kind of contraction that may be required, while still maintaining the quality of education. Such an adjustment is going to require the best efforts of the universities and the two senior levels of government working in concert, as well as the support of the public. Parallels are drawn with the situation in the United States.


Metastatic spread of primary lung adenocarcinoma to the small intestine: A case report.
Metastasis of primary lung cancer to the small intestine is rare, and the prognosis is poor. Early diagnosis of small intestinal metastasis is difficult because the incidence of clinically obvious symptoms is low. This report described a rare case of small intestine metastasis of lung adenocarcinoma. It is worth noting that the patient was diagnosed with lung adenocarcinoma (T2aN0M0, stage IB) over a year ago. However, he complained of fever, black stools, and abdominal pain for about a year after the surgery. Enhanced CT scans showed thickening of the intestinal wall and dilatation of the lumen in the right iliac area and adjacent pelvic cavity. Capsule endoscopy identified a space-occupying lesion with hemorrhaging in the ileum. A laparotomy was subsequently performed, and the histopathological confirmation revealed a metastatic lung adenocarcinoma and immunohistochemistry further showed positive results for TTF-1 and CK7. When patients with a history of primary lung cancer experience gastrointestinal symptoms, the possibility of distant metastasis of lung cancer to the digestive tract should be considered. Due to the rarity of primary lung cancer metastasis to the small intestine, we report the case of a 64-year-old male who presented with symptoms of gastrointestinal bleeding and was ultimately diagnosed with metastasis of primary lung cancer to the small intestine. When patients with lung cancer present with gastrointestinal symptoms, we cannot rule out the possibility of distant metastasis from primary lung cancer, although this possibility is unlikely.


Currents in la jolla and scripps submarine canyons.
Velocities up to 34 centimeters per second have been recorded near the floors of submarine canyons off La Jolla, California. Currents move alternately down- and upcanyon with variable periods. All 3- to 6-day measurements show net current transport downcanyon. Many of the downcanyon currents of higher velocity correlate with ebbing tides, as measured at the nearby pier. Other factors producing the currents probably include internal waves. Velocities are sufficient to transport large quantities of fine sand.


Association between statin use and lupus-like syndrome using spontaneous reports.
Several case reports of lupus-like syndrome suggest that statins could have triggered the development of this rare autoimmune disease. However, data on the association between statin use and lupus-like syndrome are scarce. We assessed whether there was an association between statin use and the occurrence of lupus-like syndrome. A case/noncase study based on individual case safety reports listed in the World Health Organization global individual case safety reports database (VigiBase) was conducted. According to World Health Organization adverse reaction terminology, cases were defined as reports of lupus-like syndrome. Each case was matched with 5 noncases by age, gender, and time of reporting. Use of statins was classified according to the Anatomical Therapeutic Chemical classification code system. Covariates, ie, use of corticosteroids, immunosuppressive drugs, nonsteroidal anti-inflammatory drugs, antidepressants, antiepileptics, proton pump inhibitors, and cardiovascular drugs, were determined. Multivariate logistic regression was used to calculate the reporting odds ratios with 95% confidence intervals. We identified 3362 reports of lupus-like syndrome as cases and 27,092 reports of other adverse drug reactions as noncases. Statins were more frequently reported as suspected drug in cases (3.2%) than in noncases (1.5%). After adjustment for several covariates, statins were associated with the reporting of lupus-like syndrome (reporting odds ratios 2.01; 95% confidence intervals 1.61-2.51). We found an association between reporting of statins and lupus-like syndrome. Further studies are needed to confirm this finding in more detail and establish causality.


Design and evaluation of effervescent floating tablets based on hydroxyethyl cellulose and sodium alginate using pentoxifylline as a model drug.
The aim of this work was to design and evaluate effervescent floating gastro-retentive drug delivery matrix tablets with sustained-release behavior using a binary mixture of hydroxyethyl cellulose and sodium alginate. Pentoxifylline was used as a highly water-soluble, short half-life model drug with a high density. The floating capacity, swelling, and drug release behaviors of drug-loaded matrix tablets were evaluated in 0.1 N HCl (pH 1.2) at 37°C±0.5°C. Release data were analyzed by fitting the power law model of Korsmeyer-Peppas. The effect of different formulation variables was investigated, such as wet granulation, sodium bicarbonate gas-forming agent level, and tablet hardness properties. Statistical analysis was applied by paired sample t-test and one-way analysis of variance depending on the type of data to determine significant effect of different parameters. All prepared tablets through wet granulation showed acceptable physicochemical properties and their drug release profiles followed non-Fickian diffusion. They could float on the surface of dissolution medium and sustain drug release over 24 hours. Tablets prepared with 20% w/w sodium bicarbonate at 50-54 N hardness were promising with respect to their floating lag time, floating duration, swelling ability, and sustained drug release profile.


Maximizing the success of bile duct cannulation studies in rats: recommendations for best practice.
Bile duct cannulation (BDC) studies are usually carried out in the rat to support the absorption, distribution, metabolism and excretion profiling of novel agrochemicals and pharmaceuticals. The different aspects of these studies (e.g. surgical preparation, dosing and collection of bile) can be intricate and/or technically complex. The animals are often kept singly housed for the duration of the studies following surgical implantation of the cannulas. The generation of insufficient data to meet the study objectives, for example due to failure in cannula patency, can result in the need to repeat these studies. A working group of contract research organizations that routinely carry out BDC studies was brought together by the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) to share their experiences, and to establish the key factors necessary to ensure routinely high success rates. Through these discussions the group has identified opportunities for best practice across various aspects of the studies. The aim of these recommendations is to support all staff involved in conducting BDC studies to maximize the amount of useful data generated using the fewest animals possible, while ensuring the highest possible standards of animal welfare.


Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'etude des Tumeurs Endocrines.
Multiple endocrine neoplasia type 1 (MEN1) disease is an autosomal dominant syndrome that is believed to equally affect men and women. This assumption has never been confirmed. The aims of this study were to evaluate the impact of gender on the prevalence of MEN1 lesions, on their lifetime probability of occurrence, and on the diagnosis of MEN1. Data regarding a study of 734 cases of MEN1 from the multicenter 'Groupe d'étude des Tumeurs Endocrines' were analyzed. There were 57.8% females. The prevalence and probability of pancreatic tumors were higher in males than in females (P=0.06, P=0.0004). This difference was due to gastrinomas. The prevalence and probability of developing pituitary tumors were significantly greater in females (P<0.001, P<0.0001). Thymic tumors were exclusively found in men. There were no significant gender differences in the prevalence and the probability of developing hyperparathyroidism, or adrenal and bronchial tumors, or in the proportion of positive genetic tests. A family history of MEN1 was more frequently found in men than in women at the time of diagnosis (P=0.02). In the case of pituitary tumor, the proportion of patients diagnosed with MEN1 at the time of the first lesion was lower in women (44.2%) than in men (67.3%). The phenotype expression of the MEN1 disease gene was different in males and females. In female patients, the possibility of MEN1 is not sufficiently taken into account. Any patient presenting a lesion that belongs to the MEN1 spectrum, such as a pituitary tumor, should be closely questioned about their family history and should be tested for hypercalcemia.