Antiretroviral treatment program retention among HIV-infected children in the Democratic Republic of Congo.
Retaining patients with HIV infection in care is still a major challenge in sub- Saharan Africa, particularly in the Democratic Republic of Congo (DRC) where the antiretroviral treatment (ART) coverage is low. Monitoring retention is an important tool for evaluating the quality of care. A review of medical records of HIV-infected children was performed in three health facilities in the DRC: the Amo-Congo Health center, the Monkole Clinic in Kinshasa, and the HEAL Africa Clinic in Goma. Medical records of 720 children were included. Kaplan Meier curves were constructed with the probability of retention at 6 months, 1 year, 2 years and 3 years. Retention rates were: 88.2% (95% CI: 85.1%-90.8%) at 6 months; 85% (95% CI: 81.5%-87.6%) at one year; 79.4% (95%CI: 75.5%-82.8%) at two years and 74.7% (95% CI: 70.5%-78.5%) at 3 years. The retention varied across study sites: 88.2%, 66.6% and 92.5% at 6 months; 84%, 59% and 90% at 12 months and 75.7%, 56.3% and 85.8% at 24 months respectively for Amo-Congo/Kasavubu, Monkole facility and HEAL Africa. After multivariable Cox regression four variables remained independently associated with attrition: study site, CD4 cell count <350 cells/µL, children younger than 2 years and children whose caregivers were member of an independent church. Attrition remains a challenge for pediatric HIV positive patients in ART programs in DRC. In addition, the low coverage of pediatric treatment exacerbates the situation of pediatric HIV/AIDS.


Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography.
To investigate the clinical usefulness of ultrasonography-based acoustic radiation force impulse (ARFI) elastography (ie, ARFI sonoelastography) in patients with a diagnosis of nonalcoholic fatty liver disease (NAFLD) and compare ARFI sonoelastography results with transient sonoelastography and serum fibrosis marker test results. Written informed consent was obtained from all subjects, and the local ethics committee approved the study. Fifty-four patients with a liver biopsy-confirmed diagnosis of NAFLD (mean age, 50.6 years +/- 13.7) were examined. All patients with NAFLD and healthy volunteers underwent ARFI sonoelastography, transient sonoelastography, and serum liver fibrosis marker testing (hyaluronic acids, type IV collagen 7 S domain). Ten healthy volunteers underwent ARFI sonoelastography. ARFI sonoelastography results were compared with liver biopsy findings, the reference standard. ARFI sonoelastography findings were compared with liver biopsy, transient sonoelastography, and serum fibrosis marker test results. Student t testing was used for univariate comparisons; Kruskal-Wallis testing, for assessments involving more than two independent groups; and areas under the receiver operating characteristic curve (A(z)), to assess the sensitivity and specificity of ARFI sonoelastography for detection of stage 3 and stage 4 fibrosis. Median velocities in the patients with NAFLD were 1.040 m/sec for those with stage 0 fibrosis, 1.120 m/sec for those with stage 1, 1.130 m/sec for those with stage 2, 1.780 m/sec for those with stage 3, and 2.180 m/sec for those with stage 4. The A(z) for the diagnosis of hepatic fibrosis stages 3 or higher was 0.973 (optimal cutoff value, 1.77 m/sec; sensitivity, 100%; specificity, 91%), while that for the diagnosis of stage 4 fibrosis was 0.976 (optimal cutoff value, 1.90 m/sec; sensitivity, 100%; specificity, 96%). Significant correlations between median velocity measured by using ARFI sonoelastography and the following parameters were observed: liver stiffness measured with transient sonoelastography (r = 0.75, P < .0001), serum level of hyaluronic acid(r = 0.459, P = .0009), and serum level of type IV collagen 7 S domain (r = 0.445, P = .0015). There is a significant positive correlation between median velocity measured by using ARFI sonoelastography and severity of liver fibrosis in patients with NAFLD. The results of ARFI sonoelastography were similar to those of transient sonoelastography.


Diabetes and cardiovascular disease: Epidemiology, biological mechanisms, treatment recommendations and future research.
The incidence of diabetes mellitus (DM) continues to rise and has quickly become one of the most prevalent and costly chronic diseases worldwide. A close link exists between DM and cardiovascular disease (CVD), which is the most prevalent cause of morbidity and mortality in diabetic patients. Cardiovascular (CV) risk factors such as obesity, hypertension and dyslipidemia are common in patients with DM, placing them at increased risk for cardiac events. In addition, many studies have found biological mechanisms associated with DM that independently increase the risk of CVD in diabetic patients. Therefore, targeting CV risk factors in patients with DM is critical to minimize the long-term CV complications of the disease. This paper summarizes the relationship between diabetes and CVD, examines possible mechanisms of disease progression, discusses current treatment recommendations, and outlines future research directions.


The Amino Acid Specificity for Activation of Phenylalanine Hydroxylase Matches the Specificity for Stabilization of Regulatory Domain Dimers.
Liver phenylalanine hydroxylase is allosterically activated by phenylalanine. The structural changes that accompany activation have not been identified, but recent studies of the effects of phenylalanine on the isolated regulatory domain of the enzyme support a model in which phenylalanine binding promotes regulatory domain dimerization. Such a model predicts that compounds that stabilize the regulatory domain dimer will also activate the enzyme. Nuclear magnetic resonance spectroscopy and analytical ultracentrifugation were used to determine the ability of different amino acids and phenylalanine analogues to stabilize the regulatory domain dimer. The abilities of these compounds to activate the enzyme were analyzed by measuring their effects on the fluorescence change that accompanies activation and on the activity directly. At concentrations of 10-50 mM, d-phenylalanine, l-methionine, l-norleucine, and (S)-2-amino-3-phenyl-1-propanol were able to activate the enzyme to the same extent as 1 mM l-phenylalanine. Lower levels of activation were seen with l-4-aminophenylalanine, l-leucine, l-isoleucine, and 3-phenylpropionate. The ability of these compounds to stabilize the regulatory domain dimer agreed with their ability to activate the enzyme. These results support a model in which allosteric activation of phenylalanine hydroxylase is linked to dimerization of regulatory domains.


Quantification of the oxidizing capacity of nanoparticulate zero-valent iron.
Addition of nanoparticulate zero-valent iron (nZVI) to oxygen-containing water results in oxidation of organic compounds. To assess the potential application of nZVI for oxidative transformation of organic contaminants, the conversion of benzoic acid (BA) to p-hydroxybenzoic acid (p-HBA) was used as a probe reaction. When nZVI was added to BA-containing water, an initial pulse of p-HBA was detected during the first 30 min, followed by the slow generation of additional p-HBA over periods of at least 24 h. The yield of p-HBA increased with increasing BA concentration, presumably due to the increasing 'ability of BA to compete with alternate oxidant sinks, such as ferrous iron. At pH 3, maximum yields of p-HBA during the initial phase of the reaction of up to 25% were observed. The initial rate of nZVI-mediated oxidation of BA exhibited a marked reduction at pH values above 3. Despite the decrease in oxidant production rate, p-HBA was observed during the initial reaction phase at pH values up to 8. Competition experiments with probe compounds expected to exhibit different affinities for the nZVI surface (phenol, aniline, o-hydroxybenzoic acid, and synthetic humic acids) indicated relative rates of reaction that were similar to those observed in competition experiments in which hydroxyl radicals were generated in solution. Examination of the oxidizing capacity of a range of Fe0 particles reveals a capacity in all cases to induce oxidative transformation of benzoic acid, but the high surface areas that can be achieved with nanosized particles renders such particles particularly effective oxidants.


The Role of LSD1 and LSD2 in Cancers of the Gastrointestinal System: An Update.
Epigenetic mechanisms are known to play a key role in cancer progression. Specifically, histone methylation involves reversible post-translational modification of histones that govern chromatin structure remodelling, genomic imprinting, gene expression, DNA damage repair, and meiotic crossover recombination, among other chromatin-based activities. Demethylases are enzymes that catalyse the demethylation of their substrate using a flavin adenine dinucleotide-dependent amine oxidation process. Lysine-specific demethylase 1 (LSD1) and its homolog, lysine-specific demethylase 2 (LSD2), are overexpressed in a variety of human cancer types and, thus, regulate tumour progression. In this review, we focus on the literature from the last 5 years concerning the role of LSD1 and LSD2 in the main gastrointestinal cancers (i.e., gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer).


Automated kinetic perimetry with two peripheral isopters in glaucoma.
An automated perimeter (Fieldmaster 5000) was used to measure the central 30 degrees of vision with static targets (suprathresholding with quantification of defects) and the peripheral visual field with two kinetic stimuli in 599 eyes of 362 patients with glaucoma or a suspicion of glaucoma. The purpose of the study was to compare the additional information gained by measuring the peripheral visual field with two isopters against the time required for this extra examination. The peripheral visual field supported the diagnosis made by central testing in approximately one fourth of all eyes and added additional diagnostic information in another quarter of the cases. In 7% of the total population, or 11% of eyes with abnormal fields, a normal central field was associated with a glaucomatous peripheral defect. Half of the latter eyes had corresponding glaucomatous optic disc changes. The more sensitive isopter uncovered the vast majority of the peripheral field defects. Measurement of each isopter accounted for 22% of the total testing time.


Hydrogen sulfide modulates sinusoidal constriction and contributes to hepatic microcirculatory dysfunction during endotoxemia.
Hydrogen sulfide (H₂S) affects vascular resistance; however, its effect on the hepatic microcirculation has not been investigated. Hepatic sinusoidal perfusion is dysregulated during sepsis, contributing to liver injury. Therefore, the present study determined the effect of H₂S on the hepatic microcirculation and the contribution of endogenous H₂S to hepatic microcirculatory dysfunction in an endotoxin model of sepsis. Portal infusion of H₂S increased portal pressure in vivo (6.8 ± 0.2 mmHg before H₂S vs. 8.6 ± 0.8 mmHg peak during H₂S infusion, P < 0.05). Using intravital microscopy, we observed decreased sinusoidal diameter (6.2 ± 0.27 μm before H₂S vs. 5.7 ± 0.3 μm after H₂S, P < 0.05) and increased sinusoidal heterogeneity during H₂S infusion (P < 0.05) and net constriction. Since hepatic H₂S levels are elevated during sepsis, we used the cystathionine γ lyase inhibitor DL-propargylglycine (PAG) to determine the contribution of H₂S to the hypersensitization of the sinusoid to the vasoconstrictor effect of endothelin-1 (ET-1). PAG treatment significantly attenuated the sinusoidal sensitization to ET-1 in endotoxin-treated animals. ET-1 infusion increased portal pressure to 175% of baseline in endotoxemic animals, which was reduced to 143% following PAG treatment (P < 0.05). PAG abrogated the increase in sinusoidal constriction after ET-1 infusion in LPS-treated rats (30.9% reduction in LPS rats vs. 11.6% in PAG/LPS rats, P < 0.05). Moreover, PAG treatment significantly attenuated the increase in NADH fluorescence following ET-1 exposure during endotoxemia (61 grayscale units LPS vs. 21 units in PAG/LPS, P < 0.05), suggesting an improvement in hepatic oxygen availability. This study is the first to demonstrate a vasoconstrictor action of H₂S on the hepatic sinusoid and provides a possible mechanism for the protective effect of PAG treatment during sepsis.


Secular Trends in Dementia Prevalence and Incidence Worldwide: A Systematic Review.
Time trends for dementia prevalence and incidence rates have been reported over the past seven decades in different countries and some have reported a decline. To undertake a systematic review to critically appraise and provide an evidence-based summary of the magnitude and direction of the global changes in dementia prevalence and incidence across time. Medline, EMBASE, and PsychINFO were searched for studies focused on secular trends in dementia prevalence and/or incidence until 18 December 2017. In total, 10,992 articles were identified and 43 retained. Overall, prevalence rates are largely increasing (evidence primarily from record-based surveys and cohort studies in Japan, Canada, and France) or have remained stable (evidence primarily from cohort studies in Sweden, Spain and China). A significant decline in prevalence has however been reported in more recent studies (i.e., from 2010 onwards) from Europe (e.g., UK and Sweden) and the USA. Incidence rates have generally remained stable or decreased in China, Canada, France, Germany, Denmark, Sweden, the Netherlands, UK, and USA. An increase has only been reported in five countries: Italy, Japan, Wales, Germany, and the Netherlands. Only one study reported findings (stability in incidence) from a low and middle-income country using data from Nigeria. The evidence on secular trends in the prevalence and incidence of dementia is mixed including contradictory findings using different (and in some cases the same) datasets in some countries (e.g., the USA, UK, and Sweden). This making it difficult to draw concrete conclusions. However, declining trends recently observed in some high-income Western countries in the most recent two decades including the UK, USA, and Sweden are encouraging. Updated dementia prevalence and incidence estimates will inform public health and financial planning as well as development of prevention strategies.


Contractile network models for adherent cells.
Cells sense the geometry and stiffness of their adhesive environment by active contractility. For strong adhesion to flat substrates, two-dimensional contractile network models can be used to understand how force is distributed throughout the cell. Here we compare the shape and force distribution for different variants of such network models. In contrast to Hookean networks, cable networks reflect the asymmetric response of biopolymers to tension versus compression. For passive networks, contractility is modeled by a reduced resting length of the mechanical links. In actively contracting networks, a constant force couple is introduced into each link in order to model contraction by molecular motors. If combined with fixed adhesion sites, all network models lead to invaginated cell shapes, but only actively contracting cable networks lead to the circular arc morphology typical for strongly adhering cells. In this case, shape and force distribution are determined by local rather than global determinants and thus are suited to endow the cell with a robust sense of its environment. We also discuss nonlinear and adaptive linker mechanics as well as the relation to tissue shape.


Prospective randomized trial of mesh fixation with absorbable versus nonabsorbable tacker in laparoscopic ventral incisional hernia repair.
The aim of this prospective randomized trial was to compare 2 main fixation devices in regard to pain and recurrence in laparoscopic ventral incisional hernia repair (LVIHR). A total of 51 patients were evaluated in this study (n = 25, nonabsorbable tack (NAT) and n = 26, absorbable tack (AT) groups). A visual analogue scale (VAS) was performed on both groups preoperatively and on the postoperative (PO) first day, second week, and sixth month. All patients were followed for recurrence by clinical examination, ultrasonography, and/or abdominal computed tomography. The median follow-up time was 31 months (15-45). The mean age and the mean body mass index (BMI) of the patients were 53.1 ± 11 years and 34 ± 5 kg/m(2), respectively. The median defect size was 60 cm(2) (35-150) and median operation time was 110 minutes (40-360). In 2 patients from AT group and 2 from NAT group (7.8%), recurrence occurred. The 2 groups had similar features regarding demographics, operation time, postoperative hospital stay, morbidity, and VAS scores. The 2 fixation methods were found similar for PO pain and recurrence. In our opinion, the choice of either of these fixation methods during surgery should not be based on the concerns of pain or recurrence. AT may be the preferable option in LVIHR due to the lower cost.


Leading Through Loss: Experiences of Nursing Home Administrators-in-Training During the COVID-19 Pandemic.
End-of-life care is a critical aspect of long-term care, yet there is limited understanding of nursing home staff's experiences and preparation in this area, particularly among facility administrators. To address this gap, two cohorts of Administrators-in-Training (2021 & 2022) were interviewed about their knowledge and practices regarding end-of-life care in skilled nursing facilities. Interviews focused on involvement in end-of-life discussions, coping strategies, grief support, and personal perspectives on death. The findings revealed a significant lack of training on death management and end-of-life care for Administrators-in-Training (AITs), with limited grief support mechanisms in place within skilled nursing facilities. Personal experiences with death influenced AITs' approach to end-of-life care, and various coping strategies were observed. The results highlight the need for comprehensive training programs and improved support for AITs to enhance end-of-life care delivery.


Race, trust, and COVID-19 vaccine hesitancy in people with opioid use disorder.
Vaccination against coronavirus disease 2019 (COVID-19) is a promising avenue for arresting the COVID-19 pandemic, yet suboptimal rates of vaccine uptake in at-risk groups may hinder efficacy and worsen existing health disparities. People with opioid use disorder (OUD) are likely to face increased vulnerability to COVID-19 due to a confluence of biological and social risk factors. We sought to assess factors associated with willingness to vaccinate against COVID-19 in people with OUD. Phone surveys were conducted from May to October 2020 with participants enrolled in an urban methadone maintenance program (MMP). Participants were adults who met DSM-5 criteria for OUD and reported injection drug use or sexual risk behavior. Participants were asked about their willingness to receive a highly or partially effective vaccine. Provider trust was assessed using the Trust in Physician scale. Multinomial regression was used to assess demographic and psychosocial factors related to vaccination willingness. We surveyed 109 people with OUD enrolled in a MMP (M = 47 years; 56% women; 59% White, 23% Black/African American, 14.4% Hispanic/Latinx; 1.8% other). Participants who identified as Black or African American were significantly less likely to endorse willingness to use a partially effective COVID-19 vaccine (adjusted odds ratio [aOR] = .10; 95% confidence interval (CI) [.02, .61], p = .012), although not necessarily less willing to receive a highly effective vaccine (aOR = .40; 95% CI [.09, 1.73], p = .219; n.s.). Trust in physician was positively associated with willingness to use a partially effective vaccine (aOR = 1.12; 95% CI [1.02, 1.23], p = .017), but was not significantly associated with willingness to receive a highly effective vaccine (aOR = 1.07; 95% CI [.98, 1.16], p = .162, n.s) Conclusions: Proactive outreach from trustworthy sources will be needed to counter vaccine hesitancy in people with OUD, especially among Black Americans with OUD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Comparisons of Handheld Retinal Imaging with Optical Coherence Tomography for the Identification of Macular Pathology in Patients with Diabetes.
Handheld retinal imaging cameras are relatively inexpensive and highly portable devices that have the potential to significantly expand diabetic retinopathy (DR) screening, allowing a much broader population to be evaluated. However, it is essential to evaluate if these devices can accurately identify vision-threatening macular diseases if DR screening programs will rely on these instruments. Thus, the purpose of this study was to evaluate the detection of diabetic macular pathology using monoscopic macula-centered images using mydriatic handheld retinal imaging compared with spectral domain optical coherence tomography (SDOCT). Mydriatic 40°-60° macula-centered images taken with 3 handheld retinal imaging devices (Aurora [AU], SmartScope [SS], RetinaVue 700 [RV]) were compared with the Cirrus 6000 SDOCT taken during the same visit. Images were evaluated for the presence of diabetic macular edema (DME) on monoscopic fundus photographs adapted from Early Treatment Diabetic Retinopathy Study (ETDRS) definitions (no DME, noncenter-involved DME [non-ciDME], and center-involved DME [ciDME]). Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each device with SDOCT as gold standard. Severity by ETDRS photos: no DR 33.3%, mild NPDR 20.4%, moderate 14.2%, severe 11.6%, proliferative 20.4%, and ungradable for DR 0%; no DME 83.1%, non-ciDME 4.9%, ciDME 12.0%, and ungradable for DME 0%. Gradable images by SDOCT (N = 217, 96.4%) showed no DME in 75.6%, non-ciDME in 9.8%, and ciDME in 11.1%. The ungradable rate for images (poor visualization in >50% of the macula) was AU: 0.9%, SS: 4.4%, and RV: 6.2%. For DME, sensitivity and specificity were similar across devices (0.5-0.64, 0.93-0.97). For nondiabetic macular pathology (ERM, pigment epithelial detachment, traction retinal detachment) across all devices, sensitivity was low to moderate (0.2-0.5) but highly specific (0.93-1.00). Compared to SDOCT, handheld macular imaging attained high specificity but low sensitivity in identifying macular pathology. This suggests the importance of SDOCT evaluation for patients suspected to have DME on fundus photography, leading to more appropriate referral refinement.


Lack of mitochondrial and nuclear-encoded subunits of complex I and alteration of the respiratory chain in Nicotiana sylvestris mitochondrial deletion mutants.
We previously have shown that Nicotiana sylvestris cytoplasmic male sterile (CMS) mutants I and II present large mtDNA deletions and that the NAD7 subunit of complex I (the main dehydrogenase of the mitochondrial respiratory chain) is absent in CMS I. Here, we show that, despite a large difference in size in the mtDNA deletion, CMS I and II display similar alterations. Both have an impaired development from germination to flowering, with partial male sterility that becomes complete under low light. Besides NAD7, two other complex I subunits are missing (NAD9 and the nucleus-encoded, 38-kDa subunit), identified on two-dimensional patterns of mitochondrial proteins. Mitochondria isolated from CMS leaves showed altered respiration. Although their succinate oxidation through complex II was close to that of the wild type, oxidation of glycine, a priority substrate of plant mitochondria, was significantly reduced. The remaining activity was much less sensitive to rotenone, indicating the breakdown of Complex I activity. Oxidation of exogenous NADH (coupled to proton gradient generation and partly sensitive to rotenone) was strongly increased. These results suggest respiratory compensation mechanisms involving additional NADH dehydrogenases to complex I. Finally, the capacity of the cyanide-resistant alternative oxidase pathway was enhanced in CMS, and higher amounts of enzyme were evidenced by immunodetection.


HCO(3)(-)-independent conductance with a mutant Na(+)/HCO(3)(-) cotransporter (SLC4A4) in a case of proximal renal tubular acidosis with hypokalaemic paralysis.
The renal electrogenic Na(+)/HCO(3)(−) cotransporter (NBCe1-A) contributes to the basolateral step of transepithelial HCO(3)(−) reabsorption in proximal tubule epithelia, contributing to the buffering of blood pH. Elsewhere in the body (e.g. muscle cells) NBCe1 variants contribute to, amongst other processes, maintenance of intracellular pH. Others have described a homozygous mutation in NBCe1 (NBCe1-A p.Ala799Val) in an individual with severe proximal renal tubular acidosis (pRTA; usually associated with defective HCO(3)(−) reabsorption in proximal tubule cells) and hypokalaemic periodic paralysis (hypoPP; usually associated with leaky cation channels in muscle cells). Using biotinylation and two-electrode voltage-clamp on Xenopus oocytes expressing NBCe1, we demonstrate that the mutant NBCe1-A (A(A799V)) exhibits a per-molecule transport defect that probably contributes towards the observed pRTA. Furthermore, we find that A(A799V) expression is associated with an unusual HCO(3)(−)-independent conductance that, if associated with mutant NBCe1 in muscle cells, could contribute towards the appearance of hypokalaemic paralysis in the affected individual. We also study three novel lab mutants of NBCe1-A: p.Ala799Ile, p.Ala799Gly and p.Ala799Ser. All three exhibit a per-molecule transport defect, but only A(A799I) exhibits an A(A799V)-like ion conductance. A(A799G) and A(A799S) exhibit unusual outward rectification in their HCO(3)(−)-dependent conductance and A(A799G) exhibits reduced sensitivity to both DIDS and tenidap. A799G is the first mutation shown to affect the apparent tenidap affinity of NBCe1. Finally we show that A(A799V) and A(A799I), which accumulate poorly in the plasma membrane of oocytes, exhibit signs of abnormal intracellular accumulation in a non-polarized renal cell-line.


Activation of inflammatory pathways in PBMCs linking type 2 diabetes in older adults without obesity.
The mechanism that underlies the dysregulation of glucose metabolism in older adults without obesity has yet to be thoroughly understood. This study investigated the risk of developing Type 2 diabetes (T2D) in older adults without obesity (BMI: 18.5 to <25 kg/m2). Data on glucose levels (measured by an oral glucose tolerance test), body composition, physical activity level, lipid profile, inflammatory cytokines, and nuclear factor kappa B (NF-κB) and Sirtuin 1 (SIRT1) signaling pathways in peripheral blood mononuclear cells (PBMCs) in older adults with normal glucose tolerance (NGT, n = 17) and those with prediabetes (n = 20) or T2D (n = 8) were gathered. As expected, participants with T2D exhibited higher insulin resistance; β-cell dysfunction; and higher levels of triglycerides and tumor necrosis factor-α (TNF-α) than those with NGT. No differences in physical activity, lean mass, body fat, or cholesterol were observed between the NGT, prediabetes, and T2D groups. Downregulation of SIRT1 and activation of NF-κB signaling in PBMCs were observed in the T2D group. Increased phosphorylation of NF-κB and low SIRT1 protein expression in PBMCs were associated with insulin resistance and β-cell dysfunction. NF-κB and its upstream inhibitor IκBα were positively and inversely correlated with TNF-α, respectively. SIRT1 expression was positively correlated with IL-10. Activation of NF-κB signaling pathways and downregulation of SIRT1 in PBMCs were associated with the inflammatory milieu in older adults without obesity.


[Rhythm of the activity of the neurosecretory cells in the supraoptic hypothalamic nucleus of C57Bl mice].
Rhythmic changes of the neurosecretory process in the hypothalamic supraoptic nucleus cells were studied in male mice C57Bl. The material was taken in 94 specimens in Leningrad, in April (during vernal equinox). Nuclear and nucleolar volumes in the neurosecretory cells, amount of the neurosecretory substance in cytoplasm served as criteria of the cellular functional activity. The circadian component of the rhythmicity cells which did not contain any neurosecretory material (the most active functionally). The peak time of the circadian component of the rhythm and the greatest range of the ultradian oscillations corresponded to the animals' day rest. The neurosecretory processes in the supraoptic nucleus reached the greatest activity at 3-4 P.M. when the nucleoli had the greatest volume and the number of cells free from the neurosecretory material was maximal.


Self-management support for cancer-related fatigue: A systematic review.
To describe and examine the theories, components, and effectiveness of self-management support interventions for individuals experiencing cancer-related fatigue. A systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 Statement. CINAHL, PubMed, Cochrane CENTRAL, and EMBASE were searched (from inception to June 2021) for randomised controlled trials examining self-management support interventions for managing cancer-related fatigue. Data were screened, extracted, and appraised by two authors. Data extraction was guided by the Self-management Support Taxonomy (i.e., a modified version of the Practical Reviews in Self-Management Support Taxonomy tailored to cancer). The Revised Cochrane Risk of Bias tool was used for study appraisal. A critical narrative synthesis was conducted. Fifty-one papers representing 50 different studies (n = 7383) were identified. Most interventions were delivered post-treatment (40%) using in-person (i.e., 'face-to-face') encounters (40%), and were facilitated by health professionals (62%). A range of intervention approaches and self-management support strategies were used across studies. The average number of Self-management Support Taxonomy components used across studies was 6.1 (of 14). Thirty-one studies (62%) described a specific behavior change theory to guide their self-management support intervention development. Twenty-nine studies (n = 29/50; 58%) reported a positive intervention effect for fatigue immediately post-intervention. Of these 29 studies, 10 (34%) reported at least one sustained positive effect on fatigue over follow-up periods between two and 12 months. Self-management support that is delivered after cancer treatment, facilitated by health professionals, and incorporating at least one in-person contact appears to produce the most favourable fatigue and behavioral outcomes. However, further work is needed to better understand how individual self-management support strategies and the application of a behavioral theory influence behavior change. Program developers should guide self-management support with a behavioral theory, and describe their theory application in intervention development, implementation, and evaluation; ensure facilitators receive adequate support training; and seek the delivery preferences of cancer survivors. Future research should incorporate adequate follow-up to sufficiently evaluate the impact of programs on cancer-related fatigue and associated self-management behaviors. Findings from this review are relevant to all healthcare professionals, but are of most relevance to nurses as the largest cancer care workforce with a key role in delivering self-management support.


[Treatment of the femoral neck pseudoarthrosis in childhood: case report].
Femoral neck fractures in children and adolescents are rare. However, their complications are frequent - avascular necrosis, femoral neck pseudoarthrosis, premature physeal closure with consequent growth disturbance and coxa vara deformity. A 9.5-year-old boy was injured in a car accident, and femoral neck fracture was diagnosed. Prior to admission at our hospital he was surgically treated several times. He was admitted at our hospital eight months following the accident. On the X-ray transcervical pseudoarthrosis of the femoral neck was found, as well as coxa vara deformity and metaphyseal avascular necrosis. He was operated at our hospital; all previously placed ostefixation material was removed, valgus osteotomy of 30 degrees was done as well as additional local osteoplasty using the commercial osteoindactive agent (Osteovit). Postoperatively, we applied skin traction, bed rest and physical therapy. At the final follow-up, the patient was recovered completely. He is now painless, the legs are of equal length, range of movements in the left hip is full, life activity is normal.The X-ray shows that the femoral neck pseudoarthrosis is fully healed. This case is presented in order to encourage other colleagues to challenge the problematic situation such as this one. Also, we would like to remind them what one should think about and what should be taken into consideration in the primary treatment of femoral neck fractures in children. Valgus femoral osteotomy, as a part of the primary treatment of femoral neck fracture in children (identically as in the adults) can prevent the occurrence of femoral neck pseudoarthrosis.


Characteristics of participants and decliners from a randomized controlled trial on physical activity in patients with rheumatoid arthritis: a retrospective register-based cross-sectional study.
A randomized controlled trial [Joint Resources - Sedentary Behaviour (JR-SB) intervention] aimed to reduce sedentary behaviour and increase light-intensity physical activity in patients with rheumatoid arthritis (RA) through motivational counselling and text messages. Since a large proportion of invited patients declined to participate, this study aims to compare sociodemographic, clinical, and lifestyle factors between included patients and patients declining to participate (non-participants) in the JR-SB study and to investigate which characteristics were associated with participation. A register-based cross-sectional study was conducted. All patients invited to participate in the JR-SB study were identified in the DANBIO registry, from which patients' clinical and lifestyle data were also retrieved. Data on sociodemography and comorbidity were extracted from national registers. Differences between participants and non-participants were determined by an independent t-test or a chi-squared test. Logistic regression analyses adjusted for various confounders tested the association of patient characteristics with the likelihood of participation in the JR-SB study. A total of 467 (58%) declined participation in the JR-SB study. Non-participants were older and less educated, more were smokers, fewer performed regular physical activity, and more had comorbidity compared to participants. Regression analyses showed that a higher educational level and absence of comorbidity in particular were associated with participation in the JR-SB study. Patients with RA who are less educated and with certain types of comorbidity are less motivated to participate in a physical activity intervention. The findings may inform the recruitment process and implementation of physical activity interventions in rheumatology clinical practice.


Ethylmalonic and methylsuccinic aciduria in ethylmalonic encephalopathy arise from abnormal isoleucine metabolism.
Ethylmalonic encephalopathy (EE), an organic aciduria of unknown etiology characterized by developmental delay, hypotonia, and vascular instability associated with lactic acidemia and urinary excretion of ethylmalonic acid (EMA) and methylsuccinic acid (MSA), has been described in 11 patients. To test the possibility that the underlying biochemical defect involves isoleucine catabolism, we determined the response to oral L-isoleucine (IIe) load (150 mg/kg) in a 5-year-old girl with EE and in three healthy, age- and sex-matched controls. Following IIe load in the patient, there was accumulation of 2-methylbutyrylglycine (2-MBG) and a delayed and lower peak urinary excretion of tiglylglycine (TGL), suggesting a partial defect in 2-methyl-branched chain acylcoenzyme A dehydrogenase (2M-BCAD). In vitro measurements 2M-BCAD activity in cultured skin fibroblasts from patients with EE have been reported to be normal. Our results show that isoleucine is a source for the elevated EMA and MSA in patients with EE, and suggest a functional, possibly secondary, deficiency of activity of 2M-BCAD in vivo.


Survival among Mexican-Americans, non-Hispanic whites, and African-Americans with end-stage renal disease: the emergence of a minority pattern of increased incidence and prolonged survival.
We undertook this study to determine whether there is a significant difference in survival on treatment for end-stage renal disease between Mexican-Americans, non-Hispanic whites, and African-Americans. A database covering the years 1975 to 1986 was obtained from the Texas Kidney Health Program. Eight-eight percent to 90% of patients starting renal replacement therapy in Texas were included in this database. The patients were followed until death, for 3 years after successful transplantation, or until they were lost to follow-up. Life table analysis as well as age-adjusted analysis using the Cox proportional hazards model were performed comparing ethnic/racial groups, disease etiology, and treatment type. In life-table analyses, African-Americans and Mexican-Americans had a survival advantage in most age, disease, and treatment groups. With age adjustment, this survival advantage remained for all etiologies combined, for diabetes and hypertension cases, and for patients receiving hemodialysis in a center. Multivariate analysis revealed a persistent survival advantage for Mexican-Americans independent of traditional predictor variables, such as age, disease etiology, treatment type, or size of the center in which they received treatment. In this same analysis, African-Americans showed an advantage in the older age groups. Both African-Americans and Mexican-Americans on renal replacement therapy have an increased survival advantage compared with non-Hispanic whites. Given the additional burden of increased incidence of end-stage renal disease in these groups, the cost of renal replacement therapy for these minorities is disproportionately high. Further study should be aimed at elucidation of the mechanisms by which minorities achieve their survival advantage.


Overtraining Syndrome Symptoms and Diagnosis in Athletes: Where Is the Research? A Systematic Review.
To understand overtraining syndrome (OTS), it is important to detail the physiological and psychological changes that occur in athletes. To systematically establish and detail the physiological and psychological changes that occur as a result of OTS in athletes. Databases were searched for studies that were (1) original investigations; (2) English, full-text articles; (3) published in peer-reviewed journals; (4) investigations into adult humans and provided (5) objective evidence that detailed changes in performance from prior to the onset of OTS diagnosis and that performance was suppressed for more than 4 weeks and (6) objective evidence of psychological symptoms. Zero studies provided objective evidence of detailed changes in performance from prior to the onset of OTS diagnosis and demonstrated suppressed performance for more than 4 weeks accompanied by changes in psychological symptoms. All studies failed to provide evidence of changes in performance and mood from "healthy" to an overtrained state with evidence of prolonged suppression of performance. While OTS may be observed in the field, little data is available describing how physiological and psychological symptoms manifest. This stems from vague terminology, difficulties in monitoring for prolonged periods of time, and the need for prospective testing. Real-world settings may facilitate the collection of such data, but the ideal testing battery that can easily be conducted on a regular basis does not yet exist. Consequently, it must be concluded that an evidence base of sufficient scientific quality for understanding OTS in athletes is lacking.


Sampling affects population genetic inference: A case study of the Allen's (Selasphorus sasin) and rufous hummingbird (Selasphorus rufus).
Gene flow can affect evolutionary inference when species are undersampled. Here, we evaluate the effects of gene flow and geographic sampling on demographic inference of 2 hummingbirds that hybridize, Allen's hummingbird (Selasphorus sasin) and rufous hummingbird (Selasphorus rufus). Using whole-genome data and extensive geographic sampling, we find widespread connectivity, with introgression far beyond the Allen's × rufous hybrid zone, although the Z chromosome resists introgression beyond the hybrid zone. We test alternative hypotheses of speciation history of Allen's, rufous, and Calliope (S. calliope) hummingbird and find that rufous hummingbird is the sister taxon to Allen's hummingbird, and Calliope hummingbird is the outgroup. A model treating the 2 subspecies of Allen's hummingbird as a single panmictic population fit observed genetic data better than models treating the subspecies as distinct populations, in contrast to morphological and behavioral differences and analyses of spatial population structure. With additional sampling, our study builds upon recent studies that came to conflicting conclusions regarding the evolutionary histories of these 2 species. Our results stress the importance of thorough geographic sampling when assessing demographic history in the presence of gene flow.


Variance decomposition using an IRT measurement model.
Large scale research projects in behaviour genetics and genetic epidemiology are often based on questionnaire or interview data. Typically, a number of items is presented to a number of subjects, the subjects' sum scores on the items are computed, and the variance of sum scores is decomposed into a number of variance components. This paper discusses several disadvantages of the approach of analysing sum scores, such as the attenuation of correlations amongst sum scores due to their unreliability. It is shown that the framework of Item Response Theory (IRT) offers a solution to most of these problems. We argue that an IRT approach in combination with Markov chain Monte Carlo (MCMC) estimation provides a flexible and efficient framework for modelling behavioural phenotypes. Next, we use data simulation to illustrate the potentially huge bias in estimating variance components on the basis of sum scores. We then apply the IRT approach with an analysis of attention problems in young adult twins where the variance decomposition model is extended with an IRT measurement model. We show that when estimating an IRT measurement model and a variance decomposition model simultaneously, the estimate for the heritability of attention problems increases from 40% (based on sum scores) to 73%.


Fluid regulation, body weight and drinking responses following hypothalamic knife cuts.
Electrolytic ablation of the periventricular tissue surrounding the anteroventral third ventricle (AV3V) alters fluid and electrolyte regulation. In addition, these lesions produce neural degeneration in the supraoptic nucleus (SON) and neural lobe, which suggests a neural pathway from the AV3V region to the SON. To determine if pathways in this brain area may mediate some of the effects which follow AV3V periventricular ablation, food and water ingestion, urine volume, and body weight, as well as drinking responses to a number of dipsogenic challenges were determined following placement of small knife cuts between the level of the organum vasculosum lamina terminalis (OVLT) and the SON. Metabolism measurements were taken daily for 7 days following either knife cuts or control operations, and again 4 weeks after surgery. Drinking responses following subcutaneous injections of angiotensin II, water deprivation, and cellular dehydration were determined at least 2 weeks after surgery. Rats with knife cuts exhibited an increase in water ingestion and urine volume, an enhanced water consumption following water deprivation and acute cellular dehydration, and did not gain weight at the same rate as control operated rats. The hyperdipsia following cellular dehydration was abolished by bilateral nephrectomy. These data indicate that a neural pathway coursing through this brain region is critical for fluid regulation and maintenance of body weight.


Transcription factors as activators of gene transcription: AP-1 and NF-kappa B.
Cells respond to a range of cytokines and other inflammatory stimuli by selectively expressing a wide range of genes. These proinflammatory signals bind to receptors and initiate intracellular signalling cascades. This results in the activation of proinflammatory deoxyribonucleic acid (DNA)-binding proteins or transcription factors such as activator protein-1 (AP-1) or nuclear factor-kappa B (NF-kappa B). Following activation, these factors bind to specific recognition sequences in the control regions (promoters) of target genes causing modulation of gene transcription. Furthermore, numerous sites for regulation of cytokine and cytokine receptor genes by these transcription factors are found in their promoter regions. Many factors affect the formation and activity of AP-1 dimers (Fos and Jun heterodimers) through protein specific interactions or by the modulation of pre-existing complexes by phosphorylation. These complexes can vary markedly in their ability to stimulate gene transcription. Thus, induction of AP-1 activity is regulated by stimuli that either induce the de novo synthesis of AP-1 subunits or increase the activity of previously formed AP-1 dimers. NF-kappa B is activated by a number of agents including tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), lipopolysaccharide (LPS) and viruses. NF-kappa B plays a central role in a range of immunological responses due to its ability to switch on inflammatory genes which lead to further activation of NF-kappa B is a heterodimer of proteins which vary in their ability to bind to DNA and/or to activate gene transcription. NF-kappa B activation is primarily regulated by sequestration of heterodimers within the cytoplasm as inactive complexes with inhibitory molecules (inhibitory-kappa B (I-kappa B)). Treatment of cells with inducing agents results in the phosphorylation of the I-kappa B molecule which is targeted for rapid degradation. This causes a rapid dissociation of the cytoplasmic NF-kappa B/I-kappa B complexes and allows translocation of the active NF-kappa B to the nucleus. Cross-coupling between NF-kappa B and AP-1 has been described which results in a synergistic increase in activity at both AP-1 and NF-kappa B sites. Elevation of both AP-1 and NF-kappa B, as reported in asthma, may therefore lead to far greater inflammation than would be present if either transcription factor alone were activated.


Evaluating Note Frequency and Velocity During Improvised Active Music Therapy in Clients With Parkinson's Disease.
The purpose of this article was to report on the findings of the note frequency and velocity measures during Improvised Active Music Therapy (IAMT) sessions with individuals with Parkinson's disease (PD). In this single-subject multiple baseline design across subjects, the article reports the note frequency (note count) and velocity of movement (mean note velocity) played by three right-handed participants while playing uninterrupted improvised music on a simplified electronic drum-set. During baseline, the music therapist played rhythmic accompaniment on guitar using a low-moderate density of syncopation. During treatment, the Music Therapist introduced rhythms with a moderate-high density of syncopation. The music content of the sessions was transformed into digital music using a musical instrument digital interface. Results of this study indicated that all participants exhibited an increase in note count during baseline until reaching a plateau at treatment condition and were found to be significantly positively correlated with the Music Therapist's note count. All participants played more notes with upper extremity (UE) across conditions than with lower extremity. All participants also scored similar total mean velocity across conditions. Two participants demonstrated higher mean note velocity with UE than right foot, whereas the other participant did not demonstrate this difference. Two participants also exhibited greater mean note velocity variability with left foot within and across conditions. More research is required to identify commonalities in note count and mean note velocity measures in individuals with PD during IAMT sessions.


Evaluation of questionnaire-based information on previous physical work loads. Stockholm MUSIC 1 Study Group. Musculoskeletal Intervention Center.
The principal aim of the present study was to evaluate questionnaire-based information on past physical work loads (6-year recall). Effects of memory difficulties on reproducibility were evaluated for 82 subjects by comparing previously reported results on current work loads (test-retest procedure) with the same items recalled 6 years later. Validity was assessed by comparing self-reports in 1995, regarding work loads in 1989, with worksite measurements performed in 1989. Six-year reproducibility, calculated as weighted kappa coefficients (k(w)), varied between 0.36 and 0.86, with the highest values for proportion of the workday spent sitting and for perceived general exertion and the lowest values for trunk and neck flexion. The six-year reproducibility results were similar to previously reported test-retest results for these items; this finding indicates that memory difficulties was a minor problem. The validity of the questionnaire responses, expressed as rank correlations (r(s)) between the questionnaire responses and workplace measurements, varied between -0.16 and 0.78. The highest values were obtained for the items sitting and repetitive work, and the lowest and "unacceptable" values were for head rotation and neck flexion. Misclassification of exposure did not appear to be differential with regard to musculoskeletal symptom status, as judged by the calculated risk estimates. The validity of some of these self-administered questionnaire items appears sufficient for a crude assessment of physical work loads in the past in epidemiologic studies of the general population with predominantly low levels of exposure.


Distinct Phospho-TDP-43 brain distribution in two cases of FTD, one associated with ALS.
TDP-43 is an intranuclear protein involved in many cellular processes. When altered, it shows a change in pattern of distribution, as well as in functioning, throughout the Central Nervous System structures. Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are examples of TDP-43 proteinopathy. These disorders form a clinical spectrum, with some patients having a pure cognitive disorder while others also exhibit motor features. We studied two donated brains from patients with a diagnosis of Frontotemporal Dementia (FTD), one of which was associated with ALS (ALS-FTD). After fixation and macroscopic examinations, sample analyses were performed. Specific regions were chosen for the application of immunohistochemistry (IHC) with anti-Aβ, AT8, anti-α-synuclein and anti-phospho-TDP-43. Both brains presented anti-phospho-TDP-43 positivity, but this was not equally distributed throughout the encephalic zones. In the FTD case, the studied brain presented phosphorylated TDP-43- in the frontal cortex, hippocampus, entorhinal cortex and mesencephalon; in the ALS-FTD case, the abnormal protein was also seen in the pons and medulla oblongata. The brain in the ALS-FTD case presented Aβ and AT8 positivity in the hippocampus and entorhinal cortex (Braak I and II). The hypothesis supported by scientific literature that these neurodegenerative diseases can have the same etiology with distinct encephalic region involvement is corroborated by the present study.


A novel combination therapy targeting ubiquitin-specific protease 5 in MYCN-driven neuroblastoma.
Histone deacetylase (HDAC) inhibitors are effective in MYCN-driven cancers, because of a unique need for HDAC recruitment by the MYCN oncogenic signal. However, HDAC inhibitors are much more effective in combination with other anti-cancer agents. To identify novel compounds which act synergistically with HDAC inhibitor, such as suberanoyl hydroxamic acid (SAHA), we performed a cell-based, high-throughput drug screen of 10,560 small molecule compounds from a drug-like diversity library and identified a small molecule compound (SE486-11) which synergistically enhanced the cytotoxic effects of SAHA. Effects of drug combinations on cell viability, proliferation, apoptosis and colony forming were assessed in a panel of neuroblastoma cell lines. Treatment with SAHA and SE486-11 increased MYCN ubiquitination and degradation, and markedly inhibited tumorigenesis in neuroblastoma xenografts, and, MYCN transgenic zebrafish and mice. The combination reduced ubiquitin-specific protease 5 (USP5) levels and increased unanchored polyubiquitin chains. Overexpression of USP5 rescued neuroblastoma cells from the cytopathic effects of the combination and reduced unanchored polyubiquitin, suggesting USP5 is a therapeutic target of the combination. SAHA and SE486-11 directly bound to USP5 and the drug combination exhibited a 100-fold higher binding to USP5 than individual drugs alone in microscale thermophoresis assays. MYCN bound to the USP5 promoter and induced USP5 gene expression suggesting that USP5 and MYCN expression created a forward positive feedback loop in neuroblastoma cells. Thus, USP5 acts as an oncogenic cofactor with MYCN in neuroblastoma and the novel combination of HDAC inhibitor with SE486-11 represents a novel therapeutic approach for the treatment of MYCN-driven neuroblastoma.


[The pathogenic role of Helicobacter pylori].
The urease test and bacterioscopy of impression smears were used to detect Helicobacter pylori (HP) in biopsies from pyloric gastric mucosa of 77 (89.5%) of 86 chronic gastritis patients, of 27 (4%) from 32 duodenal ulcer patients, of 84 (84.0%) from 100 healthy male subjects aged 18-20. There was focal hyperemia in pyloric part of the stomach in 59 patients, leukocytic infiltration of mucous membrane was found histologically in 78 ones. Close correlation between complaints, endoscopic and histological shifts, HP incidence rate was not registered. Positive results in determination of HP antibodies by enzyme immunoassay (EIA) were obtained in 32 (45.7%) of healthy subjects. EIA findings and histological evidence on HP presence failed to coincide in 42 (92.9%) duodenal ulcer patients.


Renal Cell Carcinomas: Sonographic Appearance Depending on Size and Histologic Type.
Prior studies have demonstrated that approximately 10% of malignant renal cell carcinomas are as echogenic as angiomyolipomas on sonography. However, a recent presentation suggested that small (<1-cm) echogenic renal masses are always angiomyolipomas or other benign entities. We therefore examined our own cases of renal cell carcinoma, with corresponding sonography, to confirm that some renal cell carcinomas may also be detected as hyperechoic masses on sonography. Institutional Review Board approval and Health Insurance Portability and Accountability Act compliance were maintained for this retrospective review of 91 pathologically proven cases of renal cell carcinoma, with corresponding sonography. Tumors were first differentiated by histologic cell type (clear cell, papillary, and chromophobe). Tumors were then stratified according to 2 size group parameters, falling into those that were 3 cm or larger and those that were smaller than 3 cm in diameter, with the less than 3-cm group further subdivided into 2 cm or smaller and greater than 2 cm. Tumor echogenicity was graded on a 5-point scale with respect to the renal parenchyma. Forty-six tumors (51%) were 3 cm in diameter or smaller, and most were found to be either isoechoic (35%) or mildly hyperechoic (26%) to the surrounding renal parenchyma. Of tumors smaller than 2 cm, most were either mildly hyperechoic (29%) or as hyperechoic as renal sinus fat (very hyperechoic; 29%). Tumors larger than 3 cm were found most often to be either isoechoic (49%) or mildly hyperechoic (33%), with only 4% found to be very hyperechoic. The sonographic appearances of renal cell carcinomas include a small population that are very hyperechoic on sonography and thus could potentially be misdiagnosed as angiomyolipomas.


Selection of RNA replicons capable of persistent noncytopathic replication in mammalian cells.
The natural life cycle of alphaviruses, a group of plus-strand RNA viruses, involves transmission to vertebrate hosts via mosquitoes. Chronic infections are established in mosquitoes (and usually in mosquito cell cultures), but infection of susceptible vertebrate cells typically results in rapid shutoff of host mRNA translation and cell death. Using engineered Sindbis virus RNA replicons expressing puromycin acetyltransferase as a dominant selectable marker, we identified mutations allowing persistent, noncytopathic replication in BHK-21 cells. Two of these adaptive mutations involved single-amino-acid substitutions in the C-terminal portion of nsP2, the viral helicase-protease. At one of these loci, nsP2 position 726, numerous substitution mutations were created and characterized in the context of RNA replicons and infectious virus. Our results suggest a direct correlation between the level of viral RNA replication and cytopathogenicity. This work also provides a series of alphavirus replicons for noncytopathic gene expression studies (E. V. Agapov, I. Frolov, B. D. Lindenbach, B. M. Prágai, S. Schlesinger, and C. M. Rice, Proc. Natl. Acad. Sci. USA 95:12989-12994, 1998) and a general strategy for selecting RNA viral mutants adapted to different cellular environments.


Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.
Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.


Selective binding and dynamics of imidazole alkyl sulfate ionic liquids with human serum albumin and collagen - a detailed NMR investigation.
The interaction of ionic liquid (IL) with protein is now becoming important as it stabilizes the protein due to the selective cation-anion combination of the IL. The binding and dynamics of the green solvents such as imidazole alkyl sulfate based ILs, viz., 1-butyl-3-methylimidazolium alkyl [where alkyl = hydrogen, methyl, octyl and dodecyl] sulfate, with two distinct model proteins, namely human serum albumin (HSA) and collagen in aqueous solution, have been investigated with the aid of solution nuclear magnetic resonance (NMR). Interactions of ILs with HSA and collagen have been probed at the atomistic level through NMR determined parameters, such as 1H line-shapes, selective and non-selective spin-lattice relaxation times (T1SEL & T1NS) and spin-spin relaxation times (T2). Furthermore, saturation transfer difference (STD) NMR has been used to monitor the spatial proximities of ILs with HSA and collagen. The results indicate that despite the type of protein (HSA or collagen), STD NMR of protein-IL mixtures exhibits responses only from the anionic part of the selected ILs. Also, a combination of T1SEL and T1NS measurements indicates the genuine protein-IL interaction. Furthermore, it was observed that the global binding affinity between IL and proteins is enhanced with an increase in alkyl chain length of the anionic portion of the IL. The present study thus highlights the role of the anionic part of ILs in the interaction with the selected proteins. The outcome of the present study provides an opportunity to design new ILs with a judicious choice of anionic and cationic parts for targeted functionalities.


Associations between improvement in genitourinary symptoms of menopause and changes in the vaginal ecosystem.
The aim of the study was to identify associations between improvement in genitourinary symptoms of menopause (GSM) and vaginal microbiota, vaginal glycogen, and serum estrogen. Thirty postmenopausal women enrolled in a hot flash treatment trial (oral estradiol vs venlafaxine vs placebo) who reported GSM and provided vaginal swabs at 0, 4, and 8 weeks were studied. Bacterial communities were characterized using deep sequencing targeting the 16S rRNA gene V3-V4 region. Participants selected a most bothersome genitourinary symptom (dryness, discharge, pain, itch/burn, or inability to have sex) and rated severity on a 10-point scale at baseline and 8 weeks. Vaginal glycogen and serum estradiol and estrone were measured at enrollment and 8 weeks. Comparisons according to improvement in most bothersome symptom (MBS) were made using χ, Wilcoxon signed-rank test, or Hotelling's t test. Of 30 participants, 21 (70%) had improvement in MBS over the 8-week study and 9 (30%) had no improvement or worsening of MBS. A higher proportion of women receiving estradiol or venlafaxine reported improvement in MBS (88%, 78%) compared with placebo (54%; P = 0.28). MBS improvement was associated with Lactobacillus-dominant vaginal microbiota at enrollment (57% vs 22%, P = 0.08). Vaginal glycogen, serum estradiol, and estrone significantly increased in women whose MBS improved. A larger proportion of women whose MBS improved had a Lactobacillus dominant microbiota at enrollment than those who had no improvement during the trial, though this difference was not statistically significant. Larger trials are needed to determine whether vaginal microbiota modify or mediate treatment responses in women with GSM.


Canopy photosynthesis of sugar maple (Acer saccharum): comparing big-leaf and multilayer extrapolations of leaf-level measurements.
A comparison is made between a big-leaf model (i.e., without details of the canopy profile) and two multilayer models (i.e., with details of the canopy profile) to estimate daily canopy photosynthesis of a sugar maple (Acer saccharum Marsh.) stand. The first multilayer model uses the distribution of leaf area by leaf mass per unit area (LMA) classes, the observed relationships between the parameters of a photosynthesis-irradiance curve and LMA, and the relationship between relative irradiance and LMA to estimate canopy photosynthesis. When compared with this model, the big-leaf model underestimates daily canopy photosynthesis by 26% because of an assumed proportionality between photosynthetic capacity and relative irradiance, a proportionality that is inconsistent with our data. The bias induced by this assumption is reduced when the big-leaf model is compared with the second multilayer model which, in addition to the assumptions made for the first multilayer model, accounts for the sunlit and shaded fractions of leaf area. The residual bias is almost eliminated when the big-leaf model is run using a weekly averaged irradiance. It is likely, however, that this is the result of a compensating bias that, in this particular case, compensates for the initial bias introduced by the proportionality assumption. It is also shown that canopy photosynthesis can be represented by spatially inexplicit multilayer models that use leaf mass per area as a covariable to describe leaf characteristics and environment. Such models represent an interesting alternative to the biased big-leaf approach.


Acquired amegakaryocytic thrombocytopenia after durvalumab administration.
Immune checkpoint inhibitors (ICIs), despite their ability to potentiate antitumor T-cell responses, may cause various immune-related adverse events. Most cases of thrombocytopenia induced by ICIs have revealed a pathophysiologic mechanism of immune thrombocytopenia with increased platelet destruction and preserved megakaryocytes. Acquired amegakaryocytic thrombocytopenic purpura (AATP) is an unusual disorder characterized by thrombocytopenia with markedly diminished bone marrow megakaryocytes in the presence of otherwise normal hematopoiesis. AATP caused by ICIs has not been reported on. Herein, we present the case of a 79-year-old man diagnosed with squamous cell carcinoma of the lung who developed AATP after two courses of durvalumab, a drug targeting programmed death-ligand 1. Two weeks after the second cycle, his platelet count decreased to 2.1 × 104/μL. After the patient underwent platelet transfusion, his platelet count increased to 8.1 × 104/μL the next day but subsequently decreased repeatedly even after the ICI was discontinued. Six weeks after the second cycle, he developed interstitial pneumonia and was administered prednisolone (50 mg/day). However, thrombocytopenia did not improve. Bone marrow biopsy showed scarce megakaryocytes (< 1 megakaryocyte/10 high-power fields) with preservation of myeloid and erythroid series. Myelodysplasia, myelofibrosis, or metastatic lesions were not observed. Cytogenetic analysis showed a normal male karyotype of 46XY. Hence, the patient received eltrombopag, a thrombopoietin receptor agonist, and his platelet count subsequently improved. After recovery, bone marrow aspiration revealed a normal number of megakaryocytes. AATP is rarely the type of thrombocytopenia induced by ICIs and may be successfully treated with thrombopoietin receptor agonists.


Acoustofluidic particle manipulation inside a sessile droplet: four distinct regimes of particle concentration.
In this study, we have investigated the motion of polystyrene microparticles inside a sessile droplet of water actuated by surface acoustic waves (SAWs), which produce an acoustic streaming flow (ASF) and impart an acoustic radiation force (ARF) on the particles. We have categorized four distinct regimes (R1-R4) of particle aggregation that depend on the particle diameter, the SAW frequency, the acoustic wave field (travelling or standing), the acoustic waves' attenuation length, and the droplet volume. The particles are concentrated at the centre of the droplet in the form of a bead (R1), around the periphery of the droplet in the form of a ring (R2), at the side of the droplet in the form of an isolated island (R3), and close to the centre of the droplet in the form of a smaller ring (R4). The ASF-based drag force, the travelling or standing SAW-based ARF, and the centrifugal force are utilized in various combinations to produce these distinct regimes. For simplicity, we fixed the fluid volume at 5 μL, varied the SAW actuation frequency (10, 20, 80, and 133 MHz), and tested several particle diameters in the range 1-30 μm to explicitly demonstrate the regimes R1-R4. We have further demonstrated the separation of particles (1 and 10 μm, 3 and 5 μm) using mixed regime configurations (R1 and R2, R2 and R4, respectively).


What Kind of Surgeon Will You Be? An Analysis of Specialty Interest Changes Over the Course of General Surgery Residency.
Integrated surgical residency programs and early specialization tracts have increased, with proposed benefits including shorter training time and increased exposure. Drawbacks include a loss of breadth and the need for earlier trainee career decisions. We sought to assess the rate of changing specialty interests over the course of general surgery residency, and what, if any, factors influenced that decision. An 11-question, web-based survey was sent to alumni (2009-2019) of a single academic general surgery residency training program. It queried demographics and experiences during medical school and residency, whether specialty interest changed, and if so, what factors influenced that decision. The survey was emailed to 53 alumni and completed by 59% (n = 31). The majority were male (n = 24, 77%) and Caucasian (n = 26, 84%). All 31 respondents went on to fellowship training. Three individuals (10%) did not declare a specialty interest when applying to residency. Of the 28 who declared an interest, the majority (n = 17, 61%) changed their interest over the course of residency and ultimately applied to fellowship in a different field. Amongst these, only six (25%) had previous exposure in medical school to the field they ultimately went in to. All who changed specialties (n = 17) reported an impactful clinical rotation influencing their decision. Nearly two-thirds of general surgery residents at a single academic institution changed their specialty interest over the course of residency. Our findings suggest that while integrated programs may provide benefits, many medical students are not being exposed to these potential fields.


The effects of study design and spectrum bias on the evaluation of diagnostic accuracy of confocal scanning laser ophthalmoscopy in glaucoma.
To assess the effects of study design and spectrum bias on the evaluation of diagnostic accuracy of confocal scanning laser ophthalmoscopy (CSLO) in glaucoma. Analysis 1 included 67 eyes with glaucomatous visual field loss and 56 eyes of normal volunteers. Estimates of diagnostic accuracy in this analysis were compared to those obtained from analysis 2, which included a cohort of patients with suspected glaucoma, but without visual field loss at the time of CSLO imaging. For analysis 2, 40 eyes with progressive glaucomatous optic disc change were included in the glaucoma group and 43 eyes without any evidence of progressive damage to the optic nerve that were observed untreated for an average time of 9.01 +/- 3.09 years were included in the normal group. Areas under the receiver operating characteristic (ROC) curves (AUC) were used to evaluate diagnostic accuracy of CSLO parameters. There was a statistically significant difference between the performance of the parameter with largest AUC, discriminant function Bathija, in analysis 1 (AUC = 0.91) compared with its performance in analysis 2 (AUC = 0.71; P = 0.002). For the contour-line-independent parameter glaucoma probability score, a statistically significant difference was also observed in the performance obtained in analysis 1 (AUC = 0.89) compared with analysis 2 (AUC = 0.65; P < 0.001). Estimates of diagnostic accuracy of CSLO in glaucoma can be largely different depending on the population studied and the reference standard used to define disease. Diagnostic accuracy estimates obtained from case-control studies including well-defined groups of subjects with or without disease may not be applicable to the clinically relevant population.


Endothelin 1, an endothelium-derived peptide, is expressed in neurons of the human spinal cord and dorsal root ganglia.
The localization of endothelin 1 mRNA and endothelin-like immunoreactivity was investigated in samples of neurologically normal nervous system tissue from 10 adults by using in situ hybridization and immunocytochemistry. Tissue sections of spinal cord and dorsal root ganglia were hybridized with an 35S-radiolabeled endothelin 1 complementary RNA probe. Autoradiograms showed labeled neurons in the spinal cord (laminae IV-VI and many motoneurons) and numerous small and large neurons in the dorsal root ganglia. Endothelin 1 transcripts were also found in association with the endothelial layer of some blood vessels in the white matter of the spinal cord. A similar distribution of immunoreactivity was seen using three antisera to endothelin 1, but fewer cells were immunostained than were labeled after the hybridization. Two other endothelin 1 antisera immunostained the endothelial lining of blood vessels in the spinal cord white matter but not neurons. In the ganglia, endothelin 1 transcripts were localized to all cells expressing beta-preprotachykinin and most expressing calcitonin gene-related peptide mRNAs; in the majority of the motoneurons, coexistence of endothelin 1 and calcitonin gene-related peptide mRNAs was noted. There was a similar pattern of coexistence for respective peptide immunoreactivities in the ganglia and spinal cord. The expression of endothelin 1 mRNA in distinct neuronal cell types suggests that this peptide plays a part in neural transmission/modulation and adds a further dimension to the known vascular-related actions of endothelin 1.


Evaluation of global literature for definition of dose-response relationship for hexachlorobenzene toxicity.
Numerous research groups have generated data that can be collated to define the hexachlorobenzene (HCB) dose-response relationship for subchronic/chronic target-organ toxicity, oncogenicity and reproductive toxicity. Subchronic toxicity studies in rats are typified by Kuiper-Goodman et al. (1977) and Mollenhauer et al. (1975) in which the lowest-observed-effect-level was 0.25-2.0 mg/kg per day and the no-observed-effect-level was 0.05-0.5 mg/kg per day. In the pig, den Tonkelaar et al. (1978) defined the subchronic lowest-observed-effect-level and the no-observed-effect-level as 0.5 and 0.05 mg/kg per day, respectively. In a 12-month dog study by Gralla et al. (1977) the lowest-observed-effect-level was 10 mg/kg per day and the no-observed-effect-level was 1 mg/kg per day. Rozman et al. (1978) reported a no-observed-effect-level of 0.033 mg/kg per day in a study of 18 months' duration in the monkey. Oncogenic assessment of HCB has been carried out in studies using the hamster (Cabral et al., 1977), the mouse (Cabral et al., 1979) and the rat (Arnold et al., 1978; Smith & Cabral, 1980), with responses obtained at doses of approximately 2-4 up to greater than 24 mg/kg per day, but no response at doses of approximately 0.4-0.8 up to 6 mg/kg per day. Reproductive toxicity studies of HCB have used the cat (Hansen et al., 1979a), the pig (Hansen et al., 1979b) and the rat (Grant et al., 1977), obtaining no-observed-effect-levels of 1.0, greater than 0.025-0.5 and 1-2 mg/kg per day respectively, for the three species. Overall, the substantial amount of toxicity data from these studies can be collated into a cohesive pattern that defines the dose-response relationship for HCB toxicity.


A novel sequence alignment algorithm based on deep learning of the protein folding code.
From evolutionary interference, function annotation to structural prediction, protein sequence comparison has provided crucial biological insights. While many sequence alignment algorithms have been developed, existing approaches often cannot detect hidden structural relationships in the 'twilight zone' of low sequence identity. To address this critical problem, we introduce a computational algorithm that performs protein Sequence Alignments from deep-Learning of Structural Alignments (SAdLSA, silent 'd'). The key idea is to implicitly learn the protein folding code from many thousands of structural alignments using experimentally determined protein structures. To demonstrate that the folding code was learned, we first show that SAdLSA trained on pure α-helical proteins successfully recognizes pairs of structurally related pure β-sheet protein domains. Subsequent training and benchmarking on larger, highly challenging datasets show significant improvement over established approaches. For challenging cases, SAdLSA is ∼150% better than HHsearch for generating pairwise alignments and ∼50% better for identifying the proteins with the best alignments in a sequence library. The time complexity of SAdLSA is O(N) thanks to GPU acceleration. Datasets and source codes of SAdLSA are available free of charge for academic users at http://sites.gatech.edu/cssb/sadlsa/. Supplementary data are available at Bioinformatics online.


MR imaging of the lingual thyroid. Comparison to other submucosal lesions.
To study MR findings for clues to the diagnosis of lingual thyroid. MR findings and clinical and scintigraphic data of 5 cases of lingual thyroid were reviewed and the MR findings were compared to those of 16 cases of other submucosal lesions in the base of the tongue. Four of the 5 patients with lingual thyroid were women and all had hypothyroidism. MR imaging depicted lingual thyroid in the midline in the base of the tongue (n=5) and additional ectopic thyroid glands in the floor of the mouth (n=2) or between the right and left sternohyoid muscles (n=1). Ectopic thyroid glands appeared isointense or hyperintense relative to muscle tissue on T1-weighted images and showed slight or fair contrast enhancement. All glands had low to intermediate T2 signal, which was also seen in 1 case of non-Hodgkin's lymphoma and 1 case of adenoid cystic carcinoma. All ectopic thyroid glands had well-defined margins, whereas malignant tumors tended to have ill-defined margins and to invade the surrounding structures. All but the 5 cases of lingual thyroid had an MR-demonstrable thyroid gland in the normal cervical position. A well-defined mass of low-intermediate T2 signal in the midline base of the tongue, neither with invasive tendency nor with a cervical thyroid gland in the normal site on MR imaging, may strongly indicate lingual thyroid.


Effects of stress or infection on rat behavior show robust reversals due to environmental disturbance.
Background: The behavior of animals is intricately linked to the environment; a relationship that is often studied in laboratory conditions by using environmental perturbations to study biological mechanisms underlying the behavioral change. Methods: This study pertains to two such well-studied and well-replicated perturbations, i.e., stress-induced anxiogenesis and Toxoplasma-induced loss of innate fear. Here, we demonstrate that behavioral outcomes of these experimental manipulations are contingent upon the ambient quality of the wider environment where animal facilities are situated. Results: During late 2014 and early 2015, a building construction project started adjacent to our animal facility. During this phase, we observed that maternal separation stress caused anxiolysis, rather than historically observed anxiogenesis, in laboratory rats. We also found that Toxoplasma infection caused an increase, rather than historically observed decrease, in innate aversion to predator odors in rats. Conclusion: These observations suggest that effects of stress and Toxoplasma are dependent on variables in the environment that often go unreported in the published literature.


MiR-654-3p Suppresses Non-Small Cell Lung Cancer Tumourigenesis by Inhibiting PLK4.
MiR-654-3p plays important roles in many types of malignant tumours. However, the biological function of miR-654-3p in non-small cell lung cancer (NSCLC) remains unknown. In this study, the role of miR-654-3p in NSCLC was investigated. qRT-PCR was used to evaluate the level of miR-654-3p in NSCLC tissues and cell lines, while Cell Counting Kit-8, Annexin V/propidium iodide dual staining or TUNEL staining were used to investigate proliferation and apoptosis of NSCLC cells. Luciferase assays and Western blotting were performed to validate potential targets of miR-654-3p. MiR-654-3p levels were significantly decreased in NSCLC patients and cell lines and were significantly correlated with the tumour size and tumour node metastasis stage of NSCLC patients. In A549 cells, miR-654-3p overexpression significantly increased apoptosis and inhibited growth both in vivo and in vitro, while downregulation of miR-654-3p had the opposite effects. In addition, polo-like kinase 4 (PLK4) was shown to be a target gene of miR-654-3p that is negatively regulated by miR-654-3p in A549 cells. Furthermore, PLK4 was observed to be highly expressed in NSCLC tissues and cells, and PLK4 overexpression abolished the inhibitory effects of miR-654-3p overexpression on NSCLC cell proliferation. Finally, the animal experiment results further demonstrated that miR-654-3p inhibits tumour growth and regulates PLK4 expression. Our results demonstrate that miR-654-3p functions as a growth-suppressing miRNA by targeting PLK4 in NSCLC.


Psychometric evaluation of the Moral Injury Events Scale.
Literature describing the phenomenology of the stress of combat suggests that war-zone experiences may lead to adverse psychological outcomes such as post-traumatic stress disorder not only because they expose persons to life threat and loss but also because they may contradict deeply held moral and ethical beliefs and expectations. We sought to develop and validate a measure of potentially morally injurious events as a necessary step toward studying moral injury as a possible adverse consequence of combat. We administered an 11-item, self-report Moral Injury Events Scale to active duty Marines 1 week and 3 months following war-zone deployment. Two items were eliminated because of low item-total correlations. The remaining 9 items were subjected to an exploratory factor analysis, which revealed two latent factors that we labeled perceived transgressions and perceived betrayals; these were confirmed via confirmatory factor analysis on an independent sample. The overall Moral Injury Events Scale and its two subscales had favorable internal validity, and comparisons between the 1-week and 3-month data suggested good temporal stability. Initial discriminant and concurrent validity were also established. Future research directions were discussed.


Modulation of Response Regulator CheY Reaction Kinetics by Two Variable Residues That Affect Conformation.
Microorganisms and plants utilize two-component systems to regulate adaptive responses to changing environmental conditions. Sensor kinases detect stimuli and alter their autophosphorylation activity accordingly. Signal propagation occurs via the transfer of phosphoryl groups from upstream kinases to downstream response regulator proteins. Removal of phosphoryl groups from the response regulator typically resets the system. Members of the same protein family may catalyze phosphorylation and dephosphorylation reactions with different efficiencies, exhibiting rate constants spanning many orders of magnitude to accommodate response time scales from milliseconds to days. We previously found that variable positions one or two residues to the C-terminal side of the conserved Asp phosphorylation site (D+2) or Thr/Ser (T+1/T+2) in response regulators alter reaction kinetics by direct interaction with phosphodonor or phosphoacceptor molecules. Here, we explore the kinetic effects of amino acid substitutions at the two positions immediately C-terminal to the conserved Lys (K+1/K+2) in the model Escherichia coli response regulator CheY. We measured CheY autophosphorylation and autodephosphorylation rate constants for 27 pairs of K+1/K+2 residues that represent 84% of naturally occurring response regulators. Effects on autodephosphorylation were modest, but autophosphorylation rate constants varied by 2 orders of magnitude, suggesting that the K+1/K+2 positions influence reaction kinetics by altering the conformational spectrum sampled by CheY at equilibrium. Additional evidence supporting this indirect mechanism includes the following: the effect on autophosphorylation rate constants is independent of the phosphodonor, the autophosphorylation rate constants and dissociation constants for the phosphoryl group analog BeF3- are inversely correlated, and the K+1/K+2 positions are distant from the phosphorylation site.IMPORTANCE We have identified five variable positions in response regulators that allow the rate constants of autophosphorylation and autodephosporylation reactions each to be altered over 3 orders of magnitude in CheY. The distributions of variable residue combinations across response regulator subfamilies suggest that distinct mechanisms associated with different variable positions allow reaction rates to be tuned independently during evolution for diverse biological purposes. This knowledge could be used in synthetic-biology applications to adjust the properties (e.g., background noise and response duration) of biosensors and may allow prediction of response regulator reaction kinetics from the primary amino acid sequence.


Therapeutic serum concentrations of human alpha-1-antitrypsin after adenoviral-mediated gene transfer into mouse hepatocytes.
Alpha-1-antitrypsin is a relatively common genetic deficiency that results in early emphysema. The liver as the natural source of most alpha-1-antitrypsin synthesis was the target organ selected for gene replacement therapy studies. Previous work used recombinant retroviral vectors that encode the human alpha-1-antitrypsin cDNA for ex vivo and direct in vivo transduction of hepatocytes in dogs and rodents. This approach led to low levels of human protein in the serum of recipients. In this study, recombinant adenoviral vectors that express the human alpha-1-antitrypsin cDNA under the transcriptional control of the phosphoglycerate kinase (PGK) or RSV-LTR promoters have been constructed and used for the direct transduction of mouse hepatocytes in vivo. The animals transduced with the recombinant adenoviral vectors had therapeutic serum levels of human alpha-1-antitrypsin of up to 700 micrograms/mL. Thus, adenovirus-mediated gene transfer of the hAAT cDNA into the liver was able to produce therapeutic serum concentrations of protein.


Hidden diagnosis behind viral infection: the danger of anchoring bias.
Anchoring bias is one of the most common diagnostic biases that may lead to closed-minded thinking and could result in unnecessary tests, inappropriate patient management and even misdiagnosis. A 4-year-old boy was brought to the emergency department because of shaking chills. On the basis of bilateral swollen preauricular areas, high level of serum amylase and the prevalence of mumps, he initially received a diagnosis of mumps in spite of the shaking chills. However, blood culture turned out to be positive for two different kinds of bacteria. The patient finally received a diagnosis of polymicrobial bacteraemia resulting from suppurative appendicitis. We must consider and rule out bacteraemia in the differential diagnosis for patients who present with shaking chills, even in the presence of symptoms or information consistent with a more common viral infection such as mumps. In addition, intra-abdominal infection should be ruled out in the presence of polymicrobial enterobacteriaceae bacteraemia.


[Evolution of autologous graft interface in rats: experimental study].
With purpose to study the evolution of autologous venous graft interface, an experimental model utilizing an autologous venous patch to repair an infrarenal abdominal aortic defect in rats was developed. A small piece of both the jugular vein and the aorta were first excised. After implantation and reestablishment of blood flow, the animals were subsequently sacrificed in groups of 3 at the following intervals: 10 seconds, 1 minute, 10 minutes, 30 minutes, 1 hour, 6 hours, 12 hours, 24 hours, 7 days, 30 days and 90 days. All the patches and adjacent aortae were collected and studied using scanning electron microscopy, with the following results: 1) the endothelial lining of both the autologous vein patch and the adjacent aorta is destroyed before implantation due to operative manipulation; 2) after blood flow reestablishment, the patch and adjacent aortic interfaces are reactive to platelets and other blood cells; 3) New endothelial lining begins to appear from the 7th day after implantation, but the regeneration is not complete at 3 months. From the model, it is deducted that the endothelial repair of autologous venous patch and its adjacent aorta involves a very slow process.


Tumor co-expression of progranulin and sortilin as a prognostic biomarker in breast cancer.
The growth factor progranulin has been implicated in numerous biological processes such as wound healing, inflammation and progressive tumorigenesis. Both progranulin and its receptor sortilin are known to be highly expressed in subgroups of breast cancer and have been associated with various clinical properties including tamoxifen resistance. Recent data further suggest that progranulin, via its receptor sortilin, drives breast cancer stem cell propagation in vitro and increases metastasis formation in an in vivo breast cancer xenograft model. In this retrospective biomarker analysis, we aimed to determine whether tumor co-expression of progranulin and sortilin has prognostic and treatment predictive values for breast cancer patients. We explored how co-expression of progranulin and sortilin was associated with established clinical markers by analyzing a tissue microarray including 560 randomized premenopausal breast cancer patients receiving either 2 years of tamoxifen treatment or no adjuvant treatment, with a median follow-up time of 28 years. Breast cancer-specific survival was analyzed using Kaplan-Meier and Cox Proportional Hazards regression models to assess the prognostic and predictive value of progranulin and sortilin in relation to known clinical markers. Co-expression of progranulin and sortilin was observed in 20% of the breast cancer samples. In untreated patients, prognostic considerations could be detailed separately from treatment prediction and the high progranulin and sortilin expressing subgroup was significantly associated with breast cancer-specific death in multivariable analyses (HR=2.188, CI: 1.317-3.637, p=0.003) along with tumor size, high tumor grade and lymph node positivity. When comparing the untreated patients with tamoxifen treated patients in the ERα positive subgroup, co-expression of progranulin and sortilin was not linked to tamoxifen resistance. Data suggest that co-expression of progranulin and its receptor sortilin is a novel prognostic biomarker combination identifying a highly malignant subgroup of breast cancer. Importantly, this subpopulation could potentially be targeted with anti-sortilin based therapies.


Circulating Human Neonatal Naïve B Cells are Deficient in CD73 Impairing Purine Salvage.
Extracellular purines, in particular adenosine (Ado) and adenosine-triphosphate, are critical immunoregulatory molecules. Expression and activity of purine ecto-enzymes on B cells in neonatal and adult blood may influence their function and has been incompletely characterized. Mononuclear cells were isolated from human neonatal (cord blood) or adult (peripheral blood) subjects and evaluated directly by flow cytometry for expression of purine ecto-enzymes. Additionally, B cell subsets were isolated from mononuclear cell fractions by fluorescence-activated cell sorting and gene transcription of purine ecto-enzymes (CD39 and CD73), Ado deaminase (ADA1), purine nucleoside phosphorylase, and select purine receptors (A2a) were evaluated by reverse transcription followed by qRT-PCR. Immuno-magnetic-bead isolated naïve B cells were evaluated for enzymatic activity by incubation with radio-labeled purines followed by thin-layer chromatography, and subsequent B cell Ado acquisition was evaluated by liquid scintillation quantitation of radio-labeled Ado uptake. Relative to their adult counterparts, neonatal circulating naïve B cells were markedly and selectively deficient in CD73 as observed by gene transcription, surface protein expression, and enzyme activity. Neonatal naïve B cell deficiency of CD73 expression significantly impaired their capacity to acquire extracellular purines for purine salvage. Human neonatal circulating naïve B cells are selectively deficient in CD73, impairing extracellular purine acquisition and potentially contributing to impaired B cell responses in early life.


Interferon-gamma-increased adherence of lymphocytes to high endothelial venules.
Recirculating lymphocytes specifically adhere to and migrate through endothelium lining high endothelial venules (HEV), using specific and non-specific receptor-ligand systems. Interferons (IFN) profoundly affect the traffic of lymphocytes. Therefore the effects of interferon-gamma (IFN-gamma) on lymphocytes with respect to their interaction with HEV endothelium in lymph nodes were studied using the frozen section assay. In addition the organ-specificity of T- and B-lymphocyte adherence to HEV was investigated. Lymphocytes from spleen and peripheral lymph nodes showed increased binding to HEV of up to 35% compared to control lymphocytes after in vivo administration of IFN-gamma. The specificity of their binding did not change in terms of T:B-cell ratios. Increased adherence was also found by preincubation of lymphocytes with IFN-gamma in The enhanced binding was not due to increased expression of Mel-14 homing receptors and LFA-1 molecules on T and B lymphocytes, as shown by fluorescence-activated cell sorter analysis and antibody-blocking studies in the frozen section assay. Apparently IFN-gamma induces an additional Mel-14-independent and LFA-1-independent adhesion mechanism on lymphocytes.


tDCS and exercise improve anxiety-like behavior and locomotion in chronic pain rats via modulation of neurotrophins and inflammatory mediators.
Anxiety disorders cause distress and are commonly found to be comorbid with chronic pain. Both are difficult-to-treat conditions for which alternative treatment options are being pursued. This study aimed to evaluate the effects of transcranial direct current stimulation (tDCS), treadmill exercise, or both, on anxiety-like behavior and associated growth factors and inflammatory markers in the hippocampus and sciatic nerve of rats with neuropathic pain. Male Wistar rats (n = 216) were subjected to sham-surgery or sciatic nerve constriction for pain induction. Fourteen days following neuropathic pain establishment, either bimodal tDCS, treadmill exercise, or a combination of both was used for 20 min a day for 8 consecutive days. The elevated plus-maze test was used to assess anxiety-like behavior and locomotor activity during the early (24 h) or late (7 days) phase after the end of treatment. BDNF, TNF-ɑ, and IL-10 levels in the hippocampus, and BDNF, NGF, and IL-10 levels in the sciatic nerve were assessed 48 h or 7 days after the end of treatment. Rats from the pain groups developed an anxiety-like state. Both tDCS and treadmill exercise provided ethological and neurochemical alterations induced by pain in the early and/or late phase, and a modest synergic effect between tDCS and exercise was observed. These results indicate that non-invasive neuromodulatory approaches can attenuate both anxiety-like status and locomotor activity and alter the biochemical profile in the hippocampus and sciatic nerve of rats with neuropathic pain and that combined interventions may be considered as a treatment option.


Mother-daughter communication about sexual maturation, abstinence and unintended pregnancy: experiences from an informal settlement in Nairobi, Kenya.
Parental communication and support is associated with improved developmental, health and behavioral outcomes in adolescence. This study explores the quality of mother-daughter communication about sexual maturation, abstinence and unintended pregnancy in Korogocho, an informal settlement in Nairobi, Kenya. We use data from 14 focus group discussions (n = 124) and 25 interviews with girls aged 12-17, mothers of teenage girls, and key informant teachers. Many girls and women believed that mothers are the best source of information and support during puberty but only a minority described good experiences with communication in practice. Girls preferred communication to begin early and be repeated regularly. Mothers often combined themes of sexual maturation, abstinence and avoiding pregnancy in their messages. Communication was facilitated by mothers' availability, warmth and close parent-child relationships. Challenges included communication taboos, embarrassment, ambiguous message content, and parental lack of knowledge and uncertainty. Neighborhood poverty undermined some mothers' time and motivation for communicating.