Involving patient in the early stages of health technology assessment (HTA): a study protocol.
Public and patient involvement in the different stages of the health technology assessment (HTA) process is increasingly encouraged. The selection of topics for assessment, which includes identifying and prioritizing HTA questions, is a constant challenge for HTA agencies because the number of technologies requiring an assessment exceeds the resources available. Public and patient involvement in these early stages of HTA could make assessments more relevant and acceptable to them. Involving them in the development of the assessment plan is also crucial to optimize their influence and impact on HTA research. The project objectives are: 1) setting up interventions to promote patient participation in three stages of the HTA process: identification of HTA topics, prioritization, and development of the assessment plan of the topic prioritized; and 2) assessing the impact of patient participation on the relevance of the topics suggested, the prioritization process, and the assessment plan from the point of view of patients and other groups involved in HTA. Patients and their representatives living in the catchment area of the HTA Roundtable of Université Laval's Integrated University Health Network (covering six health regions of the Province of Quebec, Canada) will be involved in the following HTA activities: 1) identification of potential HTA topics in the field of cancer; 2) revision of vignettes developed to inform the prioritization of topics; 3) participation in deliberation sessions for prioritizing HTA topics; and 4) development of the assessment plan of the topic prioritized. The research team will coordinate the implementation of these activities and will evaluate the process and outcomes of patient involvement through semi-structured interviews with representatives of the different stakeholder groups, structured observations, and document analysis, mainly involving the comparison of votes and topics suggested by various stakeholder groups. This project is designed as an integrated approach to knowledge translation and will be conducted through a close collaboration between researchers and knowledge users at all stages of the project. In response to the needs expressed by HTA producers, the knowledge produced will be directly useful in guiding practices regarding patient involvement in the early phases of HTA.


Age-related complaints in women and their determinants based on a representative community study.
To determine (a) the relationship between physical and somatoform complaints, distress, life satisfaction and ageing in the female community and (b) to identify their psychosocial determinants. Two stratified random samples of the German female population (total of 2771 women) were investigated by standardised questionnaires of complaints (MFI-20, GBB), distress (HADS) and life satisfaction (LSQ). When participants were divided into six age groups (18-30, 31-40, 41-50, 51-60, 61-70, >70 years), we found a continuous increase of physical, mental and general fatigue, inactivity and reduced motivation. Age-associated increases were also observed for exhaustion, cardiovascular and musculoskeletal complaints, but not for gastrointestinal complaints. This was accompanied by a reduced satisfaction with health and sexuality and increased depression and anxiety scores. Marked increases of complaints were mostly found in the sixth decade. However, depression already increased in the fourth decade, musculoskeletal complaints and reduced motivation peaked in the fifth decade, whereas mental fatigue did not increase significantly before the seventh decade followed by a rise of anxiety in women over 70 years. Most consistently, complaints were predicted by a combination of negative subjective health, higher age, lack of a partnership, and additional sociodemographic vulnerability (unemployment, low income, residence) and protective (religion) factors. Community data provide important reference points in evaluating the ageing female. Based on regression analyses, we could also demonstrate the contribution of psychosocial vulnerability and protective factors to the development of age-related symptoms.


Sensing viral invasion by RIG-I like receptors.
Cellular responses to pathogen invasion are crucial for maintaining cell homeostasis and survival. The interferon (IFN) system is one of the most effective cellular responses to viral intrusion in mammals. Viral recognition by innate immune sensors activates the antiviral IFN system. Retinoic acid-inducible gene I (RIG-I) like receptors (RLRs) are DExD/H box RNA helicases that sense viral invasion. RLRs recognize cytoplasmic viral RNAs and trigger antiviral responses, resulting in production of type I IFN and inflammatory cytokines. Unique and common sensing mechanisms among RLRs have been reported. In this review, recent progress in the understanding of antiviral responses by RLRs is summarized and discussed.


Further Evidence of Allergic Contact Dermatitis Caused by 2,2'-Methylenebis(6- tert -Butyl-4-Methylphenol) Monoacrylate, a New Sensitizer in the Dexcom G6 Glucose Sensor.
Since the spring of 2020, we have seen several patients experiencing severe allergic contact dermatitis (ACD) from the Dexcom G6 glucose sensor after the composition of the sensor's adhesive patch had been changed. We have previously reported the finding of a new sensitizer, 2,2'-methylenebis(6- tert -butyl-4-methylphenol) monoacrylate, in the Dexcom G6 adhesive patch. Three patients with ACD from Dexcom G6 tested positive to this sensitizer. They were also allergic to isobornyl acrylate, a sensitizer present both in Dexcom G6 and in other medical devices previously used by these patients. The aim of the study was to report the first 4 cases sensitized to 2,2'-methylenebis(6- tert -butyl-4-methylphenol) monoacrylate without a simultaneous allergy to isobornyl acrylate. The cases were patch tested their own materials, a medical device series, and 2,2'-methylenebis(6- tert -butyl-4-methylphenol) monoacrylate in several concentrations. All 4 cases tested positive to 2,2'-methylenebis(6- tert -butyl-4-methylphenol) monoacrylate at either 1.0% or 1.5% in petrolatum, whereas 20 controls tested negative to both concentrations. The cases reported here provide further evidence of 2,2'-methylenebis(6- tert -butyl-4-methylphenol) monoacrylate as a relevant culprit sensitizer in patients with ACD from Dexcom G6. However, the initially used patch test concentration (0.3%) did not suffice to elicit positive reactions in these cases, which is why patch testing at 1.5% is recommended.


Leaching of oryzalin and diuron through undisturbed vineyard soil columns under outdoor conditions.
Field studies monitoring herbicide pollution in the vineyards of Burgundy (France) have revealed that drinking water reservoirs are contaminated with several pre-emergence herbicides. An assessment of the leaching of two such herbicides, diuron and oryzalin, was therefore performed using lysimeters, under outdoor conditions, from May 2001 to May 2002. Four vineyard soils from Vosne-Romanée (Burgundy) were chosen along a topolithosequence: a rendosol and three calcosols. After 673 mm of rainfall, greater amounts of diuron than oryzalin were measured in percolates: respectively 0.10-0.84% and 0.02-0.43% of applied herbicide, depending on soils. Measurements for diuron metabolites detected greater amounts of DCPMU than DCPU in the percolates: respectively 0.05-0.13% and 0-0.04% of the applied diuron. At the end of the monitoring period, more residues of diuron than oryzalin were recovered in the soil profiles: respectively 4.6-9% and 1.4-4.4%. The oryzalin residues were found mainly in the upper 10 cm of soil columns, whereas diuron residues were present in the whole core. The mobility of both oryzalin and diuron seems fairly well-related to soil organic carbon content; the mobility of diuron is also related to soil texture (sand and coarse material contents). Under such experimental conditions, this study confirms that diuron leaching, and therefore potential groundwater contamination, is greater than that of oryzalin.


Clinical Characteristics and Outcomes of Patients With Heart Failure and Methamphetamine Abuse.
Despite a global epidemic of methamphetamine abuse, methamphetamine-associated heart failure (MethHF) remains poorly understood. We sought to evaluate characteristics and outcomes for patients with MethHF. We reviewed the electronic health records of the University of California, San Diego, from 2005 to 2016. We compared characteristics and outcomes between 896 patients with MethHF and 20,576 patients with heart failure (HF) identified using diagnosis codes, urine toxicology, and natriuretic peptides. Compared with HF, patients with MethHF were younger (50±10 vs 67±16 years), predominantly male (72% vs 54%), and had more psychiatric and substance use comorbidities, including mood/anxiety disorders (29% vs 16%) and opioid use (44% vs 7%). MethHF had a higher 5-year HF readmission rate (64±4% vs 45±1%; hazard ratio [HR] 1.53, P < .001) and a lower 10-year total mortality rate (25±3% vs 28±1%; HR 0.85, P = .09). Predictors of poor outcomes included mood/anxiety disorders (HF readmission HR 1.41, P = .04) and opioid abuse (mortality HR 1.52, P = .04). Patients with MethHF are frequently encumbered by psychiatric and substance abuse comorbidities, and carry a substantial risk of HF readmission and mortality. Comprehensive efforts are needed to stem this emerging epidemic.


Shared governance for nursing. Part II: Putting the organization into action.
Shared governance is a major departure from traditional management-drive systems. It requires commitment and investment from all of nursing. It builds on the trust developed in the nursing service between all participants who deliver nursing care. It requires management and clinical teams to work closely and redefine their roles. The need for mutual understanding and support is undeniable. Unfortunately, there has not been much reason for that trust to develop at a rate and a level it should in most health care facilities. As institutions move to higher levels of interaction to compete and survive and as the nursing shortage requires hospitals to address the role of the nurse, hospitals are laying the groundwork for nurses to play a larger role in governance and control. These circumstances, among others, stimulate interest and provide a basis on which nurses can work together, whether in management or clinical positions, to strengthen the accountability and role of nurses in managing their services and their practices. Moving to shared governance affects the way in which nurses work and relate to the organization. The use of collective bargaining strategies, movement of the nurse into areas of control over issues that institutions once considered beyond his or her role or right, and conflict management strategies will have to change to facilitate the move of nurses into the main-stream of decision making. As the institution moves from a hierarchical structure to a multiservice setting and a more responsive market-based organization is created, nurses will have to play a stronger role in marketing and managing their practices. This flexibility extends to moving health care services out of the institution and into the community and the home and requiring nurses to become more invested in processes and mechanisms that affect what they do and how they do it. If nurses are to have a place in creating policies and define their part in unfolding the future of health care, they must be able to reorganize their services, create stronger peer-based governance approaches, and exhibit stronger control in the exercise of their practices. That will not happen by accident, nor will there be many people from other disciplines who will be heralding this cause for nurses. Before others in policy-making positions move over to provide the necessary space for nurses, the practicing nurse will have to operate and manage his or her practice at the same level and in a similar manner as other professional workers who are outside of the typical dependent, vocational employee role.(ABSTRACT TRUNCATED AT 400 WORDS)


Sex differences in side effects of antiseizure medications in pediatric patients with epilepsy: A systematic review.
To perform a systematic review searching for differences in the side effects of antiseizure medications (ASMs) with respect to sex in pediatric patients with epilepsy. We carried out a comprehensive literature search of the PubMed database and all results up to April 2020 were included. Titles, abstracts, and full texts of the articles were screened by two independent reviewers. We included all studies evaluating the side effects of ASMs in patients with epilepsy younger than 18 years, with reference to the two sexes. Studies on ASMs used for indications other than epilepsy were excluded. A total of 5164 studies were identified. Sixty-seven studies were finally included, 5 of them also including adult patients in the sample. Sixteen studies revealed sex-related differences in side effects of ASMs, disclosing a higher frequency of general side effects in girls: a higher risk of overweight, hyperammonaemia, high leptin levels, and carnitine deficiency in girls on valproic acid; a lower height increase, an increased risk of weight loss, the anecdotical occurrence of acute psychosis in girls on topiramate; a higher risk of retinal toxicity in boys on vigabatrin. The effect of sex on susceptibility to side effects of ASMs is poorly investigated with sparse results, and it could be underestimated. The findings of our study point to the presence of sex differences which should be thoroughly investigated to be confirmed, highlighting the need for a systematic evaluation of sex as a determinant variable influencing the response to medications in clinical research.


Clinical guidance for diagnosis and management of suspected Pediatric Acute-onset Neuropsychiatric Syndrome in the Nordic countries.
Pediatric acute-onset neuropsychiatric syndrome is a clinical concept used to describe a subgroup of children with sudden onset of psychiatric and somatic symptoms. The diagnostic term and especially management of children differs depending on the clinical setting to which they present, and the diagnosis and management is controversial. The aim of this paper is to propose a clinical guidance including homogenous diagnostic work-up and management of paediatric acute onset neuropsychiatric syndrome within the Nordic countries. The guidance is authored by a Nordic-UK working group consisting of paediatric neurologist, child psychiatrists and psychologists from Denmark, Norway, Sweden and Great Britain, and is the result of broad consensus. CONCLUSION: Consensus was achieved in the collaboration on work-up and treatment of patients with paediatric acute-onset neuropsychiatric syndrome, which we hope will improve and homogenise patient care and enable future collaborative research in the field.


Histone deacetylase inhibitors induce medulloblastoma cell death independent of HDACs recruited in REST repression complexes.
Repressor element 1-silencing transcription factor (REST) acts as a transcriptional repressor by recruiting several chromatin modifiers, including histone deacetylase (HDAC). Elevated REST expression in medulloblastoma has been associated with tumor progression nevertheless, the tumor shows high sensitivity to HDAC inhibitors (HDACi). However, the functional implications of REST and its requirement for HDACi-induced anti-cancer effects are not well understood. In this study, the expression of REST was evaluated across the medulloblastoma subgroups and subtypes using published gene expression data. Further, the expression of REST was modulated using the CRISPR/Cas9 knockout and shRNA knockdown in the Daoy medulloblastoma cell line. The results of this study showed that the expression of REST is elevated in most medulloblastoma subgroups compared to the non-cancerous cerebellum. Blocking of REST expression resulted in increasing the expression of REST-regulated genes, a moderate decrease in the fraction of the cells in the S-phase, and reducing the cells' migration ability. However, REST deficiency did not lead to a marked decrease in the Daoy cell viability and sensitivity to HDACi. The findings of this study indicate that REST is not essential for sustaining the proliferation/viability of the Daoy cells. It also revealed that the anti-proliferative effect of HDACi is independent of REST expression.


Survival and Predictors of Mortality Among HIV Positive Adult Patients on Highly Active Antiretroviral Therapy in Public Hospitals of Kambata Tambaro Zone, Southern Ethiopia: A Retrospective Cohort Study.
Human Immune Deficiency Virus (HIV) infection remains the leading cause of morbidity and mortality. In Ethiopia, despite test and treat all HIV positives are adopted, a significant number of people eligible for Anti-Retroviral Therapy (ART) show up with advanced disease and at lower CD4 count. There is currently paucity of studies conducted that investigate predictors of mortality among adults on ART in the study area. To explore Survival and predictors of mortality among adult HIV-positive patients on ART in Kambata Tambaro Zone, Ethiopia, from August 2013 to February 2019. A health facility-based retrospective cohort study was conducted among records of 467 adult HIV-positive patients on ART selected using simple random sampling. Data were collected using standardized abstraction tool. Kaplan-Meier, Log rank tests and Cox regression model was applied to estimate survival status and identify predictors of mortality, respectively. Of the total 467 study subjects, 59 (12.63%) of them died in the study period. The median follow-up time of the cohort was 40.1 (IQR=13.6-59.0) months. The mortality rate of the cohort was 4.1 per 100 PYO. The overall survival probability of the cohort was 84.38% (95 CI=80.08-87.82) at 66 months. Bedridden function AHR=3.0 (95% CI, 1.44-6.64), Fair-adherence AHR=3.3 (95% CI, 1.50-7.07), Poor-adherence AHR=3.8 (95% CI, 1.88-7.96), presence of OIs AHR=4.2 (95% CI, 1.98-8.50), Late diagnosis (CD4 count >/=350) AHR=3.0 (95% CI, 1.91-6.42) and Immunologic failure AHR=3.5 (95% CI, 1.41-6.29) were independent predictors of time to death in Cox-Regression. Late Diagnosis, poor adherence, being bedridden, having OI and Immunologic failure were independently associated with time to death. Early diagnosis to start treatment and emphasizing on close follow-up care to improve treatment adherence should be given special emphasis.


Regulation of hippocampal long-term potentiation and long-term depression by diacylglycerol kinase ζ.
Diacylglycerol (DAG) is an important signaling molecule at neuronal synapses. Generation of synaptic DAG is triggered by the activation of diverse surface receptors including N-methyl-D-aspartate (NMDA) receptors and metabotropic glutamate receptors. The action of DAG is terminated by enzymatic conversion of DAG to phosphatidic acid (PA) by DAG kinases (DGKs). DGKζ, one of many mammalian DGKs, is localized to synapses through direct interaction with the postsynaptic scaffolding protein PSD-95, and regulates dendritic spine maintenance by promoting DAG-to-PA conversion. However, a role for DGKζ in the regulation of synaptic plasticity has not been explored. We report here that Schaffer collateral-CA1 pyramidal synapses in the hippocampus of DGKζ-knockout (DGKζ(-/-) ) mice show enhanced long-term potentiation (LTP) and attenuated long-term depression (LTD). The attenuated LTD at DGKζ(-/-) synapses involves both NMDA receptors and metabotropic glutamate receptors. These changes in LTP and LTD were reversed by phospholipase C inhibition, which blocks DAG production. Similar reversals in both LTP and LTD were also induced by inhibition of protein kinase C, which acts downstream of DAG. These results suggest that DGKζ regulates hippocampal LTP and LTD by promoting DAG-to-PA conversion, and establish that phospholipase C and protein kinase C lie upstream and downstream, respectively, of DGKζ-dependent regulation of hippocampal LTP and LTD.


The Feingold dietary treatment of the hyperkinetic syndrome.
A satisfactory explanation of the hyperkinetic syndrome in children has been lacking. Feingold has advanced the hypothesis that naturally occurring salicylates and artificial food additives may cuase this syndrome in certain children , who have a genetically determined predisposition. Following Feingold's dietary prescription, an elimination diet relevant to the foods available in Sydney was developed. The treatment regime is described, and the results of its application to 15 hyperkinetic children are presented. The parents of 10 children are "quite certain" and those of three others "fairly certain" that their children's behaviour not only improved substantially with the diet, but also relapsed promptly when significant dietary infringements occurred. A possible ecological implication of these findings is briefly discussed.


Excitation function of 54Fe(p,α)51Mn from 9.5 MeV to 18 MeV.
Excitation function of the 54Fe(p,α)51Mn reaction was measured from 9.5 to 18 MeV E 0 , p + by activating a foil stack of 54Fe electrodeposited on copper substrates. Residual radionuclides were quantified by HPGe gamma ray spectrometry. Both 51Mn (t 1/2 = 46.2 min, 〈 E β + 〉 = 963.7 keV , I β + = 97 % ; E γ = 749.1 keV, I γ = 0.265%) and its radioactive daughter, 51Cr (t 1/2 = 27.704d, E γ = 320.1 keV, I γ = 9.91%), were used to indirectly quantify formation of 51Mn. Results agree within uncertainty to the only other measurement in literature and predictions of default TALYS theoretical code. Final relative uncertainties are within ±12%.


[Risk of bacterial contamination after povidone-iodine disinfection for cataract surgery].
Povidone-iodine alone or in combination with antibiotics is commonly used for presurgical disinfection in cataract surgery. In spite of the use of the combination Povidone-iodine and ofloxacin, the rate of ocular contamination as assessed from surgical knives was reported to be as high as 26 %. The aim of this study was to investigate the efficacy of diluted Povidone-iodine alone for surgical disinfection. 126 consecutive patients undergoing elective cataract surgery with a conjunctival wound and a scleral tunnel received prior to surgery a disinfection with diluted Povidone-iodine eye drops (Braunol 1:10 diluted = 0.8 % Povidone-iodine, 3 times every 5 min). To assess residual bacteria on the ocular surface after disinfection, the surgical knives for the side ports and the scleral tunnel were cultured in thioglycolate broth. In 8 out of 126 (6 %) patients the culture from the surgical knives revealed a positive result (89 % coagulase negative Staphylococci). Four of these 8 cases occurred during a single list. All control cultures remained negative. Diluted Povidone-iodine eye drops alone are highly effective for bacterial disinfection when applied properly. The rate of contamination using 0.8 % Povidone-iodine in our series was considerably lower as compared to that of other studies.


Valproate doubles the anoxic survival time of normal developing mice: possible relevance to valproate-induced decreases in cerebral levels of glutamate and aspartate, and increases in taurine.
We have previously reported that chronic administration of valproate in developing mice decreased brain aspartic and glutamic acid levels and increased the brain taurine content. The direction of the valproate-induced changes in the cerebral levels of these neurotransmitter amino acids - excitatory in the case of aspartate and glutamate, inhibitory in the case of taurine - appeared relevant to the mechanism of its anticonvulsant action. Since the neuropathology of hypoxia-ischemia also appears to be mediated by release of glutamate/aspartate at the synapse, the valproate-induced reduction of the levels of these neuroexcitatory/neurotoxic amino acids suggested that valproate might increase the tolerance of young mice to anoxia. A doubling of the length of survival of the intact animal in an atmosphere of pure nitrogen gas and a three-fold increase in the duration of respiratory activity (gasping) of the isolated head after chronic administration of valproate support the speculation.


Efficiency and acceptance of new water allocation rules - The case of an agricultural water users association.
Water scarcity is one of the major environmental problems in Southern Europe. High levels of water stress and increasing frequency of droughts, along with a greater environmental protection, make it necessary to design water management strategies that are allocative efficient and balance supply and demand. When functioning markets cannot be developed, the allocation rules proposed in the literature of social choice have been recognized as a suitable alternative. However, the application of new water allocation rules can be impaired by a lack of acceptance and implementation problems. This paper examines these obstacles for the case of an agricultural water users association (WUA), situated in the basin of the River Ebro, in relation to the governance structure and collective decision rule of the WUA. It analyzes the extent to which the gains and losses of the farmers affect their acceptance, and examines conditions for building agreements with side payments that provide incentives for the majority of the farmers to form part of a possible agreement. The results show that the uniform and sequential rules improve the allocative efficiency under normal conditions compared to the status quo and the sequential rule even in the case of droughts. In the presence of side payments this rule is likely to be accepted and has only an insignificant impact on distributional inequality.


The synaptic lipidome in health and disease.
Adequate homeostasis of lipid, protein and carbohydrate metabolism is essential for cells to perform highly specific tasks in our organism, and the brain, with its uniquely high energetic requirements, posesses singular characteristics. Some of these are related to its extraordinary dotation of synapses, the specialized subcelluar structures where signal transmission between neurons occurs in the central nervous system. The post-synaptic compartment of excitatory synapses, the dendritic spine, harbors key molecules involved in neurotransmission tightly packed within a minute volume of a few femtoliters. The spine is further compartmentalized into nanodomains that facilitate the execution of temporo-spatially separate functions in the synapse. Lipids play important roles in this structural and functional compartmentalization and in mechanisms that impact on synaptic transmission. This review analyzes the structural and dynamic processes involving lipids at the synapse, highlighting the importance of their homeostatic balance for the physiology of this complex and highly specialized structure, and underscoring the pathologies associated with disbalances of lipid metabolism, particularly in the perinatal and late adulthood periods of life. Although small variations of the lipid profile in the brain take place throughout the adult lifespan, the pathophysiological consequences are clinically manifested mostly during late adulthood. Disturbances in lipid homeostasis in the perinatal period leads to alterations during nervous system development, while in late adulthood they favor the occurrence of neurodegenerative diseases.


Muscle fatigability and post-acute COVID-19 syndrome: A case study.
The acute phase of COVID-19 has been well studied, however with increasing post-acute COVID-19 syndrome, much is unknown about its long-term effects. A common symptom in both the acute and post-acute phases has been fatigue, assessed predominantly qualitatively. Here we present a case study objectively assessing neuromuscular fatiguability in a young male (27 year, 1.85 m, 78 kg) who continues to experience COVID-19 related fatigue and cognitive dysfunction, including other symptoms, 12+ months post-infection. Prior to infection, he was part of a neuromuscular study forming the basis of our pre-COVID-19 results. The study was repeated 12 months post-COVID-19 infection. Muscle strength, endurance, torque steadiness, voluntary activation, twitch properties, electromyography, and compound muscle action potential were obtained and compared pre- and post-COVID-19. All measurements were done using a dorsiflexion dynamometer in which the participant also was asked to produce a one-minute fatiguing maximal voluntary contraction. Muscle strength, voluntary activation, and fatigability (slope of torque) showed no meaningful differences, suggesting intrinsic neuromuscular properties are not affected. However, torque steadiness was impaired three-fold in the post- compared with pre-COVID-19 test. The participant also reported a higher level of perceived exertion subjectively and a continued complaint of fatigue. These findings indicate that muscle fatiguability in post-acute COVID-19 syndrome may not be a limitation of the muscle and its activation, but a perceptual disconnect caused by cognitive impairments relating to physical efforts. This case report suggests the potential value of larger studies designed to assess these features in post-acute COVID-19 syndrome.


Ionophore A23187 stimulates phosphorylation of the 40,000 dalton protein in human platelets without phospholipase C activation.
The Ca2+ ionophore A23187 (0.2-5 microM) stimulates the phosphorylation of the substrates of protein kinase C (40,000 dalton protein) and myosin light chain kinase (20,000 dalton protein) in the presence or absence of cyclooxygenase inhibitors. In the presence of cyclooxygenase inhibitors or millimolar Ca2+ there is no stimulation of phospholipase C by A23187. Fingerprints of the 32P-labeled 40,000 dalton protein isolated from platelets that have been stimulated with A23187, thrombin, phorbol 12,13-dibutyrate and 1,2-didecanoylglycerol were identical. Higher concentrations of A23187 (1-5 microM) induced the loss of polyphosphoinositides through phosphomonoesterase activity.


Preventing maternal mental health disorders in the context of poverty: pilot efficacy of a dyadic intervention.
The United States Preventive Services Task Force recommends that clinicians provide or refer pregnant and postpartum women who are at an increased risk of perinatal depression to counseling interventions. However, this prevention goal requires effective interventions that reach women at risk of, but before, the development of a depressive disorder. We describe a pilot efficacy trial of a novel dyadic intervention to prevent common maternal mental health disorders, that is, Practical Resources for Effective Postpartum Parenting, in a sample of women at risk of maternal mental health disorders based on poverty status. We hypothesized that Practical Resources for Effective Postpartum Parenting compared with enhanced treatment as usual would reduce symptoms of maternal mental health disorders after birth. A total of 60 pregnant women who were recruited from obstetrical practices at Columbia University Irving Medical Center were randomized to the Practical Resources for Effective Postpartum Parenting (n=30) or enhanced treatment as usual (n=30) intervention. The Edinburgh Postnatal Depression Scale, Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and Patient Health Questionnaire were used to compare maternal mood at 6 weeks, 10 weeks, and 16 weeks after delivery. At 6 weeks after delivery, women randomized to Practical Resources for Effective Postpartum Parenting had lower mean Edinburgh Postnatal Depression scores (P=.018), lower mean Hamilton Depression scores (P<.001), and lower mean Hamilton Anxiety scores (P=.041); however, the incidence of postpartum mental disorders did not differ by treatment group. The Practical Resources for Effective Postpartum Parenting, which is an intervention integrated within obstetrical care, improves subclinical symptomology for at-risk dyads at a crucial time in the early postpartum period; however, our study did not detect reductions in the incidence of postpartum mental disorders.


Acute fulminant colitis caused by idiopathic mesenteric inflammatory veno-occlusive disease.
Mesenteric inflammatory veno-occlusive disease (MIVOD) is an uncommon but important cause of bowel inflammation. MIVOD is characterised by lymphocytic inflammation and non-thrombotic occlusion of the mesenteric venules and veins. We present the case of a young man who presented with acute fulminant colitis, requiring colectomy. The differential diagnosis, pathogenesis and treatment are discussed. This case illustrates the rapid progression from 'well' to 'colectomy' that can occur with MIVOD. MIVOD should be considered in the differential diagnosis of colitis that does not respond to conventional medical treatment.


Regional changes in brain 14C-2-deoxyglucose uptake after feeding-inducing intrahypothalamic norepinephrine injections.
Although norepinephrine (NE) injections into the paraventricular hypothalamus (PVN) have been extensively documented to induce feeding in satiated rats, there have been few systematic attempts to elucidate the neural circuitry subserving this response. In this study quantitative 14C-2-deoxyglucose (14C-2DG) autoradiography was used to map regional brain changes induced by PVN NE injections. Male Wistar rats, bearing PVN cannulae and previously shown to be positive responders for NE-induced feeding, were given 125 microCi/kg 14C-2DG IV immediately following a PVN injection of either 40 nmol NE or vehicle, then killed 45 min later. 14C-2DG uptake was examined in 97 brain structures using computerized densitometry. PVN NE injections resulted in small, localized changes in brain 14C-2DG uptake. Forebrain structures affected included the somatosensory parietal cortex (+15%), the CA3 hippocampal field (-8%), and the reticular thalamic nucleus (+14%). Midbrain changes involved the anterior pretectal area (+8%) and the central gray area (-11%). At the hindbrain level, the lateral reticular nucleus showed the most pronounced changes of all brain regions examined (-24%), followed by the nucleus of the solitary tract (-16%) and the laterodorsal tegmental nucleus (+16%). No changes were seen in the median eminence or in other hypothalamic areas. This pattern of results largely agrees with recent proposals for the circuitry of a PVN-hindbrain system subserving NE-induced as well as hypothalamic lesion-induced feeding effects. In addition, however, they suggest the possibility that altered activity in some forebrain structures may also be involved in the NE response.


Comparative analysis of male androgen responsiveness to social environment in birds: the effects of mating system and paternal incubation.
Male androgen responses to social challenges have been predicted to vary with mating system, male-male aggressiveness, and the degree of paternal investment in birds ("challenge hypothesis," Am. Nat. 136 (1990), 829). This study focused on the interspecific predictions of the challenge hypothesis. Comparative methods were used to control for effects of the phylogenetic relatedness among the sampled species. Male androgen data of 84 bird species were collected from literature records on seasonal androgen patterns. From these, the androgen responsiveness (AR) was calculated as described in the original challenge hypothesis (i.e., maximum physiological level/breeding baseline). Scatterplots of AR versus mating strategy, male-male aggressiveness, and the degree of paternal care confirmed the expected interspecific patterns. When phylogenetic analyses were performed among all of the sampled species, the effects of paternal investment disappeared while the AR remained covarying to a high degree with mating system and male-male aggressiveness. Although these mechanisms may be different at the intraspecific level, this suggests that interspecific differences of AR in male birds may have evolved in response to changes of mating strategies, rather than in response to altered paternal duties. However, control for phylogeny among the subsample of 32 passerine species revealed that if any paternal investment contributed to the observed variance in AR, then the change from "no male incubation" to "male shares incubation duties" represented the most effective, whereas the male's contribution to feeding offspring did not explain the observed variation of AR.


Pharmacogenetic-based management of depression: Role of traditional Persian medicine.
Depression is one of the most common mental disorders worldwide. The genetic factors are linked to depression and anti-depressant outcomes. Traditional Persian medicine (TPM) manuscripts have provided various anti-depressant remedies, which may be useful in depression management. This review has studied the bioactive compounds, underlying mechanisms, and treatment outcomes of the medicinal plants traditionally mentioned effective for depression from "The storehouse of medicament" (a famous pharmacopeia of TPM) to merge those with the novel genetics science and serve new scope in depression prevention and management. This review paper has been conducted in two sections: (1) Collecting medicinal plants and their bioactive components from "The storehouse of medicament," "Physician's Desk Reference (PDR) for Herbal Medicines," and "Google scholar" database. (2) The critical key factors and genes in depression pathophysiology, prevention, and treatment were clarified. Subsequently, the association between bioactive components' underlying mechanism and depression treatment outcomes via considering polymorphisms in related genes was derived. Taken together, α-Mangostin, β-carotene, β-pinene, apigenin, caffeic acid, catechin, chlorogenic acid, citral, ellagic acid, esculetin, ferulic acid, gallic acid, gentiopicroside, hyperoside, kaempferol, limonene, linalool, lycopene, naringin, protocatechuic acid, quercetin, resveratrol, rosmarinic acid, and umbelliferone are suitable for future pharmacogenetics-based studies in the management of depression.


Aggregatibacter actinomycetemcomitans osteomyelitis in a 12 year old boy: case report emphasizing the importance of tissue culture, and review of literature.
Aggregatibacter actinomycetemcomitans most commonly causes periodontitis but has been reported to infect heart valves, soft tissue, brain and lungs, and distal bones. Osteomyelitis distal to the jaw is rarely described. We report an unusual and rare case of chronic osteomyelitis caused by A. actinomycetemcomitans in the toe of a paediatric patient, and review the available literature. The infection was managed with intravenous antibiotics followed by oral antibiotics. This is an unusual presentation of A. actinomycetemcomitans causing chronic osteomyelitis presumed due to nidation in a minimally damaged bone, associated with bacteraemia of an oral commensal. It occurred in the toe, without obvious dental predisposition; associated with minimal clinical disturbance and with muted immune response.


[Treatment of urethral stricture in man using one-stage urethroplasty with subcutaneous pedicle graft].
It is reported on a new one stage urethroplasty which, using a subcutaneous pedicle graft, is based on the spontaneous formation of a tube of a urethra-skin-strip submerged into the depth. The procedure was tested on a clinical material of 140 cases and is recommended as method of choice in strictures of the urethra.


Challenges to recruitment and retention of Black forensic pathologists.
Informal estimates place the number of practicing Black forensic pathologists (BFPs) in the United States (US) at somewhere between 35 and 45 which is less than 10% the estimated total of 600. The legacy of medical and institutional racism means that BFPs in the US encounter particular challenges to training and career development that their White peers do not have to contend with. A survey developed on SurveyMonkey in English, was distributed through social media networks and by direct email to known BFPs. Their responses to questions about the challenges they faced in training and as qualified specialists and factors that eased or facilitated their progress were collected and analyzed. BFPs report challenges to recruitment and retention that are like those faced by Black peers in other medical specialties. While personal determination is an essential ingredient to career success as a BFP, there are certain structural barriers that must be eliminated to increase the total number of BFPs. The pipeline that produces BFPs must be nurtured, reimagined, and reinvigorated.


FoxO3a functions as a key integrator of cellular signals that control glioblastoma stem-like cell differentiation and tumorigenicity.
Glioblastoma is one of the most aggressive types of human cancer, with invariable and fatal recurrence even after multimodal intervention, for which cancer stem-like cells (CSLCs) are now being held responsible. Our recent findings indicated that combinational inhibition of phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways effectively promotes the commitment of glioblastoma CSLCs to differentiation and thereby suppresses their tumorigenicity. However, the mechanism by which these two signaling pathways are coordinated to regulate differentiation and tumorigenicity remains unknown. Here, we identified FoxO3a, a common phosphorylation target for Akt and ERK, as a key transcription factor that integrates the signals from these pathways. Combinational blockade of both the pathways caused nuclear accumulation and activation of FoxO3a more efficiently than blockade of either alone, and promoted differentiation of glioblastoma CSLCs in a FoxO3a expression-dependent manner. Furthermore, the expression of a constitutively active FoxO3a mutant lacking phosphorylation sites for both Akt and ERK was sufficient to induce differentiation and reduce tumorigenicity of glioblastoma CSLCs. These findings suggest that FoxO3a may play a pivotal role in the control of differentiation and tumorigenicity of glioblastoma CSLCs by the PI3K/Akt/mTOR and MEK/ERK signaling pathways, and also imply that developing methods targeting effective FoxO3a activation could be a potential approach to the treatment of glioblastoma.


Healthy blood donors with selective absence of immunoglobulin A: prevention of anaphylactic transfusion reactions caused by antibodies to IgA.
Gel diffusion analysis of sera from 73,569 healthy volunteer blood donors revealed apparent lack of IgA in 113 (1:650) samples, all with normal levels of IgG and IgM. Of these, 30 sera had low levels of IgA, while the remaining 83 had no IgA detectable by a more sensitive hemagglutination inhibition assay. The frequency of absent IgA (algA) was 1:886. High-titer anti-IgA was detected in the sera of 13 algA donors; only two had any known history of parenteral injection of IgA. Passive transfusion of high-titer anti-IgA in the units of blood elicited no clinical reaction in the recipients. Precipitating antibodies to ruminant IgM were present in 14 of the 83 donors. The incidence of hepatitis B surface antigen (HB-sAg), anti-HB-sAG, and antinuclear antibodies was the same in IgA-deficient and control sera. The algA donors form a unique resource for blood components for the clinical management of patients with anapylactic reactions caused by anti-IgA.


An atypical presentation for primary sclerosing cholangitis.
We describe the clinical course of a group of patients with primary sclerosing cholangitis who at presentation were diagnosed to have autoimmune hepatitis. The history of one such patient is described in detail. We also compare this atypical sclerosing cholangitis (group I) to typical sclerosing cholangitis (group II) and to autoimmune hepatitis with (group III) and without (group IV) cholestasis. At presentation, mean AST in groups I and III was similar and significantly higher than in group II (P < 0.05). Mean ALP was higher in sclerosing cholangitis than in autoimmune hepatitis but not significantly so. Triaditis was present in all patients in groups I, III, and IV. Piecemeal necrosis and multilobular collapse/fibrosis were equally frequent in groups I, III, and IV. Only the response to corticosteroids helped differentiate among groups. Groups III and IV responded by normalizing AST. In group I, AST improved, but never became normal. As ALP became disproportionately abnormal (ALP-predominant pattern), cholangiography was performed, and the diagnosis of primary sclerosing cholangitis was made in all group I patients. We recommend that cholangiography be performed early in patients with suspected autoimmune hepatitis who partially respond to corticosteroids and develop an ALP-predominant pattern.


Dissecting the common and compartment-specific features of COVID-19 severity in the lung and periphery with single-cell resolution.
Severe COVID-19 is accompanied by rampant immune dysregulation in the lung and periphery, with immune cells of both compartments contributing to systemic distress. The extent to which immune cells of the lung and blood enter similar or distinct pathological states during severe disease remains unknown. Here, we leveraged 96 publicly available single-cell RNA sequencing datasets to elucidate common and compartment-specific features of severe to critical COVID-19 at the levels of transcript expression, biological pathways, and ligand-receptor signaling networks. Comparing severe patients to milder and healthy donors, we identified distinct differential gene expression signatures between compartments and a core set of co-directionally regulated surface markers. A majority of severity-enriched pathways were shared, whereas TNF and interferon responses were polarized. Severity-specific ligand-receptor networks appeared to be differentially active in both compartments. Overall, our results describe a nuanced response during severe COVID-19 where compartment plays a role in dictating the pathological state of immune cells.


A rapid, inexpensive and easily quantified assay for phagocytosis and microbicidal activity of macrophages and neutrophils.
The objective of the present study was to develop a technique to quantitate the phagocytic and intracellular microbicidal activity in different populations of phagocytes, i.e. neutrophils and macrophages. Elicited peritoneal neutrophils and macrophages as well as alveolar macrophages and adherent splenic macrophages were used as representative cell types. The method to assess intracellular killing was based upon dye uptake and concentration by a dead micro-organism; methylene blue was used as the indicator dye and the test organism was Saccharomyces cerevisiae. Phagocytosis was measured by counting, microscopically, the number of ingested yeast (Saccharomyces cerevisiae) within the neutrophils or macrophages. A number of killed yeast, i.e., those which took up the dye, were readily visualized. The temporal pattern of phagocytosis and killing was determined concurrently. Splenic macrophages demonstrated the slowest phagocytic activity whereas neutrophils and alveolar macrophages manifested a similar phagocytic activity. Peritoneal macrophages exhibited a continuous increase in activity throughout the test period. Microbicidal activity was similar for all 4 cells types. The new technique for measuring phagocytosis and killing provides a rapid, inexpensive and easily quantified assay for assessing discrete phagocytic cell functions.


Effects of repeated injections of sucrose on the kidney. Histologic, cytochemical and functional studies in an animal model.
In previous experiments (Monserrat, Gotelle, and Garay, 1969) we have found that the administration to rats of a single injection of 1.12 M sucrose induces a hydropic reversible vacuolation of the proximal convoluted tubules of the kidney. Along with the vacuolation the PAS and acid phosphatase positive, as well as autofluorescent granules (lysosomes) disappear and vice versa. We now report the effects of multiple intraperitoneal injections of 1.12 M sucrose. The aim of the study was to determine whether the renal cells are able to adapt to this situation or the modifications are permanent. Wistar male rats were allotted to 4 different groups (A : experimental, B, C, and D, controls) and placed in metabolic cages. Animals from group A were injected with 3.0 ml/100 gm body weight of 1.12 M sucrose at 0, 24, 48, 72, and 96 hours after the beginning of the experiment; rats of groups B and C were injected respectively at 0 and 96 hours, and finally, rats of group D were used as normal controls. All rats were killed at 120 hours. The results showed a striking vacuolation in the proximal convoluted tubules of the rats of group C, and complete regression of vacuolar changes in those of group B. Rats of group A, although they maintained the osmotic diuresis, showed mild vacuolation with persistence of acid phosphatase and PAS positive granules, as well as autofluorescent droplets (lysosomes). We postulate that these results are indicative of adaptive changes, whose mechanisms are at present being studied.


Analysis of a salinity induced BjSOS3 protein from Brassica indicate it to be structurally and functionally related to its ortholog from Arabidopsis.
Arabidopsis has been a favorite model system for plant biologist. It is anticipated that comparative analysis of this plant with other members of Brassicaceae may aid in identification of orthologs playing role as key genetic determinants for salinity response. In this endeavor, we have recently identified SOS family members from Brassica juncea in our laboratory and reported their salinity responsive transcriptional induction in seedlings of various diploid and amphidiploids species. In the present study, we have carried out detailed time kinetics for BjSOS3 expression in a salinity tolerant B. juncea var. CS52. Transcript analysis at the sensitive growth stages of plants viz. seedling and reproductive stage indicated clear differential transcriptional regulation of BjSOS3 under non-induced as well as salinity induced conditions in a time and organ specific manner, mirroring their respective tolerance physiology. Similar to its ortholog from Arabidopsis thaliana, the modeled BjSOS3 protein show typical features of a Ca(2+) binding protein with four conserved EF-hands. We have also attempted to study the binding of SOS3 protein with the modeled SOS2 protein. It has been established that SOS3 protein senses Ca(2+) though the binding is very weak; we show the down regulation of BjSOS3 mRNA in presence of calcium chelator - EGTA under the various stress conditions including ABA. In situ localization of BjSOS3-GFP fusion protein in onion peel has shown its presence strongly in plasma membrane as well as cytosol. The leads presented in the paper will assist in understanding and establishing the SOS signaling machinery in B. juncea.


Association between vascular endothelial growth factor polymorphism and recurrent pregnancy loss: A systematic review and meta-analysis.
Some studies have reported that vascular endothelial growth factor (VEGF) genetic polymorphisms are associated with recurrent pregnancy loss (RPL), but the results are controversial. This study is aimed to quantify the strength of this association. A systematic review of the published literature from Medline, Springer, and China National Knowledge Infra structure (CNKI) databases was conducted and investigations of VEGF genetic polymorphisms in RPL were selected. We estimated the pooled odds ratio (OR) to assess this possible association. Fifteen case-control studies comprising 2702 cases and 2667 controls and including five genetic polymorphisms (rs3025039, rs833061, rs15703060, rs2010963 and rs699947) were eligible for this meta-analysis. The overall analysis suggested that only two genetic polymorphisms (rs1570360, rs3025039) were associated with increased risk of RPL. A significant increased risk between VEGF rs1570360 polymorphism and RPL was only found under the dominant model in Caucasians (OR=1.70, 95% CI 1.02-2.82, P=0.04). Whereas, we found that VEGF rs3025039 polymorphism was significantly associated with RPL both under the dominant and recessive model in East Asians, and their summary odd ratios and 95% CIs were 1.26, 1.04-1.53, P=0.02 and 2.94, 1.80-4.83, P=0, respectively. This meta-analysis showed that only rs1570360 (especially in Caucasians) and rs3025039 (especially in East Asians) may be risk factors for RPL.


Spatial Abundance, Diversity, and Activity of Ammonia-Oxidizing Bacteria in Coastal Sediments of the Liaohe Estuary.
Ammonia-oxidizing bacteria (AOB) play an important role in nitrification in estuaries. The aim of this study was to examine the spatial abundance, diversity, and activity of AOB in coastal sediments of the Liaohe Estuary using quantitative PCR, high-throughput sequencing of the amoA gene coding the ammonia monooxygenase enzyme active subunit, and sediment slurry incubation experiments. AOB abundance ranged from 8.54 × 104 to 5.85 × 106 copies g-1 of wet sediment weight and exhibited an increasing trend from the Liaohe Estuary to the open coastal zone. Potential nitrification rates (PNRs) ranged from 0.1 to 336.8 nmol N g-1 day-1 along the estuary to the coastal zone. Log AOB abundance and PNRs were significantly positively correlated. AOB richness decreased from the estuary to the coastal zone. High-throughput sequencing analysis indicated that the majority of amoA gene sequences fell within the Nitrosomonas and Nitrosomonas-like clade, and only a few sequences were clustered within the Nitrosospira clade. This finding indicates that the Nitrosomonas-related lineage may be more adaptable to the specific conditions in this estuary than the Nitrosospira lineage. Sites with high nitrification rates were located in the southern open region and were dominated by the Nitrosomonas-like lineage, whereas the Nitrosospira lineage was found primarily in the northern estuary mouth sites with low nitrification rates. Thus, nitrification potentials in Liaohe estuarine sediments in the southern open region were greater than those in the northern estuary mouth, and the Nitrosomonas-related lineage might play a more important role than the Nitrosospira lineage in nitrification in this estuary.


Achievement of optimal average relative dose intensity and correlation with survival in diffuse large B-cell lymphoma patients treated with CHOP.
The treatment of diffuse large B-cell lymphoma with chemotherapy was retrospectively evaluated in 348 patients who had received at least three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like, ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone)-like or CHVmP-BV (cyclophosphamide, hydroxorubicin, Vm-26, prednisone, vincristine and bleomycin) treatment in Belgium between 1995 and 2000. In our sample, the proportion who received each of the three regimens was 78.4, 16.4, and 5.2%, respectively. Of those prescribed CHOP-like regimens, 15% received <80% average relative dose intensity (ARDI). In 210 patients treated with CHOP-21 (77% of the CHOP-like group), median survival was 7.08 years in those who received >90% of the ARDI, significantly longer than in those who received < or = 90% of the ARDI (p = 0.002). Dose reductions and/or delays, mainly due to hematological toxicities, resulted in a reduction in treatment intensity. These data indicate that patient outcome is improved when the intensity of chemotherapy treatment is optimal.


Tissue-specific modifier alleles determine Mertk loss-of-function traits.
Knockout (KO) mouse models play critical roles in elucidating biological processes behind disease-associated or disease-resistant traits. As a presumed consequence of gene KO, mice display certain phenotypes. Based on insight into the molecular role of said gene in a biological process, it is inferred that the particular biological process causally underlies the trait. This approach has been crucial towards understanding the basis of pathological and/or advantageous traits associated with Mertk KO mice. Mertk KO mice suffer from severe, early-onset retinal degeneration. MERTK, expressed in retinal pigment epithelia, is a receptor tyrosine kinase with a critical role in phagocytosis of apoptotic cells or cellular debris. Therefore, early-onset, severe retinal degeneration was described to be a direct consequence of failed MERTK-mediated phagocytosis of photoreceptor outer segments by retinal pigment epithelia. Here, we report that the loss of Mertk alone is not sufficient for retinal degeneration. The widely used Mertk KO mouse carries multiple coincidental changes in its genome that affect the expression of a number of genes, including the Mertk paralog Tyro3. Retinal degeneration manifests only when the function of Tyro3 is concomitantly lost. Furthermore, Mertk KO mice display improved anti-tumor immunity. MERTK is expressed in macrophages. Therefore, enhanced anti-tumor immunity was inferred to result from the failure of macrophages to dispose of cancer cell corpses, resulting in a pro-inflammatory tumor microenvironment. The resistance against two syngeneic mouse tumor models observed in Mertk KO mice is not, however, phenocopied by the loss of Mertk alone. Neither Tyro3 nor macrophage phagocytosis by alternate genetic redundancy accounts for the absence of anti-tumor immunity. Collectively, our results indicate that context-dependent epistasis of independent modifier alleles determines Mertk KO traits.


Risk of Radiation Dermatitis in Patients With Skin of Color Who Undergo Radiation to the Breast or Chest Wall With and Without Regional Nodal Irradiation.
Acute radiation dermatitis (ARD) is common after radiation therapy for breast cancer, with data indicating that ARD may disproportionately affect Black or African American (AA) patients. We evaluated the effect of skin of color (SOC) on physician-reported ARD in patients treated with radiation therapy. We identified patients treated with whole breast or chest wall ± regional nodal irradiation or high tangents using 50 Gy in 25 fractions from 2015 to 2018. Baseline skin pigmentation was assessed using the Fitzpatrick scale (I = light/pale white to VI = black/very dark brown) with SOC defined as Fitzpatrick scale IV to VI. We evaluated associations among SOC, physician-reported ARD, late hyperpigmentation, and use of oral and topical treatments for RD using multivariable models. A total of 325 patients met eligibility, of which 40% had SOC (n = 129). On multivariable analysis, Black/AA race and chest wall irradiation had a lower odds of physician-reported grade 2 or 3 ARD (odds ratio [OR], 0.110; 95% confidence interval [CI], 0.030-0.397; P = .001; OR, 0.377; 95% CI, 0.161-0.883; P = .025), whereas skin bolus (OR, 8.029; 95% CI, 3.655-17.635; P = 0) and planning target volume D0.03cc (OR, 1.001; 95% CI, 1.000-1.001; P = .028) were associated with increased odds. On multivariable analysis, SOC (OR, 3.658; 95% CI, 1.236-10.830; P = .019) and skin bolus (OR, 26.786; 95% CI, 4.235-169.432; P = 0) were associated with increased odds of physician-reported late grade 2 or 3 hyperpigmentation. There was less frequent use of topical steroids to treat ARD and more frequent use of oral analgesics in SOC versus non-SOC patients (43% vs 63%, P < .001; 50% vs 38%, P = .05, respectively). Black/AA patients exhibited lower odds of physician-reported ARD. However, we found higher odds of late hyperpigmentation in SOC patients, independent of self-reported race. These findings suggest that ARD may be underdiagnosed in SOC when using the physician-rated scale despite this late evidence of radiation-induced skin toxicity.


Downregulation of estrogen receptor-α36 expression attenuates metastasis of hepatocellular carcinoma cells.
This study aimed to examine the role of estrogen receptor (ER)-α36 in the metastasis of hepatocellular carcinoma (HCC) and in the epithelial-mesenchymal transition (EMT). HCC HepG2 and Huh7 cells with the knocked-down level of ER-α36 expression were established. Cell growth and migration of the HepG2 and Huh7 cell variants were studied using MTS, transwell, and wound-healing assays, and the metastatic abilities of HepG2 cell variants were examined using a tail-vein injection model in nude mice. Levels of EMT markers, Src phosphorylation in HepG2 and Huh7 cell variants, and tumors formed by HepG2 cell variants in the nude mice were examined using Western blot and immunohistochemistry. We found that the growth and metastatic abilities of HepG2 and Huh7 cells with the knocked-down level of ER-α36 expression (HepG2/Si36 and Huh7/Si36) were significantly reduced, with increased levels of cytokeratin and E-Cadherin expression, and decreased levels of Vimentin, Snail, Slug and the Src phosphorylation, compared to the HCC cells transfected with an empty vector (HepG2/Vector and Huh7/Vector). We also found ER-α36 knockdown suppressed the lung metastasis of HepG2 cells with the involvement of EMT and the Src pathway in vivo. The Src inhibitor PP2 suppressed the growth and migration of HepG2/Vector and Huh7/Vector cells with decreased Vimentin, Snail, and Slug and increased cytokeratin and E-Cadherin expressions, but failed to induce the migration and the EMT markers in HepG2/Si36 and Huh7/Si36 cells. ER-α36 is involved in the metastasis of HCC cells through the regulation of EMT and the Src signaling pathway.


About "axial" and "radial" diffusivities.
This article presents the potential problems arising from the use of "axial" and "radial" diffusivities, derived from the eigenvalues of the diffusion tensor, and their interpretation in terms of the underlying biophysical properties, such as myelin and axonal density. Simulated and in vivo data are shown. The simulations demonstrate that a change in "radial" diffusivity can cause a fictitious change in "axial" diffusivity and vice versa in voxels characterized by crossing fibers. The in vivo data compare the direction of the principle eigenvector in four different subjects, two healthy and two affected by multiple sclerosis, and show that the angle, alpha, between the principal eigenvectors of corresponding voxels of registered datasets is greater than 45 degrees in areas of low anisotropy, severe pathology, and partial volume. Also, there are areas of white matter pathology where the "radial" diffusivity is 10% greater than that of the corresponding normal tissue and where the direction of the principal eigenvector is altered by more than 45 degrees compared to the healthy case. This should strongly discourage researchers from interpreting changes of the "axial" and "radial" diffusivities on the basis of the underlying tissue structure, unless accompanied by a thorough investigation of their mathematical and geometrical properties in each dataset studied.


Radiation-free quantitative assessment of scoliosis: a multi center prospective study.
Accurate quantitative measurements of the spine are essential for deformity diagnosis and assessment of curve progression. There is much concern related to the multiple exposures to ionizing radiation associated with the Cobb method of radiographic measurement, currently the standard procedure for diagnosis and follow-up of the progression of scoliosis. In addition, the Cobb method relies on 2-D analysis of a 3-D deformity. The aim of this prospective study was to investigate the clinical value of Ortelius800 that provides a radiation-free method for scoliosis assessment in three planes (coronal, sagittal, apical), with simultaneous automatic calculation of the Cobb angle in both coronal and sagittal views. Analysis of the clinical value of the device for assessing spinal deformities was performed on patients with adolescent idiopathic scoliosis, deformity angles ranging from 10 degrees to 48 degrees. Correlation between Cobb angles measured manually on standard erect posteroanterior radiographs and those calculated by Ortelius800 showed an absolute difference between the measurements to be significantly less than +/- 5 degrees for coronal measurements and significantly less than +/- 6 degrees for sagittal measurements indicating good correlation between the two methods. The measurements from four independent sites and six independent examiners were not significantly different. We found the novel clinical tool to be reliable for following mild and moderate idiopathic curves in both coronal and sagittal planes, without exposing the patient to ionizing radiation. Considering the need for further validation of this new method, any change in treatment protocol should still be based on radiographic control.


Clinical implication of the circumferential crescents lesions in immunoglobulin A nephropathy: a single-center study of Han Chinese population.
A crescentic lesion in renal biopsy could be segmental or circumferential, but the distribution and clinical implication of the circumferential crescents in immunoglobulin A nephropathy (IgAN) remains unknown. A total of 384 crescentic IgAN patients between 2011 and 2019 were included. The subjects were classified as the circumferential crescent who have at least one crescent involving ≥50% circumference of Bowman's capsule, otherwise as to the segmental crescent. Clinical, pathological, and prognostic relationships were analyzed. The primary endpoint was a 30% decline in eGFR, and the secondary endpoint was more than 3.5 g/d proteinuria during follow-up. Of the 384 patients, 72 (18.8%) patients had more than one circumferential crescent. 52 (17.6%) Oxford C1 patients have circumferential crescent. During a mean follow-up of 32.3 months, both the primary and secondary endpoints have occurred more in the circumferential crescent patients. Kaplan-Meier analysis showed the patient with the circumferential crescent had significantly lower renal survival than those without. In multivariable Cox analyses, having the circumferential crescents in at least one-fifth of glomeruli was independently associated with primary endpoint (hazard ratio:3.60, 95% CI:1.46-8.83), after adjusting for Oxford-score, eGFR, systolic blood pressure, and proteinuria. Furthermore, those patients who scored C1 in Oxford and presenting with circumferential crescents, had better renal survival if they received the other immunosuppressants therapy. The circumferential crescents lesion was associated with adverse outcomes in IgAN, and more than one-fifth of glomeruli circumferential crescents is an independent predictor of 30% eGFR decline after adjusting for clinical and histological parameters.


Synthesis and biological evaluation of 2,5-diaryl-1,3,4-oxadiazole derivatives as novel Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) inhibitors.
The Src homology-2 domain containing-protein tyrosine phosphatase-2 (SHP2) is a convergent node for oncogenic cell-signaling cascades including the PD-L1/PD-1 pathway. As an oncoprotein as well as a potential immunomodulator, SHP2 has now emerged as an attractive target for novel anti-cancer agents. Although significant progress has been made in identifying chemotypes of SHP2 inhibitors, these specific compounds might not be clinically useful to inhibit frequently encountered mutated SHP2 variants. Consequently, it is highly desirable to develop chemically different SHP2 inhibitors sensitive to SHP2 mutants. This work developed a new type of SHP2 inhibitors with 2,5-diaryl-1,3,4-oxadiazole scaffold. The representative compound 6l exhibited SHP2 inhibitory activity with IC50 of 2.73 ± 0.20 µM, showed about 1.56-fold, 5.26-fold, and 7.36-fold selectivity for SHP2 over SHP1, PTP1B and TCPTP respectively. Further investigations confirmed that 6l behaved as mixed-type inhibitor sensitive to leukemia cell TF-1 and inhibited SHP2 mediated cell signaling and proliferation. Molecular dynamics simulation provided more detailed information on the binding modes of compounds and SHP2 protein. These preliminary results could provide a possible opportunity for the development of novel SHP2 inhibitors sensitive to SHP2 mutants with optimal potency and improved pharmacological properties.


Dose reduction factors when increasing dose rate in LDR or MDR brachytherapy of carcinoma of the cervix.
The detailed summary of results from Bristol where 270 patients with carcinoma of the cervix were treated with either 75 cGy/h from manually loaded caesium or 150 cGy/h by remote afterloading (Newman, G. Increased morbidity following the introduction of remote afterloading, with increased dose rate, for cancer of the cervix. Radiother. Oncol. 39: 97-103, 1996) can be analysed to study the radiobiological factors that could have contributed to the different outcomes reported. The increases in grade 3 late complications from 4 to 22%, and in grade 2 + 3 from 12 to 32%, in spite of a reduction of 20% in dose, imply a rather large difference in biological effect between the two systems, which might or might not be due to dose rate differences. The possibility that a significant part of the effect might have been due to the dose rate is investigated, with particular attention to what values of radiobiological parameters might explain it, or can be excluded. A similar set of clinical data from Tilsburg (Rodrigus, P., de Winter, K., Venselaar, J. and Leers, W.H. Evaluation of late morbidity in patients with carcinoma of the uterine cervix following a dose rate change. Radiother. Oncol. 42: 137-141, 1997), where dose rate was doubled from 54 to 107 cGy/h with a dose reduction of 20%, is also considered. Linear quadratic modelling is employed to calculate Biologically Effective Doses (or ERDs) corresponding to the clinical protocols used. Repair of sublethal radiation damage at a range of half-times is assumed, both for mono- and bi-exponential components. When the LDR is doubled it is called MDR in the present study. The maximum ratios calculated for the BEDs of 16 Gy at MDR to 20 Gy at LDR were 1.06-1.15, assuming alpha/beta = 4-2 Gy, the latter being an unlikely extreme for rectal or urinary complications. These maxima occurred over a narrow range of t1/2 values from 1.5 to 2.5 h. If t1/2 were as long as 4-7 h or as short as 0.5-0.75 h, the biological effects would have been equal. The theoretically ideal dose reduction factors, calculated using the t1/2 values derived from the clinical data, are in the range of 24-29% instead of 20%. Somewhat greater dose reduction factors for late complications were suggested by this analysis than the 20% that has been commonly used when the dose rate is increased, both from the Bristol and Tilsburg data. The Bristol data showed no loss of therapeutic ratio on changing from manual to remote afterloading. Due to the close-to-optimum choice of the dose reduction factor which was actually used, some values for the half-time of repair of late complications in gynaecological brachytherapy could be estimated and used to calculate the theoretical dose reduction factors.


Impact of downstream effects of glucocorticoid receptor dysfunction on organ function in critical illness-associated systemic inflammation.
Glucocorticoids (GCs) are stress hormones that regulate developmental and physiological processes and are among the most potent anti-inflammatory drugs to suppress chronic and acute inflammation. GCs act through the glucocorticoid receptor (GR), a ubiquitously expressed ligand-activated transcription factor, which translocates into the nucleus and can act via two different modes, as a GR monomer or as a GR dimer. These two modes of action are not clearly differentiated in practice and may lead to completely different therapeutic outcomes. Detailed aspects of GR mechanisms are often not taken into account when GCs are used in different clinical scenarios. Patients, with critical illness-related corticosteroid insufficiency, treated with natural or synthetic GCs are still missing a clearly defined therapeutic strategy. This review discusses the different modes of GR function and its importance on organ function in vivo.


Phase behavior of binary and ternary fluoropolymer (PVDF-HFP) solutions for single-ion conductors.
A fluoropolymer poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) has a dielectric constant of ∼11, providing charge screening effects. Hence, this highly polar PVDF-HFP material has been employed as a matrix for solid polymer electrolytes (SPEs). In this study, the phase behavior of binary PVDF-HFP solutions was analyzed using the Flory-Huggins theory, in which ethylene carbonate, propylene carbonate, dimethyl carbonate, γ-butyrolactone, and acetone were employed as model solvents. In particular, for the binary PVDF-HFP/acetone system, the solid-liquid and liquid-liquid phase transitions were qualitatively described. Then, the phase diagram for ternary acetone/PVDF-HFP/polyphenolate systems was constructed, in which the binodal, spinodal, tie-line, and critical point were included. Finally, when a polyelectrolyte lithium polyphenolate was mixed with the PVDF-HFP matrix, it formed a single-ion conductor with a Li+ transference number of 0.8 at 23 °C. In the case of ionic conductivity, it was ∼10-5 S cm-1 in solid state and ∼10-4 S cm-1 in gel state, respectively.


Artifactual phosphate binding due to impurities in [32P]orthophosphate.
Many commercial preparations of [32P]orthophosphate contain radioactive impurities that interfere with binding and transport studies in biological systems. One type of impurity is micro-particulate whereas another may be pyrophosphate. Methods of removing these impurities from radiolabeled orthophosphate solutions are described.


One-step percutaneous nephrolithotomy sheath versus standard two-step technique.
Advances in technique and equipment have allowed urologists to perform percutaneous stone removal with increasing efficacy and decreasing complications. The procedure of choice for large renal calculi is percutaneous nephrolithotomy. At our institution, percutaneous access is achieved by a two-step process using either Amplatz dilators or placement of a high-pressure balloon catheter for tract dilation, followed by advancement of a sheath over the balloon. A novel device, the Pathway Access Sheath (PAS) has been developed that allows for balloon tract dilation and percutaneous access sheath placement in one simple step. Our study population consisted of 21 patients, who were randomized to one of two arms. Of the 21 patients, 10 underwent standard two-step access using a high-pressure balloon catheter and 11 underwent percutaneous nephrolithotomy using the novel PAS. We compared the insertion time, blood loss, and cost between the two techniques. The average insertion time was shorter in the PAS group (3 minutes) compared with the high-pressure balloon catheter (5 minutes, 42 seconds); a difference that was statistically significant (P <0.01). The estimated blood loss and cost were similar between the two groups. The increased sheath flexibility of the PAS was noted to be an advantage in some patients. The results of our study have shown that a novel single-step renal access device is safe and efficacious and results in a shorter insertion time for percutaneous nephrolithotomy. Blood loss was less in the PAS group as well, although the difference was not statistically significant. Additional studies will establish whether this device will provide a new standard of obtaining renal access.


ZnO and cobalt phthalocyanine hybridized graphene: efficient photocatalysts for degradation of rhodamine B.
A novel method has been developed to synthesize graphene-ZnO composite as a highly efficient catalyst by reduction of graphite oxide and in situ deposition of ZnO nanoparticles by chemical reduction reaction. The graphene-ZnO catalyst is capable of complete degradation of rhodamine B under exposure to natural sunlight. Further, the catalytic efficiency of graphene-ZnO catalyst was enhanced by sensitizing with cobalt phthalocyanine. The formation of graphene-ZnO photocatalyst and its further sensitization with cobalt phthalocyanine was characterized using UV-vis, ATR-IR and Raman spectroscopy, powder XRD and thermogravimetric analysis. The morphology of both graphene-ZnO and graphene-ZnO-CoPC catalysts was analyzed using scanning and transmission electron microscopes.


Shoulder kinetics and ultrasonography changes after performing a high-intensity task in spinal cord injury subjects and healthy controls.
This corrects the article DOI: 10.1038/sc.2015.140.


Conifer-killing bark beetles locate fungal symbionts by detecting volatile fungal metabolites of host tree resin monoterpenes.
Outbreaks of the Eurasian spruce bark beetle (Ips typographus) have decimated millions of hectares of conifer forests in Europe in recent years. The ability of these 4.0 to 5.5 mm long insects to kill mature trees over a short period has been sometimes ascribed to two main factors: (1) mass attacks on the host tree to overcome tree defenses and (2) the presence of fungal symbionts that support successful beetle development in the tree. While the role of pheromones in coordinating mass attacks has been well studied, the role of chemical communication in maintaining the fungal symbiosis is poorly understood. Previous evidence indicates that I. typographus can distinguish fungal symbionts of the genera Grosmannia, Endoconidiophora, and Ophiostoma by their de novo synthesized volatile compounds. Here, we hypothesize that the fungal symbionts of this bark beetle species metabolize spruce resin monoterpenes of the beetle's host tree, Norway spruce (Picea abies), and that the volatile products are used as cues by beetles for locating breeding sites with beneficial symbionts. We show that Grosmannia penicillata and other fungal symbionts alter the profile of spruce bark volatiles by converting the major monoterpenes into an attractive blend of oxygenated derivatives. Bornyl acetate was metabolized to camphor, and α- and β-pinene to trans-4-thujanol and other oxygenated products. Electrophysiological measurements showed that I. typographus possesses dedicated olfactory sensory neurons for oxygenated metabolites. Both camphor and trans-4-thujanol attracted beetles at specific doses in walking olfactometer experiments, and the presence of symbiotic fungi enhanced attraction of females to pheromones. Another co-occurring nonbeneficial fungus (Trichoderma sp.) also produced oxygenated monoterpenes, but these were not attractive to I. typographus. Finally, we show that colonization of fungal symbionts on spruce bark diet stimulated beetles to make tunnels into the diet. Collectively, our study suggests that the blends of oxygenated metabolites of conifer monoterpenes produced by fungal symbionts are used by walking bark beetles as attractive or repellent cues to locate breeding or feeding sites containing beneficial microbial symbionts. The oxygenated metabolites may aid beetles in assessing the presence of the fungus, the defense status of the host tree and the density of conspecifics at potential feeding and breeding sites.


Healthy life expectancy for selected race and gender subgroups: the case of Tennessee.
To analyze healthy life expectancy (HLE) for major racial and gender subgroups, based on the diverse population of Tennessee and compared with the United States. We use life table methodology and the HLE calculation model of the National Center for Health Statistics (NCHS), using two databases for 2001: NCHS National Vital Statistics Reports life tables and CDC Behavioral Risk Factor Surveillance System (BRFSS) survey. For Tennessee, although average total life expectancy (TLE) is 73.6 years at birth, only 61.1 years of "good" health are expected. Substantial racial and gender differences are found in both TLEs and HLEs with black males having the lowest and white females the highest. Although females have longer TLE, they spend more years in an unhealthy state than males. The findings raise new challenges for researchers and health policy makers for accomplishing the dual goals of longer life expectancy and elimination of health disparities among population subgroups.


[201Thalium SPECT in the detection of recurrent laryngeal carcinoma].
To evaluate the diagnostic yield of (201)Thallium SPECT in the detection of local and/or regional lymph node dissemination of pharyngolaryngeal carcinoma. 29 patients who had been diagnosed with pharyngolaryngeal carcinoma were studied (mean age: 60.9 years). These patients had been treated by surgery, chemotherapy and radiotherapy. At between 3 to 6 month after finishing the treatment, all of them underwent a planar and SPECT study at one hour after the administration of 148 MBq of (201)Thallium. Uptake was scored on four grades: from 0 (no uptake) to 3 (very intense uptake). The presence or non-presence of lymph nodes with uptake was also evaluated. All the results on the scintigraphy were correlated with long term clinical and radiological follow-up (mean: 2.5 years). The studies were classified as positive for recurrence when the uptake was 2-3 and/or with presence of lymph nodes with uptake. We obtained 9 true positive, 14 true negative, 3 false positive and 3 false negative results. Sensitivity was 75%, specificity was 82.4%, positive predictive value was 75% and negative predictive value was 82.4%. Two out of three false positives corresponded to the surgical bed uptake and one was attributed to the laterocervical lymph nodes. The three false negatives had grade 1 uptakes, two of them corresponding to pulmonary metastasis without evidence of local recurrence. The use of (201)Thallium SPECT in the prognostic evaluation in patients with a treated laryngeal carcinoma shows very acceptable results in the detection of local recurrence and/or regional lymph node dissemination.


Effects of leukotriene B4 and prostaglandin E2 on the differentiation of murine Foxp3+ T regulatory cells and Th17 cells.
Leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) are shown to be potent immunoregulatory lipid mediators. Here, we examined the effects of LTB4 and PGE2 on the differentiation of immunosuppressive CD4+CD25+Foxp3+ T regulatory cells (Treg) and pro-inflammatory IL-17-producing cells (Th17) from murine naïve CD4+ T cells. Using MACS-purified murine CD4+CD62L+ naïve T cells, we found that three days later in the presence of TGF-beta1, (28.65+/-6.83)% cells were converted into Treg cells, the mRNA expression of the key transcription factor Foxp3 peaked at 36h. Both LTB4 and PGE2 dose-dependently decreased the percentage of Treg cells and the mRNA expression of Foxp3. When the CD4+CD62L+ T cells were activated under Th17-promoting conditions in the presence of TGF-beta1 plus IL-6, three days later the production of IL-17 was markedly increased and the key transcription factor RORgammat mRNA peaked at 48h. LTB4 dose-dependently increased the secretion of IL-17 and the expression of RORgammat mRNA, whereas PGE2 decreased the secretion of IL-17 and the RORgammat mRNA expression. Our results suggest a distinct mode of immunoregulative action by PGE2 and LTB4, which may further our understanding of the role for lipid inflammatory mediators in the physiopathology of autoimmune diseases such as rheumatoid arthritis.


Reporting only relative effect measures was potentially misleading: some good practices for improving the soundness of epidemiological results.
In the medical and epidemiological literature there is a growing tendency to report an excessive number of decimal digits (often three, sometimes four), especially when measures of relative occurrence are small; this can be misleading. We combined mathematical and statistical reasoning about the precision of relative risks with the meaning of the decimal part of the same measures from biological and public health perspectives. We identified a general rule for minimizing the mathematical error due to rounding of relative risks, depending on the background absolute rate, which justifies the use of one or more decimal digits for estimates close to 1. We suggest that both relative and absolute risk measures (expressed as a rates) should be reported, and two decimal digits should be used for relative risk close to 1 only if the background rate is at least 1/1,000 py. The use of more than two decimal digits is justified only when the background rate is high (ie, 1/10 py).


Field evaluation of the fertilizing potential of biologically treated sanitation products.
Among different approaches of treating source-separated urine and feces for agronomic utilization, the treatment by addition of nitrifying bio-seeds seems to be useful in increasing the fertilizing potential of these sanitation products by modifying and stabilizing the nitrogen profile. In this study, biological treatment was applied to an onsite resource-oriented sanitation system by adding nitrifying microorganism bio-seeds. Further, the potential of the sanitation products to be utilized as fertilizer for white radish (Raphanus sativus var. longipinnatus) cultivation was examined and compared with that of a commercial fertilizer. This was done through the measurement of nutrients released in soil samples as well as measurements of root mass, root length, and the measurement of accumulated nitrogen, sugar, and water content in plant tissues. Our results show that soil fertilized with a mixture of biologically treated urine and feces exhibits a statistically similar nutrient release trend to soil fertilized using a commercial fertilizer. Moreover, soil fertilized with a mixture of biologically treated urine and feces yielded larger white radishes with a higher sugar and water content, as well as a higher accumulation of nutrients in the plant tissues, than soil fertilized with a commercial fertilizer.


Effects of SK&F 105685, a novel anti-arthritic agent, on immune function in the dog.
SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4,5]decane-2-propanamine+ ++ dihydrochloride) is a novel azaspirane with beneficial activity in animal models of autoimmune disease such as adjuvant-induced arthritis and experimental encephalomyelitis in the Lewis rat and lupus-like disease in the MRL mouse. The activity of SK&F 105685 in these models is associated with the induction of non-specific suppressor cell (SC) activity as defined by the ability of cells from drug-treated animals to inhibit the proliferative response of lymphocytes from control animals to concanavalin A. To evaluate the immunotoxicologic potential of SK&F 105685, the effect on immune function of one month of dosing with 1 mg/kg/day of SK&F 105685 was examined in the dog. Differential blood cell counts and ex vivo immune function assays were performed using blood collected before dosing on days 1 (baseline), 15 and 29, of the study. Immune function assays were performed on spleen cells on day 30. Under the conditions of the study, SK&F 105685 displayed pharmacological activity as demonstrated by the induction of splenic SC activity. The drug did not affect the total number or relative percentages of the various white blood cell types present in peripheral blood and did not cause generalized immunosuppression. The ability of peripheral blood lymphocytes or spleen cells to produce IL-2 or proliferate in response to mitogenic stimulation was not affected by drug treatment. SK&F 105685 also failed to affect the candidacidal activity of polymorphonuclear leucocytes and spleen cells indicating that it is unlikely to compromise nonspecific resistance to infection. SK&F 105685 however, was able to inhibit the generation of a specific in vitro antibody response to sheep red blood cells (SRBC) by splenocytes from treated animals. Inhibition of the anti-SRBC antibody response was also observed upon addition of the drug to normal spleen cells. Addition of the drug at different time points during the culture period indicated that SK&F 105685 was interfering with an event(s) occurring during the first 72 h of culture. Taken together, these results suggest that, in a therapeutic setting, SK&F 105685 is unlikely to compromise the immune status of the host as it can down-regulate a specific immune response without causing generalized immunosuppression.


An extremely rare association of coarctation of aorta with double chambered right ventricle: double-trouble causing bi-ventricular failure in a child.
Double chambered right ventricle is a rare cardiac defect characterised by an obstructive hypertrophied muscle bundle in the right ventricle. The common associated lesions are ventricular septal defect followed by sub-aortic membrane. We report a child who had coarctation of aorta in association with double chambered right ventricle. This case is being reported for its rarity and challenges in management.


Thoron levels in traditional Chinese residential dwellings.
A survey on radon (222Rn), thoron (220Rn) and its decay products (220RnD) was conducted in Chinese traditional residential dwellings constructed with loam bricks or soil wall. The activity concentrations in 164 dwellings under investigation were 72.4+/-59.2 (arithmetic mean, AM) and 57.5+/-2.0 Bq m-3 (geometric mean, GM) for 222Rn, and 318+/-368 and 162+/-3.7 Bq m-3 for 220Rn, respectively. For 220RnD, 67 dwellings were studied. The AM of the 220RnD equilibrium equivalent concentration was 3.8+/-3.3 Bq m-3 with a maximum value of 15.8 Bq m-3. On the basis of these results, the average annual effective doses to the local residents due to radon and thoron exposure were 1.44-4.62 mSv. Thoron contributes 12.9-56.6% to the total doses. Preliminary results show that there is a relation between 220RnD in air and 232Th in soil. The correlation factors of outdoor and indoor were 0.88 and 0.40. The 232Th activity content of Chinese soil is estimated to be about two times the world average. The traditional residential dwellings with soil construction are still common in China. Further investigations on the 220Rn level in these dwelling with the aim of dose reduction are proposed.


Indocyanine Green Drives Computer Vision Based 3D Augmented Reality Robot Assisted Partial Nephrectomy: The Beginning of "Automatic" Overlapping Era.
Augmented reality robot-assisted partial nephrectomy (AR-RAPN) is limited by the need of a constant manual overlapping of the hyper-accuracy 3D (HA3D) virtual models to the real anatomy. To present our preliminary experience with automatic 3D virtual model overlapping during AR-RAPN. To reach a fully automated HA3D model overlapping, we pursued computer vision strategies, based on the identification of landmarks to link the virtual model. Due to the limited field of view of RAPN, we used the whole kidney as a marker. Moreover, to overcome the limit of similarity of colors between the kidney and its neighboring structures, we super-enhanced the organ, using the NIRF Firefly fluorescence imaging technology. A specifically developed software named "IGNITE" (Indocyanine GreeN automatIc augmenTed rEality) allowed the automatic anchorage of the HA3D model to the real organ, leveraging the enhanced view offered by NIRF technology. Ten automatic AR-RAPN were performed. For all the patients a HA3D model was produced and visualized as AR image inside the robotic console. During all the surgical procedures, the automatic ICG-guided AR technology successfully anchored the virtual model to the real organ without hand-assistance (mean anchorage time: 7 seconds), even when moving the camera throughout the operative field, while zooming and translating the organ. In 7 patients with totally endophytic or posterior lesions, the renal masses were correctly identified with automatic AR technology, performing a successful enucleoresection. No intraoperative or postoperative Clavien >2 complications or positive surgical margins were recorded. Our pilot study provides the first demonstration of the application of computer vision technology for AR procedures, with a software automatically performing a visual concordance during the overlap of 3D models and in vivo anatomy. Its actual limitations, related to the kidney deformations during surgery altering the automatic anchorage, will be overcome implementing the organ recognition with deep learning algorithms.


Bilateral congenital oval window microfistulae in a mother and son.
This article details case histories of a son and his mother who were studied over a seven-year period before making the diagnosis of bilateral oval window microfistulae in both of them. The boy demonstrated a slowly progressive bilateral and symmetrical sensorineural hearing loss closely resembling that of his mother. The case reports emphasize their respective histories, diagnostic evaluation, surgical observations, and treatment.


A Single-Step Digestion for the Quantification and Characterization of Trace Particulate Silica Content in Biological Matrices Using Single Particle Inductively Coupled Plasma-Mass Spectrometry.
The increased use of amorphous silica nanoparticles (SiNPs) in food products, materials science, cosmetics, and pharmaceuticals has raised questions about potential hazards in the environment and in human health. Although SiNPs are generally thought to be benign, recent studies have demonstrated toxicity in different cell and animal models. Despite their ubiquitous use, SiNPs are rarely analyzed quantitatively. Often, the methods used to analyze silicon and SiNPs are difficult, costly, require the use of dangerous reagents, and are prone to interferences. Additionally, characterization of SiNPs in complex matrices requires extensive sample preparation. To address this, we propose a single-step digestion method for the determination of trace SiNP content in biological matrices. For conventional inductively coupled plasma-mass spectrometry (ICP-MS) analysis, biological samples are often digested with concentrated HNO3. We found that with conventional ICP-MS, lower limits of detection (LLOD) of silicon are too high for trace analysis. However, we found that SiNPs are stable at a strong acidic pH; thus, concentrated HNO3 could be used to digest biological samples leaving SiNPs intact. Then, by analysis with single particle ICP-MS, we found that the smallest SiNP that could be read was 185 nm in size. The concentration for the LLOD was found to be 0.032 ppb with interday variability in sizing and concentration at 2.5% and 6.8% respectively. Utilizing this method, SiNPs were accurately sized and counted in cell pellets and media. Our proposed method can be used to accurately quantify and characterize SiNPs (or agglomerated SiNPs) larger than the derived LLOD in a variety of biological matrices and will assist in determining relationships between exposures of SiNPs and toxicity in humans and the environment.


Hepatocyte growth factor promotes an anti-inflammatory cytokine profile in human abdominal aortic aneurysm tissue.
Abdominal aortic aneurysm (AAA) is characterized by the destruction of tissue architecture due to chronic inflammation of unknown etiology. Recent studies have indicated that control of inflammation is a promising therapeutic strategy; however, no established pharmacological intervention is currently available for AAA. We found that hepatocyte growth factor (HGF) was expressed in aneurysmal tissue, and colocalized with von Willebrand factor, the endothelial cell marker, in the most damaged part of the aneurysmal walls. In ex vivo cultures of human AAA tissue, exogenously added HGF in the presence of tumor necrosis factor-alpha (TNF-α) enhanced the secretion of anti-inflammatory cytokine interleukin-10 (IL-10) and suppressed the secretion of proinflammatory monocyte/macrophage chemotactic protein-1 (MCP-1). The angiotensin converting enzyme (ACE) inhibitors, imidaprilat and perindoprilat, enhanced the secretion of endogenous HGF, augmented the TNF-α-induced IL-10 secretion and suppressed MCP-1 secretion from AAA tissue. The ACE inhibitors also augmented the expression of HGF in the presence of bradykinin in human aortic endothelial cells in culture (HAECs). In contrast, HGF secretion was not affected by either an angiotensin II type 1 receptor (AT1) antagonist or angiotensin II in AAA tissue or in HAECs. These results suggested that angiotensin converting enzyme inhibitors may be useful in controlling chronic inflammation in AAA, partly due to their enhancement of HGF secretion.


Diagnostic workup of Cushing's syndrome.
Cushing's syndrome (CS) is a rare but detrimental endocrine disorder. Early diagnosis and prompt treatment are essential since the duration of hypercortisolism has an adverse impact on the extent of comorbidities and overall survival. The diagnostic approach involves a stepwise process that includes (1) screening and confirming the diagnosis and (2) establishing the aetiology of CS. The tests currently used to confirm the diagnosis of CS include urinary free cortisol measurements, the dexamethasone suppression test and late- night salivary cortisol or midnight serum cortisol measurements. None of these tests are ideal; all have pitfalls and require careful interpretation. Following confirmation of CS, measurement of ACTH discriminates between ACTH-dependent and non-ACTH dependent causes of CS. Adrenal imaging provides clues for the aetiology of non-ACTH dependent forms. Differentiation between the ACTH-dependent forms that involve pituitary corticotroph adenomas and ectopic ACTH sources is more complex and include pituitary MRI imaging, the high dose dexamethasone suppression test, the CRH test, bilateral inferior petrosal sinus sampling and, when required imaging modalities to detect ectopic ACTH secreting lesions. This review, which is part of a special issue on "Update of Cushing's syndrome: 100 years after Minnie G" will provide an update on our current diagnostic workup for the confirmation and differential diagnosis of CS.