Representational dynamics of memories for real-life events.
The continuous flow of experience that characterizes real-life events is not recorded as such in episodic memory but is condensed as a succession of event segments separated by temporal discontinuities. To unravel the neural basis of this representational structure, we recorded real-life events using wearable camera technology and used fMRI to investigate brain activity during their temporal unfolding in memory. We found that, compared to the representation of static scenes in memory, dynamically unfolding memory representations were associated with greater activation of the posterior medial episodic network. Strikingly, by analyzing the autocorrelation of brain activity patterns at successive time points throughout the retrieval period, we found that this network showed higher temporal dynamics when recalling events that included a higher density of event segments. These results reveal the key role of the posterior medial network in representing the dynamic unfolding of the event segments that constitute real-world memories.


Fetal and neonatal genistein exposure aggravates to interfere with ovarian follicle development of obese female mice induced by high-fat diet.
With epidemic of obesity, it affects aspects of female reproduction. Genistein could ameliorate obesity in people and animals, but might exert adverse effects on the female reproductive system. To evaluate the effects of fetal and neonatal genistein exposure on the ovarian health of F1 obese female mice with obesity induced by high-fat diet after weaning, we simulated a diet-induced obesity model to observe and determine biological effects of genistein exposure on the ovarian follicle of overfed female mice. Results showed that F1 female mice with obesity induced by high-fat diet significantly prolonged the estrus cycle, disrupted sex hormonal balance and ovarian follicle development after they were exposed to 25 mg/kg b.w./day of genistein during the fetal and neonatal stages. Genistein significantly up-regulated the ovarian mRNA expression of estrogen receptor beta in F1 obese female mice, and high-fat diet influenced the ovarian mRNA expression of estrogen receptor alpha, luteinizing hormone receptor and follicle-stimulating hormone receptor. Hence, genistein exposure from the fetal stage might increase the risk of reproductive diseases in obese females in later life. Thus, the long-term risks of genistein to obese females should be thoroughly assessed.


Stigma Towards Mental Illness Among Tanta University Students, Egypt.
A "mental disorder" can be defined as a "behavioral or psychological syndrome that occurs in an individual. It represents about 13% of the global disease burden which is expected increase to 15% by 2020. Moreover, by 2020, depression is expected to be second to ischemic heart disease as a contributor in the global disease burden. This study aimed to assessment of stigmatizing beliefs towards mental illness among students, in Tanta University, Egypt. The study was conducted on medical, pharmaceutical and science faculties, Tanta University, Egypt during October and November 2018. The methods were a self administered questionnaire consisted of two parts sociodemographic factors and Belief about Mental Illness Scale. The results were: the pharmaceutical students have more negative beliefs towards mental illness than other students. The study concluded that: science students showing a more positive belief towards mental illness followed by medical then pharmaceutical students.


Cebranopadol for the Treatment of Chronic Pain.
Regardless of the etiology, if pain persists chronically, it can detrimentally impact multiple aspects of a patient's well-being. Both physical and psychological effects are significant in many chronic pain patients. In this regard, psychological consequences can alter a patient's quality of life, functionality, and social functioning. Opioids have been the long-established gold standard for acute pain treatment in settings such as the postoperative period. An alternative to opioids in pain management has been highly sought after. Through a non-selective mechanism, cebranopadol is a first-in-class oral drug which combines agonism of the mu and nociceptin opioid peptide (NOP) receptors to provide improved analgesia, while reducing the occurrence of many typically opioid side effects. This manuscript is a narrative review of the possible use of cebranopadol in pain management. In pre-clinical studies, cebranopadol was similar to morphine in its pain control efficacy. In a phase IIa trial, cebranopadol was superior to placebo in reducing pain. In a randomized clinical trial, cebranopadol was superior to morphine. Another study concluded that cebranopadol had a lower misuse potential when compared to hydromorphone. In summary, cebranopadol offers new opportunities in treating chronic moderate to severe pain, while also countering risks of addiction. Additional studies are warranted to further evaluate the safety and efficacy of cebranopadol. In this regard, cebranopadol could prove to be a promising alternative to current pain treatment options.


Electrochemical and DFT studies of brass corrosion inhibition in 3% NaCl in the presence of environmentally friendly compounds.
The effects of adenine, salicylaldoxime and 4(5)-methylimidazole on brass corrosion in NaCl were investigated. The investigation comprised electrochemical techniques, scanning electron microscopy and quantum chemical calculation. The results obtained by polarization measurements show that the examined compounds successfully inhibited the corrosion of brass. Additionally, the quantum mechanical calculations indicate that there is a correlation between energy gap and inhibition efficiency. Moreover, the inhibition mechanism includes the adsorption of the inhibitor on active sites on the electrode surface, which was confirmed by SEM-EDS analysis of the brass.


Effect of repeated treatment with a gamma-aminobutyric acid receptor agonist on postnatal neural development in rats.
The effect of treatment with the gamma-aminobutyric acid (GABA) agonist tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) on neural development was monitored in rats by following the expression of the neuron-specific proteins neural cell adhesion molecule (NCAM), D1, and D3 as well as the enzymes glutamate decarboxylase (GAD) and glutamate dehydrogenase (GLDH). As judged from the effect of the treatment on the expression of NCAM and GAD, GABA agonists have the capacity to accelerate and enhance neuronal development during the early postnatal period. However, as judged from the expression of D1- and D3-protein some adverse late effects may result from prolonged treatment with high doses of GABA agonists. The decrease in GLDH specific activity observed in THIP-treated rats during their late postnatal development possibly indicates a repression of glutamatergic neurons.


Idiosyncratic hepatic toxicity in autosomal dominant polycystic kidney disease (ADPKD) patient in combined treatment with tolvaptan and amoxicillin/clavulanic acid: a case report.
Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease characterized by the presence of renal cysts. Over time the expanding cysts lead to progressive renal failure. The use of tolvaptan, a V2-receptor antagonist, was recently approved in ADPKD patients. It was demonstrated that tolvaptan get slower decline in Kidney function compared with placebo. Idiosyncratic hepatic toxicity was described in patients receiving tolvaptan, with elevations in aminotransferases levels. We describe the first case reported in the literature in which hepatic toxicity is caused by the association of amoxicillin/clavulanic acid and tolvaptan. A 41 years old woman with diagnosis of ADPKD had been in treatment with tolvaptan for 16 weeks when an elevation of liver enzyme levels was detected. She had taken autonomously amoxicillin/clavulanic acid (in doses of 825/175 mg twice a day for 7 days) about 5 weeks before. The timing of the event and the kind of hepatocellular injury could be attributed to the concomitance of medication of tolvaptan and amoxicillin/clavulanic acid. We highlight the need to careful monitor hepatic enzyme levels in order to recognize early hepatic side effects in ADPKD patients in treatment with tolvaptan and amoxicillin/clavulanic acid.


Does OSA Increase Risk for Cancer?: A Large Historical Sleep Clinic Cohort Study.
The relationship between OSA and cancer is unclear. What is the association between OSA and cancer prevalence and incidence in a large Western Australian sleep clinic cohort (N = 20,289)? OSA severity was defined by apnea-hypopnea index (AHI) and nocturnal hypoxemia (duration and percentage at oxygen saturation < 90%) measured by in-laboratory polysomnogram. Measures of potential confounding included age, sex, BMI, smoking status, socioeconomic status, and BP. Outcomes were determined from the Western Australian cancer and death registries. Analyses were confined within periods using consistent AHI scoring criteria: January 1, 1989, to July 31, 2002 (American Sleep Disorders Association criteria), and August 1, 2002, to June 30, 2013 (Chicago criteria). We examined associations of AHI and nocturnal hypoxemia with cancer prevalence using logistic regression and cancer incidence using Cox regression analyses. Cancer prevalence at baseline was 329 of 10,561 in the American Sleep Disorders Association period and 633 of 9,728 in the Chicago period. Nocturnal hypoxemia but not AHI was independently associated with prevalent cancer following adjustment for participant age, sex, BMI, smoking status, socioeconomic status, and BP. Of those without prevalent cancer, cancer was diagnosed in 1,950 of 10,232 (American Sleep Disorders Association) and 623 of 9,095 (Chicago) participants over a median follow-up of 11.2 years. Compared with the reference category (no OSA, AHI < 5 events per hour), univariable models estimated higher hazard ratios for cancer incidence for mild (AHI 5-15 events per hour), moderate (AHI 15.1-30 events per hour), and severe (AHI > 30 events per hour) OSA. Multivariable analyses consistently revealed associations between age and, in some cases, sex, BMI, and smoking status, with cancer incidence. After adjusting for confounders, multivariable models showed no independent association between OSA severity and increased cancer incidence. Nocturnal hypoxemia is independently associated with prevalent cancer. OSA severity is associated with incident cancer, although this association seems secondary to other risk factors for cancer development. OSA is not an independent risk factor for cancer incidence.


Effects of enzyme replacement therapy with agalsidase alfa on glomerular filtration rate in patients with Fabry disease: preliminary data.
Progressive deposition of globotriaosylceramide results in severe complications involving the kidney, heart and brain in both hemizygous male and heterozygous female patients with Fabry disease. Analysis of renal data from FOS--the Fabry Outcome Survey--suggests that enzyme replacement therapy with agalsidase alfa can significantly improve renal function in patients with Fabry disease, at least in those with a mild decrease in glomerular filtration rate, and may also be able to slow down the natural decline in renal function in patients with a moderate reduction in glomerular filtration rate. Initial results from the large cohort of patients within FOS indicate that treatment with agalsidase alfa has beneficial effects on kidney function in patients with Fabry disease.


Complications in Interventional Radiology: the role of clinical governance and iterative hospital systems in quality improvement.
As modern Interventional Radiology (IR) evolves, and expands in scope and complexity, it will push the boundaries of existing literature. However, with all intervention comes risk and it is the shared judgement of the risk-benefit analysis which underpins the ethical and legal principles of care in IR.Complications in medicine are common, said to occur in 9.2% of in-hospital healthcare interactions. Healthcare complications also come at considerable cost. It is estimated that in the UK, prolonging hospital stays to manage complications can cost ₤2 billion per year.However, complications can't be viewed in isolation. Clinical governance is the umbrella within which complications are viewed. It can be defined as a broadly integrated and systematic approach to clinical care and accountability, that seeks to focus on quality of healthcare. This concept incorporates complications but acknowledges their interplay within a complex healthcare system in which negative adverse events are influenced by a range of intrinsic and extrinsic factors. It also includes the processes that result from monitoring and learning from complications, with feedback leading to systems-based improvements in care moving forward. The reality is that complications are uncommonly the result of medical negligence, but rather they are an unfortunate by-product of a healthcare industry with inherent risk.It is also important to remember that complications are not just a number on an audit sheet, but a potentially life-changing event for every patient that is affected. The events that follow immediately from an adverse outcome such as open disclosure are vital, and have implications for how that patient experiences healthcare and trusts healthcare professionals for the rest of their life. We must ensure that the patient and their family maintain trust in healthcare professionals into the future.Credentialling and accreditation are imperative for Interventional Radiologists to meet existing standards as well deal with challenging situations. These should integrate and align within the structure of an organization that has a safety and learning culture. It is the many layers of organisational clinical governance that arguably play the most important role in IR-related complications, rather than apportioning blame to an individual IR.


Selvester QRS score predicts improvement of LVEF in atrial fibrillation patients with systolic heart failure.
Left-ventricular systolic dysfunction (LVSD) comorbid with atrial fibrillation is reversible, but recovery is limited in a subset of patients. The Selvester QRS (S-QRS) score is an electrocardiogram-based assessment that reportedly reflects myocardial scar/damage. We evaluated the predictability of S-QRS score for the recovery of left-ventricular ejection fraction (LVEF) in persistent AF (PeAF) patients with LVSD undergoing catheter ablation (CA). CA was performed in 51 PeAF patients with reduced LVEF (<40%); S-QRS scores were measured after restoration of sinus rhythm. LVEF was re-evaluated at one year after CA; LVEF recovery was related to the S-QRS score. The median [interquartile range] S-QRS score was 1 point [0-2]. LVEF increased from 32% [28-37] at baseline to 56% [49-57] at 1 year after CA. Thirty-seven patients achieved normalization of LVEF (≥50%, Group A); 14 patients did not (Group B). Group A had significantly lower S-QRS scores than Group B (0 point [0-2] vs. 2 points [2-3], p < .05). In univariate/multivariate analyses, S-QRS score was an independent predictor of LVEF normalization. In the receiver operating characteristic curve, the cut-off value of S-QRS score was 2 points for prediction of the LVEF normalization (AUC = 0.79). Patients with low S-QRS score (<2 points) had greater LVEF improvement than those with high S-QRS score (≥2 points, ΔLVEF: 23% [17-28] vs. 17% [12-24], p < .05). S-QRS scoring noninvasively assesses the improvement of LVEF in PeAF patients with LVSD after CA. A high S-QRS score may indicate underlying myocardial scar/damage associated with unknown etiologies for LVSD other than PeAF.


Virus-induced diabetes in mice: a quantitative evaluation of islet cell population by immunofluorescence technique.
The endocrine cell populations of pancreatic islets in encephalomyocarditis (EMC)-virus infected mice were assessed quanititatively by immunofluorescence using specific antisera against 4 islet hormones. A marked reduction of the volume of insulin-containing (B-) cells (up to one tenth of control values) was observed at all stages studied in the hyperglycaemic mice. This was accompanied by the inversion of the normal ratio between B- and non B-cells. The volume of the latter cell types was also modified at different time points after infection: glucagon-cells were augmented 14 days after infection; PP-cells were decreased 2--3 days and 21 days after infection; somatostatin-cells decreased to one-fourth of control values in hyperglycaemic animals 21 days after infection. The latter results suggest that non B-cells are also involved in islet reaction to virus infection.


Bioinformatic analysis of the origin, sequence and diversification of mu opioid receptors in vertebrates.
Opioid receptors are a class of G protein-coupled receptors that mediate the effects of the different families of endogenous opioid peptides and natural alkaloid drugs such as morphine and its synthetic derivatives. In particular, the mu opioid receptor (MOR) represents the principal molecular target for morphine and it plays key roles in opioid analgesia and addiction. In this work, new putative MORs from different vertebrate species were identified in silico and their gene organization and predicted protein products are compared with the previously characterized MORs. Also, for the first time a new genomic organization in euteleleostei teleosts has been identified. Moreover, we suggest that MORs may be specific to craniate lineage. The analysis of functional mapping of MORs we present is an important contribution to the identification of their evolutionarily conserved regions.


Applying safety lessons from aviation to pre-licensure health professions education: A narrative critical review.
Significant numbers of patients continue to be harmed annually by healthcare systems in the United States (US) and around the world. Through a lens of safety, the fields of aviation and healthcare share many similarities in the non-technical skills required by team members, including situational awareness, communication, problem-solving, and leadership. Despite these links and evidence of effective interventions in the clinical setting, there is a lack of a guidance on how to incorporate non-technical skills training into pre-licensure health professions curricula. Following guidance for a narrative critical review, a comprehensive literature search was conducted looking for studies incorporating non-technical skills training including crew resource management (CRM) and human factors and ergonomics (HFE) into pre-licensure health professions curricula. Eleven example articles were organized into three broad themes: (1) changing the teaching paradigm around errors, (2) targeted curricular interventions, and (3) interprofessional team training. Several useful tools for evaluating training effectiveness were highlighted, but consistent measures of efficacy for CRM/HFE training are lacking. Interprofessional team training may have the most tangible and broadly applicable link to pre-licensure curricula. Additional research is needed to identify best practices for consistent incorporation of non-technical skills into pre-licensure curricula. A cultural shift to focus on error management (vs. solely error avoidance) is also needed early in training with development of a common language to discuss patient safety issues and opportunities for improvement across various healthcare settings.


Robust, high brightness, degenerate entangled photon source at room temperature.
We report on a compact, simple and robust high brightness entangled photon source at room temperature. Based on a 30-mm-long periodically-poled potassium titanyl phosphate crystal, the source produces non-collinear, type-0, phase-matched, degenerate photons at 810 nm with spectral brightness as high as ~0.41 ± 0.02 (~0.025 ± 0.02) MHz/mW/nm for multi (single) mode fiber coupling. So far, this is the highest number of degenerate photons generated using a continuous-wave laser pumped bulk crystal and detected using multimode fiber. We have studied the dependence of pump focusing on the brightness of the generated photons collected using both multimode, and single mode fibers. For a fixed pump power and crystal parameters, the SPDC source has an optimum pump waist radius producing maximum number of paired photons. Combining the crystal in a novel system architecture comprised with Sagnac interferometer and polarizing optical elements, the source produces polarization entangled photon states with high spectral brightness. Even in the absence of any phase compensation, the entangled photon states detected using single mode fiber have a Bell's parameter, S = 2.63 ± 0.02, violating the Bell's inequality by nearly 32 standard deviations and fidelity of 0.975. The compact footprint, robust design, and room temperature operation, make our source ideal for various quantum communication experiments.


The Lumipulse G HBsAg-Quant assay for screening and quantification of the hepatitis B surface antigen.
Qualitative HBsAg assay is used to screen HBV infection for decades. The utility of quantitative assay is also rejuvenated recently. We aimed to evaluate and compare the performance of a novel ultra-sensitive and quantitative assay, the Lumipulse assay, with the Architect and Elecsys assays. As screening methods, specificity was compared using 2043 consecutive clinical routine samples. As quantitative assays, precision and accuracy were assessed. Sera from 112 treatment-naïve chronic hepatitis B patients, four patients undergoing antiviral therapy and one patient with acute infection were tested to compare the correlations. Samples with concurrent HBsAg/anti-HBs were also quantified. The Lumipulse assay precisely quantified ultra-low level of HBsAg (0.004 IU/mL). It identified additional 0.98% (20/2043) clinical samples with trance amount of HBsAg. Three assays displayed excellent linear correlations irrespective of genotypes and S-gene mutations (R(2)>0.95, P<0.0001), while minor quantitative biases existed. The Lumipulse assay did not yield higher HBsAg concentrations in samples with concomitant anti-HBs. Compared with other assays, the Lumipulse assay is sensitive and specific for detecting HBsAg. The interpretation of the extremely low-level results, however, is challenging. Quantitative HBsAg results by different assays are highly correlated, but they should be interpreted interchangeably only after conversion to eliminate the biases.


Expression of myb, myc and fos proto-oncogenes during the differentiation of a murine myeloid leukaemia.
It is widely thought that c-onc genes (or proto-oncogenes)--the cellular progenitors of retroviral transforming genes--are involved in cellular differentiation and/or proliferation. Such ideas originate primarily from the ability of v-onc genes and 'activated' c-onc genes to induce uncontrolled cellular proliferation, and their capacity to arrest or interfere with differentiation processes in some systems. Haematopoietic cell populations provide additional support for these ideas as c-myb RNA is present in cell lines corresponding to immature, but not mature, cell types, and elevated levels have been found in tissues that are active in haematopoiesis. We have now examined the effects of induced differentiation on c-onc gene expression in a murine myeloid leukaemia cell line, WEHI-3B ('D+' subline). Our results show that the expression of c-myb and c-myc, at the level of transcription, decreases only at late stages in the monocytic differentiation of WEHI-3B cells, while expression of c-fos increases markedly. We suggest that c-myb and c-myc do not themselves control myeloid differentiation, but that they function in the maintenance of the proliferative state of myeloid cells. The induction of c-fos may reflect its role in some macrophage-specific functions.


Echocardiographic assessment in cardiogenic shock.
Echocardiography is the most helpful diagnostic modality in cardiogenic shock, the management of which still remains challenging despite advances in therapeutic options. The presence of cardiogenic shock portends high mortality rates. Therefore, rapid recognition, identification of the underlying cause, and evaluation of the severity of hemodynamic dysfunction are vital for correct management. Whether the cause of shock is unknown, suspected, or established, echocardiography is utilized in its diagnosis and management as well as to monitor progress. It is recommended as the modality of first choice. No other investigative bedside tool can offer comparable diagnostic capability, allowing for exact targeting of the underlying cardiac and hemodynamic problems. Echocardiography can promptly provide an impression of the etiology of shock and the potential line of treatment. Normal left ventricular and right ventricular systolic function, normal cardiac chamber dimensions, absence of any significant valvular pathology, and absence of any pericardial effusion virtually rule out a cardiac cause of shock. This review discusses the role of echocardiography as a decision-making tool in the evaluation and management of cardiogenic shock.


Effects of fish oil, corn oil and lard diets on lipid peroxidation status and glutathione peroxidase activities in rat heart.
In this study, we investigated the effect of various types of fats on heart lipid peroxidation status and on blood lipid parameters. Rats were fed either a low-fat diet (2.2% lard plus 2.2% corn oil), a corn oil diet (17%), a salmon oil diet (12.5%) supplemented with 4.5% corn oil, or a lard diet (15%) supplemented with 2% corn oil. All diets were supplemented with 1% cholesterol. Rats were fed for eight weeks. When compared with the low-fat diet, the salmon oil-diet intake resulted in a lower blood cholesterol, triglyceride and phospholipid concentrations (-50, -56 and -30%, respectively). Corn oil only tended to lower blood lipids; this decrease was significant for triglycerides only (-40%). The hypocholesterolemic effect of salmon oil diet is even more pronounced, if blood cholesterol values are compared with those of rats fed the lard diet. Heart lipid composition was not affected by dietary manipulations. Fatty acid composition of cardiac phosphatidylcholines and phosphatidylethanolamines, however, were altered by high-fat diets. In phosphatidylcholine, salmon oil induced a twelvefold decrease in the n-6/n-3 ratio and a 26% increase in the unsaturation index. For phosphatidylethanolamine, the n-6/n-3 ratio decreased 7.7-fold and the unsaturation index increased by 13%. A 50% decrease of the n-6/n-3 ratio was observed in animals fed the lard diet. Ultramicroscopic examination of ventricles revealed that those of the salmon oil group significantly accumulated lipofuscin-like or ceroid material, whereas this accumulation was barely detectable in hearts of the other groups.(ABSTRACT TRUNCATED AT 250 WORDS)


A plasminogen silent allele detected in a Swiss family.
An apparent incompatibility between mother and child in the plasminogen system has been clarified by the demonstration of a silent allele in the family.


Oral health in the Longitudinal Study of Australian Children: An age, period, and cohort analysis.
Oral health policy and funding must be informed by well-designed studies which monitor oral health and the factors which influence it. This study aimed to analyse the oral health of the Longitudinal Study of Australia Children (LSAC). The LSAC is a dual-cohort cross-sequential study run biennially since 2004. Carer-report measures for oral health were measured across six biennial waves and included frequency of tooth brushing, dental service use, and dental problems since the previous wave. A total of 10 090 Australian children participated at baseline (birth [B] n = 5017 and kindergarten [K] n = 4983). Most carers reported that children brushed daily and had regular access to dental care. Increasing age was a significant predictor of dental caries, whereas no differences were observed between time periods and cohorts. Dental caries was more frequently reported than dental injuries. Caries was highest at age eight for the B (n = 1234, 30.5%) and K (n = 1355, 31.5%) cohorts. By the age of six, caries prevalence had already begun to climb despite the majority of carers reporting good oral health behaviours for their children. Early intervention in the prevention of dental caries is essential, as children appear to attend dental services when caries is already occurring.


[Sarcoidosis of the larynx (author's transl)].
The isolated case of sarcoidosis of the larynx is very rare. We are referred to a case of histologically confirmed by the kweim-test of sarcoidosis of the false vocal cord. The problems of the case are discussed.


The therapeutic potential of colchicine in the complications of COVID19. Could the immunometabolic properties of an old and cheap drug help?
The present study analyzes the importance of the inflammasome that involves the NLRP3 complex in the state of hypercytokinemia observed in patients with COVID-19, significantly increasing IL-1β, IL18, IL-6, and TNF. Unfortunately, improving the immune response can sometimes worsen the outcome of the disease. Studies show that colchicine, among other actions, inhibits the assembly of NLRP3 complex that is responsible for generating the active form of Caspase-1 that will convert Pro-IL-1β and Pro-IL-18 into their active forms. We suggest using colchicine, a class of drugs with low-cost, extensively tested, well-tolerated medicine as a complementary treatment for patients with COVID-19, in early stages of the disease based on knowledge of its immunomodulatory properties.


Matt waste from glass separated collection: an eco-sustainable addition for new building materials.
Matt waste (MW), a by-product of purification processes of cullet derived from separated glass waste collection, has been studied as filler for self-compacting concrete and as an addition for newly blended cement. Properties of self-compacting concrete compared to reference samples are reported. They include characteristics at the fresh and hardened states, and the compressive strength and porosity of mortar samples that were formulated with increasing amounts of MW to be used as cement replacement (up to 50wt.%). The effects of matt waste are discussed with respect to the mechanical and microstructural characteristics of the resulting new materials.


CN-3 increases TMZ sensitivity and induces ROS-dependent apoptosis and autophagy in TMZ-resistance glioblastoma.
Many glioma patients develop resistance to temozolomide (TMZ) treatment, resulting in reduced efficacy and survival rates. TMZ-resistant cell lines SHG44R and U87R, which highly express O6 -methylguanine DNA methyltransferase (MGMT) and P-gp, were established. CN-3, a new asterosaponin, showed cytotoxic effects on TMZ-resistant cells in a dose- and time-dependent manner via reactive oxygen species (ROS)-mediated apoptosis and autophagy. Transmission electron microscopy and monodansylcadaverine (MDC) staining showed turgidity of the mitochondria and autophagosomes in CN-3-treated SHG44R and U87R cells. The autophagy inhibitor 3-methyladenine was used to confirm the important role of autophagy in CN-3 cytotoxicity in TMZ-resistant cells. The ROS scavenger N-acetyl- l-cysteine (NAC) attenuated the levels of ROS induced by CN-3 and, therefore, rescued the CN-3 cytotoxic effect on the viability of SHG44R and U87R cells by Cell Counting Kit-8 assays and JuLI-Stage videos. MDC staining also confirmed that NAC rescued an autophagosome increase in CN-3-treated SHG44R and U87R cells. Western blotting revealed that CN-3 increased Bax, cleaved-caspase 3, cytochrome C, PARP-1, LC3-Ⅱ, and Beclin1, and decreased P-AKT, Bcl-2, and p62. Further rescue experiments revealed that CN-3 induced apoptosis and autophagy through ROS-mediated cytochrome C, cleaved-caspase 3, Bcl-2, P-AKT, PARP-1, and LC3-Ⅱ. In addition, CN-3 promoted SHG44R and U87R cells sensitive to TMZ by reducing the expression of P-gp, MGMT, and nuclear factor kappa B p65, and it had a synergistic cytotoxic effect with TMZ. Moreover, CN-3 disrupted the natural cycle arrest and inhibited the migration of SHG44R and U87R cells by promoting cyclin E1 and D1, and by decreasing P21, P27, N-cadherin, β-catenin, transforming growth factor beta 1, and Smad2.


Slc20a2 deficiency results in fetal growth restriction and placental calcification associated with thickened basement membranes and novel CD13 and lamininα1 expressing cells.
The essential nutrient phosphorus must be taken up by the mammalian embryo during gestation. The mechanism(s) and key proteins responsible for maternal to fetal phosphate transport have not been identified. Established parameters for placental phosphate transport match those of the type III phosphate transporters, Slc20a1 and Slc20a2. Both members are expressed in human placenta, and their altered expression is linked to preeclampsia. In this study, we tested the hypothesis that Slc20a2 is required for placental function. Indeed, complete deficiency of Slc20a2 in either the maternal or embryonic placental compartment results in fetal growth restriction. We found that Slc20a2 null mice can reproduce, but are subviable; ∼50% are lost prior to weaning age. We also observed that 23% of Slc20a2 deficient females develop pregnancy complications at full term, with tremors and placental abnormalities including abnormal vascular structure, increased basement membrane deposition, abundant calcification, and accumulation of novel CD13 and lamininα1 positive cells. Together these data support that Slc20a2 deficiency impacts both maternal and neonatal health, and Slc20a2 is required for normal placental function. In humans, decreased levels of placental Slc20a1 and Slc20a2 have been correlated with early onset preeclampsia, a disorder that can manifest from placental dysfunction. In addition, preterm placental calcification has been associated with poor pregnancy outcomes. We surveyed placental calcification in human preeclamptic placenta samples, and detected basement membrane-associated placental calcification as well as a comparable lamininα1 positive cell type, indicating that similar mechanisms may underlie both human and mouse placental calcification.


Insulin Aspart in the Management of Diabetes Mellitus: 15 Years of Clinical Experience.
Limiting excessive postprandial glucose excursions is an important component of good overall glycemic control in diabetes mellitus. Pharmacokinetic studies have shown that insulin aspart, which is structurally identical to regular human insulin except for the replacement of a single proline amino acid with an aspartic acid residue, has a more physiologic time-action profile (i.e., reaches a higher peak and reaches that peak sooner) than regular human insulin. As expected with this improved pharmacokinetic profile, insulin aspart demonstrates a greater glucose-lowering effect compared with regular human insulin. Numerous randomized controlled trials and a meta-analysis have also demonstrated improved postprandial control with insulin aspart compared with regular human insulin in patients with type 1 or type 2 diabetes, as well as efficacy and safety in children, pregnant patients, hospitalized patients, and patients using continuous subcutaneous insulin infusion. Studies have demonstrated that step-wise addition of insulin aspart is a viable intensification option for patients with type 2 diabetes failing on basal insulin. Insulin aspart has shown a good safety profile, with no evidence of increased receptor binding, mitogenicity, stimulation of anti-insulin antibodies, or hypoglycemia compared with regular human insulin. In one meta-analysis, there was evidence of a lower rate of nocturnal hypoglycemia compared with regular human insulin and, in a trial that specifically included patients with a history of recurrent hypoglycemia, a significantly lower rate of severe hypoglycemic episodes. The next generation of insulin aspart (faster-acting insulin aspart) is being developed with a view to further improving on these pharmacokinetic/pharmacodynamic properties.


The impact of greyscale inversion for nodule detection in an anthropomorphic chest phantom: a free-response observer study.
The aim of this work was to assess the impact of greyscale inversion on nodule detection on posteroanterior chest X-ray images. Previous work has attempted this, with no consensus opinion formed. We assessed the value of "fast-flicking" between standard and inverted display modes for nodule detection. Six consultant radiologists (with 5-32 years' reporting experience) completed an observer task under the free-response paradigm. An anthropomorphic chest phantom was loaded with 50 different configurations of simulated nodules (1-4 nodules per case) measuring 5, 8, 10 and 12 mm in spherical diameter; each configuration represented a single case. In addition, 25 cases contained no nodules. Images were displayed in three modes: (i) standard, (ii) inverted and (iii) fast-flicking between standard and inverted display modes. Each observer completed the study in a different order of display (i, ii, iii) using a calibrated 5-megapixel monitor. Nodules were localized with mouse clicks and ratings assigned using a 1-10 discrete slider-bar confidence scale. Rjafroc (Pittsburgh, PA) was used for data analysis; differences in nodule detection performance were considered significant at 0.05. The observer-averaged weighted jackknife alternative free-response receiver-operating characteristic figures of merit were 0.715 (standard), 0.684 (inverted) and 0.717 (fast-flicking). Random-reader fixed-case analysis revealed no statistically significant difference between any treatment pair [F(2,8) = 1.22; p = 0.345]. No statistically significant difference in nodule detection was found for the three display conditions. We have investigated the impact of fast-flicking between standard and inverted display modes for the detection of nodules. We found no benefit.


Intra-cellular storage, transport and exocytosis of halogenated compounds in marine red alga Laurencia obtusa.
The production of secondary metabolites in seaweed have been related to a capability to partition compounds into cellular specialized storage structures, like gland cells and the corps en cerise (CC) or cherry bodies. The possible mechanisms that bring these compounds to the thallus surface remain poorly understood. Therefore, the aim of this work is perform a characterization of the CC and determine the intra-cellular dynamics of halogenated compounds in Laurencia obtusa. The dynamics of CC and the mechanisms related to the intra-cellular transport of halogenated compounds were evaluated by using optical tweezers and time-lapse video microscopy. The CC were isolated and its elemental composition was characterized using X-ray microanalysis. The cellular distribution of halogenated compounds was also demonstrated by fluorescence microscopy. Three-dimensional reconstruction technique was used to provide a visualization of the structures that connect CC to cell periphery. As main findings, we confirmed that the halogenated compounds are mainly found in CC and also in vesicles distributed along the cytoplasm and within the chloroplasts. We demonstrated that CC is mechanically fixed to cell periphery by a stalk-like connection. A vesicle transport though membranous tubular connections was seen occurring from CC to cell wall region. We also demonstrated a process of cortical cell death event, resulting in degradation of CC. We suggested that the vesicle transportation along membranous tubular connections and cell death events are related to the mechanisms of halogenated compounds exudation to the thallus surface and consequently with defensive role against herbivores and fouling.


Adeno-associated virus vectors and neurotoxicity-lessons from preclinical and human studies.
Over 15 years after hepatotoxicity was first observed following administration of an adeno-associated virus (AAV) vector during a hemophilia B clinical trial, recent reports of treatment-associated neurotoxicity in animals and humans have brought the potential impact of AAV-associated toxicity back to prominence. In both pre-clinical studies and clinical trials, systemic AAV administration has been associated with neurotoxicity in peripheral nerve ganglia and spinal cord. Neurological signs have also been seen following direct AAV injection into the brain, both in non-human primates and in a clinical trial for late infantile Batten disease. Neurotoxic events appear variable across species, and preclinical animal studies do not fully predict clinical observations. Accumulating data suggest that AAV-associated neurotoxicity may be underdiagnosed and may differ between species in terms of frequency and/or severity. In this review, we discuss the different animal models that have been used to demonstrate AAV-associated neurotoxicity, its potential causes and consequences, and potential approaches to blunt AAV-associated neurotoxicity.


Breast cancer correlates in a cohort of breast screening program participants in Riyadh, KSA.
Breast cancer is the first cancer among females in the Kingdom of Saudi Arabia, accounting for 27.4% of all newly diagnosed female cancers in 2010. There are several risk factors affecting the incidence of breast cancer where some factors influence the risk more than the others. We aimed to identify the different risk factors related to breast cancer among females participating in the breast-screening program in Riyadh, KSA. Based on data from phase-I of the breast-screening program, a case-control study was conducted on women living in Riyadh, KSA. A sample of 349 women (58 cases and 290 controls) was recruited to examine the different breast cancer correlates. Multivariate regression model was built to investigate the most important risk factors. The mean age of cases was 48.5±7.1 years. Age at marriage, number of pregnancy, age at menopause, oral contraceptive pills, breast feeding and family history of breast cancer in first-degree relative were identified as the most important correlates among the studied cohort. The findings of the current work suggested that age at marriage, age at menopause ⩾50 years and 1st degree family history of breast cancer were risk factors for breast cancer, while, age at menopause <50 years, number of pregnancies and practicing breast feeding were protective factors against breast cancer. There was no effect of body mass index or physical inactivity. Further studies are needed to explore the hereditary, familial and genetic background risk factors in Saudi population.


Cellular mechanisms in congestive heart failure.
There is substantial, although not yet conclusive, evidence that the failing heart is in an energy-depleted state. Such an imbalance between energy production and energy utilization would have important implications for the management of patients with congestive heart failure (CHF), most important of which is that therapeutic measures that increase myocardial energy demand could have long-term detrimental effects on the heart. By increasing energy expenditure, vasoconstrictors and positive inotropic agents could worsen cell damage, exacerbate relaxation abnormalities and promote arrhythmias. Conversely, therapy that improved the balance between energy delivery and energy expenditure might be expected to improve prognosis in CHF. For this reason, vasodilators and reduced inotropic drive to the failing heart could prolong survival in these patients. Further understanding of the energetics of the failing heart will be of considerable importance in the formulation of hypotheses regarding long-term therapy that could be evaluated in controlled clinical trials.


Findings of clinical and radiographic caries among several adult age groups.
The purpose of this study was to determine whether there are aged-based variations in the association between clinically detected and radiographically detected caries and whether the prevalence of clinically undetected radiographic caries varies across adult age groups. The data for the analysis were from a clinical study that evaluated the efficacy of guidelines for prescribing dental radiographs. A total of 460 subjects had clinical examinations and interpretation made on full-mouth radiographs. Analysis was conducted to determine the tooth-specific and subject-specific prevalences of clinically undetected caries and to establish whether the association between clinical signs and radiographic signs varied by subject age. In total, approximately 5.8% of clinically sound teeth showed radiographic evidence of dentinal caries, and the prevalence increased with patient age. The prevalence of clinical signs of medium and large caries was 7.8% in 12,358 teeth in which caries was both clinically and radiographically present. However, for more than 80% of the teeth with clinically undetected caries, the lesions were evident on the interproximal radiographs. The associations between clinical and radiographic signs of dentinal caries were homogeneous across age groups. The findings demonstrate that adolescents and adults continue to have medium and large caries, although the location of the caries differs by age group, with higher proportions of gingival caries in older patients.


Balance of pro- and anti-inflammatory cytokines in cirrhotic patients undergoing liver transplantation.
This study was prospectively aimed at having better information about the natural history of serum cytokines in cirrhotic patients undergoing liver transplant surgery and at assessing their ability to set up an appropriate dynamic relationship between pro-inflammation and anti-inflammation. The levels of six cytokines (TNF-α, IL-1, IL-2, IL-6, IL-8, IL-10) were measured in blood samples collected at different time points before, during and after (48 h) the transplant procedure from the radial artery of 62 consecutive cirrhotic patients who underwent orthotopic liver transplantation. IL-1 always stayed within the normal range; IL-2 showed elevated baseline levels but decreased up to half at the end of the study (p<0.0001). IL-6 peaked at the end of surgery and returned to baseline 48 h afterwards. The same happened to IL-8 concentrations. IL-10 levels shown above the normal threshold at baseline, peaked at the end of surgery (p<0.0001) and were halved at the end of the study (p<0.0001). TNF-α peaked at the end of surgery without, however, being different from baseline levels (p=0.6). The physiologic pattern of cytokine release and their dynamic relationship was found to be preserved with a quick return to a balance between pro-inflammation and anti-inflammation as shown by the IL-6/IL-10 and TNF-α/IL 10 ratios (used to assess the inflammatory balance). A correlation was found between perioperative pro-inflammatory cytokine levels and the severity of the liver disease necessitating OLT. In summary, cirrhotic patients can achieve a balanced inflammatory response to surgery which is considered a primary requirement for uneventful grafts and patients' postoperative recovery.


Formal Synthesis of 4-diphosphocytidyl-2-C-methyl D-erythritol From D-(+)-Arabitol.
2-C-methyl-D-erythritol-4-phosphate (MEP) is a key chemical intermediate of the non-mevalonate pathway for isoprenoid biosynthesis employed by many pathogenic microbes. MEP is also the precursor for the synthesis of 4-diphosphocytidyl-2-C-methyl D-erythritol (CDP-ME), another key intermediate of the non-mevalonate pathway. As this pathway is non-existent in higher animals, including humans, it represents great opportunities for novel antimicrobial development. To facilitate the in-depth studies of this pathway, we reported here a formal synthesis of CDP-ME through a new synthesis of 2-C-Methyl-D-erythritol-4-phosphoric acid from D-(+)-arabitol.


Raman spectroscopy study of isolated double-walled carbon nanotubes with different metallic and semiconducting configurations.
A double-walled carbon nanotube (DWNT) provides the simplest system to study the interaction between concentric layers in carbon nanotubes. The inner and outer walls of a DWNT can be metallic (M) or semiconducting (S), and each of the four possible configurations (M@M, M@S, S@S, S@M) has different electronic properties. Here we report, for the first time, detailed Raman spectroscopy experiments carried out on individual DWNTs, where both concentric tubes are measured under resonance conditions, in order to understand the dependence of their electronic and optical properties according to their configuration. Interestingly, for the three DWNTs that were studied, the inner-outer tube distance (e.g., 0.31-0.33 nm) was less than the interlayer spacing in graphite. We believe these results have important implications in the fabrication of electronic devices using different types of S and M tubular interconnects.


Serum levels of soluble interleukin-2 receptor at acute asthma exacerbation: relationship with severity of exacerbation and bronchodilator response.
T lymphocytes play a central role in the regulation of airway inflammation in asthma, and T cell activation appears to be a characteristic feature of acute asthma. It is not clear, however, whether this is proportional to the severity of acute asthma and is directly related to airway inflammation relevant to airflow obstruction during acute asthma. It is presumed that the extent to which bronchoconstriction or inflammation contributes to airflow obstruction in acute asthma may determine responsiveness to bronchodilator therapy. Fifty asthmatic children who visited the emergency room due to acute exacerbation were studied. Serum levels of soluble interleukin-2 receptor (sIL-2R), a marker of T cell activation, were measured at the time of acute exacerbation and of clinical remission. At acute exacerbation, FEV1 was assessed before and after the administration of aerosolized salbutamol. The mean (+/-SD) serum level of sIL-2R at acute exacerbation (854+/-248 U/ml) was significantly higher (p<0.01) than at clinical remission (676+/-211 U/ml). It correlated positively with the severity of exacerbation (r = 0.47, p<0.01), but showed no significant relationship with bronchodilator response (r = -0.17, p = 0.20). A higher serum level of sIL-2R at acute exacerbation was associated with more severe exacerbation but not with lower bronchodilator response. These findings suggest that in the context of acute asthma, T cell activation is proportional to disease activity, but its relationship to airway inflammation relevant to the genesis of airflow obstruction remains obscure.


Nerve fiber transfer by end-to-side coaptation.
To bring some light into the ongoing controversy concerning end-to-side coaptation in brachial plexus surgery, the authors organized a symposium in 2006 titled How To Improve Peripheral Nerve Surgery. The authors sought the participation of experienced surgeons and researchers who had made personal contributions to the field. This article contains information collected at this symposium and presents the authors' clinical results and ideas illustrating the potential of nerve fiber transfer by end-to-side coaptation.


Spinal canal stenosis in children with achondroplasia: the role of augmentation laminoplasty-a 15-year single institution experience.
Achondroplasia typically results in compressive spinal canal stenosis in one-third of children, but rare under the age of 15 years. Laminectomy is the mainstay of treatment but this leads to instability and progressive deformity requiring complex fixation. In order to reduce that risk, we developed a novel modified augmented laminoplasty that increases spinal canal diameter while preserving the posterior column stability. All laminoplasty cases for spinal compressive achondroplasia from 2006 to 2020 were included. Ten augmentation laminoplasty procedures were performed in 7 children with regular clinical and radiological post-operative follow-up. Kyphotic deformity and clinical outcomes (neurological and urological) were evaluated. At presentation, clinical features included radiculopathy, neurogenic claudication or acute cauda equina compression with sphincter dysfunction. The average age at initial surgery was 11.2 (range 5-16) with a mean follow-up of 5 (range 2-8) years. All patients demonstrated improvement in neurogenic claudication symptoms after surgery; however, bladder dysfunction persisted in some children. In one child, cervical and lumbar augmentation laminoplasties were performed for concomitant disease. Augmentation laminoplasty effectively prevented deformity progression over time in all cases except one where a further revision laminoplasty with extension was required for screw loosening. Despite this, progressive symptomatic kyphotic deformity led to a 360° fixation. Minor complications included one dural breach (repaired intraoperatively) and one superficial wound infection. Augmentation laminoplasty is a viable surgical option following laminectomy in achondroplasia patients as an alternative to surgical fixation. Fixation can be reserved for cases where there is progressive deformity and kyphosis.


Purification and characterisation of a non-specific lipid transfer protein from goat liver.
A non-specific lipid transfer protein has been purified from the pH 5.1 supernatant of goat liver by DEAE-cellulose, CM-cellulose and Sephadex G-75 column chromatography. The protein shows a single band on polyacrylamide gel electrophoresis and transfers 450 nmol of phosphatidylcholine per min per mg of protein under the present assay condition. This protein has a subunit molecular weight of 12,000 and an isoelectric point of 8.65. Amino acid analysis reveals the absence of methionine. Histidine has been identified as the only N-terminal amino acid. Besides phosphatidylcholine, the protein transfers phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine and cholesterol. Chemical modification studies showed the involvement of free amino and thiol groups in the maintenance of the transfer activity of the goat liver protein.


Connectional analysis of the ipsilateral and contralateral afferent neurons of the superior temporal region in the rhesus monkey.
The interhemispheric and ipsilateral afferents of the superior temporal region (STR) were investigated with the aid of fluorescent retrograde tracers (Diamidino Yellow and Fast Blue). Different tracers were injected in selected cortical areas of the STR of each hemisphere of four rhesus monkeys. The results show that the interhemispheric afferents originate not only from the homotopic but also from heterotopic areas. The heterotopic areas giving rise to interhemispheric projections correspond to cortical areas of the origin of the ipsilateral projections. Although there is considerable overlap of labeled neurons of both afferent systems, only occasional double-labeled neurons are found. Whereas the laminar patterns of ipsilateral neurons of origin vary considerably, the interhemispheric projection neurons are located mainly in cortical layer III. This study provides additional information about the ipsilateral connectional organization of the superior temporal region. That is, the primary auditory area receives projections not only from adjacent lateral and medial cortical regions but also from adjoining rostral and caudal cortical regions. Thus, the highly differentiated primary auditory cortical area receives strong projections from the surrounding less-differentiated cortical regions. This connectional pattern is discussed from the perspective of the growth ring concept of cortical development.


Low- versus high-dose azithromycin triple therapy for Helicobacter pylori infection.
We report a clinical trial which evaluated the effectiveness of triple therapy containing low- and high-dose azithromycin to treat Helicobacter pylori infection. From March 1997 to March 1998, patients infected with H. pylori were assigned to receive either: Treatment 1: ranitidine bismuth citrate (RBC) (400 mg b.d.) and amoxycillin (1 g b.d.) for 10 days with azithromycin 500 mg o.m. for 3 days: or Treatment 2: RBC and amoxycillin for 10 days with azithromycin 1 g o.m. for 3 days. H. pylori eradication was established by a urea breath test at least 4 weeks after therapy. Side-effects and compliance were assessed using a diary. Sixty-eight patients were enrolled. Fifty-seven per cent of patients were treated for active peptic ulcer disease or a history of peptic ulcer disease. Treatment 1 cured H. pylori in 44% and 44% by per protocol and intention-to-treat analysis, respectively. The corresponding eradication rates for Treatment 2 were 79% and 75%. Two patients taking Treatment 2 dropped out of the study because of side-effects. With RBC and amoxycillin for 10 days, azithromycin at a dose of 1 g/day for 3 days was significantly better at curing H. pylori infection than azithromycin 500 mg/day for 3 days.


Modeling desertification change in Minqin County, China.
Monitoring environmental processes is becoming increasingly important wherever there is increasing population and economic development pressure placed on fragile environments. Remote sensing, digital image processing, and spatial analysis have proven to be useful technologies in both assessing and monitoring environmental change. In this study, they were used to assess desertification processes and change in Minqin County, China from 1988 to 1997. The results suggest that wind erosion was the dominant cause of desertification in more than half of the study area. Coupled with this were increases in salinization processes, affecting 33.62% of the land area in 1997. Overall, moderate desertification was found to be the dominant desertification grade (43.64% of total area), followed by extreme/severe desertification (26.15% of total area) in 1997. In addition, examination of landscape pattern changes indicated that desertification processes at the landscape level were becoming evident at increasing levels of fragmentation, complexity in shape, and isolation of patches. Major fluctuations in desertification type and grade were found at the fringes of oases, where an ongoing shift was taking place between cultivation, abandonment, and reclamation.


The capacity of visual short-term memory is not a fixed number of objects.
Luck and Vogel (1997) have reported several striking results in support of the view that visual short-term memory (VSTM) has a fixed capacity of four objects, irrespective of how many relevant features those objects comprise. However, more recent studies have challenged this account, indicating only a weak effect of the number of objects once other factors are more evenly equated across conditions. Here, we employed a symmetry manipulation to verify object segmentation in our displays, to demonstrate that when spatial and masking factors are held constant, the number of objects per se has no effect on VSTM. Instead, VSTM capacity may reflect the number of object "parts" or feature conjunctions in a given display.


Open-label, randomised controlled trial found that a green banana mixed rice suji diet was most effective for persistent diarrhoea in children in Bangladesh.
Persistent diarrhoea continues for at least 14 days and kills more children than acute diarrhoea. We assessed whether rice suji, green banana mixed rice suji or 75% rice suji improved persistent diarrhoea in young children. This open-labelled randomised controlled trial was carried out between December 2017 and August 2019 at the Dhaka Hospital of icddr,b, Bangladesh, with 135 children aged 6-35 months with persistent diarrhoea. The children were randomly assigned to green banana mixed rice suji, rice suji or 75% rice suji, with 45 in each group. The primary outcome was the percentage who recovered from diarrhoea by day 5 using an intention-to-treat analysis. The children's median age was 8 months (interquartile range: 7-10 months). By day 5, the recovery rate was 58%, 31% and 58% for children in the green banana mixed rice suji, rice suji and 75% rice suji groups, respectively. The green banana mixed rice suji group had fewer relapses (7%) than the 75% rice suji group (24%). Enteroaggregative Escherichia coli, rotavirus, norovirus, Enteropathogenic Escherichia coli, astrovirus and Campylobacter were the major pathogens for persistent diarrhoea. Green banana mixed rice suji was the most effective option for managing persistent diarrhoea in young children.


The Tortoise and the Hare: Evolving Regulatory Landscapes for Biosimilars.
Challenges in demonstrating interchangeability and safety, as well as the ongoing evolution of regulations governing biosimilars, have meant that the development of the biosimilars industry has not been, and will not be, a carbon copy of the generics industry. Complexity in the development process reduces the cost advantages for biosimilars that generics offer over originators. There has been a marked difference in the number of biosimilars approved by the European Medicines Agency (EMA) and US FDA due to a lack of consensus and the different rates of progress in establishing both law and stable evidence-based regulatory guidelines for biosimilars. In this review, we provide a précis of the history and status of the regulatory regimes in the USA and Europe. Included is an assessment of market and nonmarket factors that may continue to influence the development of the biosimilars industry.


Cytosine-arabinoside-induced colitis and peritonitis: nonoperative management.
Cytosine arabinoside is known to cause severe gastrointestinal side effects in an already very ill patient population. Three cases are reviewed in which apparent surgical peritonitis was managed conservatively, with very careful clinical monitoring. Two of the patients recovered completely, and one died of systemic fungal infection. No patient had a surgically remediable condition, and all were extremely poor surgical risks. A review of our experience and the literature leads us to recommend careful conservative management in patients receiving cytosine arabinoside who appear to have a "surgical abdomen," but in whom a definitive surgical diagnosis cannot be made.


Low-Dose Pioglitazone does not Increase ROS Production in Chronic Granulomatous Disease Patients with Severe Infection.
We sought to further investigate the efficacy and safety of pioglitazone for chronic granulomatous disease (CGD) patients with severe infection. CGD patients with severe infection were enrolled and treated with pioglitazone for 90 days. The degree of improvement in infection and the changes of dihydrorhodamine-123 (DHR) were used to evaluate the efficacy of pioglitazone. The adverse reaction of pioglitazone was also investigated. We planned to enroll 30 patients at first in the study. However, the study was terminated due to negative results from all 3 enrolled patients. The 3 patients were diagnosed with CGD by clinical characteristics, DHR analysis, and genetics analysis. Mutations were CYBB (c.177C>A; p.C59X) in P1, CYBB (c.1498G>T; p.D500Y) in P2, and NCF2 (c.137T>G; p.M46R) in P3, respectively. The age of onset of the 3 patients was within 2 years after birth. The most common sites of infection were lung, lymph node, skin, and soft tissue, which were experienced in all 3 patients. The age of administration with pioglitazone was 5.2 years, 16 years and 11.1 years, respectively. The 3 patients experienced no improvement in severity of infection and stimulation index of the DHR did not also improve after receiving pioglitazone 10, 45 and 90 days, respectively. No drug-related adverse reaction was found during the period of pioglitazone. Low dose of pioglitazone did not improve the severity of infection and production of ROS in CGD patients with severe infection.


Relationship between leg extensor muscle strength and knee joint loading during gait before and after total knee arthroplasty.
The aim of the present study was to evaluate an isometric maximal voluntary contraction (MVC) force of the leg extensor muscles and its relationship with knee joint loading during gait prior and after total knee arthroplasty (TKA). Custom-made dynamometer was used to assess an isometric MVC force of the leg extensor muscles and 3-D motion analysis system was used to evaluate the knee joint loading during gait in 13 female patients (aged 49-68 years) with knee osteoarthritis. Patients were evaluated one day before, and three and six months following TKA in the operated and non-operated leg. Six months after TKA, MVC force of the leg extensor muscles for the operated leg did not differ significantly as compared to the preoperative level, whereas it remained significantly lower for the non-operated leg and controls. The knee flexion moment and the knee joint power during mid stance of gait was improved six months after TKA, remaining significantly lowered compared with controls. Negative moderate correlation between leg extensor muscles strength and knee joint loading for the operated leg during mid stance was noted three months after TKA. The correlation analysis indicates that due to weak leg extensor muscles, an excessive load is applied to knee joint during mid stance of gait in patients, whereas in healthy subjects stronger knee-surrounding muscles provide stronger knee joint loading during gait. III (correlational study).


Added value of trabecular bone score to bone mineral density for prediction of osteoporotic fractures in postmenopausal women: the OPUS study.
The objective of this study was to consider whether trabecular bone score (TBS) improves on areal bone mineral density (aBMD) measurement alone for the prediction of incident fractures in postmenopausal women. The OPUS study was conducted in ambulatory European women aged above 55years, recruited in 5 centers followed over 6years. For the assessment of the performance of TBS, baseline Hologic scans from 3 centers (Kiel, Paris and Sheffield) were available. Follow-up for incident fractures was available for 1007 women (mean age 65.9±6.9years). We compared the performance of TBS, aBMD, and their combination, by using net reclassification improvement (NRI, primary analysis) and receiver operator characteristic (ROC) c-statistical analysis with ORs and areas under the curves (AUCs) (secondary analyses). 82 (8.1%) subjects with incident clinical osteoporotic fractures, and 46 (4.6%) with incident radiographic vertebral fractures were recorded over 6years. Performance of TBS was significantly better than lumbar spine (LS) aBMD for the prediction of incident clinical osteoporotic fractures (NRI=16.3%, p=0.007). For radiographic vertebral fractures, TBS and LS aBMD had similar predictive power but the combination of TBS and LS aBMD increased the performance over LS aBMD alone (NRI=8.6%, p=0.046) but the prediction is similar to hip and femoral neck aBMD. In non osteoporotic women, TBS predicted incident fragility fractures similarly to LS aBMD. This prospective study shows that in general population, TBS is a useful tool to improve the performance of lumbar spine aBMD for vertebral osteoporotic fractures.


Partial determination of the primary structure of a variant surface glycoprotein from Trypanosoma equiperdum. Composition and location of a carbohydrate moiety.
Salivarian trypanosomes have the ability to evade the immune response of their hosts by the sequential expression of different cell surface glycoproteins. Among the isolated specific antigens from cloned variants of Trypanosoma equiperdum, a structural study was undertaken on two immunologically cross-reacting variant surface glycoproteins, and results concerning the basic antigenic type are reported. The glycoprotein was cleaved by cyanogen bromide, and amino acids of several purified fractions obtained by gel filtration chromatography of this cleavage mixture were sequenced by automated Edman degradation. Sequencing in particular allowed the identification of the N-terminal portion of the molecule (residues 1-74). Sugar compositions of the fractions have demonstrated the presence of at least two carbohydrate moieties in the glycoprotein. Using a subsequent enzymatic subcleavage we were able to locate the first glycosylation site in position 57. An important observation was that the first oligosaccharide identified was rich in mannose and devoid of galactose.


Sexually deviant behavior and schizotypy: a theoretical perspective with supportive data.
Sexual offenses against adults and children continue to increase annually. Although theory and research have helped explain the personality functioning and motivation of sexual offenders, most treatment approaches have been found to have high recidivism rates and have failed to address the heterogeneity of sex offender populations. In the present paper, we utilize the growing literature on schizotypic personality organization to describe a subgroup of sex offenders. Data from the sex offender personality literature which indicates signs of thought disturbances among some sex offenders are reviewed in the context schizotypy. We conclude that treatment programs which address the heterogeneity of sex offenders and employ interventions to treat cognitive disturbances will likely result in greater efficacy.


Assessing opioid administration in pediatric burn patients with nonsurgical management.
Despite the vast literature studying the opioid crisis, sparse data describe this in the pediatric burn population. This study sought to assess patient-level characteristics and their potential effects on opioid administration in nonsurgical pediatric burn inpatients. Admitted burn patients from 2013 to 2018 with nonsurgical management at an American Burn Association (ABA) verified pediatric burn center were retrospectively identified. Morphine milligram equivalents by weight (MME/kg) per admission were evaluated through a multiple loglinear regression with race, sex, age, total body surface area burned (TBSA), and burn depth as predictors. Simple linear regression was used to evaluate the temporal trend of median opioid utilization. A total of 806 patients (55% White, 35% Black, 5% Hispanic, 5% Other) were included. In an adjusted analysis, no differences in opioid administration were seen by sex, burn degree, or for Blacks and Hispanics when compared with Whites. Increased MME/kg was associated with older age (10-18 years; p<0.0001) and larger burns (>5% TBSA burned; p<0.0001). From 2013 to 2018, median MME/kg per admission declined significantly (2013:0.21, 2018:0.09; p=0.0103). Nonsurgical burn patients who were older and presented with larger TBSA experienced marked increases in opioid utilization. Overall, opioid administration decreased over time.


Prevalence and risk factors for MSDs in vegetable greenhouse farmers: a cross-sectional survey from Shandong rural area, China.
The aim of the research is a cross sectional survey on the prevalence of symptoms related to MSDs in vegetable greenhouse farmers from Shandong rural area and on the risk factors that may influence it. This cross-sectional survey was selected 249 farmers working in vegetable greenhouse from different districts of Shandong Province, China. The Questionnaire and the Rapid Upper Limb Assessment (RULA) technique were used to identify ergonomic risks. χ2 analysis was used to find the relationship between MSDs and various factors. Also, logistic regression methodology was applied to get the most influencing factor for MSDs. The prevalence of MSDs in farmers working in vegetable greenhouse is 87.5%, and the top 3 prevalent areas of MSDs in various parts of the body are: lower back (47.4%), neck (33.3%), and shoulder (31.7%). The results of Logistic regression analysis showed that age, years working in vegetable greenhouses, keeping their backs in the same position for a long time, and working hours greater than 10 hours per day were the risk factors for MSDs in the farmers. The outcome of the RULA grand score had been found to be higher than 5 in the overwhelming majority of the farmers. All findings infer that each task of greenhouse vegetable growing inflicts different levels of disorder in a farmers' musculoskeletal structure. Interventions should be increased and reduce the bad ergonomic load level as soon as possible, provided to reduce the impact of such disorders.


Case study to illustrate a multidisciplinary approach to a case of critical limb ischaemia and the role of chemical lumbar sympathectomy.
This case study illustrates the role of the Podiatrist in the primary health care team and how a multidisciplinary approach to treatment promotes successful diagnosis and treatment regimes. It also outlines the role for chemical lumbar sympathectomies in treating critical lower limb ischaemia, a procedure regarded as having been superseded by more effective treatments but which proved to be the treatment of choice in this case. The subject of this case study presented at a community podiatry clinic exhibiting the signs of acute ischaemia, together with two recently developed ulcers on her right foot. After further vascular investigations, including angiograms and doppler studies, a blockage in the popliteal artery was revealed. Due to anatomically slender arteries, angioplasty and by-pass surgery were contra indicated. A chemical lumbar sympathectomy was performed in an attempt to increase blood flow to the tissues and to reduce the extreme pain being experienced by the patient. This proved successful, allowing the lesions to heal and also the collateral circulation to develop, resulting in a re-vascularized, viable foot.


The calcineurin-NFAT-angiopoietin-2 signaling axis in lung endothelium is critical for the establishment of lung metastases.
The premetastatic niche is a predetermined site of metastases, awaiting the influx of tumor cells. However, the regulation of the angiogenic switch at these sites has not been examined. Here, we demonstrate that the calcineurin and nuclear factor of activated T cells (NFAT) pathway is activated specifically in lung endothelium prior to the detection of tumor cells that preferentially metastasize to the lung. Upregulation of the calcineurin pathway via deletion of its endogenous inhibitor Dscr1 leads to a significant increase in lung metastases due to increased expression of a newly identified NFAT target, Angiopoietin-2 (ANG2). Increased VEGF levels specifically in the lung, and not other organ microenvironments, trigger a threshold of calcineurin-NFAT signaling that transactivates Ang2 in lung endothelium. Further, we demonstrate that overexpression of DSCR1 or the ANG2 receptor, soluble TIE2, prevents the activation of lung endothelium, inhibiting lung metastases in our mouse models. Our studies provide insights into mechanisms underlying angiogenesis in the premetastatic niche and offer targets for lung metastases.


Establishment of reference range for thyroid hormones in normal pregnant Indian women.
Interpretation of thyroid function tests during pregnancy needs trimester-related reference intervals from pregnant populations with minimal risk for thyroid dysfunction. While India has become iodine sufficient after two decades of salt iodisation, there is no normative data for thyroid function from healthy pregnant women of this country. To determine trimester-specific reference ranges for free triiodothyronine (FT(3)), free thyroxine (FT(4)) and thyrotropin (TSH) from healthy pregnant Indian women. Cross-sectional study in a reference population of pregnant women. Primary care level obstetric department in India. Women with uncomplicated pregnancy in any trimester. Five hundred and forty-one apparently healthy pregnant women with uncomplicated single intrauterine gestations reporting to the Armed Forces Clinic in any trimester were consecutively recruited. Clinical examination, thyroid ultrasound for echogenicity and nodularity and estimation of FT(3), FT(4), TSH and antithyroid antibodies (antithyroperoxidase [anti-TPO] and antithyroglobulin [anti-Tg]) using electrochemiluminescence technique were carried out. From this entire sample, a disease- and risk-free reference population was obtained by excluding those with any known factor that could affect thyroid function or those who were being treated for thyroid dysfunction. None. Of the 541 consecutive pregnant women in different trimesters enrolled for the study, 210 women were excluded. The composition of reference population comprising 331 women was 107 in first trimester, 137 in second trimester and 87 in third trimester. The 5th and 95th percentiles values were used to determine the reference ranges for FT(3), FT(4) and TSH. The trimester-wise values in the first, second and third trimesters were: FT(3) (1.92-5.86, 3.2-5.73 and 3.3-5.18 pM/l), FT(4) (12-19.45, 9.48-19.58 and 11.32-17.7 pM/l) and TSH (0.6-5.0, 0.44-5.78 and 0.74-5.7 iu/ml), respectively. Analysis of mean, median values for FT(3), FT(4) and TSH between each trimester showed no significant difference in FT(3) and TSH values (95% CI). However, FT(4) showed significant variation between trimesters with values decreasing with advancing gestational age (P value: first versus second = 0.015, first versus third = 0.003 and second versus third = not significant). Women with antibody positivity and hypoechogenicity of thyroid gland had significantly higher TSH values when compared with women with antibody negativity and normoechogenicity. Reference ranges of FT(3), FT(4) and TSH have been established for pregnant Indian women using 5th and 95th percentiles.


Heat shock treatment of macrophages causes increased release of superoxide anion.
Heat shock treatment of murine macrophages and the J774 cell line resulted in an enhanced capacity to release superoxide anion (O2-) upon stimulation. There was no concomitant increase in hydrogen peroxide production, and the macrophage microbicidal activity against Mycobacterium tuberculosis, Mycobacterium avium complex, and Staphylococcus aureus was not altered.


Sonographic appearances of small organizing hematomas and thrombi mimicking superficial soft tissue tumors.
We retrospectively reviewed 2 cases of organizing hematomas and 2 cases of intravascular organizing thrombi and investigated correlations between sonographic and pathologic findings. In all 4 cases, a well-defined hypoechoic heterogeneous mass with surrounding increased echogenicity was evident in the subcutaneous fat layer. Organizing hematomas and thrombi have sonographic features similar to those of benign-looking soft tissue tumors. These lesions should therefore be considered in the differential diagnosis of superficial soft tissue masses.


Virtual screening-driven discovery of dual 5-HT6/5-HT2A receptor ligands with pro-cognitive properties.
A virtual screening campaign aimed at finding structurally new compounds active at 5-HT6R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT6R Ki = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT6R Ki = 25, 5-HT2AR Ki = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties.


Accommodation stimulus-response function and retinal image quality.
Accommodation stimulus-response function (ASRF) and its relationship to retinal image quality were investigated using a modified wavefront sensor. Ten subjects were presented with six vergence stimuli between 0.17 D and 5 D. For each vergence distance, ocular wavefronts and subjective visual acuity were measured. Wavefronts were analysed for a fixed 3-mm pupil diameter and for natural pupil sizes. Visual Strehl ratio computed in the frequency domain (VSOTF) and retinal images were calculated for each condition tested. Subjective visual acuity was significantly improved at intermediate vergence distances (1D and 2D; p < 0.01), and only decreased significantly at 5 D compared with 0.17 D (p < 0.05). VSOTF magnitude was associated with subjective visual acuity and VSOTF peak location correlated with accommodation error. Apparent accommodation errors due to spherical aberration were highly correlated with accommodation lead and lag for natural pupils (R(2) = 0.80) but not for fixed 3-mm pupils (R(2) < 0.00). The combination of higher-order aberrations and accommodation errors improved retinal image quality compared with accommodation errors or higher order aberrations alone. Pupil size and higher order aberrations play an important role in the ASRF.


When there is more than a cleft: psychological adjustment when a cleft is associated with an additional condition.
In spite of studies reporting a relatively high frequency of additional conditions in children with a cleft lip and/or cleft palate (CL/P), almost no research has focused on this clinically important subgroup. The objective of this study was to compare psychosocial adjustment in children with CL/P with and without an additional condition. Cross-sectional data based on routine psychological assessments at age 10 years, with comparisons to national reference groups. Centralized treatment, Norway. Two hundred five children with CL/P (participation rate: 80.1%) from three consecutive birth cohorts. The Strengths and Difficulties Questionnaire (self-report and parent report) and the Child Experience Questionnaire (self-report). Eighty-one children (39.5%) were identified as having at least one condition in addition to the cleft. These children reported significantly more psychosocial difficulties than children with a cleft alone. Differences between specific conditions were minor. Children with a cleft alone (n = 124) reported mean scores that were comparable to those reported by the reference group. There were no differences in adjustment between children with a visible versus a non-visible cleft. The present study highlights the need for research to be conducted in children with CL/P who have additional conditions to provide better knowledge and clinical care for a potentially vulnerable subgroup of children and their parents.


Effects of dietary di(2-ethylhexyl)phthalate on the metabolism of tryptophan to niacin in mice.
We have reported the effect of di(2-ethylhexyl)phthalate (DEHP) on the tryptophan (Trp)-niacin pathway in rats. To clarify the universal effect of DEHP on rodents, we studied whether DEHP also has an effect on Trp metabolism in mice. Mice were fed a niacin-free, 20% casein diet supplemented with DEHP for 21 days. Feeding with DEHP decreased the body weight gain and increased the liver weight in correlation with the dose level of DEHP. The administration of DEHP significantly increased the formation of quinolinic acid and the lower metabolites of the Trp-niacin pathway. The flux of niacin in the lower part of the Trp-niacin pathway in mice was enhanced by feeding with DEHP.


The expression of FOXJ1 in neurogenesis after transient focal cerebral ischemia.
FOXJ1 is a member of the Forkhead/winged-helix (Fox) family of transcription factors, which is required for the differentiation of the cells acting as adult neural stem cells which participate in neurogenesis and give rise to neurons, astrocytes, oligodendrocytes. The expression pattern of FOXJ1 in the brain after cerebral ischemia has so far not been described. In the current study, we investigated the expression pattern of FOXJ1 in the rat brain after cerebral ischemia by animal model. We performed a middle cerebral artery occlusion (MCAO) model in adult rats and investigated the expression of FOXJ1 in the brain by Western blotting and immunochemistry; double immunofluorescence staining was used to analyze FOXJ1's co-expression with Ki67. Western blot analysis showed that the expression of FOXJ1 was lower than normal and sham-operated brain after cerebral ischemia, but the level of FOXJ1 gradually increased from Day 1 to Day 14. Immuohistochemical staining suggested that the immunostaining of FOXJ1 deposited strongly in the ipsilateral and contralateral hemisphere in the cortical penumbra (CP). There was no FOXJ1 expression in the ischemic core (IC). The positive cells in the cortical penumbra might migrate to the ischemic core. In addition, double immunofluorescence staining revealed that FOXJ1 was co-expressed with mAP-2 and gFAP, and Ki67 had the colocalization with NeuN, GFAP, and FOXJ1. All our findings suggest that FOXJ1 plays an important role on neuronal production and neurogenesis in the adult brain after cerebral ischemia.


Time-course, negative-stain electron microscopy-based analysis for investigating protein-protein interactions at the single-molecule level.
Several biophysical approaches are available to study protein-protein interactions. Most approaches are conducted in bulk solution, and are therefore limited to an average measurement of the ensemble of molecular interactions. Here, we show how single-particle EM can enrich our understanding of protein-protein interactions at the single-molecule level and potentially capture states that are unobservable with ensemble methods because they are below the limit of detection or not conducted on an appropriate time scale. Using the HIV-1 envelope glycoprotein (Env) and its interaction with receptor CD4-binding site neutralizing antibodies as a model system, we both corroborate ensemble kinetics-derived parameters and demonstrate how time-course EM can further dissect stoichiometric states of complexes that are not readily observable with other methods. Visualization of the kinetics and stoichiometry of Env-antibody complexes demonstrated the applicability of our approach to qualitatively and semi-quantitatively differentiate two highly similar neutralizing antibodies. Furthermore, implementation of machine-learning techniques for sorting class averages of these complexes into discrete subclasses of particles helped reduce human bias. Our data provide proof of concept that single-particle EM can be used to generate a "visual" kinetic profile that should be amenable to studying many other protein-protein interactions, is relatively simple and complementary to well-established biophysical approaches. Moreover, our method provides critical insights into broadly neutralizing antibody recognition of Env, which may inform vaccine immunogen design and immunotherapeutic development.


Aquatic ecotoxicity assessment of a new natural formicide.
Agrochemicals could reach aquatic ecosystems and damage ecosystem functionality. Natural formicide could be an alternative to use in comparison with the more toxic formicides available on the market. Thus, the objective of this study was to assess the ecotoxicity of the new natural formicide Macex® with a battery of classical aquatic ecotoxicity tests. Bacteria (Aliivibrio fischeri), algae (Pseudokirchneriella subcapitata), hydra (Hydra attenuata), daphnids (Daphnia magna), and fish (Danio rerio) tests were performed in accordance with international standardized methodologies. In the range of formicide concentrations tested (0.03 to 2.0 g L(-1)) EC(50) values varied from 0.49 to >2.0 g L(-1), with P. subcapitata being the most sensitive species and H. attenuata and D. rerio the most tolerant species to this product in aqueous solutions. This new formicide preparation can be classed as a product of low toxicity compared to the aquatic ecotoxicity of the most common commercialized formicides.


A thin foot switch.
A common problem in determining a number of important gait parameters is a convenient means for indicating foot/floor contact. Various foot switches have been used in many forms, but still an ideal, commercially available switch has yet to materialize. This note describes one method for constructing very thin, (1 mm), durable, switches that have worked well in the Gait Analysis Lab at Texas Scottish Rite Hospital.


CO2 environment, microclimate and photosynthetic characteristics of the moss Hylocomium splendens in a subarctic habitat.
In order to document the natural CO2 environment of the moss Hylocomium splendens, and ascertain whether or not the moss was adapted to this, and its interactions with other microenvironmental factors, two studies were carried out. Firstly, the seasonal variations of CO2 concentration, photosynthetically active radiation (PAR), tissue water content and temperature were measured in the natural microenvironment of H. splendens in a subarctic forest during the summer period (July-September). Secondly, the photosynthetic responses of the species to controlled CO2 concentrations, PAR, temperature, and hydration were measured in the laboratory. CO2 concentrations around the upper parts of the plant, when PAR was above the compensation point (30 μmol m-2 s-1), were mostly between 400 and 450 ppm. They occasionally increased up to 1143 ppm for short periods. PAR flux densities below saturating light levels for photosynthesis (100 μmol m-2 s-1), occurred during 65% (July), 76% (August) and 96% (September) of the hours of the summer period. The temperature optimum of photosynthesis was 20° C: this temperature coincided with PAR above the compensation point during 5%, 6% and 0% of the time in July, August and September, respectively. Optimal hydration of tissues was infrequent. Hence PAR, temperature and water limit CO2 uptake for most of the growing season. Our data suggest that the higher than normal ambient CO2 concentration in the immediate environment of the plant counteracts some of the limitations in PAR supply that it experiences in its habitat. This species already experiences concentrations of atmospheric CO2 predicted to occur over the next 50 years.


Peripheral and central alterations affecting spinal nociceptive processing and pain at adulthood in rats exposed to neonatal maternal deprivation.
The nociceptive system of rodents is not fully developed and functional at birth. Specifically, C fibers transmitting peripheral nociceptive information establish synaptic connections in the spinal cord already during the embryonic period that only become fully functional after birth. Here, we studied the consequences of neonatal maternal deprivation (NMD, 3 h/day, P2-P12) on the functional establishment of C fiber-mediated neurotransmission in spinal cord and of pain-related behavior. In vivo recording revealed that C fiber-mediated excitation of spinal cord neurons could be observed at P14 only in control but not in NMD rats. NMD was associated with a strong alteration in the expression of growth factors controlling C nociceptor maturation as well as two-pore domain K+ channels known to set nociceptive thresholds. In good agreement, C-type sensory neurons from NMD animals appeared to be hypoexcitable but functionally connected to spinal neurons, especially those expressing TRPV1 receptors. In vivo and in vitro recordings of lamina II spinal neurons at P14 revealed that the NMD-related lack of C fiber-evoked responses resulted from an inhibitory barrage in the spinal cord dorsal horn. Eventually, C-type sensory-spinal processing could be recovered after a delay of about 10 days in NMD animals. However, animals remained hypersensitive to noxious stimulus up to P100 and this might be due to an excessive expression of Nav1.8 transcripts in DRG neurons. Together, our data provide evidence for a deleterious impact of perinatal stress exposure on the maturation of the sensory-spinal nociceptive system that may contribute to the nociceptive hypersensitivity in early adulthood.


Right hemisphere language processing: lateral difference with imageable and nonimageable ambiguous words.
Influence of imageability on hemispheric processing difference is studied in a lexical decision task with semantic priming. Homographs and ambiguous words were biased according to the prime toward their low or high imageable meanings and unilaterally presented in the visual field. A right visual field (RVF) superiority was observed; it was nonsignificant for the high imageable (HI) meaning but significant for the low imageable (LI) meaning of the ambiguous words. Thus the results seem to favor a bilateral hemispheric representation of HI words and a unilateral left representation of LI words. Theoretical implications of the results are discussed to the various models of ambiguous word access processing.


Bio-functional hydrogel membranes loaded with chitosan nanoparticles for accelerated wound healing.
Wounds are often recalcitrant to traditional wound dressings and a bioactive and biodegradable wound dressing using hydrogel membranes can be a promising approach for wound healing applications. The present research aimed to design hydrogel membranes based on hyaluronic acid, pullulan and polyvinyl alcohol and loaded with chitosan based cefepime nanoparticles for potential use in cutaneous wound healing. The developed membranes were evaluated using dynamic light scattering, proton nuclear magnetic resonance, Fourier transform infrared spectroscopy, thermogravimetric analysis, and scanning electron microscopy. The results indicated the novel crosslinking and thermal stability of the fabricated hydrogel membrane. The in vitro analysis demonstrates that the developed membrane has water vapors transmission rate (WVTR) between 2000 and 2500 g/m2/day and oxygen permeability between 7 and 14 mg/L, which lies in the range of an ideal dressing. The swelling capacity and surface porosity to liberate encapsulated drug (cefepime) in a sustained manner and 88% of drug release was observed. The cefepime loaded hydrogel membrane demonstrated a higher zone of inhibition against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli and excisional rat model exhibit expeditious recovery rate. The developed hydrogel membrane loaded with cefepime nanoparticles is a promising approach for topical application and has greater potential for an accelerated wound healing process.


Association of leptin receptor gene Q223R polymorphism on lipid profiles in comparison study between obese and non-obese subjects.
Leptin is a hormone secreted from adipocytes. It regulates metabolism and energy homeostasis through the leptin receptor (LEPR) which is localized centrally in hypothalamus as well as in peripheral tissues. The aim of this study was to investigate the association of leptin receptor gene Q223R polymorphism on obesity in association with body mass index (BMI), lipid parameters, plasma leptin levels and homeostasis model assessment of insulin resistance (HOMA-IR). The study included 110 obese and 90 non-obese subjects. The LEPR Q223R polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Plasma leptin levels, serum lipid and antropometric parameters were measured. No association was found between LEPR gene Q223R polymorphism and BMI in both study and control groups. Strikingly study group with non-obese subjects and with the RR genotype (homozygous mutant) had significantly higher serum total cholesterol (p<0.001) and low density lipoprotein cholesterol (LDL-cholesterol) levels (p<0.05) than QR (heterozygous) and QQ (wild type) genotypes. In obese group, subjects with the RR genotypes had significantly higher triglycerides (p<0.05) levels, waist (p<0.05) and hip circumferences (p<0.001) than the QQ and QR genotypes. Our results suggest that the LEPR gene Q223R polymorphism has an association with waist and hip circumferences in obese group but no direct association with obesity although there is a significant influence on lipid profile both in obese and non-obese subjects.


Benign follicular thyroid nodule composed of signet-ring-like cells with PAS-negative thyroglobulin accumulation in dilatated rough endoplasmic reticulums.
A benign follicular thyroid nodule composed of signet-ring-like cells in a 46-year-old Japanese euthyroid woman is reported. Thyroglobulin was positive, and periodic acid-Schiff (PAS) and other mucin stainings were negative in the cytoplasm of signet-ring-like cells. Ultrastructurally their cytoplasm contained many dilatated rough endoplasmic reticulums (rERs), the largest of which compressed the nucleus toward the cellular apical portion. Functional disturbance of rER or Golgi apparatus might be the cause of this characteristic cellular change.


The role of echocardiography in heart transplantation.
Echocardiography has gained increasing importance as an imaging modality in the care of the cardiac transplant recipient. Its utility in detecting the complications of transplantation, with special reference to the diagnosis of rejection and graft arteriosclerosis, is discussed. On the basis of a review of the current literature, an outline for serial echocardiographic studies is proposed.


The presence of doping agents in dietary supplements: A glimpse into the Brazilian situation.
Dietary supplements (DS) are intended for healthy people to maintain or improve their overall health. Its consumption is widespread in large part of the general population and at all levels of athletes. Nevertheless, DS use can also pose health risks to individuals and, in the case of athletes, may lead to adverse analytical findings (AAFs) due to the possibility of DS contamination or adulteration with doping agents banned by the World Anti-Doping Agency. Although educational initiatives are being performed in Brazil to warn the sports community about inadvertent doping cases, AAFs connected to the DS administration have been increasingly growing. The findings of DS analyzed by the Brazilian Doping Control Laboratory (LBCD), between 2017 and 2022, after Testing Authorities (TAs) analysis requests, showed an alarming number of tainted samples. Diuretics were the most common adulterants found in all supplement types. However, the profile of prohibited substances in manufactured and compounded dietary supplements (MDS and CDS, respectively) were distinct, with stimulants being most prevalent in MDS and anabolic agents in CDS products. Additionally, MDS samples generally presented higher estimated concentrations of banned substances (mg/g) than CDS samples (μg/g). The common practice of DS intake by athletes continues to be of great concern for a doping-free sport, given the high prevalence of prohibited substances detected in the analyzed samples by the LBCD. The current Brazilian scenario reinforces the importance of raising awareness in the sports community of the possible consequences of an unintentional doping case linked to DS use.