Adherence to paroxetine CR compared with paroxetine IR in a Medicare-eligible population with anxiety disorders.
There are many challenges in the pharmacologic management of elderly patients with anxiety disorders, including an increased sensitivity to drug effects, reduced drug metabolism, and socioeconomic barriers leading to poor medication adherence. As such, the purpose of this study was to evaluate differential rates of adherence between paroxetine controlled release (CR) and paroxetine immediate release (IR) in the treatment of anxiety disorders in a Medicare-eligible population. Patients aged 65 years or older initiating therapy with paroxetine CR or paroxetine IR with a diagnosis of anxiety were identified from the Integrated Healthcare Information Services National Managed Care Benchmark database from July 2001 to February 2004. Logistic regression models were used to assess differences in 6-month adherence rates, controlling for differences in multiple background characteristics. Adherence was defined as having a minimum medication possession ratio of 80% over 180 days without evidence of a 15-day gap before 90 days of therapy. Of the 604 patients included in the study, 18% received paroxetine CR and 82% received paroxetine IR; comorbid anxiety and depression were present in 37.3% of patients. Overall, only 37.3% of patients adhered to therapy, with a greater percentage of patients adhering to paroxetine CR (45.0%) compared with paroxetine IR (35.6%). After controlling for background characteristics, patients receiving paroxetine IR were 38.7% less likely to adhere to therapy compared with patients receiving paroxetine CR (P = .0328). When stratified by those with comorbid anxiety and depression, patients receiving paroxetine IR were 55.1% less likely to adhere to therapy compared with patients receiving paroxetine CR (P = .0292). This study demonstrates that antidepressant nonadherence is common in patients older than 65 years of age, with overall rates of nonadherence at 62.7% and patients receiving paroxetine IR having the lowest levels of adherence. Future work should assess differences in all available selective serotonin reuptake inhibitors while also directly assessing the economic impact of nonadherence in the elderly population.


Immunity to Escherichia coli in pigs. The role of milk in protective immunity to e. coli enteritis.
Milk whey from immunized sows increased the survival time of gnotobiotic piglets infected with Escherichia coli. The survival time of infected piglets fed milk whey from non-vaccinated sow's was the same as that of similar pigs fed condensed cow milk. The significance of milk antibodies in immune protection against E. coli enteritis is discussed and compared with that of absorbed colostral antibodies. From calculations presented it would appear that seven day old piglets receive approximately 1 g of gamma globulin daily from milk and that this is equal to the piglets total serum gamma globulin content. After seven days of age the gamma globulin content of piglet serum falls, whereas that of milk remains constant; milk is, therefore, potentially a major source of immunoglobulins with protective activity against E. coli associated enteritides.


Real-Time fast PCR amplification using designated and conventional real time thermal cycler systems: COVID-19 perspective.
The study aimed to shorten multiplex RT-PCR run time for detection of SARS CoV-2 N1 and N2 sequences and human RNase P (RP) sequence as internal mRNA control using conventional and designated real time thermal cycler systems. Optimization of Fast PCR protocol using plasmid-based N1 and N2 positive control and synthetic version of human RP was done on Applied Biosystems (ABI) QuantStudioTM5 (conventional), ABI 7500 Fast Dx (designated), and CFX96 Touch Real Time Detection System, Bio-Rad (conventional). Finally, a performance evaluation of Fast PCR was performed in terms of sensitivity, specificity, and precision. For a 40-cycle PCR with optimized Fast PCR protocols on QuantStudioTM5, ABI 7500 Fast Dx, and CFX96 Touch (conventional), standard/regular versus Fast PCR run times (min) were 84 vs. 49, 96 vs. 48, and 103 vs. 61, thereby saving 35, 48, and 43 min, respectively. For each thermal cycler, Standard and Fast PCR generated identical shapes of fluorescence curves, Ct values, and (3) R2 (0.95 to 0.99) for 5 10-log dilution panels of each positive control. The fast PCR approach generated results with 100% sensitivity and specificity. Median test comparisons between standard PCR and Fast PCR Cts of COVID-19 samples did not produce significance (p>0.5), suggesting that Fast PCR and Standard PCR were comparable. Also, the median and mean of each target had closely-related values, further suggesting that the two approaches were comparable. That is, there is an equivalency between Conventional and Fast PCR instruments for detection of COVID-19.


Potential Role of the Gut/Liver/Lung Axis in Alcohol-Induced Tissue Pathology.
Both Alcoholic Liver Disease (ALD) and alcohol-related susceptibility to acute lung injury are estimated to account for the highest morbidity and mortality related to chronic alcohol abuse and, thus, represent a focus of intense investigation. In general, alcohol-induced derangements to both organs are considered to be independent and are often evaluated separately. However, the liver and lung share many general responses to damage, and specific responses to alcohol exposure. For example, both organs possess resident macrophages that play key roles in mediating the immune/inflammatory response. Additionally, alcohol-induced damage to both organs appears to involve oxidative stress that favors tissue injury. Another mechanism that appears to be shared between the organs is that inflammatory injury to both organs is enhanced by alcohol exposure. Lastly, altered extracellular matrix (ECM) deposition appears to be a key step in disease progression in both organs. Indeed, recent studies suggest that early subtle changes in the ECM may predispose the target organ to an inflammatory insult. The purpose of this chapter is to review the parallel mechanisms of liver and lung injury in response to alcohol consumption. This chapter will also explore the potential that these mechanisms are interdependent, as part of a gut-liver-lung axis.


Spontaneous esophageal hematoma in a patient with atrial fibrillation.
We report a case of a spontaneous esophageal hematoma in an anticoagulated patient with atrial fibrillation previously complicated by a cerebrovascular accident. A multidisciplinary discussion resulted in holding of anticoagulation until the esophageal hematoma resolved. The patient was managed nonoperatively and discharged, but returned with a new neurologic deficit 3 weeks later. Aspirin treatment was resumed. After complete resolution of hematoma on outpatient scans, warfarin treatment was restarted. The challenges of managing an esophageal hematoma in a patient requiring anticoagulation are discussed.


Epstein-Barr virus-associated lymphoma in a child undergoing an autologous stem cell rescue.
Epstein-Barr virus-associated lymphoproliferative disease (EBV-LPD) is a serious disorder seen in various states of immunodeficiency, often with a fatal outcome. In this article, a patient with EBV-lymphoma after autologous stem cell rescue for treatment of a nonhematologic solid tumor is described. The child, a 4-year-old boy, had unilateral retinoblastoma with metastatic spread to the central nervous system. He had previously received both local tumor bed and craniospinal radiation therapy together with intensive myeloablative alkylator chemotherapy before autologous stem cell rescue. Histologically confirmed lymphoma with evidence of active EBV proliferation developed within cervical lymph nodes 3 weeks after his first autologous stem cell rescue. A complete clinical remission of the lymphadenopathy was obtained after infusions of rituximab (an anti-CD20 monoclonal antibody), acyclovir, and high-titer anticytomegalovirus immunoglobulin. The patient died approximately 6 months later of persistent and progressive retinoblastoma without any clinical evidence of lymphoma. It is concluded that EBV-LPD should be included in the differential diagnosis in patients in whom lymphadenopathy develops after autologous stem cell rescue.


New insights from Gorongosa National Park and Niassa National Reserve of Mozambique increasing the genetic diversity of Trypanosoma vivax and Trypanosoma vivax-like in tsetse flies, wild ungulates and livestock from East Africa.
Trypanosoma (Duttonella) vivax is a major pathogen of livestock in Africa and South America (SA), and genetic studies limited to small sampling suggest greater diversity in East Africa (EA) compared to both West Africa (WA) and SA. Multidimensional scaling and phylogenetic analyses of 112 sequences of the glycosomal glyceraldehyde phosphate dehydrogenase (gGAPDH) gene and 263 sequences of the internal transcribed spacer of rDNA (ITS rDNA) were performed to compare trypanosomes from tsetse flies from Gorongosa National Park and Niassa National Reserve of Mozambique (MZ), wild ungulates and livestock from EA, and livestock isolates from WA and SA. Multidimensional scaling (MDS) supported Tvv (T. vivax) and TvL (T. vivax-like) evolutionary lineages: 1) Tvv comprises two main groups, TvvA/B (all SA and WA isolates plus some isolates from EA) and TvvC/D (exclusively from EA). The network revealed five ITS-genotypes within Tvv: Tvv1 (WA/EA isolates), Tvv2 (SA) and Tvv3-5 (EA). EA genotypes of Tvv ranged from highly related to largely different from WA/SA genotypes. 2) TvL comprises two gGAPDH-groups formed exclusively by EA sequences, TvLA (Tanzania/Kenya) and TvLB-D (MZ). This lineage contains more than 11 ITS-genotypes, seven forming the lineage TvL-Gorongosa that diverged from T. vivax Y486 enough to be identified as another species of the subgenus Duttonella. While gGAPDH sequences were fundamental for classification at the subgenus, major evolutionary lineages and species levels, ITS rDNA sequences permitted identification of known and novel genotypes. Our results corroborate a remarkable diversity of Duttonella trypanosomes in EA, especially in wildlife conservation areas, compared to the moderate diversity in WA. Surveys in wilderness areas in WA may reveal greater diversity. Biogeographical and phylogenetic data point to EA as the place of origin, diversification and spread of Duttonella trypanosomes across Africa, providing relevant insights towards the understanding of T. vivax evolutionary history.


The baculovirus anti-apoptotic p35 protein promotes transformation of mouse embryo fibroblasts.
The baculovirus p35 protein is a potent inhibitor of programmed cell death induced by a variety of stimuli in insects, nematodes, and mammalian cell lines. The broad ability of p35 in preventing apoptosis has led us to investigate its effect on mouse embryo fibroblasts in vitro and in vivo. For this purpose, we have used R- cells (3T3-like fibroblasts derived from mouse embryos with a targeted disruption of the insulin-like growth factor I receptor (IGF-IR) genes) and R508 cells (derived from R- and with 15 x 10(3) IGF-IRs per cell). Both cell lines grow normally in monolayer, but they do not form colonies in soft agar, and they are non-tumorigenic in nude mice. We show here that, in addition to its anti-apoptotic effect, p35 causes transformation of R508 cells, as evidenced by the following: 1) decreased growth factor requirements, 2) ability to form foci in monolayer and colonies in soft agar, and 3) ability to form tumors in nude mice. Since R- cells stably transfected with p35 do not transform, our observations suggest that in addition to its effect as an inhibitor of apoptosis, the baculovirus p35 protein has transforming potential that requires the presence of the IGF-IR. The possibility that these two properties could be separated was confirmed by demonstrating that R508 cells expressing another anti-apoptotic protein, Bcl-2, could not form tumors in nude mice.


Opposing roles for JNK and Aurora A in regulating the association of WDR62 with spindle microtubules.
WD40-repeat protein 62 (WDR62) is a spindle pole protein required for normal cell division and neuroprogenitor differentiation during brain development. Microcephaly-associated mutations in WDR62 lead to mitotic mislocalization, highlighting a crucial requirement for precise WDR62 spatiotemporal distribution, although the regulatory mechanisms are unknown. Here, we demonstrate that the WD40-repeat region of WDR62 is required for microtubule association, whereas the disordered C-terminal region regulates cell-cycle-dependent compartmentalization. In agreement with a functional requirement for the WDR62–JNK1 complex during neurogenesis, WDR62 specifically recruits JNK1 (also known as MAPK8), but not JNK2 (also known as MAPK9), to the spindle pole. However, JNK-mediated phosphorylation of WDR62 T1053 negatively regulated microtubule association, and loss of JNK signaling resulted in constitutive WDR62 localization to microtubules irrespective of cell cycle stage. In contrast, we identified that Aurora A kinase (AURKA) and WDR62 were in complex and that AURKA-mediated phosphorylation was required for the spindle localization of WDR62 during mitosis. Our studies highlight complex regulation of WDR62 localization, with opposing roles for JNK and AURKA in determining its spindle association.


Multiple sensory G proteins in the olfactory, gustatory and nociceptive neurons modulate longevity in Caenorhabditis elegans.
The life span of the nematode Caenorhabditis elegans is under control of sensory signals detected by the amphid neurons. In these neurons, C. elegans expresses at least 13 Galpha subunits and a Ggamma subunit, which are involved in the transduction and modulation of sensory signals. Here, we show that loss-of-function mutations in the Galpha subunits odr-3, gpa-1 and gpa-9, in the Ggamma subunit gpc-1 and the introduction of extra copies of the Galpha subunit gpa-11 extend the life span of C. elegans. Loss-of-function of odr-3 and extra copies of gpa-11 act synergistically and can together extend life span more than two-fold, indicating that sensory signals play an important role in regulating life span. We show that gpa-1, gpa-11, odr-3 and gpc-1 all signal via the daf-16 FOXO family transcription factor. In addition, odr-3 and gpa-11 might suppress life span extension partially independent of the insulin/IGF-1 like receptor homologue daf-2. Our results suggest that the previously unanticipated nociceptive ASH and/or ADL neurons regulate longevity. We expect that the implication of specific G proteins will eventually contribute to the identification of the sensory cues that determine the rate of aging in C. elegans.


[Seroepidemiological investigation of hepatitis C virus in Zhejiang Province: a hospital-based study].
Objective: To study serum HCV antibody (anti-HCV) with geographic distribution characteristics in Zhejiang Province. Methods: A stratified random cluster sampling method was used. Serum samples of the surveyed population were collected from selected hospitals, anti-HCV antibodies were examined, then hepatitis C infection rates among different genders, regions and age groups were analyzed. The anti-HCV rate was compared using the χ (2) test. Results: The average anti-HCV positive rate in Zhejiang Province was 0.24% [95% confidence interval (CI): 0.16% ~ 0.32%]. The antibody positive rate in the plain area was 0.32% (95% CI: 0.19% ~ 0.45%), which was significantly higher than the coastal islands 0.05%(95% CI: 0.00% ~ 0.12%, χ (2) = 7.638, P < 0.05). There was no significant difference between plain area and hilly area 0.22% (95% CI: 0.03% - 0.41%). There was no statistically significant difference in anti-HCV positive rates between males and females (χ (2) = 2.238, P = 0.135). The highest positive rate of anti-HCV (0.93%) was in the population aged 56-60 years and the lowest in the population aged less than 20 years. Anti-HCV positive rate of all age groups in 2017 was lower than that of 2006 seroepidemiological study of hepatitis C. Conclusion: Zhejiang Province is a region with low anti-HCV positive rate and the disease prevalence further reduced than 10 years ago. The positive rate of anti-HCV in plain areas is higher than islands. Middle-aged and elderly people are the age group with high prevalence, and the anti-HCV positive rate in people under 20 years old is exceptionally low. Gender differences in anti-HCV positive rate have little effect.


The association of motor neuron disease and Alzheimer-type dementia.
An elderly woman is described who developed senile dementia of the Alzheimer type, followed within eight months by classical and electromyographic features of sporadic motor neuron disease. Although amyotrophic lateral sclerosis is generally believed to affect the voluntary motor system and spare intellectual function, with the exception of certain familial forms and geographic isolates in the Pacific, pathological involvement of the cerebral cortex and posterior columns has often been demonstrated. A small number of cases of concomitant amyotrophic lateral sclerosis have been reported, but an association has not thereby been proven. With the incidence of dementia increasing, it is possible that epidemiologic studies may show an increase in the incidence of motor neuron disease, and thereby suggest an association. A unitary hypothesis for causation of amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease has been proposed. Closer investigation of patients with motor neuron disease for dementia, and inquiry into the incidence of motor dysfunction in demented patients, may yield evidence in support of such a hypothesis.


Cultural Hitchhiking in the Matrilineal Whales.
Five species of whale with matrilineal social systems (daughters remain with mothers) have remarkably low levels of mitochondrial DNA diversity. Non-heritable matriline-level demography could reduce genetic diversity but the required conditions are not consistent with the natural histories of the matrilineal whales. The diversity of nuclear microsatellites is little reduced in the matrilineal whales arguing against bottlenecks. Selective sweeps of the mitochondrial genome are feasible causes but it is not clear why these only occurred in the matrilineal species. Cultural hitchhiking (cultural selection reducing diversity at neutral genetic loci transmitted in parallel to the culture) is supported in sperm whales which possess suitable matrilineal socio-cultural groups (coda clans). Killer whales are delineated into ecotypes which likely originated culturally. Culture, bottlenecks and selection, as well as their interactions, operating between- or within-ecotypes, may have reduced their mitochondrial diversity. The societies, cultures and genetics of false killer and two pilot whale species are insufficiently known to assess drivers of low mitochondrial diversity.


Intermittent Fasting Applied in Combination with Rotenone Treatment Exacerbates Dopamine Neurons Degeneration in Mice.
Intermittent fasting (IF) was suggested to be a powerful nutritional strategy to prevent the onset of age-related neurodegenerative diseases associated with compromised brain bioenergetics. Whether the application of IF in combination with a mitochondrial insult could buffer the neurodegenerative process has never been explored yet. Herein, we defined the effects of IF in C57BL/6J mice treated once per 24 h with rotenone (Rot) for 28 days. Rot is a neurotoxin that inhibits the mitochondrial complex I and causes dopamine neurons degeneration, thus reproducing the neurodegenerative process observed in Parkinson's disease (PD). IF (24 h alternate-day fasting) was applied alone or in concomitance with Rot treatment (Rot/IF). IF and Rot/IF groups showed the same degree of weight loss when compared to control and Rot groups. An accelerating rotarod test revealed that only Rot/IF mice have a decreased ability to sustain the test at the higher speeds. Rot/IF group showed a more marked decrease of dopaminergic neurons and increase in alpha-synuclein (α-syn) accumulation with respect to Rot group in the substantia nigra (SN). Through lipidomics and metabolomics analyses, we found that in the SN of Rot/IF mice a significant elevation of excitatory amino acids, inflammatory lysophospholipids and sphingolipids occurred. Collectively, our data suggest that, when applied in combination with neurotoxin exposure, IF does not exert neuroprotective effects but rather exacerbate neuronal death by increasing the levels of excitatory amino acids and inflammatory lipids in association with altered brain membrane composition.


Clinical experience with prophylactic fondaparinux in critically ill patients with moderate to severe renal impairment or renal failure requiring renal replacement therapy.
Fondaparinux has an increased bleeding risk in patients with a CrCl ≤ 50 mL/min and is contraindicated if CrCl < 30 mL/min. Data regarding dosing and anti-Xa monitoring are lacking in this population. To describe dosing, monitoring, and safety outcomes of prophylactic fondaparinux in critically ill patients with moderate to severe renal impairment, including renal replacement therapy (RRT). Retrospective analysis from October 2006 to November 2012 of patients ≥ 18 years old who received fondaparinux for ≥ 72 hours with ≥ 1 dose in an intensive care unit and a CrCl ≤ 50 mL/min or RRT during therapy. Participants were divided into 4 cohorts: moderate impairment (CrCl = 30-50 mL/min), severe impairment (CrCl < 30 mL/min), hemodialysis (HD), or continuous venovenous hemofiltration (CVVH). Outcomes included the incidence of clinically significant bleeding and thromboembolic events. Fondaparinux dose, dosing frequency, and anti-Xa level monitoring are described. Pharmacokinetic modeling was performed to assess drug accumulation. In all, 95 patients met inclusion criteria: 64 (67.4%) with moderate impairment, 10 (10.5%) with severe impairment, 5 (5.3%) with HD, and 16 (16.8%) with CVVH. The median defined daily doses in the moderate, severe, HD, and CVVH cohorts were 2.5, 2.5, 0.9, and 1.9 mg. Anti-Xa monitoring occurred in 19 (20%) patients, although few concentrations were peaks. Clinically significant bleeding occurred in 4 (4.2%) patients. A pharmacokinetic model demonstrated drug accumulation. Empirical dose adjustments may be prudent in critically ill patients with renal dysfunction; however, the optimal fondaparinux dosage in this population remains unknown. Peak anti-Xa concentrations may help guide therapy.


Prevalence of enteroviruses in healthy populations and excretion of pathogens in patients with hand, foot, and mouth disease in a highly endemic area of southwest China.
Etiological carriers and the excretion of the pathogens causing hand, foot, and mouth disease (HFMD) in healthy persons, patients, and asymptomatic persons infected with HFMD as ongoing infection sources may play an important role in perpetuating and spreading epidemics of HFMD. The aims of this study were to determine the carrier status of EV-A71 and CV-A16 in healthy populations, as well as the duration of EV-A71 and CV-A16 shedding in the stools of HFMD patients in an epidemic area of southwest China. A cross-sectional study and a follow-up study were conducted in three HFMD endemic counties of Yunnan Province. Six hundred sixty-seven healthy subjects were recruited to participate in the cross-sectional study, and two stool specimens were collected from each subject. Among the healthy subjects, 90 (13.5%) tested positive for viral isolation, but neither EV-A71 nor CV-A16 was detected in healthy individuals. Of the 150 patients with probable HFMD, 55.3% (83/150) tested positive for viral isolation with presented serotypes such as EV-A71 (51.81%, 43/83), CV-A16 (32.53%, 27/83), other EVs (13.25%, 11/83), and mixed EV-A71 and CV-A16 (2.41%, 2/83). The longest duration of EV-A71 and CV-A16 shedding in stool specimens from patients with HFMD was >46 days after onset. The positive rate of EV-A71 in the stool specimens of confirmed patients dropped to 50% by the end of the third week, and the same occurred with CV-A16 by the end of approximately the seventh week after onset. Although carriers of major causative agents of HFMD in healthy populations are fewer in number, the prolonged shedding of pathogens in patients with HFMD may serve as an important factor in perpetuating and spreading HFMD epidemics.


Type 3 deiodinase deficiency results in functional abnormalities at multiple levels of the thyroid axis.
The type 3 deiodinase (D3) is a selenoenzyme that inactivates thyroid hormones and is highly expressed during development and in the adult central nervous system. We have recently observed that mice lacking D3 activity (D3KO mice) develop perinatal thyrotoxicosis followed in adulthood by a pattern of hormonal levels that is suggestive of central hypothyroidism. In this report we describe the results of additional studies designed to investigate the regulation of the thyroid axis in this unique animal model. Our results demonstrate that the thyroid and pituitary glands of D3KO mice do not respond appropriately to TSH and TRH stimulation, respectively. Furthermore, after induction of severe hypothyroidism by antithyroid treatment, the rise in serum TSH in D3KO mice is only 15% of that observed in wild-type mice. In addition, D3KO animals rendered severely hypothyroid fail to show the expected increase in prepro-TRH mRNA in the paraventricular nucleus of the hypothalamus. Finally, treatment with T(3) results in a serum T(3) level in D3KO mice that is much higher than that in wild-type mice. This is accompanied by significant weight loss and lethality in mutant animals. In conclusion, the absence of D3 activity results in impaired clearance of T(3) and significant defects in the mechanisms regulating the thyroid axis at all levels: hypothalamus, pituitary, and thyroid.


[Ultrastructure of microbial biofilms during intercellular interactions of bacteria in communities].
Analysis of summarized data obtained by us on ultrastructure of microbial biofilms of opportunistic bacteria is presented. A complex ultrathin organization of lactobacilli, enterobacteria, staphylococci and enterococci biofilms discovered during electron microscopy is described. The presence of surface film and polysaccharide matrix that determine increased resistance of intrabiofilm bacteria against the effect of protective immune factors of the organism and etiotropic preparations is demonstrated in all the studied comminutes. A varied response of bacterial cells contained in the biofilm during antagonistic effect of symbiont probiotic bacteria was discovered.


Activation, differentiation, and migration of naive virus-specific CD8+ T cells during pulmonary influenza virus infection.
The low precursor frequency of individual virus-specific CD8(+) T cells in a naive host makes the early events of CD8(+) T cell activation, proliferation, and differentiation in response to viral infection a challenge to identify. We have therefore examined the response of naive CD8(+) T cells to pulmonary influenza virus infection with a murine adoptive transfer model using hemagglutinin-specific TCR transgenic CD8(+) T cells. Initial activation of CD8(+) T cells occurs during the first 3 days postinfection exclusively within the draining lymph nodes. Acquisition of CTL effector functions, including effector cytokine and granule-associated protease expression, occurs in the draining lymph nodes and differentially correlates with cell division. Division of activated CD8(+) T cells within the draining lymph nodes occurs in an asynchronous manner between days 3 and 4 postinfection. Despite the presence of Ag for several days within the draining lymph nodes, dividing T cells do not appear to maintain contact with residual Ag. After multiple cell divisions, CD8(+) T cells exit the draining lymph nodes and migrate to the infected lung. Activated CD8(+) T cells also disseminate throughout lymphoid tissue including the spleen and distal lymph nodes following their emigration from draining lymph nodes. These results demonstrate an important role for draining lymph nodes in orchestrating T cell responses during a local infection of a discrete organ to generate effector CD8(+) T cells capable of responding to infection and seeding peripheral lymphoid tissues.


Grey-blue regression in melanoma in situ-evaluation on 111 cases.
As fibrosis and melanosis are often seen in malignant melanoma, the presence of dermoscopic signs of regression may represent a clue for the diagnosis of malignancy. Our aim was to assess the frequency and extent of 11 dermoscopic features of regression evaluating dermoscopic images of 111 melanomas in situ (MIS). Regression structures (grey-blue areas, white areas, peppering, and/or blue-whitish veil) were present in 80.1% of the lesions. Approximately 80% of the lesions showed regression of dermoscopic structures and light brown areas. Most lesions showed the presence of grey-blue areas (74.7%), whereas peppering was observable in 30.6% of MIS. Areas of fibrosis were mainly observable as structureless areas with a pinkish hue (50.4%). Based on our data, the reticular pattern of blue regression and light brown areas can be considered a significant discriminator and a reliable predictor of MIS.


Total Synthesis of (+)-Dendrowardol C.
The first total synthesis of the tetracyclic sesquiterpenoid (+)-dendrowardol C is described. It relies on an intramolecular aldol reaction to forge the central bicyclic scaffold and subsequent cyclobutane formation by cyclization of a γ-triflyloxy ketone. Key is the treatment of the latter with lithium naphthalenide. Finally, the diastereoselective hydroboration of a 1,1-disubstituted double bond is enabled by a chiral CoI catalyst.


Effect and accuracy of emergency dispatch telephone guidance to bystanders in trauma: post-hoc analysis of a prospective observational study.
Emergency medical communication centres (EMCCs) dispatch and allocate ambulance resources, and provide first-aid guidance to on-scene bystanders. We aimed to 1) evaluate whether dispatcher guidance improved bystander first aid in trauma, and 2) to evaluate whether dispatchers and on-scene emergency medical services (EMS) crews identified the same first aid measures as indicated. For 18 months, the crew on the first EMS crew responding to trauma calls used a standard form to assess bystander first aid. Audio recordings of the corresponding telephone calls from bystanders to the EMCC were reviewed. A total of 311 trauma calls were included. The on-scene EMS crew identified needs for the following first-aid measures: free airway in 26 patients, CPR in 6 patients, and hypothermia prevention in 179 patients. EMCC dispatchers advised these measures, respectively, in 16 (62%), 5 (83%), and 54 (30%) of these cases. Dispatcher guidance was not correlated with correctly performed bystander first aid. For potentially life saving first aid measures, all (20/20) callers who received dispatcher guidance attempted first aid, while only some few (4/22) of the callers who did not receive dispatcher guidance did not attempt first aid. Overall, the EMCC dispatchers had low sensitivity and specificity for correctly identifying trauma patients requiring first-aid measures. Dispatcher guidance did not significantly influence whether on-scene bystander first aid was performed correctly or attempted in this study setting, with a remarkably high willingness to perform first-aid. However, the findings for potentially lifesaving measures suggests that there may be differences that this study was unable to detect. This study found a high rate of first-aid willingness and performance, even without dispatcher prompting, and a low precision in dispatcher advice. This underlines the need for further knowledge about how to increase EMCC dispatchers' possibility to identify trauma patients in need of first aid. The correlation between EMCC-guidance and bystander first aid should be investigated in study settings with lower spontaneous first-aid rates.


An optimal range of transcription potency is necessary for efficient cell transformation by c-Rel to ensure optimal nuclear localization and gene-specific activation.
c-Rel is overexpressed in several B-cell lymphomas and c-rel gene overexpression can transform primary chicken lymphoid cells and induce tumors in animals. Although c-Rel is generally a stronger transcriptional activator than its viral derivative v-Rel, its oncogenic activity is significantly weaker. Among the mutations acquired during c-Rel's evolution into v-Rel are deletion of c-Rel's transactivation domain 2 (cTAD2) and mutations in cTAD1. Given the critical role of the Rel TADs in cell transformation, we investigated how mutations in c-Rel's cTAD1 and cTAD2 contribute to its oncogenicity and that of v-Rel. Mutations in cTAD2 noticeably increased c-Rel's transforming activity by promoting its nuclear localization and gene-specific transactivation, despite an overall decrease in kappaB site-dependent transactivation potency. Conversely, substitution of vTAD by cTAD1 increased v-Rel's transactivation and transforming efficiencies, whereas its substitution by the stronger cTAD2 compromised activation of mip-1beta but not irf-4 and was detrimental to cell transformation. These results suggest that the Rel TADs differentially contribute to gene-specific activation and that an optimal range of transcription potency is necessary for efficient transformation. These findings may have important implications for understanding how Rel TAD mutations can lead to a more oncogenic phenotype.


Organocatalytic enantioselective addition of thiols to ketimines derived from isatins.
The first catalytic enantioselective addition of thiols to ketimines derived from isatins has been developed. Excellent yields and enantioselectivities were observed for the reaction of various ketimines and thiols using a cinchona alkaloid sulfonamide catalyst. Both enantiomers of products could be obtained by using pseudoenantiomeric chiral catalysts.


Augmented Reality in Neurosurgery, State of Art and Future Projections. A Systematic Review.
The use of augmented reality (AR) is growing in medical education, in particular, in radiology and surgery. AR has the potential to become a strategic component of neurosurgical training courses. In fact, over the years, there has been a progressive increase in the application of AR in the various fields of neurosurgery. In this study, the authors aim to define the diffusion of these augmented reality systems in recent years. This study describes future trends in augmented reality for neurosurgeons. A systematic review of the literature was conducted to identify research published from December 1st, 2011 to November 30th, 2021. Electronic databases (PubMed, PubMed Central, and Scopus) were screened. The methodological quality of studies and extracted data were assessed for "augmented reality" and "neurosurgery". The data analysis focused on the geographical distribution, temporal evolution, and topic of augmented reality in neurosurgery. A total of 198 studies have been included. The number of augmented reality applications in the neurosurgical field has increased during the last 10 years. The main topics on which it is mostly applied are spine surgery, neuronavigation, and education. The geographical distribution shows extensive use of augmented reality in the USA, Germany, China, and Canada. North America is the continent that uses augmented reality the most in the training and education of medical students, residents, and surgeons, besides giving the greatest research contribution in spine surgery, brain oncology, and surgical planning. AR is also extensively used in Asia for intraoperative navigation. Nevertheless, augmented reality is still far from reaching Africa and other countries with limited facilities, as no publications could be retrieved from our search. The use of AR is significantly increased in the last 10 years. Nowadays it is mainly used in spine surgery and for neurosurgical education, especially in North America, Europe and China. A continuous growth, also in other aspects of the specialty, is expected in the next future.


Reduced mRNA expression in paraffin-embedded tissue identifies MLH1- and MSH2-deficient colorectal tumours and potential mutation carriers.
Based on the principle of nonsense-mediated mRNA decay, we sought to identify MLH1 or MSH2-deficient colorectal tumours through relative quantification of mRNA expression with real-time PCR (RT-PCR) analysis. MLH1 and MSH2 mRNAs were almost equally expressed as defined by MLH1 to MSH2 transcript ratio (mean 1.41) in microsatellite stable, mismatch repair (MMR) proficient tumours (n = 16). A close correlation between loss of protein expression and MMR-mRNA levels was found in highly microsatellite instable (MSI-H) tumours deficient of MLH1 or MSH2. MLH1/MSH2 ratio was low in 11 sporadic and nine hereditary MLH1-deficient carcinomas (mean 0.51), whereas the ratio was high in 17 MSH2-deficient hereditary non-polyposis colorectal cancer (HNPCC) associated carcinomas (mean 6.8). Notably, in the normal tissues of HNPCC patients with MSH2 mutations, the MLH1/MSH2 transcript ratios were significantly elevated (ratio > 2.0) as compared to the ratios of normal mucosa in patients with MMR-proficient tumours (27 of 32 ratio < 2.0; p = 0.00113). Analysis of B-lymphocytes of HNPCC patients with proven MMR gene mutation confirmed these findings. In conclusion, RT-PCR allows relative quantification of MMR gene mRNA expression in formalin-fixed and paraffin-embedded tissue. Furthermore, this approach enables quantification of haploinsufficiency due to nonsense-mediated mRNA decay in normal tissue and B-lymphocytes from patients carrying MSH2 germline mutations and may be useful for identification of asymptomatic carriers of pathogenic germline mutations.


MicroRNA-125b predicts clinical outcome and suppressed tumor proliferation and migration in human gallbladder cancer.
We intended to investigate the functional role and clinical relevance of microRNA-125b in human gallbladder cancer. Quantitative real-time polymerase chain reaction was used to examine microRNA-125b expression in gallbladder cancer cell lines, and 79 pairs of gallbladder cancer and normal gallbladder clinical tissues. Clinical correlations between tumorous microRNA-125b expression and gallbladder cancer patients' clinicopathological variances or overall survivals were statistically analyzed. In gallbladder cancer cell lines, TYGBK-8 and G-415 cells, microRNA-125b was upregulated to examine its regulatory effect on gallbladder cancer proliferation and migration in vitro. MicroRNA-125b was significantly downregulated in gallbladder cancer cell lines and human gallbladder cancer tumors. MicroRNA-125b in gallbladder cancer was significantly correlated with patients' clinical stage, tumor differentiation, lymph metastasis, and tumor invasion. Low tumorous microRNA-125b expression was also found to be associated with poor overall survivals among gallbladder cancer patients. In vitro studies demonstrated that microRNA-125b upregulation significantly suppressed proliferation and migration in TYGBK-8 and G-415 cells. Tumorous microRNA-125b is an independent prognostic biomarker for patients with gallbladder cancer and possibly acts as a tumor suppressor in gallbladder cancer.


Results of a Targeted Screening Program for Congenital Cytomegalovirus Infection in Infants Who Fail Newborn Hearing Screening.
Congenital cytomegalovirus (CMV) infection is a major cause of sensorineural hearing loss. By law, newborns in Connecticut who fail newborn hearing screening are tested for infection with CMV. This targeted screening is controversial, because most children with congenital CMV infection are asymptomatic, and CMV-related hearing loss can have a delayed onset. Our hospital uses a saliva polymerase chain reaction (PCR) assay (confirmed by a urine PCR assay) to detect CMV. Here, we report the results of the first year of our screening program. We reviewed the medical records of newborns in the Yale New Haven Health System who failed the newborn hearing screening test between January 1 and December 31, 2016. Of 10964 newborns, 171 failed newborn hearing screening, and 3 of these newborns had positive saliva CMV PCR test results. Of these 3 newborns, 2 had positive results on the confirmatory test (for 1 of them the confirmatory test was not performed until the infant was 10 weeks old), and 1 had a negative result on the confirmatory test. Three additional newborns with congenital CMV infection were tested because of clinical indications (1 for ventriculomegaly on prenatal ultrasound and 2 for CMV infection of the mother). Results of audiology follow-up were available for 149 (87.1%) of the 171 newborns who failed newborn hearing screening; 127 (85.2%) had normal results. Our targeted screening program for congenital CMV infection had a low yield. Consideration should be given to other strategies for identifying children at risk of hearing loss as a result of congenital CMV infection.


Reactivity of aqua coordinated monoporphyrinate lanthanide complexes: synthetic, structural and photoluminescent studies of lanthanide porphyrinate dimers.
Dimerization of monoporphyrinate lanthanide complexes [Yb(Por)(H(2)O)(3)]Cl, (Por = TTP(2-), TMPP(2-) and TPP(2-)) in the presence of sterically hindered tripodal ligand, zinc Schiff-base, dilute HCl, K(2)CO(3) solution, 4,4'-bipyridine (bipy), and basic 8-hydroxyquinaldine (HQ) solution was observed in CH(2)Cl(2) at room temperature. Six neutral dimeric lanthanide porphyrinate complexes, [Yb(TTP)(mu-OH)](2)(mu-THF) (1), [Yb(TMPP)(mu-OH)(H(2)O)](2) (2), [Yb(TPP)(mu-OH)(mu-H(2)O)](2) (4), [Yb(TMPP)(mu-Cl)(H(2)O)](2) (5), [Yb(TMPP)(mu-OH)](2)(THF) (6) and [Yb(TPP)](2)(mu-OH)(mu-Q) (7), were obtained. X-Ray diffraction studies showed that for the dimers, the two lanthanide ions were bridged by OH(-), Cl(-) or H(2)O. Photoluminescent studies showed that the porphyrinate dianion acted as an antenna, transferred its absorbed visible energy to the lanthanide ion and enabled the latter emitting in the near-infrared (NIR) region. In general, the NIR emission is more intense for the dimers than for the monomers, and the NIR emission intensity decreases as the number of O-H oscillators present in the molecule increases.


Lysosomal targeting of SIDT2 via multiple YxxΦ motifs is required for SIDT2 function in the process of RNautophagy.
RNA degradation is an essential process for maintaining cellular homeostasis. Previously, we discovered a novel RNA degradation system, RNautophagy, during which direct import of RNA into lysosomes in an ATP-dependent manner followed by degradation takes place. The putative nucleic acid transporter SID-1 transmembrane family member 2 (SIDT2) predominantly localizes to lysosomes and mediates the translocation of RNA into lysosomes during RNautophagy. However, little is known about the mechanisms of sorting SIDT2 to lysosomes. Here, we show that three cytosolic YxxΦ motifs (in which x is any amino acid and Φ is an amino acid with a bulky hydrophobic side chain) are required for the lysosomal localization of SIDT2, and that SIDT2 interacts with adaptor protein complexes AP-1 and AP-2. We also find that localization to lysosomes by these three motifs is necessary for SIDT2 function in the process of RNautophagy, and that SIDT2 strikingly increases endogenous RNA degradation at the cellular level. To our knowledge, this is the first study to report an endogenous intracellular protein for which overexpression substantially increased intracellular RNA degradation. This study provides new insight into lysosomal targeting of proteins and intracellular RNA degradation, and further confirms the critical function of SIDT2 in RNautophagy.This article has an associated First Person interview with the first author of the paper.


Complement and glomerular diseases.
The complement pathway is a central part of the innate immune system and also modulates adaptive immunity. It is implicated in the pathogenesis of glomerular disease by a number of clinical findings. These include the presence of complement components in renal biopsy samples, decreases in circulating levels indicating consumption, the presence of autoantibodies to complement proteins and the association of genetic mutations with disease either in individuals or within families. Further support and mechanistic insights comes from animal models. This review provides an overview of the role of complement in glomerular diseases and discusses the data from patients and animal models with reference to specific diseases. These include atypical haemolytic uraemic syndrome, C3 glomerulopathy, anti-neutrophil cytoplasmic antibody vasculitis, lupus nephritis and membranous nephropathy. The implications for therapy are also discussed.


Genetic organization of the lexA, recA and recX genes in Xanthomonas campestris.
A gene cluster containing lexA, recA and recX genes was previously identified and characterized in Xanthomonas campestris pathovar citri (X. c. pv. citri). We have now cloned and sequenced the corresponding regions in the Xanthomonas campestris pv. campestris (X. c. pv. campestris) and Xanthomonas oryzae pathovar oryzae (X. o. pv. oryzae) chromosome. Sequence analysis of these gene clusters showed significant homology to the previously reported lexA, recA and recX genes. The genetic linkage and the deduced amino acid sequences of these genes displayed very high identity in different pathovars of X. campestris as well as in X. oryzae. Immunoblot analysis revealed that the over-expressed LexA protein of X. c. pv. citri functioned as a repressor of recA expression in X. c. pv. campestris, indicating that the recombinant X. c. pv. citri LexA protein was functional in a different X. campestris pathovar. The abundance of RecA protein was markedly increased upon exposure of X. c. pv. campestris to mitomycin C, and an upstream region of this gene was shown to confer sensitivity to positive regulation by mitomycin C on a luciferase reporter gene construct. A symmetrical sequence of TTAGTAGTAATACTACTAA present within all three Xanthomonas lexA promoters and a highly conserved sequence of TTAGCCCCATACCGAA present in the three regulatory regions of recA indicate that the SOS box of Xanthomonas strains might differ from that of Escherichia coli.


GDF15 promotes EMT and metastasis in colorectal cancer.
Metastasis is the major cause of cancer deaths, and the epithelial-mesenchymal transition (EMT) has been considered to be a fundamental event in cancer metastasis. However, the role of growth differentiation factor 15 (GDF15) in colorectal cancer (CRC) metastasis and EMT remains poorly understood. Here, we showed that GDF15 promoted CRC cell metastasis both in vitro and in vivo. In addition, the EMT process was enhanced by GDF15 through binding to TGF-β receptor to activate Smad2 and Smad3 pathways. Clinical data showed GDF15 level in tumor tissues, and the serum was significantly increased, in which high GDF15 level correlated with a reduced overall survival in CRC. Thus, GDF15 may promote colorectal cancer metastasis through activating EMT. Promisingly, GDF15 could be considered as a novel prognostic marker for CRC in the clinic.


Functional Identification and Structural Analysis of a New Lipoate Protein Ligase in Mycoplasma hyopneumoniae.
Mycoplasma hyopneumoniae (M. hyopneumoniae) is the causative agent of pandemic pneumonia among pigs, namely, swine enzootic pneumonia. Although M. hyopneumoniae was first identified in 1965, little is known regarding its metabolic pathways, which might play a pivotal role during disease pathogenesis. Lipoate is an essential cofactor for enzymes important for central metabolism. However, the lipoate metabolism pathway in M. hyopneumoniae is definitely unclear. Here, we identified a novel gene, lpl, encoding a lipoate protein ligase in the genome of M. hyopneumoniae (Mhp-Lpl). This gene contains 1,032 base pairs and encodes a protein of 343 amino acids, which is between 7.5 and 36.09% identical to lipoate protein ligases (Lpls) of other species. Similar to its homologs in other species, Mhp-Lpl catalyzes the ATP-dependent activation of lipoate to lipoyl-AMP and the transfer of the activated lipoyl onto the lipoyl domains of M. hyopneumoniae GcvH (Mhp H) in vitro. Enzymatic and mutagenesis analysis indicate that residue K56 within the SKT sequence of Mhp H protein is the lipoyl moiety acceptor site. The three-dimensional structure showed typical lipoate protein ligase folding, with a large N-terminal domain and a small C-terminal domain. The large N-terminal domain is responsible for the full enzymatic activity of Mhp-Lpl. The identification and characterization of Mhp-Lpl will be beneficial to our understanding of M. hyopneumoniae metabolism. Lipoic acid is an essential cofactor for the activation of some enzyme complexes involved in key metabolic processes. Lipoate protein ligases (Lpls) are responsible for the metabolism of lipoic acid. To date, little is known regarding the Lpls in M. hyopneumoniae. In this study, we identified a lipoate protein ligase of M. hyopneumoniae. We further analyzed the function, overall structure and ligand-binding site of this protein. The lipoate acceptor site on M. hyopneumoniae GcvH was also identified. Together, these findings reveal that Lpl exists in M. hyopneumoniae and will provide a basis for further exploration of the pathway of lipoic acid metabolism in M. hyopneumoniae.


Genetic variation of macronutrient tolerance in Drosophila melanogaster.
Carbohydrates, proteins and lipids are essential nutrients to all animals; however, closely related species, populations, and individuals can display dramatic variation in diet. Here we explore the variation in macronutrient tolerance in Drosophila melanogaster using the Drosophila genetic reference panel, a collection of ~200 strains derived from a single natural population. Our study demonstrates that D. melanogaster, often considered a "dietary generalist", displays marked genetic variation in survival on different diets, notably on high-sugar diet. Our genetic analysis and functional validation identify several regulators of macronutrient tolerance, including CG10960/GLUT8, Pkn and Eip75B. We also demonstrate a role for the JNK pathway in sugar tolerance and de novo lipogenesis. Finally, we report a role for tailless, a conserved orphan nuclear hormone receptor, in regulating sugar metabolism via insulin-like peptide secretion and sugar-responsive CCHamide-2 expression. Our study provides support for the use of nutrigenomics in the development of personalized nutrition.


Increased brain age in adults with Prader-Willi syndrome.
Prader-Willi syndrome (PWS) is the most common genetic obesity syndrome, with associated learning difficulties, neuroendocrine deficits, and behavioural and psychiatric problems. As the life expectancy of individuals with PWS increases, there is concern that alterations in brain structure associated with the syndrome, as a direct result of absent expression of PWS genes, and its metabolic complications and hormonal deficits, might cause early onset of physiological and brain aging. In this study, a machine learning approach was used to predict brain age based on grey matter (GM) and white matter (WM) maps derived from structural neuroimaging data using T1-weighted magnetic resonance imaging (MRI) scans. Brain-predicted age difference (brain-PAD) scores, calculated as the difference between chronological age and brain-predicted age, are designed to reflect deviations from healthy brain aging, with higher brain-PAD scores indicating premature aging. Two separate adult cohorts underwent brain-predicted age calculation. The main cohort consisted of adults with PWS (n = 20; age mean 23.1 years, range 19.8-27.7; 70.0% male; body mass index (BMI) mean 30.1 kg/m2, 21.5-47.7; n = 19 paternal chromosome 15q11-13 deletion) and age- and sex-matched controls (n = 40; age 22.9 years, 19.6-29.0; 65.0% male; BMI 24.1 kg/m2, 19.2-34.2) adults (BMI PWS vs. control P = .002). Brain-PAD was significantly greater in PWS than controls (effect size mean ± SEM +7.24 ± 2.20 years [95% CI 2.83, 11.63], P = .002). Brain-PAD remained significantly greater in PWS than controls when restricting analysis to a sub-cohort matched for BMI consisting of n = 15 with PWS with BMI range 21.5-33.7 kg/m2, and n = 29 controls with BMI 21.7-34.2 kg/m2 (effect size +5.51 ± 2.56 years [95% CI 3.44, 10.38], P = .037). In the PWS group, brain-PAD scores were not associated with intelligence quotient (IQ), use of hormonal and psychotropic medications, nor severity of repetitive or disruptive behaviours. A 24.5 year old man (BMI 36.9 kg/m2) with PWS from a SNORD116 microdeletion also had increased brain PAD of 12.87 years, compared to 0.84 ± 6.52 years in a second control adult cohort (n = 95; age mean 34.0 years, range 19.9-55.5; 38.9% male; BMI 28.7 kg/m2, 19.1-43.1). This increase in brain-PAD in adults with PWS indicates abnormal brain structure that may reflect premature brain aging or abnormal brain development. The similar finding in a rare patient with a SNORD116 microdeletion implicates a potential causative role for this PWS region gene cluster in the structural brain abnormalities associated primarily with the syndrome and/or its complications. Further longitudinal neuroimaging studies are needed to clarify the natural history of this increase in brain age in PWS, its relationship with obesity, and whether similar findings are seen in those with PWS from maternal uniparental disomy.


Asthma inhalers and subsurface enamel demineralisation: an in situ pilot study.
The purpose of this pilot study was to identify the subsurface enamel demineralising potential of two possible acidogenic lactose-based powders and their corresponding generic pump inhalers. Ten healthy non-asthmatic adults participated in a 5- leg randomised crossover study including a 10% sucrose control. A twice-daily 400 microg dose of inhaler was applied in vitro to a demineralised enamel slab on the buccal flange of a mandibular removable appliance before in situ placement for 14 days each. Lesion parameters were determined using transverse microradiography and digitised image analysis. Minimal demineralisation occurred with sucrose, both pump and one powder inhaler. The remaining powder was associated with remineralisation (p = 0.29). Overall, mean lesion depth increased (p = 0.12). Asthma inhalers failed to demonstrate a significant acidogenic/cariogenic effect.


Evaluating a scalable ARCHES (Addressing Reproductive Coercion in Health Settings) model in government health facilities in Uasin Gishu county, Kenya: study protocol for a cluster-randomized controlled trial.
Since 2013, the World Health Organization has recommended that reproductive coercion (RC) and intimate partner violence (IPV) be addressed within reproductive health services and, in 2018, the Lancet Commission on Sexual and Reproductive Health and Rights found that RC and IPV were significant contributors to unmet need for family planning (FP) and unintended pregnancy. In Kenya, the Ministry of Health (MOH) has made reduction of unintended pregnancy and gender-based violence a primary objective. Despite this need and guidance, no clinic-based intervention models outside of the U.S. (apart from the one described here) have demonstrated efficacy to improve FP use and reduce IPV or RC thereby reducing unintended pregnancy. ARCHES (Addressing Reproductive Coercion in Health Settings) is a brief, clinic-based intervention delivered by existing FP providers aiming to: (1) Increase women's ability to use FP without interference, (2) Provide a safe and supportive environment for IPV disclosure and referral to support services, and (3) Improve quality of FP counseling, including addressing RC and IPV. The objective of this study is to generate evidence on scaling integrated FP services (including FP, RC, and IPV) in public sector health facilities in Uasin Gishu county, Kenya via adaptation and implementation of ARCHES in partnership with the Kenya MOH. A cluster-randomized controlled trial paired with concurrent implementation science assessments will test effectiveness of the ARCHES model, adapted for scale by the Kenya MOH, in reducing unintended pregnancy. Female FP clients aged 15-49 years at selected sites will complete baseline surveys (immediately prior to receiving care), immediately post-visit exit surveys, and 6-month follow-up surveys. Provider surveys will assess changes in gender-equitable attitudes and self-efficacy to address violence reported by their clients. Costs associated with scaling ARCHES will be tracked and utilized in combination with results of the effectiveness trial to assess costs and cost-effectiveness relative to the standard of care. This study will provide evidence of the effectiveness of a facility-based intervention to address RC and IPV within public sector FP services at scale, as adapted and implemented in Uasin Gishu county, Kenya. Trial registration Trial registered on 28 September 2023 with clinicaltrials.gov NCT06059196.


Retinal detachment following congenital cataract surgery.
It is hoped that the results of surgery for retinal detachment after surgery for congenital cataract, when discission and aspiration or phacoemulsification under the microscope are used, will approach the present reattachment rate that has been achieved with improved examination, instrumentation, and surgical technique in cases of senile retinal detachment. Further studies of the role of retinal pathology as lattice degeneration, vitreous pathology, and the place for prophylactic cryotherapy all must be reevaluated. In summary, the low incidence of retinal detachment following the extraction of congenital cataracts as seen in major retinal referral centers suggests that the risks of detachment are not as high as previously reported, that the cure rate approaches that of senile aphakic detachment; therefore early operative intervention to prevent amblyopia, nystagmus, and strabismus is indicated.


Controlled mud-crack patterning and self-organized cracking of polydimethylsiloxane elastomer surfaces.
Exploiting pattern formation - such as that observed in nature - in the context of micro/nanotechnology could have great benefits if coupled with the traditional top-down lithographic approach. Here, we demonstrate an original and simple method to produce unique, localized and controllable self-organised patterns on elastomeric films. A thin, brittle silica-like crust is formed on the surface of polydimethylsiloxane (PDMS) using oxygen plasma. This crust is subsequently cracked via the deposition of a thin metal film - having residual tensile stress. The density of the mud-crack patterns depends on the plasma dose and on the metal thickness. The mud-crack patterning can be controlled depending on the thickness and shape of the metallization - ultimately leading to regularly spaced cracks and/or metal mesa structures. Such patterning of the cracks indicates a level of self-organization in the structuring and layout of the features - arrived at simply by imposing metallization boundaries in proximity to each other, separated by a distance of the order of the critical dimension of the pattern size apparent in the large surface mud-crack patterns.


Virologic and immunologic outcomes and programmatic challenges of an antiretroviral treatment pilot project in Abidjan, Côte d'Ivoire.
In Côbte d'Ivoire, a pilot project was developed by UNAIDS and the Ministry of Health to improve access to AIDS care, including antiretroviral therapy, for adults and children infected with HIV. This evaluation of the project is the first to provide results of a large number of HIV-infected patients receiving antiretroviral therapy in West Africa. We evaluated records of persons who presented for care from August 1998 to August 2000 at six accredited centers in Abidjan. Patients were treated with two nucleoside reverse transcriptase inhibitors (2NRTI) or highly active antiretroviral therapy (HAART). Of 2878 patients who were screened, 2351 (83%) were HIV-infected and eligible (CD4 T lymphocyte count < 500 x 10(6) cells/l or plasma HIV-RNA level > 10 000 copies/ml) for antiretroviral therapy. Of those who were eligible, 81% were symptomatic, 63% had a CD4 cell count < 200 x 10(6) cells/l, 12% had previously taken antiretroviral drugs, and 56% returned to the clinic for follow-up. Of the patients screened, 768 (27%) were started on antiretroviral therapy, including 450 on HAART, 296 on 2NRTI, and 22 on other regimens. We analyzed data from 480 HIV-1-infected adults, who were naive to therapy, were prescribed HAART or 2NRTI, and had at least one clinic visit after starting therapy. In an intent-to-treat analysis of patients who received HAART, the estimated plasma HIV-1 RNA level was approximately 1.9 log10 copies/ml (80-fold) lower, while estimated CD4 cell count was > 100 x 10(6) cells/l higher than baseline values, after 1 year of therapy. Approximately 25% of adults on 2NRTI and 50% of those on HAART had < 200 copies/ml, after 1 year of therapy. The probability of an adverse event occurring within 6 months after starting therapy was 0.20. The probability of survival for at least 1 year was 0.84 (95% confidence interval, 0.80-0.89). After starting antiretroviral therapy, these HIV-1-infected patients in West Africa had similar virologic and immunologic outcomes, probability of an adverse event, and estimated survival, as patients enrolled in clinical trials in the USA and Europe. However, only one-third of eligible patients received therapy, highlighting the importance of providing adequate education and support for initiating and adhering to therapy in this and similar programmes.


[Difficult conversations in medicine: an experiential, optional course with medical students].
A 24 hrs optional course was realized with 15 students at the Medical School of Milan, with the aim of undertaking the management of the emotional aspects in a difficult communication in medicine. The course was realized through the use of active teaching tools; issues resulted from what literature consider as "difficult communication". Photolangage was used as pre-post test to assess the effects of the course; a satisfaction questionnaire was also used. From the content analysis of the data the course resulted effective both for the students' satisfaction and for the enhancing of their self reflective skills.


Intrabronchial lesion on computed tomography secondary to blood clot.
A case of a blood clot simulating an intrabronchial neoplasm on computed tomography is presented. Although an intrabronchial lesion in a patient with hemoptysis is usually a malignancy, other etiologies must be considered. Computed tomography is an excellent modality for detecting and evaluating intrabronchial pathology but bronchoscopy is necessary for tissue diagnosis.


Implementation of transdiagnostic treatment for emotional disorders in residential eating disorder programs: A preliminary pre-post evaluation.
Objective: Data are lacking from empirically supported therapies implemented in residential programs for eating disorders (EDs). Common elements treatments may be well-suited to address the complex implementation and treatment challenges that characterize these settings. This study assessed the preliminary effect of implementing a common elements therapy on clinician treatment delivery and patient (N = 616) symptom outcomes in two residential ED programs. Method: The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders was adapted to address ED and co-occurring psychopathology and implemented across sites. Therapists' treatment fidelity was rated independently to assess implementation success. Additionally, longitudinal (pre-post) design compared treatment outcomes among patients treated before and after implementation. Patient outcomes included ED and depressive symptoms, experiential avoidance, anxiety sensitivity, and mindfulness. Results: Following training and implementation, clinicians demonstrated adequate to good fidelity. Relative to pre-implementation, post-implementation patients showed significantly greater improvements in experiential avoidance, anxiety sensitivity, and mindfulness at discharge (ps ≤ .04) Relative to patients who were treated during the pre-implementation phase, patients in the post-implementation phase experienced more favorable outcomes on ED symptom severity, depression, mindfulness, and anxiety sensitivity at 6-month-follow-up (ps ≤ .001). A similar result was observed for experiential avoidance, yet this interaction effect was no longer statistically significant (p = .10) when the time x length of stay effect/covariate was added to the model. Conclusions: Preliminary pilot data support the feasibility of implementing transdiagnostic common elements therapy in residential ED treatment, and suggest that implementation may benefit transdiagnostic outcomes for patients. Clinical or methodological significance of this article: Limited data are available to guide evidence-based residential treatment for eating disorders. This study represents a unique effort to adapt, implement, and test an evidence-based therapy protocol across a large private network of intensive eating disorder treatment programs.


Anthracycline-dependent cardiotoxicity and extracellular matrix remodeling.
The mechanisms of anthracycline-dependent cardiotoxicity have been studied widely, with the suggested principal mechanism of anthracycline damage being the generation of reactive oxygen species by iron-anthracycline complexes, leading to lipid peroxidation and membrane damage. An increasing number of researchers studying cardiovascular events associated with anthracycline-based chemotherapy are addressing cardiac extracellular matrix (ECM) remodeling. The heart is an efficient muscular pump, with the cardiomyocytes and intramural coronary vasculature of the heart tethered in an ECM consisting of a network of fibrillar, structural proteins, mostly collagens. Increasing evidence suggests that the ECM plays a complex and diverse role in the processes initiated by anthracycline-class drugs that lead to cardiac damage. This review discusses adverse myocardial remodeling induced by anthracyclines and focuses on their mechanisms of action.


Concentrations of glycerides and phospholipids in rat heart and gastrocnemius muscles. Effects of alloxan-diabetes and perfusion.
1. Methods are described for the extraction of lipid and assay of mono-, di- and tri-glyceride glycerol and phospholipid phosphorus in rat heart and gastrocnemius muscles. 2. In hearts from normal animals, concentrations found were: monoglyceride, 0.6; diglyceride, 0.1; triglyceride, 12.6mumoles of glyceride glycerol/g. of dry muscle; phospholipid, 171mug.atoms of phospholipid phosphorus/g. of dry muscle. Concentrations of glycerides in gastrocnemius muscle were similar to heart muscle but those of phospholipids were lower (64mug.atoms of phospholipid phosphorus/g. of dry muscle). 3. Alloxan-diabetes increased the concentration of triglyceride in the muscles twofold. This increase was shown to be dependent in the heart on the availability of growth hormone and cortisol but not on the availability of dietary lipid. Total glyceride in the heart was increased after 48 and 72hr. starvation but not after 96hr. Changes in glyceride concentration seen in starvation and diabetes were not associated with significant changes in phospholipid concentration. It is suggested that mobilization of free fatty acids in diabetes leads to the synthesis of additional glyceride in muscle. 4. The possible contribution of glyceride fatty acid in the heart to respiration during perfusion has been calculated from the net loss of glyceride during perfusion, and also from the relative rates of lipolysis and esterification and compared with oxidation of fatty acid required for the balance of oxygen consumption (oxygen not utilized in the oxidation of glucose or glycogen glucose). In the normal or diabetic heart perfused with glucose and insulin the breakdown of glyceride can account for the balance of oxygen consumption. In the normal heart perfused without substrate the balance of oxygen consumption is not entirely accounted for by the breakdown of glyceride.


Imatinib dose escalation versus sunitinib as a second line treatment in KIT exon 11 mutated GIST: a retrospective analysis.
We retrospectively reviewed data from 123 patients (KIT exon 11 mutated) who received sunitinib or dose-escalated imatinib as second line.All patients progressed on imatinib (400 mg/die) and received a second line treatment with imatinib (800 mg/die) or sunitinib (50 mg/die 4 weeks on/2 off or 37.5 mg/day). Deletion versus other KIT 11 mutation was recorded, correlated with clinical benefits.64% received imatinib, 36% sunitinib. KIT exon 11 mutation was available in 94 patients. With a median follow-up of 61 months, median time to progression (TTP) in patients receiving sunitinib and imatinib was 10 (95% CI 9.7-10.9) and 5 months (95% CI 3.6-6.7) respectively (P = 0.012). No difference was found in overall survival (OS) (P = 0.883). In imatinib arm, KIT exon 11 deletions was associated with a shorter TTP (7 vs 17 months; P = 0.02), with a trend in OS (54 vs 71 months P = 0.063). No difference was found in patients treated with sunitinib (P = 0.370).A second line with sunitinib was associated with an improved TTP in KIT exon 11 mutated patients progressing on imatinib 400 mg/die. Deletions in exon 11 seemed to be correlated with worse outcome in patients receiving imatinib-based second line.


Development and validation of a quantitative PCR assay for detection of Emydoidea herpesvirus 1 in free-ranging Blanding's turtles (Emydoidea blandingii).
Blanding's turtles (Emydoidea blandingii), an endangered species in Illinois, have experienced range-wide declines because of habitat degradation and fragmentation, predation, and road mortality. While ongoing studies are crucial to a thorough understanding of the natural history and demographics in these disjointed Illinois populations, infectious disease threats have been largely unevaluated. Herpesvirus outbreaks have been associated with high morbidity and mortality in populations of captive tortoises and turtles worldwide, including the family Emydidae (pond and box turtles). However, novel herpesviruses including Terrapene herpesvirus 1, Emydid herpesvirus 1 and 2, and Glyptemys herpesvirus 1 and 2, have recently been identified in apparently healthy free-ranging freshwater turtles. In 2015, 20 free-ranging Blanding's turtles in DuPage County, Illinois were screened for a herpesvirus using consensus PCR. A novel herpesvirus species (Emydoidea herpesvirus 1; EBHV1) was identified in two animals and shared a high degree of sequence homology to other freshwater turtle herpesviruses. Two quantitative real-time PCR assays, using EBHV1 primer-1 and primer-2, were developed to target an EBHV1-specific segment of the DNA-dependent DNA polymerase gene and validated. Both assays performed with high efficiency (slope = -3.2; R2 = 1), low intra-assay variability, and low inter-assay variability (coefficient of variation <2% at all dilutions). However, EBHV1 primer-2 displayed less variation and was selected to test clinical samples and five closely related herpesvirus control samples. Results indicate that this assay is specific for EBHV1, has a linear range of detection from 108 to 101 viral copies per reaction, and can categorically detect as few as 1 viral copy per reaction. This qPCR assay provides a valuable diagnostic tool for future characterization of EBHV1 epidemiology.


Aging, disability, and employment.
The older population is one of the fastest growing age cohorts in the United States. This population has a higher incidence of disabling conditions than does the younger population. Many older adults may wish to be employed due to economic or personal reasons. This desire to work is consistent with the general older population's perspective on work, however certain barriers to employment exist for this group. Special considerations regarding employment are discussed.


Impact of CdCl2 on biochemical changes in planaria, Dugesia bengalensis Kawakatsu.
Cadmium induces different anomalous behavioral changes with dose and time dependent mortality and change in the macromolecular patterns of D. bengalensis. Bio-accumulation of heavy metal in planarians could be used to detect the level of water pollution.


Dental caries and associated factors in 12-year-old schoolchildren in Thiruvananthapuram, Kerala, India.
The aims of the present study were to describe the dental health status of 12-year-old schoolchildren in Thiruvananthapuram, Kerala, India, and to identify sociodemographic factors, oral health behaviours, attitudes and knowledge related to dental caries experience. The study took the form of a cross-sectional survey of 838 children in upper primary schools. A two-stage cluster sampling technique was used. Dental caries was measured using World Health Organization criteria. Sociodemographic factors, oral health behaviours, attitudes and knowledge were assessed by a self-administered questionnaire. The prevalence of dental caries in the permanent dentition was 27%. The mean number of decayed, missing and filled teeth was 0.5 (SD=0.9). The decayed component (D) constituted 91% of the total number of decayed, missing and filled teeth (DMFT). Multiple logistic regression analysis showed that children had a higher risk of having dental caries if they lived in urban area [OR=1.5, 95% confidence interval (CI)=1.1-2.1], had visited a dentist (OR=1.6, 95% CI=1.2-2.2), did not use a toothbrush (OR=1.9, 95% CI=1.2-2.9), consumed sweets (OR=1.4, 95% CI=1.0-1.9) or performed poorly in school (OR=1.7, 95% CI=1.0-2.3). The prevalence of caries in this sample of 12-year-old schoolchildren was low compared to that in other developing countries. The present study indicated that urban living conditions were associated with more dental caries. Since urbanization is rapid in India, oral health promotion at the present time would be valuable to prevent increased caries prevalence.


Comparison of Transatlantic Approaches to Lipid Management: The AHA/ACC/Multisociety Guidelines vs the ESC/EAS Guidelines.
The 2018 American Heart Association/American College of Cardiology/Multisociety (AHA/ACC) guidelines and the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines on lipid management were published less than a year apart. Both guidelines focus on reducing cardiovascular risk, but they follow different approaches in terms of methods of risk estimation, definitions of at-risk groups, and treatment goals to achieve this common underlying objective. Both recommend achieving risk-based percentage reductions of low-density lipoprotein cholesterol (LDL-C) levels with statin therapy. The ESC/EAS guidelines additionally recommend target LDL-C levels and are more liberal in supporting the use of both statin and nonstatin therapies across broader patient groups. The AHA/ACC guidelines may be considered more conservative, reserving the addition of nonstatins to maximally tolerated statins for only select patient groups based on specific LDL-C thresholds. One of the main reasons for these differences is incorporation of cost value considerations by the AHA/ACC guidelines, whereas the ESC/EAS guidelines consider an ideal setting with unlimited resources while making recommendations. In this review, we discuss similarities and differences between the 2 lipid guidelines to help clinicians become more cognizant of these recommendations and provide the best individualized patient care.


Antimicrobial Properties of Copper Nanoparticles and Amino Acid Chelated Copper Nanoparticles Produced by Using a Soya Extract.
This paper reports a comparison of the antibacterial properties of copper-amino acids chelates and copper nanoparticles against Escherichia coli, Staphylococcus aureus, and Enterococcus faecalis. These copper-amino acids chelates were synthesized by using a soybean aqueous extract and copper nanoparticles were produced using as a starting material the copper-amino acids chelates species. The antibacterial activity of the samples was evaluated by using the standard microdilution method (CLSI M100-S25 January 2015). In the antibacterial activity assays copper ions and copper-EDTA chelates were included as references, so that copper-amino acids chelates can be particularly suitable for acting as an antibacterial agent, so they are excellent candidates for specific applications. Additionally, to confirm the antimicrobial mechanism on bacterial cells, MTT assay (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) was carried out. A significant enhanced antimicrobial activity and a specific strain were found for copper chelates over E. faecalis. Its results would eventually lead to better utilization of copper-amino acids chelate for specific application where copper nanoparticles can be not used.


Processing of membrane protein crystal using ultraviolet laser irradiation.
We demonstrated the processing of a membrane protein crystal, using a pulsed UV laser soft ablation (PULSA) technique. Irradiation with deep-UV laser pulses at a wavelength of 193 nm successfully processed not only single crystals of the membrane transporter protein AcrB but also nylon loops and cryoprotectants at a cryogenic temperature. Nonprocessed parts of the crystals exhibited no signs of crack or denaturation after the laser exposure. The trimmed crystals were found to be of high resolution for X-ray diffraction data collection. The results described here indicate that PULSA processing is an effective tool for membrane protein crystals, as well as for soluble protein crystals.


Forecasting renewable energy for environmental resilience through computational intelligence.
Wind power forecasting plays a key role in the design and maintenance of wind power generation which can directly help to enhance environment resilience. Offshore wind power forecasting has become more challenging due to their operation in a harsh and multi-faceted environment. In this paper, the data generated from offshore wind turbines are used for power forecasting purposes. First, fragmented data is filtered and Deep Auto-Encoding is used to select high dimensional features. Second, a mixture of the CNN and LSTM models is used to train prominent wind features and further improve forecasting accuracy. Finally, the CNN-LSTM deep learning hybrid model is fine-tuned with various parameters for reliable forecasting of wind energy on three different offshore Windfarms. A state-of-the-art comparison against existing models is presented based on root mean square error (RMSE) and mean absolute error (MAE) respectively. The forecasting analyses indicate that the proposed CNN-LSTM strategy is quite successful for offshore wind turbines by retaining the lowest RMSE and MAE along with high forecasting accuracy. The experimental findings will be helpful to design environment resilient energy transition pathways.


Fluorescein angiography in syphilitic retinal vasculitis.
A case of ocular syphilis with severe ischemic retinopathy, rubeosis iridis and secondary glaucoma is described. Fluorescein angiography revealed a complete blockage of all the vessels around the macula, with dye leakage from numerous bifurcations of veins and an infiltrative mass in the macular area of both eyes. Combined treatment with steroids and penicillin brought no improvement in this condition of severe, ischemic ophthalmia.


Walking for recreation and perceptions of the neighborhood environment in older Chinese urban dwellers.
Engagement in walking for recreation can contribute to healthy aging. Although there is growing evidence that the neighborhood environment can influence walking for recreation, the amount of such evidence in relation to older adults is scarce and limited to Western low-density urban locations. Asian urban environments are typified by distinctive environmental and cultural characteristics that may yield different patterns to those observed in Western countries. Therefore, the main aim of this study was to examine associations of perceived environmental attributes with overall and within-neighborhood walking for recreation in Chinese elders (65+ years) residing in Hong Kong, an ultradense Asian metropolis. A sample of 484 elders was recruited from 32 neighborhoods stratified by socio-economic status and walkability (dwelling and intersection densities). Validated questionnaires measuring perceived neighborhood environment and weekly minutes of overall and within-neighborhood walking for recreation were interviewer administered. Results showed that the level of recreational walking was twice to four times higher than that reported in Western adults and elders. While overall walking for recreation showed a general lack of associations with perceived environmental attributes, within-neighborhood recreational walking was positively related with proximity of recreational facilities, infrastructure for walking, indoor places for walking, and presence of bridge/overpasses connecting to services. Age and educational attainment moderated the associations with several perceived environmental attributes with older and less-educated participants showing stronger associations. Traditional cultural views on the benefits of physical activity and the high accessibility of facilities and pedestrian infrastructure of Hong Kong may explain the high levels of walking. Although specific neighborhood attributes, or their perception, may influence recreational walking within the neighborhood, the compactness and public transport affordability of ultradense metropolises such as Hong Kong may make it easy for elders to compensate for the lack of favorable neighborhood attributes by walking outside the neighborhood.


Proteomic characterization of metabolites, protein adducts, and biliary proteins in rats exposed to 1,1-dichloroethylene or diclofenac.
A proteome profiling approach was used to compare effects of two toxicants, 1,1-dicloroethylene (DCE) and diclofenac, which covalently adduct hepatic proteins. Bile was examined as a potential source of protein alterations since both toxicants target the hepatic biliary canaliculus. Bile was collected before and after toxicant treatment. Biliary proteins were separated by one-dimensional SDS-PAGE and analyzed by liquid chromatography-tandem mass spectrometry (LC-MS-MS) with data-dependent scanning. Comprehensive analysis of biliary proteins was performed by using SEQUEST and BLAST database searching, in combination with de novo interpretation. Bile not subjected to tryptic digestion was analyzed for DCE metabolites. DCE treatment resulted in a marked increase in the overall number of biliary proteins, whereas few changes in the proteomic profile were apparent in bile after diclofenac treatment. This is consonant with prior observations of more profound effects of DCE on canalicular membrane integrity. LC-MS-MS analyses for DCE metabolites revealed the presence of S-carboxymethyl glutathione, S-(cysteinylacetyl)glutathione, and a product of the intramolecular rearrangement of the DCE metabolite, ClCH(2)COSG, not previously described in vivo. In addition, several S-carboxymethylated proteins were identified in bile from DCE-treated animals. This investigation has produced the first comprehensive baseline characterization of the content of the rat biliary proteome and the first documentation of alterations in the proteome of bile by toxicant treatment. In addition, the results provide direct in vivo evidence for DCE metabolic routes proposed in the formation of covalent adducts.


ONO-5046, an elastase inhibitor, attenuates endotoxin-induced acute lung injury in rabbits.
Endotoxin causes acute lung injury resembling acute respiratory distress syndrome. Elastase, as well as reactive oxygen species released from activated neutrophils, are thought to play pivotal roles in the pathogenesis of this lung injury. This study investigated whether ONO-5046, a specific elastase inhibitor, can attenuate acute lung injury induced by endotoxin in rabbits. Thirty-two male anesthetized rabbits were randomly assigned to receive one of four treatments (n = 8 for each group): infusion of saline without ONO-5046 treatment (Group S-S), infusion of saline with ONO-5046 (Group S-O), infusion of Escherichia coli endotoxin (100 micrograms/kg over 60 min) without ONO-5046 (Group E-S), and infusion of endotoxin with ONO-5046 (Group E-O). Fifteen minutes before the infusion of endotoxin (Groups E-O and E-S) or saline (Groups S-S and S-O), the animals received a bolus injection of ONO-5046 (10 mg/kg) followed by continuous infusion (10 mg.kg-1.h-1: Groups S-O and E-O) or saline (Groups S-S and E-S). The lungs of the rabbits were ventilated with 40% oxygen. Hemodynamics, peripheral leukocyte and platelet counts, and PaO2 were recorded during the ventilation period (6 h). Lung mechanics, cell fraction of the bronchoalveolar lavage fluid (BALF), activated complement, cytokines, and arachidonic acid metabolite concentrations in the BALF were measured at 6 h. The wet- to dry (W/D)-weight ratio of the lung and albumin concentrations in BALF were analyzed as indices of pulmonary edema. Endotoxin decreased lung compliance and PaO2, and increased the W/D weight ratio, neutrophil counts, and albumin concentration in the BALF. Concentrations of activated complement C5a, interleukin-6, interleukin-8, and thromboxane B2 in the BALF were increased by the infusion of endotoxin. ONO-5046 treatment attenuated these changes. Endotoxin caused extensive morphologic lung damage, which was lessened by ONO-5046. In conclusion, intravenous ONO-5046 pretreatment attenuated endotoxin-induced lung injury in rabbits. This beneficial effect of ONO-5046 may be due, in part, to a reduction in the levels of mediators that activate neutrophils, in addition to the direct inhibitory effect on elastase.


Knowing is not enough: a qualitative report on HIV testing among heterosexual African-American men.
Despite having higher rates of HIV testing than all other racial groups, African-Americans continue to be disproportionately affected by the HIV epidemic in the United States. Knowing one's status is the key step to maintaining behavioral changes that could stop the spread of the virus, yet little is known about the individual- and socio-structural-level barriers associated with HIV testing and communication among heterosexual African-American men. To address this and inform the development of an HIV prevention behavioral intervention for heterosexual African-American men, we conducted computerized, structured interviews with 61 men, focus group interviews with 25 men in 5 different groups, and in-depth qualitative interviews with 30 men living in high HIV prevalence neighborhoods in New York City. Results revealed that HIV testing was frequent among the participants. Even with high rates of testing, the men in the study had low levels of HIV knowledge; perceived little risk of HIV; and misused HIV testing as a prevention method. Factors affecting HIV testing, included stigma, relationship dynamics and communication, and societal influences, suggesting that fear, low perception of risk, and HIV stigma may be the biggest barriers to HIV testing. These results also suggest that interventions directed toward African-American heterosexual men must address the use of "testing as prevention" as well as correct misunderstandings of the window period and the meaning of HIV test results, and interventions should focus on communicating about HIV.


Neonatal Antiepileptic Medication Treatment Patterns: A Decade of Change.
This study aims to describe the frequency and characteristics of anticonvulsant medication treatments initiated in the neonatal period. We analyzed a cohort of neonates with a seizure diagnosis who were discharged from institutions in the Pediatric Health Information System between 2007 and 2016. Adjusted risk ratios and 95% confidence intervals for characteristics associated with neonatal (≤ 28 days postnatal) anticonvulsant initiation were calculated via modified Poisson regression. A total of 6,245 infants from 47 institutions were included. There was a decrease in both phenobarbital initiation within the neonatal period (96.9 to 91.3%, p = 0.015) and continuation at discharge (90.6 to 68.6%, p <0.001). Levetiracetam (7.9 to 39.6%, p < 0.001) initiation within the neonatal period and continuation at discharge (9.4 to 49.8%, p < 0.001) increased. Neonates born at ≥ 37 weeks' gestation and those diagnosed with intraventricular hemorrhage, ischemic/thrombotic stroke, other hemorrhagic stroke, and hypoxic ischemic encephalopathy (HIE) had a higher probability of anticonvulsant administration. The most prevalent diagnosis was HIE (n = 2,223, 44.4%). Phenobarbital remains the most widely used neonatal seizure treatment. Levetiracetam is increasingly used as a second line therapy. Increasing levetiracetam use indicates a need for additional study to determine its effectiveness in reducing seizure burden and improving long-term outcomes.


Quantifying the effects of drought on abrupt growth decreases of major tree species in Switzerland.
Drought entails important effects on tree physiology, which may result in short- to long-term radial growth decreases. While the majority of studies have focused on annual drought-related variability of growth, relatively little is known about sustained growth decreases following drought years. We apply a statistical framework to identify climatic factors that induce abrupt growth decreases and may eventually result in tree mortality. We used tree-ring data from almost 500 standing dead trees and 200 living trees in eight sites of the Swiss network of strict forest reserves, including four of the most important Central European tree species (Abies alba, Picea abies, Fagus sylvatica and Quercus spp.). First, to assess short-term growth responses to drought under various climate and site conditions, we calculated correlations and linear mixed-effects models between ring-width indices (RWIs) and drought based on the Standardized Precipitation Evapotranspiration Index (SPEI). Second, to quantify drought effects on abrupt growth decreases, we applied distributed lag nonlinear models (DLNMs), which account for both delayed effects and the nonlinear relationship between the SPEI and the occurrence of abrupt growth decreases. Positive correlations between RWIs and the SPEI indicated short-term growth responses of all species, particularly at arid sites. Results of the DLNMs revealed species-specific growth responses to drought. For Quercus spp., abrupt growth decreases were more likely to occur several years following severe drought, whereas for P. abies, A. alba, and F. sylvatica abrupt growth decreases started frequently immediately in the drought year. We conclude that the statistical framework allows for quantifying the effects of drought intensity on the probability of abrupt growth decreases, which ultimately contributes to an improved understanding of climate impacts on forest community dynamics.


Intestinally derived bacterial products stimulate development of nonalcoholic steatohepatitis.
Fatty livers are susceptible to factors that cause inflammation and fibrosis, but fat deposition and the inflammatory response can be dissociated. While nonalcoholic fatty liver disease (NAFLD), caused by pathologic fat accumulation inside the liver, can remain stable for several years, in other cases NAFLD progresses to nonalcoholic steatohepatitis (NASH), which is characterized by fat accumulation and inflammation and is not a benign condition. In this review, we discuss the NASH host cells and microbial mechanisms that stimulate inflammation and predispose the liver to hepatocyte injury and fibrotic stages via increased lipid deposition. We highlight the interactions between intestine-derived bacterial products, such as lipopolysaccharide, and nutritional models of NAFLD and/or obese individuals. The results of modulating enteric microbiota suggest that gut-derived endotoxins may be essential determinants of fibrotic progression and regression in NASH.


Midterm Results of a Minimally Invasive Approach in David Procedure.
The David procedure is a well-known technique in selected patients with aortic root pathology. A minimally invasive approach in heart surgery increases open interest. From 1991 to 2015, the David technique was performed in 296 patients in our unit. In 90 cases, operations were performed through partial upper sternotomy. The patient mean age was 57 ± 14 years in the minimally invasive group (n = 90) and 58 ± 14 years in the complete sternotomy group (n = 206; p = 0.2). The neosinus modification was performed in 80 patients (89%) in the minimally invasive group and in 79 patients (38%) in the complete sternotomy group (p < 0.01). Mean follow-up was 3 ± 2 years in the minimally invasive group and 8 ± 4 years in the complete sternotomy group. Thirty-day mortality was zero in the minimally invasive group and was 3% (n = 6) in the complete sternotomy group (p = 0.1). The need for packed red blood cells was significantly lower in the minimally invasive group (1.6 ± 3 U) than in the complete sternotomy group (3.7 ± 6 U; p < 0.01). Thirty late deaths (2% per patient-year) were observed in the complete sternotomy group versus zero in the minimally invasive group (p < 0.01). One patient (0.5% per patient-year) in the minimally invasive group and 12 patients (0.8% per patient-year) in the complete sternotomy group required reoperation in the follow-up period (p = 0.05). Minimally invasive David technique for patients with ascending aortic aneurysm and aortic valve insufficiency offers a good solution with low perioperative blood transfusion rate. Our midterm results show low valve-related complications and reoperation rate. However, long-term follow-up of the minimally invasive group is necessary.


Axonal branching pattern and coupling mechanisms of the cerebral giant neurones in the snail, Lymnaea stagnalis.
The axonal branching pattern of the two cerebral giant neurones (CGCs) of Lymnaea stagnalis was studied with intrasomatically applied horseradish peroxidase. The cells are symmetrical. Each CGC projects to the ipsilateral n. labialis medius and n. arteriae labialis, the subcerebral commissure, and to all ipsi- and contralateral buccal nerves. The contralateral buccal nerves are reached via the ipsilateral cerebro-buccal connective and the buccal commissure. The CGC fire action potentials 1:1 in a driver-follower relationship. Each cell is capable of both driving and following. The relationship depends on the membrane potentials of the somata. In driving CGC spikes are initiated in a cerebral spike trigger zone located near the soma. In following cells spikes are initiated in a distal zone located in the buccal ganglia. The buccal zone is only affected by the partner CGC. CGC are synchronized by three coupling mechanisms: mutual excitatory chemical synapses, electrotonic coupling, and common input. The chemical and electrotonic connections are located in the buccal ganglia. All spikes are relayed to the partner cell via the chemical synapses. The electrotonic coupling improves the efficiency of the chemical synapses. The dual connection selectively synchronizes the CGC-axonal spikes from each side of the buccal mass. Common excitatory input affects the cerebral spike trigger zones and can initiate simultaneously spikes in both cells. This results in bilateral synchrony of spikes in the CGC-axons in both the buccal and the lip nerves.


Bioabsorbable lag screw fixation of knee osteochondritis dissecans in the skeletally immature.
Osteochondritis dissecans (OCD) of the knee in children is associated with more morbidity than previously recognized. Sixteen knees in 13 children with symptomatic OCD lesions in the knee diagnosed with MRI underwent arthroscopic fixation using polylactide biodegradable lag screws, after failing a minimum of 6 months conservative treatment. The mean age was 12.3 years; 14 lesions were in the medial condyle, two in the lateral condyle, and the mean area was 244 mm. Early physiotherapy was prescribed with no period of immobilization and the patients were followed for a mean of 27 months. One patient, who required a concomitant meniscal repair, developed a transient neurapraxia of the peroneal nerve but went on to full recovery. All patients but this one had returned to sport at 4-month follow-up. There was significant improvement in the knee function scores and all patients reported their knees as improved or much improved. We propose that simple arthroscopic fixation of OCD with SmartScrews is an effective treatment in the pediatric population leading to a rapid recovery of premorbid function.


Negative regulation of Lyn protein-tyrosine kinase by c-Cbl ubiquitin-protein ligase in Fc epsilon RI-mediated mast cell activation.
Recent studies have demonstrated that c-Cbl functions as a ubiquitin-protein ligase toward immune receptors and non-receptor protein-tyrosine kinase Syk by facilitating their ubiquitination and subsequent targeting to proteasomes. However, it was not clear whether Src family kinase Lyn is regulated by the Cbl family of ubiquitin-protein ligases. Aggregation of the high affinity IgE receptor (Fc epsilon RI) induces the rapid ubiquitination of Lyn in rat basophilic leukaemia RBL-2H3 cells. Treatment of cells with a proteasome inhibitor enhances the ubiquitination of Lyn. Stimulation of Fc epsilon RI results in the association of Lyn with c-Cbl and Cbl-b, both of which then become tyrosine phosphorylated. Co-transfection study shows that both c-Cbl and Cbl-b could induce the ubiquitination of activated Lyn in COS cells. Furthermore, over-expression of membrane-anchored form of c-Cbl inhibits the Fc epsilon RI-mediated degranulation and cytokine gene production in RBL-2H3 cells by the down-regulation of the kinase activity of Lyn through the enhanced ubiquitination. These results demonstrate that Lyn is down-regulated by c-Cbl-mediated ubiquitination and subsequent degradation in proteasome after Fc epsilon RI stimulation in mast cells. Targeting of c-Cbl in the lipid raft results in the inhibition of Fc epsilon RI-mediated mast cell activation.