Peritoneal hydatidosis: An exceptional case report.
Hydatidosis is a cosmopolitan parasitic disease which presents a real public health problem especially in endemic countries of which Morocco is part. The objective of the present work is to analyze the clinical, paraclinical, therapeutic, evolutionary and prognostic aspects of disseminated peritoneal hydatidosis with multiple localization.Peritoneal hydatidosis represents the whole of the phenomena due to :The seeding, essentially secondary, of the peritoneal serosa by Echinococcus Granulosus larvae, Peritoneal hydatidosis is characterized by its polymorphic symptomatology, and the diagnosis is based on a combination of epidemiological, clinical, biological and imaging findings. We report a case of a particular form of peritoneal hydatidosis in the department of visceral surgery I of the ibn rochd hospital in casablanca. Our patient was admitted for management of disseminated peritoneal hydatidosis. The clinical examination, apart from an epigastric crust, was unremarkable. The biological work-up showed a slightly disturbed liver balance and the hydatid serology was strongly positive. The preoperative diagnosis of HP was established by CT scan showing a supra- and sub-mesocolic peritoneal hydatidosis with a multi-cystic spleen and a liver with a type V segment V hydatid cyst measuring 4 cm by 6 cm.The treatment consisted of a total cystectomy of the hydatid cysts, almost 100 cysts with multiple peritoneal and parietal locations, one of which was fistulized in the skin, associated with a total splenectomy, retrograde appendectomy and a disconnection of the cholecysto-duodenal fistula with duodenal closure and a retrograde cholecystectomy associated with a choledecotomy with extraction of 3 stones at the level of the choledochus and drainage of the VBP by Kehr drain. The postoperative course was simple and the patient was discharged on the sixth day with an adjuvant treatment with albendazole for three months.Through this observation and in the light of the data in the literature, we were able to insist in our present work on the diagnostic difficulties generated by this unusual location of the hydatid cyst as well as the considerable contribution of imaging (CT++) allowing both a positive and very precise topographic diagnosis. We were also able to focus on surgical treatment as an indispensable pillar of the management of this disease as well as the increasingly fundamental role of medical treatment, particularly in the prevention of recurrences. Peritoneal hydatidosis is a rare but serious complication of hydatid disease.The positive diagnosis is based on epidemiological, clinical, and paraclinical arguments represented essentially by CT scan.Early diagnosis and treatment of primary sites as well as optimal surgical management of peritoneal hydatidosis determine the prognosis.


Neonatal seizures associated with maternal hydroxyzine hydrochloride in late pregnancy.
This is the first report of a neonatal withdrawal syndrome associated with maternal hydroxyzine treatment (150 mg/day) confirmed by measurements of hydroxyzine plasma concentrations in the mother and infant after birth. Hydroxyzine plasma concentrations were measured by liquid chromatography-mass spectrometry. Neurological symptoms with low neonatal concentrations of hydroxyzine may be due to a withdrawal syndrome. According to previous observations and this case report, clinicians should be warned of this possible rare neurological complication of hydroxyzine in neonates born from long term treated mothers.


Chemical constituents of the root of Jasminum giraldii.
Two new compounds, ethylconiferin and (-)-lariciresinol 4-(6'''-O-cinnamyl-β-D-glucopyranoside), along with the three known compounds (+)-pinoresinol, (+)-cycloolivil, nobiletin, were isolated from the root of Jasminum girialdii. All these compounds were isolated for the first time from this source. Their structures were elucidated on the basis of extensive spectroscopic analysis and chemical methods. In addition, the in vitro cytotoxic activity of these compounds was evaluated. The results showed that none of the compounds had any significant inhibitory activities on the proliferation of HCT-116 and SW-620 cells.


Clinical Impact of Tricuspid Regurgitation on Transcatheter Edge-to-Edge Mitral Valve Repair for Mitral Regurgitation.
This study aimed to evaluate whether baseline tricuspid regurgitation (TR) impacted clinical outcomes after mitral valve transcatheter edge-to-edge repair (M-TEER) for severe secondary mitral regurgitation (MR). Baseline TR is common among patients undergoing M-TEER for secondary MR, although its impact on clinical outcomes is unclear. The Cochrane Library, PubMed/MEDLINE, and Google Scholar were searched according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines from January 1, 2011 through January 31, 2021. Randomized controlled trials and nonrandomized prospective studies that evaluated baseline TR by echocardiography before M-TEER for MR were included. The primary outcome was a composite of mortality and heart failure hospitalization (HFH) at 1-year. A total of 5 studies (n = 1395 patients) were included in the primary analysis. Concurrent moderate/severe TR was associated with a worse 1 year composite of all-cause mortality and HFH (OR: 2.13; 95% CI: 1.12-4.05; p = 0.02) after M-TEER for severe MR. In studies that reported TR grade pre- and post-M-TEER for severe MR, 32% of patients with moderate-to-severe baseline TR had a reduction in TR severity after the intervention. Baseline moderate-to-severe TR was associated with increased 1-year mortality and heart failure hospitalizations among patients undergoing M-TEER. Further randomized studies are needed to assess the interaction of TR among patients undergoing M-TEER.


Molecular basis for Rho GTPase signaling specificity.
There is now considerable evidence for the involvement of aberrant Rho GTPase activation in breast cancer development. Like Ras, Rho GTPases function as signaling nodes regulated by diverse extracellular stimuli. Rho GTPase activation is facilitated by multiple regulatory proteins, in particular guanine nucleotide exchange factors (GEFs) such as Dbl family proteins. Activated Rho GTPases in turn interact with and regulate a spectrum of functionally diverse downstream effectors, initiating a network of cytoplasmic and nuclear signaling cascades. Thus, Rho GTPases represent points of signaling convergence as well as relay switches that disseminate signaling divergence. In this review, we highlight issues relating to the structural basis by which Dbl family GEFs facilitate signaling convergence and Rho GTPase activation, and how Rho GTPases promote signal dissemination through downstream effectors.


Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects.
The effect of the C3435T mutation at exon 26 of the MDR1 gene on the expression levels of MDR1 messenger ribonucleic acid (mRNA) was evaluated by means of real-time polymerase chain reaction in 51 biopsy specimens of duodenum obtained from 13 healthy Japanese subjects. The mRNA levels of MDR1 were 0.38 +/- 0.15, 0.56 +/- 0.14, and 1.13 +/- 0.42 (mean value +/- SE) in the subjects with the homozygote of wild-type allele (C/C), compound heterozygote with mutant T allele (C/T), and the homozygote of the mutant allele (T/T), respectively, reasonably explaining the lower digoxin serum concentration after administration of a single oral dose to subjects harboring a mutant T allele. Good correlation (r =.797; P <.01) was observed between the mRNA concentrations of MDR1 and CYP3A4 in the individual biopsy specimens. This finding suggested a lower plasma concentration of the substrates for CYP3A4 in subjects harboring the C3435T mutation of the MDR1 gene.


Subciliary Rotating Sutures Combined With Modified Hotz Procedure for Correction of Congenital Lower Eyelid Entropion.
Standard techniques for the treatment of congenital lower eyelid entropion may not yield suitable outcomes or may result in overcorrection if disinsertion of the lower eyelid retractors is not the primary cause. Herein, we propose and evaluate a technique using subciliary rotating sutures combined with a modified Hotz procedure for repair of lower eyelid congenital entropion that addresses these concerns. A retrospective chart review was conducted of all patients who underwent lower eyelid congenital entropion repair by a single surgeon using subciliary rotating sutures combined with a modified Hotz procedure between 2016 and 2020. Study variables included patient demographics, follow-up period, postoperative complications, operative success, and recurrence. Twelve patients (19 eyelids) met the study inclusion criteria. The mean patient age was 7.1 ± 6.1 years (range, 0.2-22 years). Nine of the patients were female (75%) and 3 were male (25%). The distribution of eyelids was 8 right (42%) and 11 left (58%). The mean follow-up time was 19.5 ± 15 (range 2.5-45) months. There were two eyelids (11%) that had entropion recurrence after initial repair in patients with concomitant compound disease processes. Repeated repair resulted in success with no recurrence at last follow-up. Overall, the described entropion repair technique was successful and without recurrence in 17 eyelids (89%). There were no cases of ectropion, lid retraction, or other complications. Subciliary rotating sutures combined with a modified Hotz procedure are effective for correction of congenital lower eyelid entropion. As the technique does not manipulate the posterior layer of the lower eyelid retractors, it may be useful for when retractor reinsertion does not yield adequate improvement and may also reduce the risk of eyelid retraction and overcorrection in particular cases.


Arachnoiditis ossificans after revision adolescent idiopathic scoliosis surgery: a 22-year follow-up and review.
Case report. To report the clinical and imaging findings of a patient with arachnoiditis ossificans (AO) 22 years after revision surgery for adolescent idiopathic scoliosis (AIS). To our knowledge, there are no reports in the literature that describe AO developing after primary or revision surgery for AIS. Ararchnoiditis ossificans is a rare finding and we provide a review of its presentation and management. We report the patient's history, physical examination, radiographical findings, and management in addition to providing a literature review. A 43 year-old-male who underwent revision surgery for AIS due to intradural migration of a laminar hook presented 22 years after surgery with subjective leg weakness. On physical examination, no weakness was elicited and radiographs demonstrated the instrumentation to be intact. Computed tomographic imaging was performed to assess for adjacent segment disease and diffuse ossification or AO of the thecal sac from L3 to S1 was noted. We recommended observation and nonoperative management because the patient's symptoms were relatively mild. To our knowledge, this is the first report of AO after surgical management of primary or revision AIS. A discussion on the management of AO and a literature review is presented.


Low-carbon innovation, economic growth, and CO2 emissions: evidence from a dynamic spatial panel approach in China.
Low-carbon innovation plays an essential role in carbon reduction worldwide. This study investigates the nexus between low-carbon innovation, economic growth, and carbon emissions by the dynamic spatial Durbin model from 2007 to 2020. First, the Moran index results verify the provincial spatial agglomeration of carbon emissions. High-emission provinces concentrate in major economic zones and energy extraction areas. Second, the effect decomposition results show that long-term and short-term effects are consistent. Low-carbon innovation has a significant mitigation effect on carbon emissions in local regions, which effect, however, is not significant in the adjacent areas. The environmental Kuznets curve hypothesis is validated locally, but all provinces and cities have not reached the inflection point of the environmental Kuznets curve, and the linkage effect in adjacent regions remains insignificant. The above results have been tested to be robust. Third, the results of the mechanism analysis show that environmental policies, absorptive capacity, and financial development play a moderating role in the relationship between low-carbon innovation and carbon emissions. Finally, the heterogeneity test showed significant differences between Eastern, Central, and Western. The direct effect of low-carbon innovation exists in Eastern and central regions; the spillover effect of low-carbon innovation is only in the eastern region. In addition, corresponding measures are proposed based on the conclusions.


Ultrasonographic refraction of aphakic infants and children.
A simple method of aphakic refraction using ultrasonographic axial length measurement and corneal curvature determination is presented. This method was compared with skiascopy in refraction eleven eyes of aphakic infants. No significant differences were found between the relative errors measured by these two methods.


Beyond the cytoskeleton: mesoscale assemblies and their function in spatial organization.
Recent studies have identified a growing number of mesoscale protein assemblies in both bacterial and eukaryotic cells. Traditionally, these polymeric assemblies are thought to provide structural support for the cell and thus have been classified as the cytoskeleton. However a new class of macromolecular structure is emerging as an organizer of cellular processes that occur on scales hundreds of times larger than a single protein. We propose two types of self-assembling structures, dynamic globules and crystalline scaffolds, and suggest they provide a means to achieve cell-scale order. We discuss general mechanisms for assembly and regulation. Finally, we discuss assemblies that are found to organize metabolism and what possible mechanisms may serve these metabolic enzyme complexes.


CEACAM1 regulates insulin clearance in liver.
We hypothesized that insulin stimulates phosphorylation of CEACAM1 which in turn leads to upregulation of receptor-mediated insulin endocytosis and degradation in the hepatocyte. We have generated transgenic mice over-expressing in liver a dominant-negative, phosphorylation-defective S503A-CEACAM1 mutant. Supporting our hypothesis, we found that S503A-CEACAM1 transgenic mice developed hyperinsulinemia resulting from impaired insulin clearance. The hyperinsulinemia caused secondary insulin resistance with impaired glucose tolerance and random, but not fasting, hyperglycemia. Transgenic mice developed visceral adiposity with increased amounts of plasma free fatty acids and plasma and hepatic triglycerides. These findings suggest a mechanism through which insulin signaling regulates insulin sensitivity by modulating hepatic insulin clearance.


Calcium and magnesium in China's public drinking water and their daily estimated average requirements.
Calcium (Ca) and magnesium (Mg) in drinking water and the relevant health effects have been ignored for too long. This study aims to reveal the concentrations, spatial distributions, origins and contributions to the daily estimated average requirements of Ca and Mg in public drinking water. Using hydrochemical data of collected samples of public drinking water in 314 cities across China, the contributions of Ca and Mg intakes from public drinking water to their daily estimated average requirements (EARs) were assessed. And the significance of Ca/Mg ratio and total hardness (TH) was evaluated as well. The Ca and Mg concentrations of the samples were in the range of 2.5-155.1 mg/L and 0.2-81.9 mg/L, with an average of 40.4 mg/L and 12.4 mg/L, respectively. There exist obvious differences in Ca and Mg concentrations in different regions, under the impact of climate conditions and water-rock interactions. The intake of Ca via the consumption of public drinking water for adults may be twice as much as that for other age groups. In cities with high Ca levels in public drinking water, the Ca contributions to EAR could reach up to 51.59% for adults. By contrast, Mg in drinking water is an important and even the main pathway to ingest Mg for infants and children. Therefore, public drinking water is critical for Ca and Mg intake among urban residents of China. Besides, attention should be paid to the health effects of high Ca/Mg ratio and low TH in public drinking water, especially in southern China. This research is the first systematic and comprehensive national scale study of Ca and Mg in public drinking water and can provide an important reference to improve healthy public drinking water standards around the world.


Time-dependent inhibition of sucrase and isomaltase from rat small intestine by castanospermine.
Castanospermine (1,6,7,8-tetrahydroxyoctahydroindolizine) is a potent time-dependent inhibitor of the sucrase-isomaltase complex purified from rat small intestine, in vitro. First-order kinetics for the inactivation of sucrase and isomaltase by castanospermine were observed. Protection studies showed that castanospermine competes for the glucosyl subsite with the substrates of sucrase and isomaltase. The second-order rate constants (k1) for the association reaction between castanospermine and the protein complex were calculated to be 6.5 X 10(3) and 0.3 X 10(3) M-1 s-1 for sucrase and isomaltase, respectively. Only barely detectable reactivation of the inhibited isomaltase was detectable over 24 h, whereas about 30% reactivation of the inhibited sucrase was observed in 24 h (k2 = 3.6 X 10(-6) s-1). These results suggest that castanospermine functions as a transition-state analog that binds extremely tightly to sucrase and isomaltase.


Physiological characteristics of platelet serotonin in rats.
Physiological characteristics of platelet serotonin (5-HT) levels in rats of Wistar origin were investigated by use of a recently developed method. By comparison of populations of male and female rats (N = 281) similar unimodal frequency distributions, with a tendency to higher values in females (1.61 vs. 1.70 micrograms 5HT/mg platelet protein; p less than 0.01), were found. For a group of 55 animals, monitored twice for this parameter within a week interval, a remarkable intraindividual constancy in time, the mean difference between two determinations being 5.5%, was shown. No age-dependence could be demonstrated for platelet serotonin concentrations in 5- to 30-week-old rats, nor were there significant circadian or seasonal oscillations.


Improved quality of life after lung volume reduction surgery.
Lung volume reduction surgery (LVRS) improves dyspnoea, pulmonary function, and physical performance in patients with severe pulmonary emphysema. This study investigated the impact of LVRS on health-related quality of life (HRQL) over a 2-yr period following surgery. Thirty-nine consecutive patients were prospectively assessed before LVRS, and followed over 24 months postoperatively. The assessments included pulmonary function, dyspnoea (Medical Research Council (MRC) dyspnoea score), 6-min walking distance (6MWD) and HRQL using the Short Form 36-item questionnaire (SF-36). Several domains of SF-36 improved considerably over 2 yrs after surgery: Physical Functioning: 39 +/- 4 (mean +/- SEM) versus 16 +/- 2 (p<0.01); Vitality: 51 +/- 3 versus 32 +/- 3 (p<0.01); Social Functioning: 72 +/- 4 versus 51 +/- 5 (p<0.01). Also, improvements in pulmonary function (forced expiratory volume in one second (FEV1): 27 +/- 1% predicted, residual volume (RV)/total lung capacity (TLC): 0.65 +/- 0.01), 6 MWD (274 +/- 16 m) and dyspnoea (MRC: 3.9 +/- 01) were sustained for up to 2 yrs after LVRS (FEV1 36 +/- 2% pred, RV/TLC: 0.58 +/- 0.02; 6 MWD: 342 +/- 19 m; MRC: 2.0 +/- 0.2; p<0.05). In patients with severe emphysema, lung volume reduction surgery had positive effects on health-related quality of life and pulmonary function over 2 yrs.


Understanding Outcomes in Behavior Change Interventions to Prevent Pediatric Obesity: The Role of Dose and Behavior Change Techniques.
Behavioral interventions to prevent pediatric obesity have shown inconsistent results across the field. Studying what happens within the "black box" of these interventions and how differences in implementation lead to different outcomes will help researchers develop more effective interventions. To compare the implementation of three features of a phone-based intervention for parents (time spent discussing weight-related behaviors, behavior change techniques used in sessions, and intervention activities implemented by parents between sessions) with study outcomes. A random selection of 100 parent-child dyads in the intervention arm of a phone-based obesity prevention trial was included in this analysis. Sessions were coded for overall session length, length of time spent discussing specific weight-related behaviors, number of behavior change techniques used during the sessions, and number of intervention-recommended activities implemented by the parents between sessions (e.g., parent-reported implementation of behavioral practice/rehearsal between sessions). The primary study outcome, prevention of unhealthy increase in child body mass index (BMI) percentile, was measured at baseline and 12 months. Overall session length was associated with decreases in child BMI percentile ( b = -0.02, p = .01). There was no association between the number of behavior change techniques used in the sessions and decreases in child BMI percentile ( b = -0.29, p = .27). The number of activities the parents reported implementing between sessions was associated with decreases in child BMI percentile ( b = -1.25, p = .02). To improve future interventions, greater attention should be paid to the intended and delivered session length, and efforts should be made to facilitate parents' implementation of intervention-recommended activities between sessions (ClinicalTrials.gov, No. NCT01084590).


Rehabilitation of schizophrenics in a developing country (five years of Fountain House, Lahore, Pakistan).
Facilities for psychiatric treatment in Pakistan are extremely limited. While efforts are in the offing for the extension of Mental Health Services by the Government, a voluntary organization has been running a rehabilitation centre for the mentally ill in Lahore, called Fountain House, since 1971. An important aspect of this pioneer venture is the collaborative links with Fountain House, New York. The results of follow-up studies conducted over a period of 4 years show that programmes and ideas developed in one country can be profitably utilized in another country.


The efficiency of pollen transfer and rates of embryo initiation in Cryptantha (Boraginaceae).
The efficiency of pollination and rates of embryo initiation were compared in two species of Cryptantha (Boraginaceae) which differ greatly in their patterns of seed (nutlet) production. Cryptantha flava normally matures only one of the four ovules per ovary while C. flavoculata often matures all four. The general floral morphology and composition of insect floral visitors were found to be nearly identical in the two species, but C. flavoculata produces twice as much pollen per flower as C. flava. Despite this difference, the amount of pollen deposited on stigmas by pollinators is similar. This may be due to the larger stigmatic surface area in C. flava. In both species, the abortion of fertilized ovules, rather than insufficient amounts of pollen, appears to be the primary factor regulating the number of seeds per flower. The pollination ecology of these species is discussed in relation to current theories regarding the allocation of resources to the production of pollen and seeds.


Interaction-induced reduction in differential maternal responsiveness: an effect of cue-reduction or behavior?
Litters from donor mothers received differential treatments (handling or shocking) and were then placed in wire-mesh baskets affixed to the cage tops of test mothers. Pup-produced cues from donor litters elicited different patterns of maternal behavior from test mothers that interacted with their own litters. In addition to these differences in maternal behavior, cues from the donor litters elicited a differential pattern of pituitary-adrenal activity. Shocked pups elicited larger corticosterone elevations than handled pups. These data suggest that the elimination of differential pituitary-adrenal responsiveness evidenced when mothers interact directly with pups subseuqent to pup treatment resllts from the termination of pup-produced cues that normally accompany active mother-infant interactions.


Similarity of 5-HT2 receptor sites in dominant and subordinate vervet monkeys.
Pharmacological studies using serotonergic agents have revealed status-linked behavioral effects in dominant and subordinate vervet monkeys. A possible explanation for the greater drug response observed in dominant animals is that there is a CNS difference between dominant and subordinate animals. Such differences could exist at the level of serotonin receptor sites, membrane responsiveness, or interaction with other neurotransmitters. We have examined the specific 3H-ketanserin binding in various regions of vervet monkey brain to evaluate the hypothesis that dominant and subordinate vervet monkeys differ in CNS 5-HT2 receptor sites. No differences were found in the number or affinity of 3H-ketanserin binding sites between dominant and subordinate animals. Further, no differences were found in the displacement of 3H-ketanserin binding by the serotonin agonist quipazine. These results suggest the conclusion that differences at 5-HT2 binding sites do not account for status-linked differences in behavioral drug response in vervet monkeys and that other or additional mechanisms must underlie status-related drug response differences.


Increased Expression of CD74 in Atherosclerosis Associated with Inflammatory Responses of Endothelial Cells and Macrophages.
To clarify the relationship between CD74 and atherosclerosis (AS) and the mechanisms in oxidized LDL (ox-LDL)-induced endothelial cell and macrophage injury. Datasets obtained from the Gene Expression Omnibus database are integrated. Differentially expressed genes (DEGs) were obtained using R software. Weighted gene co-expression network analysis (WGCNA) was performed to screen the target genes. The endothelial cell injury model and macrophage foaming model were established using ox-LDL, and CD74 expression was detected by Quantitative reverse transcription PCR (RT-qPCR) and Western blot (WB). Then, after silencing CD74, cell viability and ROS production were measured, and WB detected the expression of p-p38 MAPK and NF-κB. There were 268 DEGs associated with AS, of which CD74 was up-regulated. The turquoise module containing CD74 in WGCNA was positively associated with AS. Cell viability was significantly decreased in the endothelial cell injury and macrophage foaming models, while CD74, ROS production, NF-κB, and p-p38MAPK expression increased (P < 0.05). After silencing CD74, ROS production, NF-κB, and p-p38MAPK expression were decreased and cell viability was higher than the model group (P < 0.05). CD74 is up-regulated in endothelial cell injury and macrophage foaming models and is involved in AS progression via the NF-κB and MAPK signaling pathways.


Acute and chronic alcohol-cocaine interactions in rats.
The widespread combined use of alcohol and cocaine across the United States underscores the importance of understanding how the actions of those two agents interact upon important physiological regulatory processes. In an experiment exploring acute ethanol-cocaine interactions, 16 rats were given 2.0 g/kg (IP) doses of ethanol at time zero. Two hours later, half of the rats were given cocaine (20 mg/kg, IP), while the other half were given injections of saline. The group given cocaine displayed a prolongation of the hypothermia condition induced by ethanol injection. In a chronic experiment, three groups of rats (n = 6-8) were exposed for an 11-day period to daily IP injections of 10 mg/kg cocaine, 20 mg/kg of cocaine, or saline. On day 12 these groups did not differ in their response to loss of the righting reflex induced by a 3.0 g/kg dose of ethanol. However, recovery from ethanol hypothermia was more rapid in the rats exposed to chronic cocaine. In summary, these initial studies provide evidence for exacerbation of the acute hypothermic effects of ethanol when a cocaine challenge is given 2 h after ethanol. In contrast, ethanol hypothermia was observed to be reduced when tested on day 12 after an 11-day chronic regimen of cocaine. Other dosage regimens and response measures need to be tested to understand the full scope of acute and chronic cocaine-ethanol interactions and the possible health consequences.


Neuroadaptive Fault-Tolerant Control With Guaranteed Performance for Euler-Lagrange Systems Under Dying Power Faults.
This article investigates the tracking control problem for Euler-Lagrange (EL) systems subject to output constraints and extreme actuation/propulsion failures. The goal here is to design a neural network (NN)-based controller capable of guaranteeing satisfactory tracking control performance even if some of the actuators completely fail to work. This is achieved by introducing a novel fault function and rate function such that, with which the original tracking control problem is converted into a stabilization one. It is shown that the tracking error is ensured to converge to a pre-specified compact set within a given finite time and the decay rate of the tracking error can be user-designed in advance. The extreme actuation faults and the standby actuator handover time delay are explicitly addressed, and the closed signals are ensured to be globally uniformly ultimately bounded. The effectiveness of the proposed method has been confirmed through both theoretical analysis and numerical simulation.


Modulation of the oxidative damage, inflammation, and apoptosis-related genes by dicinnamoyl-L-tartaric acid in liver cancer.
Cancer cells can become resistant to existing treatments over time, so it is important to develop new treatments that target different pathways to stay ahead of this resistance. Many cancer treatments have severe side effects that can be debilitating and even life-threatening. Developing drugs that can effectively treat cancer while minimizing the risks of these side effects is essential for improving the quality of life of cancer patients. The study was designed to explore whether the combination of dicinnamoyl-L-tartaric (CLT) and sorafenib ((SOR), an anti-cancer drug)) could be used to treat hepatocellular carcinoma (HCC) in the animal model and to assess whether this combination would lead to changes in certain biomarkers associated with the tumour. In this study, 120 male mice were divided into 8 groups of 15 mice each. A number of biochemical parameters were measured, including liver functions, oxidative stress (malondialdehyde, (MDA); nitric oxide (NO)), and antioxidative activity (superoxide dismutase (SOD), and glutathione peroxidase (GPx)). Furthermore, the hepatic expressions of Bax, Beclin1, TNF-α, IL1β, and BCl-2 genes were evaluated by qRT-PCR. The combination of SOR and CLT was found to reduce the levels of liver enzymes, such as AST, ALT, ALP, and GGT, and reduce the pathological changes caused by DAB and PB. The upregulation of TNF-α, IL1β, and Bcl-2 genes suggests that the CLT was able to initiate an inflammatory response to combat the tumor, while the downregulation of the Bax and Beclin1 genes indicates that the CLT was able to reduce the risk of apoptosis in the liver. Furthermore, the combination therapy led to increased expression of cytokines, resulting in an enhanced anti-tumor effect.


Epidemiology and morbidity of scabies and pediculosis capitis in resource-poor communities in Brazil.
Pediculosis capitis and scabies are common parasitic skin diseases, especially in resource-poor communities, but data on epidemiology and morbidity are scanty. To assess the prevalence, seasonal variation and morbidity of pediculosis capitis and scabies in poor neighbourhoods in north-east Brazil. The study comprised cross-sectional surveys of a representative population of an urban slum (n = 1460) in Fortaleza, the capital of Ceará State (Brazil) and a fishing community 60 km south of the city (n = 605). Study participants were examined for the presence of scabies and pediculosis capitis. In a longitudinal study in the slum, variation of prevalence in different seasons of the year was assessed. Prevalence of pediculosis capitis was 43.4% in the slum and 28.1% in the fishing community. Children aged 10-14 years and females were most frequently affected. Scabies was present in 8.8% of the population in the slum and in 3.8% of the population in the fishing community. There was no consistent pattern of age distribution. Superinfection was common in patients with scabies, and cervical lymphadenopathy in patients with pediculosis capitis. Multivariate analysis showed that age < or = 15 years, being of female sex and living in the urban slum were independent factors contributing to the simultaneous coinfestation with pediculosis capitis and scabies. The longitudinal data from the urban slum showed a characteristic seasonal variation of pediculosis capitis, but no fluctuation of scabies. Pediculosis capitis and scabies are hyperendemic in the study areas and are associated with considerable morbidity. There is an urgent need to develop control measures for these parasitic skin diseases in resource-poor communities. This is the first community-based study describing in detail the epidemiology and morbidity of scabies and head lice infestation in Brazil.


Phosphoinositides, inositol phosphates, and phospholipase C in embryonic stem cells.
The stimulation of inositol phospholipid metabolism via phospholipase C (PLC) is an important signal transduction pathway in a wide variety of cell types. Activation of the pathway is associated with many aspects of cellular activity, including cell growth and differentiation. Activation of hormone-sensitive PLC results in the rapid breakdown of polyphosphoinositides to generate two second messengers: inositol trisphosphate and diacylglycerol. The water-soluble inositol trisphosphate is involved in the release of intracellular calcium from internal stores, whereas the lipophilic diacylglycerol is involved in protein kinase C activation. Inositol supplementation is essential for the in vitro growth of rabbit blastocysts, and studies have shown that the components of the signaling system are present in mouse and cattle embryos and in mouse embryonic stem (ES) cells. In ES cells, the signaling system appears to be constitutively active and essential for normal ES cell proliferation. Here, we describe in detail the materials required and some of techniques involved in studying the phosphoinositide signaling system in mouse ES cells. Furthermore, we describe methods of analyzing the effects of modulating the PtdIns signaling system on ES cell proliferation and the induction of apoptosis.


Iron Oxide (α-Fe2O3) Nanoparticles as an Anode Material for Lithium Ion Battery.
α-Fe2O3 nanoparticles were synthesized by facile hydrothermal process at low-temperature and used as efficient anode material for the fabrication of lithium ion battery. The prepared nanoparticles were characterized in detail by various techniques such as X-ray diffraction pattern, field emission scanning electron microscopy (FESEM) combined with energy dispersive spectroscopy (EDS), transmission electron microscopy (TEM) equipped with high-resolution TEM, Fourier transform infrared (FTIR) and Raman-scattering spectroscopy. The detailed characterizations revealed that the nanoparticles are synthesized in large quantity and possessing well-crystalline rhombohedral α-Fe2O3 structure. For application point of view, the synthesized nanoparticles were used as an anode material for fabrication of Li-ion battery. A coin cell of type-2032 was assembled using as-synthesized α-Fe2O3 nanoparticles and its charge-discharge profile was analyzed. Interestingly, it was observed that the cell delivered the first-charge capacity of 870 mAh g(-1) and the cell delivered a discharge capacity of 1500 mAh g(-1) during its first cycle.


Nitric oxide metabolites and arginase I levels in β-thalassemic patients: an Egyptian study.
Stored red blood cells become deficient in nitric oxide that limits their ability to transfer oxygen to tissues that need it. The aims of this study are to assess the endogenous nitric oxide metabolites (NOx) and arginase I levels in transfusion-dependent β-thalassemic patients; to compare these levels in patients transfused with fresh RBCs with patients transfused with old RBCs, β-thalassemic minor patients, and normal control; and to correlate these levels with some clinical variables. Group I was composed of 23 patients with homozygous β-thalassemia on hypertransfusion regimen. They were adequately transfused with fresh RBC. Group II was composed of 17 patients with homozygous β-thalassemia on hypertransfusion regimen. They were adequately transfused with old RBCs. Group III was composed of 30 patients with homozygous β-thalassemia. They were adequately transfused with fresh RBCs. Group IV was composed of 18 patients with homozygous β-thalassemia. They were adequately transfused with old RBCs. Both group III and group IV were supposed to be on hypertransfusion regimen, but they did not follow the regimen. Group V was composed of 21 patients of β-thalassemia minor. Nineteen apparently healthy individuals (HbAA) served as a control group (group VI). In addition to routine laboratory investigations, plasma levels of NOx and serum levels of arginase I were assessed in all subjects. The mean values of plasma NOx were significantly decreased in groups III and IV compared to the other groups. Also, the levels of NOx were significantly decreased in patients who received old RBCs compared to the other groups. There were high serum levels of arginase I in groups III and IV compared to the other groups. There were significant negative correlations between plasma NOx and some hemolytic biochemical markers in groups III and IV. There were significant positive correlations between serum arginase I and some hemolytic biochemical markers in groups III and IV. Also, there was a significant negative correlation between plasma NOx and serum arginase I levels in groups III and IV. In non-adequately transfused patients with β-thalassemia major, inactivation of NO correlates with hemolytic rate and is associated with the erythrocyte release of cell-free hemoglobin, which consumes NO directly, and the simultaneous release of the arginine-metabolizing enzyme arginase, which limits bioavailability of the NO synthase substrate, arginine, during the process of hemolysis. New treatments aimed at improving arginine and NO bioavailability through arginase inhibition, suppression of hemolytic rate, oral arginine supplementation, predonation testing, and transfusion of fresh RBCs or use of NO donors represent potential therapeutic strategies for this common hemolytic disorder.


Four-year experience with the routine use of the programmable Hakim valve in the management of children with hydrocephalus.
Cerebrospinal fluid (CSF) over- and underdrainage symptoms are frequent sequelae of shunt placement in patients with hydrocephalus, sometimes requiring repeated operations. To achieve more adequate CSF drainage, the non-invasively programmable Hakim valve has been developed. Because the clinical experiences with this valve so far are confined to adults, we describe our experiences with the routine use of the programmable Hakim valve in childhood hydrocephalus. Sixty children (mean age of 3.4 years) with hydrocephalus of various aetiologies have been shunted with the programmable Hakim valve. In the majority of cases, initial opening pressures of between 100 and 120 mm H2O were selected. The mean follow-up period was 2.1 years. Thirty-three readjustment of the pressure setting of the valve were performed in 20 children because of CSF overdrainage (low intracranial pressure syndrome n = 13, slit ventricle syndrome n = 2, hygroma n = 1), CSF underdrainage (n = 3) and CSF leakage through the operation wound (n = 1). The symptoms of inadequate CSF drainage were cured in 18 of the 20 children. The necessity for valve readjustments was independent of the aetiology of the hydrocephalus. Thirty-one complications requiring repeated operation occurred during the follow-up period, accounting for an annual complication rate of 24.6%. Three complications were valve-related. In the majority of cases, the programmable Hakim valve allows the successful management of symptoms related to CSF over- and underdrainage by non-invasive change of the initial pressure setting of the valve. Therefore, the programmable Hakim valve should be considered as an alternative to non-programmable valves of advanced design.


Sex differences and the prognosis of depressive and nondepressive patients with cardiovascular risk factors: the Japan Morning Surge-Home Blood Pressure (J-HOP) study.
Depression is associated with mortality in patients with cardiovascular risk factors. The frequency and severity of depression and the association between depression and cardiovascular events have sex-specific and ethnic differences. We conducted this study to evaluate the sex-specific difference in the association between depression and cardiovascular prognosis in patients with cardiovascular risk factors. We enrolled 4025 patients (64.7 ± 10.9 years, 53% women, 47% men) with cardiovascular risk factors in the Japan Morning Surge-Home Blood Pressure study. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). The follow-up period was 47 ± 24 months. The primary end points were all-cause mortality and nonfatal cardiovascular events. The BDI scores and the prevalence of depression were significantly higher in women than in men. When a BDI score of 16 was the cutoff, the primary end points in the depression group (n = 217) were significantly higher than those in the nondepression group (n = 1677) among men (adjusted hazard ratio 1.76, 95% confidence interval: 1.17, 2.64; P = 0.007). In women, the primary end points in the depression and nondepression groups were similar when BDI scores of 16, 14, and 10 were the cutoffs. In conclusion, depression defined by a BDI score ≥16 was associated with cardiovascular events in men with cardiovascular risk factors.


Microfracture for knee chondral defects: a survey of surgical practice among Canadian orthopedic surgeons.
The purpose of this study was to describe the practice of microfracture surgery for knee chondral defects among Canadian orthopedic surgeons. All orthopedic surgeon members of the Canadian Orthopaedic Association were invited to participate in a survey, designed to explore the microfracture technique used by orthopedic surgeons in the treatment for knee chondral defects The primary outcome measure was an emailed 26-item questionnaire, which explored indications for microfracture surgery, surgical techniques, types of postoperative rehabilitation regimes used and assessment of outcome. In addition, responses were compared between orthopedic surgeons with a sports medicine practice to surgeons with a non-sports medicine practice. The survey response rate was 24.6% (299/1,216), with 131 regularly performing microfracture. 41% of surgeons indicated that they had no upper limit for age at the time of surgery, and 87% indicated no upper limit for body mass index. The majority of respondents (97%) resected cartilage back to a stable margin, while 69% of respondents removed the calcified cartilage layer prior to creating holes. Only 11% of respondents used continuous passive motion (CPM) postoperatively, and 39% did not restrict weight bearing. Sports surgeons were more likely than non-sports surgeons to remove the calcified cartilage layer, use a 45° pick, use CPM and restrict weight bearing postoperatively (all P values < 0.05). This survey on microfracture for knee chondral defects revealed widespread variation among surgeons regarding the indications for surgery, surgical technique, postoperative rehabilitation and assessment of outcome. Sports surgeons demonstrate better evidence-based practice than non-sports surgeons for a few important parameters. Cross-sectional survey, Level II.


Vein grafts in microvascular surgery.
The judicious use of vein grafts will lessen the incidence of thrombosis in microvascular surgery and allow digits to be replanted without excessive shortening. In 38 vein grafts only 5 thromboses occurred.


Impact of being overweight on outcomes of hematopoietic SCT: a meta-analysis.
The impact of being overweight on outcome after hematopoietic SCT (HSCT) is controversial. We performed meta-analyses to evaluate the impact of being overweight on acute graft-versus-host disease (aGVHD) risk and survival. Original data were obtained from MEDLINE, and studies that evaluated being overweight before transplantation in recipients as a risk factor for aGVHD or a prognostic factor for overall survival (OS) were extracted. Study-specific relative risks on the log scale comparing overweight with non-overweight patients were used to obtain a pooled RR with 95% confidence interval (CI). We identified 8 studies of aGVHD and 21 of OS. In allogeneic HSCT, the meta-analysis determined statistically significant associations of overweight recipients with aGVHD risk and OS. Meta-analysis of the 8 studies of aGVHD indicated that the RR for overweight to non-overweight patients was 1.186 (95% CI: 1.072-1.312). Regarding OS, meta-analysis of 11 allogeneic HSCT studies indicated that the RR for overweight to non-overweight patients was 1.163 (1.009-1.340). Our results indicate that being overweight before transplantation in recipients is associated with a high aGVHD rate and worse survival after allogeneic HSCT. Potential heterogeneity especially in adult/pediatric patients limits the interpretability of our finding. Further, well-designed large cohort studies are warranted.


Abnormal coordination of upper extremity during target reaching in persons post stroke.
Understanding abnormal synergy of the upper extremity (UE) in stroke survivors is critical for better identification of motor impairment. Here, we investigated to what extent stroke survivors retain the ability to coordinate multiple joints of the arm during a reaching task. Using an exoskeleton robot, 37 stroke survivors' arm joint angles (θ) and torques (τ) during hand reaching in the horizontal plane was compared to that of 13 healthy controls. Kinematic and kinetic coordination patterns were quantified as variances of the multiple-joint angles and multiple-joint torques across trials, respectively, that were partitioned into task-irrelevant variance (TIVθ and TIVτ) and task-relevant variance (TRVθ and TRVτ). TIVθ and TRVθ (or TIVτ and TRVτ) led to consistent and inconsistent hand position (or force), respectively. The index of synergy (ISθ and ISτ) was determined as [Formula: see text] and [Formula: see text] for kinematic and kinetic coordination patterns, respectively. Both kinematic ISθ and kinetic ISτ in the stroke group were significantly lower than that of the control group, indicating stroke survivors had impaired reaching abilities in utilizing the multiple joints of the UE for successful completion of a reaching task. The reduction of kinematic ISθ in the stroke group was mainly attributed to the lower TIVθ as compared to the control group, while the reduction of kinetic ISτ was mainly due to the higher [Formula: see text] as well as lower TIVτ. Our results also indicated that stroke may lead to motor deficits in formation of abnormal kinetic synergistic movement of UE, especially during outward movement. The findings in abnormal synergy patterns provides a better understanding of motor impairment, suggesting that impairment-specific treatment could be identified to help improve UE synergies, focusing on outward movements.


Cost-effectiveness of osteoporosis treatments in postmenopausal women using FRAX™ thresholds for decision.
FRAX™ is a fracture prediction algorithm to determine a patient's absolute fracture risk. There is a growing consensus that osteoporosis treatment should be based on individual 10-year fracture probability, as calculated in the FRAX™ algorithm, rather than on T-scores alone. Our objective was to evaluate the cost-effectiveness of five years of branded alendronate therapy in postmenopausal French women with a known FRAX™ score. A Markov cohort state transition model using FRAX™ values and whenever possible population-specific data and probabilities. We estimated the incremental cost-effectiveness ratio (ICER) of alendronate versus no treatment in postmenopausal women with FRAX™ ranging from 10 to 3%. Number of women to treat (NNT) for preventing hip fracture, costs, quality-adjusted life-years, incremental cost-effectiveness ratios. The incremental cost-effectiveness ratios (ICER) compared to no treatment at age 70 ranged from €104,183 to €413,473 per QALY when FRAX™ decreased from 10 to 3%. The NNTs for preventing one hip fracture ranged from 97 to 388 according to age (50-80 years) and FRAX™. Sensitivity analyses showed that the main determinants of cost-effectiveness were adherence to therapy and cost of treatment. Using French costs of branded drug and current estimates of treatment efficacy, alendronate therapy for 70-year-old women with 10-year probability of hip fracture of 10% just meets the accepted cost-effectiveness threshold. Improving treatment adherence and/or decreasing treatment cost lowers the ICER. The model however underestimates the potential benefit by excluding other fractures.


Factors Affecting the Outcome of Symptomatic Carotid Stenosis Surgical Treatment in a Single Center Series.
The aim of this study is to evaluate the role of preoperative ischemic brain lesion (IBL) volume, assessed by Diffusion-weighted magnetic resonance brain imaging (DW-MRI) with RAPID® processing, and surgery timing in predicting post-operative neurological outcomes in symptomatic carotid stenosis (SCS) patients treated with carotid endarterectomy (CEA). All patients with SCS who underwent CEA between January 2010 and June 2020 were considered. IBLs ipsilateral to the stenosis were identified in the preoperative magnetic resonance brain (MRI). The volume was quantified in mL and correlated with 30-day rates of stroke and stroke/death by χ2 and receiver operating characteristic (ROC) curve. One hundred thirty-four patients were surgically treated for SCS during the entire study period. CEA procedures were defined as emergent, urgent, or elective if performed within 48 hr, between 48 hr and 14 days, or after 14 days from symptoms onset, respectively. Cumulative new ipsilateral stroke rate was 4,5%, with a statistically higher neurological complications in emergent patients compared to urgent and elective patients (10,6%, 1,47% and 0% respectively, P 0,039). ROC curve analysis showed a volume of 10 mL was predictive of postoperative stroke with 100% sensitivity and 80% specificity. An IBL volume >10 mL was an independent risk factor for postoperative stroke. In fact, the perioperative neurological complication rate was significantly different in high-IBL volume patients (>10 mL) compared with low-IBL volume patients (<10 mL) (P 0,003) CONCLUSIONS: The present study suggests that the optimal timing for CEA is between 48 hr and 14 days. Furthermore, the present study suggests that the presence of the IBL, by itself, is not definitively related with an unsatisfactory neurological outcome. However, an IBL higher than 10 mL should be as a reliable threshold value adverse neurological result in SCS patients.


Affinity maturation of human CD4 by yeast surface display and crystal structure of a CD4-HLA-DR1 complex.
Helper T-cell activation generally requires the coreceptor CD4, which binds MHC class II molecules. A remarkable feature of the CD4-MHC class II interaction is its exceptionally low affinity, which ranges from K(D) = ∼200 μM to >2 mM. Investigating the biological role of the much lower affinity of this interaction than those of other cell-cell recognition molecules will require CD4 mutants with enhanced binding to MHC class II for testing in models of T-cell development. To this end, we used in vitro-directed evolution to increase the affinity of human CD4 for HLA-DR1. A mutant CD4 library was displayed on the surface of yeast and selected using HLA-DR1 tetramers or monomers, resulting in isolation of a CD4 clone containing 11 mutations. Reversion mutagenesis showed that most of the affinity increase derived from just two substitutions, Gln40Tyr and Thr45Trp. A CD4 variant bearing these mutations bound HLA-DR1 with K(D) = 8.8 μM, compared with >400 μM for wild-type CD4. To understand the basis for improved affinity, we determined the structure of this CD4 variant in complex with HLA-DR1 to 2.4 Å resolution. The structure provides an atomic-level description of the CD4-binding site on MHC class II and reveals how CD4 recognizes highly polymorphic HLA-DR, -DP, and -DQ molecules by targeting invariant residues in their α2 and β2 domains. In addition, the CD4 mutants reported here constitute unique tools for probing the influence of CD4 affinity on T-cell activation and development.


Identification and comprehensive analysis of MIPSs in Rosaceae and their expression under abiotic stresses in rose (Rosa chinensis).
The Myo-Inositol-1-phosphate synthase (MIPS) gene family is involved in the myo-inositol synthesis and plays a significant role in signal transduction, membrane biogenesis, oligosaccharides synthesis, auxin storage and transport, programmed cell death and abiotic stress tolerance in plants. This study comprehensively identified the MIPS genes in Rosaceae plant species, and 51 MIPS genes were identified from 26 Rosaceae species. The phylogenetic analysis divided the MIPSs into two clades (clade I; subfamily Amygdaloideae specific, and clade II; subfamily Rosoideae specific). MIPS genes of all 26 Rosaceae species consist of similar gene structure, motif and domain composition, which shows their conserved nature. The cis-regulatory elements (CREs) analysis revealed that most Rosaceae MIPS genes play a role in growth, development, and stress responses. Furthermore, the qRT-PCR analysis also revealed the involvement of RcMIPS gene in plant development and response to abiotic stresses, including drought and heat. The results of the present study contribute to the understanding of the biological function of Rosaceae MIPS genes, and that could be used in further functional validations.


Analysis of fatty acids in lung tissues using gas chromatography-mass spectrometry preceded by derivatization-solid-phase microextraction with a novel fiber.
In this article, a laboratory-made sol-gel derived fiber with butyl methacrylate/hydroxy-terminated silicone oil (BMA/OH-TSO) coating was first used for headspace solid-phase microextraction (HS-SPME) of medium and long chain fatty acids after derivatization and applied to the analysis of fatty acids in lung tissues by coupling to gas chromatography-mass spectrometry (GC-MS). The experimental parameters for derivatization, HS-SPME and desorption were optimized. Fatty acids in cancerous lung tissues from five patients with lung cancer were determined under the optimized conditions. Normal lung tissues from the same five patients were used as controls. This fiber showed higher extraction efficiency for fatty acids after derivatization when compared with commercial polydimethylsiloxane (PDMS) and polydimethylsiloxane-divinylbenzene (PDMS/DVB) fibers due to the three-dimensional network in the coating. The method presented in this paper showed satisfactory precision, accuracy, linearity and limits of detection (LODs). The relative standard deviation values were below 13.3% (n=5) and the recoveries obtained ranged from 76.35% to 107.0%. The results obtained using the SPME method were also compared with those got by using liquid-liquid extraction (LLE) technique. It was found that the sensitivity could be enhanced by the SPME method. The analysis of the cancerous lung tissues and normal controls from five patients with lung cancer indicated that the main components of lung tissue were palmitic acid (C16:0), stearic acid (C18:0) and lignoceric acid (C24:0). A comparison between the levels of the fatty acids in cancerous lung tissues and normal controls from the same a patient with lung cancer shows that most of the saturated fatty acids showed higher levels in cancerous lung tissues, while unsaturated fatty acids showed higher levels in normal controls on the whole.


An appraisal of radical pancreatoduodenectomy based on insulin secretion.
The effect of pancreatoduodenectomy on insulin secretion was determined in seven patients with periampullary malignant tumors. As a uniform stimulus for secreting insulin, 100 gm of glucose was administered orally to all patients and glucose tolerance tests were carried out. Glucose intolerance and poor insulin secretion were obvious both pre- and postoperatively. Indexes of an initial insulin response, of a maximum insulin increment, and of total secretion of insulin responding to the stimulus of glucose were significantly lower in these patients before and after pancreatoduodenal resection, as compared with normal subjects. It was also observed that these three indexes, which express the ability of the pancreas to secrete insulin, decreased without exception after pancreatoduodenectomy. In light of these data it is postulated that radical pancreatoduodenectomy further diminishes the already insufficient secretion of insulin indicated by the oral glucose tolerance test in patients with periampullary malignant tumors.


[On the subject of longevity. Study of a case of a 105-year-old man].
The Authors describes the case of male subjects who has got a very old age (105) with no particular "biological trouble". Some considerations about it are discussed.


Evaluation of the modal structure of light beams composed of incoherent mixtures of Hermite-Gaussian modes.
A new, to our knowledge, technique for determining the modal content of partially coherent beams that are made up of an incoherent superposition of Hermite-Gaussian modes is studied. The algorithm makes use of the intensity profile of the beam at an arbitrarily chosen transverse plane. Analytical derivations are presented for a Gaussian Schell-model source and flat-topped beams, as well as an analysis of their performances in the presence of experimental errors and noise. Numerical simulations are performed to test the accuracy and the stability of the recovery algorithm.


Animal- and human-based evidence for the protective effects of stem cell therapy against cardiovascular disorders.
The increasing rate of mortality and morbidity because of cardiac diseases has called for efficient therapeutic needs. With the advancement in cell-based therapies, stem cells are abundantly studied in this area. Nearly, all sources of stem cells are experimented to treat cardiac injuries. Tissue engineering has also backed this technique by providing an advantageous platform to improve stem cell therapy. After in vitro studies, primary treatment-based research studies comprise small and large animal studies. Furthermore, these studies are implemented in human models in the form of clinical trials. Purpose of this review is to highlight the animal- and human-based studies, exploiting various stem cell sources, to treat cardiovascular disorders.


Body composition, maximal aerobic performance and inflammatory biomarkers in endurance-trained athletes.
This study was designed to examine the relationships between body composition, cardiorespiratory fitness and simultaneously measured inflammatory parameters in endurance-trained athletes. In 20 well-trained rowers (19·0 ± 2·9 years; 185·6 ± 4·8 cm; 85·7 ± 10·8 kg; 17·1 ± 5·1% body fat; maximal oxygen consumption [VO2 max]: 63·9 ± 8·5 ml min-1 kg-1 ), body composition was measured by dual-energy X-ray absorptiometry and cardiorespiratory fitness by direct VO2 max test. Twelve inflammatory factors [interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, vascular endothelial growth factor, interferon-gamma (IFN-γ), tumour necrosis factor-alpha, IL-1α, IL-1β, monocyte chemoattractant protein-1 (MCP-1), epidermal growth factor (EGF)] were analysed from serum samples. Serum IFN-γ was related (P<0·05) to fat-free mass (FFM) (r = -0·56) and muscle mass (r = -0·50). The stepwise regression analysis showed that IFN-γ explained 27·5%, and IFN-γ and IL-6 together explained 39·8% of the variability of FFM, while IFN-γ explained 21·1%, and IFN-γ together with EGF explained 36·6% of the variability of muscle mass in male rowers. Serum IL-8 (r = -0·65) and VEGF (r = -0·48) correlated (P<0·05) with VO2 max kg-1 . Serum IL-8 explained 38·5% of the variability of VO2 max kg-1 . Significant correlations were also found among several inflammatory parameters, indicating that various inflammatory cytokines act on the body as an ensemble. In conclusion, this cross-sectional study in endurance-trained male rowers showed that FFM and muscle mass were negatively correlated with serum IFN-γ level, whereas cardiorespiratory fitness was negatively related to serum IL-8 level.


Pharmacokinetics and metabolism of moxestrol in animals--rat, dog and monkey.
The pharmacokinetics and metabolism of moxestrol have been compared in the rat, dog and monkey (rhesus and baboon) and, in some instances, confronted with data simultaneously obtained for ethynl estradiol and previously obtained in humans. The apparent initial volume of distribution (AIVD) of total radioactivity after i.v. administration was of the order of body volume in all species under study; the AIVD of intact moxestrol was even higher. This is in agreement with moxestrol's low binding to specific and non-specific plasma proteins. The half-life of total radioactivity elimination was 14-18 h in the rat and rhesus monkey, but longer (43 and 78 h, i.v. and oral respectively) in the baboon. In the dog, the elimination phase could not be distinguished from the distribution phase and had a half-life of 2 h. The half-life of unchanged moxestrol elimination was shorter and very similar in the rhesus, baboon and human (6.6, 7.5 and 8.2 h respectively) and only 1.4 h in the dog. Regardless of the route of administration or the species under study, the clearance and elimination rate of unchanged moxestrol were higher than of total radioactivity implying that metabolites and/or conjugation products were eliminated more slowly than intact product from plasma. Orally administered moxestrol was rapidly absorbed in all species. Since clearance of total radioactivity and of moxestrol was faster after i.v. than oral administration, but the radioactivity levels excreted in the urine were identical for the two routes, a significant first-pass-effect probably occurred in the liver. Radioactivity distribution in tissues was examined in the rat. Total radioactivity was higher 24 h after administration of labelled moxestrol than of labelled ethynyl estradiol in endocrine tissues; it was equivalent or less in the other tissues. For all tissues, the elimination rate of moxestrol was greater than, or equal to, that of ethynyl estradiol. In dog urine, the only product identified was moxestrol; in rhesus or baboon monkey urine, the principal metabolites were catechol estrogens, which were also present in appreciable amount in rat bile (as methyl ethers) but were minor metabolites in human urine. Hydroxylation in position 16 occurred in rats and humans only, in position 15 alpha in humans and, to a much lesser extent, in rats and monkeys. Thus, the metabolic profile of moxestrol in rats most closely resembles that in humans.


The role of SAMHD1 expression and its relation to HIV-2 (Vpx) gene production.
SAMHD1 (sterile alpha motif and HD domain 1) is a protein that is found in myeloid cells, which restricts HIV1 replication. It depletes the de-oxy-nucleoside tri-phosphate (dNTPs) pool needed for a viral cDNA synthesis leading to inhibition of viral replication inside the cells. However, it does not restrict HIV2 replication in myeloid cells due to the presence of viral Vpx protein. Vpx is a virion-associated protein which augments viral infectivity and it only exists in HIV2 and it has been recently shown in Simian Immunodeficiency Virus (SIV) and which can induce degradation of SAMHD1 protein. This increases the amount of dNTPs for viral reverse transcription in cytoplasm and HIV infection. HIV2 reverse transcription is believed to be less active than HIV1 and this could be the reason for the absence of Vpx from HIV1. Protein expression and interaction between Vpx and SAMHD1 remains unclear. The interaction of SAMHD1 and HIV2-VPx patients' cells can be considered as a first step to help in the development for more effective anti-HIV drugs and possible novel intervention therapy in the future. Present review article provides comprehensive insights on the above issue. We performed a comprehensive literature search in the bibliographic database "Pubmed," looking at studies discussing the SAMHDI and Vpx interactions.


Pharmacokinetics and follicular dynamics of corifollitropin alfa versus recombinant FSH during ovarian stimulation for IVF.
A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. This double-blind randomized controlled trial assessed the pharmacokinetics and pharmacodynamics of 150μg corifollitropin alfa versus daily 200IU rFSH in 1509 patients. Comparative analyses were performed on serum concentrations of FSH immunoreactivity (pharmacokinetics), and the number and size of growing follicles, and inhibin B and oestradiol concentrations as biomarkers of ovarian response (pharmacodynamics). The rate of follicular development was similar in both treatment groups. By stimulation day 8, 33% of patients treated with corifollitropin alfa reached the criterion for human chorionic gonadotrophin (HCG) injection. The number of follicles ⩾11mm was slightly higher after corifollitropin alfa compared with daily rFSH at stimulation day 8 (difference, 1.2; 95% confidence interval (CI) 0.5-1.8; P<0.01) and on the day of HCG injection (difference, 2.1; 95% CI 1.4-2.8; P<0.01). The rise of inhibin B and oestradiol concentrations was similar in both treatment groups. Although the pharmacokinetics of corifollitropin alfa and rFSH are quite different their pharmacodynamic profiles at the dosages used are similar. A single injection of corifollitropin alfa can replace seven daily injections of recombinant FSH (rFSH) using a gonadotrophin-releasing hormone antagonist protocol in ovarian stimulation prior to IVF or intracytoplasmic sperm injection. The objective of this study was to compare the pharmacokinetics and pharmacodynamics of corifollitropin alfa versus daily rFSH. A total of 1509 patients were randomized in a double-blind, controlled trial to either a single injection of 150μg corifollitropin alfa or to daily injections of 200IU rFSH for the first 7 days of ovarian stimulation. Serum levels of FSH immunoreactivity were analysed (pharmacokinetic analysis), together with the number and size of growing follicles and serum inhibin B and oestradiol concentrations as biomarkers of the ovarian response (pharmacodynamic analysis). Serum FSH immunoreactivity levels were higher up to stimulation day 5 for corifollitropin alfa compared with the daily rFSH regimen but were similar from day 8 onwards, when patients started rFSH if the criteria for human chorionic gonadotrophin were not yet reached. Corifollitropin alfa treatment resulted in a similar growth rate of follicles though a slightly higher number of follicles were recruited compared with daily rFSH. It is concluded that the pharmacokinetics of corifollitropin alfa and rFSH are quite different but their induced pharmacodynamic effects at the dosages used are similar.


Post-translational control of ribosomal protein L1 accumulation in Xenopus oocytes.
A functional ribosomal protein mRNA, encoding the 60 S subunit protein L1, has been synthesized in vitro using bacteriophage SP6 RNA polymerase. This mRNA directs the synthesis of a product indistinguishable from L1 protein purified from Xenopus ovarian ribosomes. Our results show that L1 synthesis in stage VI oocytes increases in response to microinjection of exogenous SP6-L1 mRNA, but excess L1 protein is not stably accumulated. These results indicate that dosage compensation does not occur at the translational level for this ribosomal protein mRNA and that the abundance of this protein in fully grown oocytes is subject to post-translational regulation.


Dynamic conformal arc radiotherapy with rectum hollow-out technique for localized prostate cancer.
To report the feasibility of dynamic conformal arc radiotherapy with rectum hollow-out technique (DCAT-HO) for localized prostate cancer. Between October 2000 and April 2007, 204 patients with clinically localized or locally advanced prostate cancer were treated with DCAT-HO. All patients were given neoadjuvant total androgen deprivation (AD) therapy (median 6 months, range 2-27 months). All patients with T3 or T4 stage received post-irradiation AD for 24 months. A total of 128 patients (63%) were treated with 70Gy, and 76 patients (37%) were treated with 74Gy. Acute and late toxicities were scored by the Radiation Therapy Oncology Group morbidity grading scales. PSA relapse was defined as three successive PSA elevations after a post-treatment nadir. The median follow-up was 37 months. Both the acute Grade 2 rectal and urinary toxicities were 1.0%, and no patients experienced acute Grade 3 or higher symptoms. The 3-year rates of both late Grade 2 rectal and urinary toxicities were 3.4%. The 3-year PSA relapse-free survival for low, intermediate, and high-risk group patients treated with 70 Gy were 54%, 75%, and 87%, respectively. These findings demonstrate the feasibility of DCAT-HO in a large number of patients with short follow-up. DCAT-HO reduced the volume of the rectum exposed to higher doses and this led to an overall reduction in late rectal toxicity.


Prospective memory impairments in heavy social drinkers are partially overcome by future event simulation.
Recent research suggests that alcohol acutely impairs prospective memory (PM), and this impairment can be overcome using a strategy called 'future event simulation' (FES). Impairment in event-based PM found in detoxifying alcohol-dependent participants is reversed through FES. However, the impact of the most common problematic drinking patterns that do not involve alcohol dependence on PM remains unclear. Here, we examine the impact of frequent heavy drinking on PM and the degree to which any impairments can be reversed through FES. PM was assessed in 19 heavy drinkers (AUDIT scores ≥ 15) and 18 matched control participants (AUDIT scores ≤ 7) using the 'Virtual Week' task both at baseline and again following FES. Heavy drinkers performed significantly worse than controls on regular and irregular time-based PM tasks. FES improved the performance of controls but not of heavy drinkers on time-based tasks. In contrast, FES improved heavy drinkers' performance on event-based PM tasks. These findings suggest that heavy drinkers experience deficits in strategic monitoring processing associated with time-based PM tasks which do not abate after FES. That the same strategy improves their event-based PM suggests that FES may be helpful for individuals with problematic drinking patterns in improving their prospective memory.


Suppressive role of endogenous regucalcin in the enhancement of deoxyribonucleic acid synthesis activity in the nucleus of regenerating rat liver.
The role of endogenous regucalcin in the regulation of deoxyribonucleic acid (DNA) synthesis activity in the nuclei of regenerating rat liver after partial hepatectomy was investigated. The addition of regucalcin (0.25 and 0.5 microM) in the reaction mixture caused a significant decrease in the nuclear DNA synthesis activity of normal rat liver. This decrease was also seen in the presence of Ca2+-chelator EGTA (0.4 mM), indicating that the effect of regucalcin is not related to nuclear Ca2+. Nuclear DNA activity was significantly increased in the presence of anti-regucalcin monoclonal antibody (10-50 ng/ml) in the reaction mixture. The effect was completely abolished by the addition of regucalcin (0.5 microM). Nuclear DNA synthesis activity was significantly increased at 24, 48, and 72 h after partial heptectomy. The effect of anti-regucalcin monoclonal antibody (25 ng/ml) in increasing nuclear DNA synthesis activity was significantly enhanced at 24 and 48 h after partial hepatectomy. The presence of staurospone (10(-6) M), trifluoperazine (2 x 10(-5) M), or PD98059 (10(-5) M) in the reaction mixture caused a significant decrease in DNA synthesis activity in the nuclei obtained at 24 after partial hepateactomy. The effect of these inhibitors in the presence of anti-regucalcin monoclonal antibody (25 ng/ml) was greater than that in the absence of the antibody. The present study suggests that endogenous regucalcin plays a suppressive role in the enhancement of nuclear DNA synthesis activity in regenerating liver with cell proliferation after partial hepatectomy in rats.


[Instructions for the documentation of neoplasms in the area of the head and neck following the TNM system. Contribution to the validation of the TNM system].
As the only international classification scheme the TNM-system allows classification of practically all tumours of all organs according to uniform rules. In the interest of international comparison of findings and results the TNM-system alone can be recommended for classification. Checklists are used for extension of the basic documentation for the head and neck. Directions for initial and follow up analysis are given. The TNM-system in this proposed practice allows clear determination of the pre-therapeutic findings, recurrences to be taken into account, the course of the disease to be recorded, and the survival rate to be calculated. The data are suitable for recording on a computer. Finally uniform recommendations for treatment may be deduced.


Serum cholesterol-decreasing effect of heat-moisture-treated high-amylose cornstarch in cholesterol-loaded rats.
Rats were fed on a diet containing cholesterol (Chol) at a level corresponding to the standard Chol intake in humans, and the influence of heat-moisture-treated high-amylose cornstarch (HHA) on their serum Chol level was investigated. HHA decreased the serum level of Chol in rats fed on the diet containing 0.1% Chol, which corresponds to a Chol intake in humans of 800 mg/d, although the liver levels of Chol increased in these rats. HHA did not influence the fecal excretion of Chol/bile acids. It is possible that the decrease in serum Chol level in the rats fed on the high-Chol diet can be attributed to the promotion of Chol uptake in the liver.


Glucocorticoids improve acute dizziness symptoms following acute unilateral vestibulopathy.
Acute unilateral vestibulopathy (AUV) is characterized by acute vertigo, nausea, and imbalance without neurological deficits or auditory symptomatology. Here, we explore the effect of glucocorticoid treatment on the degree of canal paresis in patients with AUV, and critically, establish its relationship with dizziness symptom recovery. We recruited consecutive patients who were retrospectively assigned to one of the two groups according to whether they received glucocorticoid treatment (n = 32) or not (n = 44). All patients underwent pure-tone audiometry, bithermal caloric testing, MRI brain imaging, and were asked to complete a dizziness handicap inventory on admission to hospital and just prior to hospital discharge. In the treatment group, the canal paresis at discharge was significantly lower than in the control group (mean ± SD % 38.04 ± 21.57 versus 82.79 ± 21.51, p < 0.001). We also observed a significant reduction in the intensity of nystagmus in patients receiving glucocorticoid treatment compared to the non-treatment group (p = 0.03). DHI test score was significantly lower at discharge in the treatment group (mean ± SD % 23.15 ± 12.40 versus 64.07 ± 12.87, p < 0.001), as was the length of hospital stay (2.18 ± 1.5 days versus 3.6 ± 1.7 days, p = 0.002). Glucocorticoid treatment leads to acute symptomatic improvement, with a reduced hospital stay and reduction in the intensity of acute nystagmus. Our findings suggest that glucocorticoids may accelerate vestibular compensation via a restoration of peripheral vestibular function, and therefore has important clinical implications for the treatment of AUV.


Promoting exercise, reducing sedentarism or both for diabetes prevention: The "Seguimiento Universidad De Navarra" (SUN) cohort.
Both physical activity (PA) and sedentary behaviors have demonstrated independent associations with the development of type 2 diabetes mellitus (T2DM). However, the combination of both, has been less explored. We aimed to compare the associations of PA-only versus the simultaneous effect of PA and sedentary behaviors on T2DM in a Mediterranean cohort. Participants (n = 19,524) initially free of T2DM from the SUN Project were followed-up for a median of 10.4 years. Analyses were conducted in 2018. PA and sedentary parameters (TV viewing time and sitting time) were assessed through a validated questionnaire. The amount of each PA was expressed in METs-h/wk. After that, a previously developed 8-item active + sedentary lifestyle score was computed. T2DM was defined according to ADA criteria. To adjust for potential confounders, Cox regression models were adjusted. Among 19,524 participants, 175 cases of new-onset T2DM were observed during follow-up. After multivariable adjustment, higher PA was strongly inversely associated with T2DM, showing highly significant differences between extreme quartiles (HR = 0.51; 95% CI 0.32-0.79 p for trend<0.001). When considering not only PA, but also the more comprehensive active + sedentary lifestyle combined score, even stronger differences were found between the lowest and the highest categories (HR = 0.40; 95%CI 0.20-0.80; p for trend<0.001). Sedentary lifestyles, in addition to PA patterns, should be included in the assessment of T2DM risk. Promoting PA should be coupled with the avoidance of a sedentary lifestyle to lower the risk of T2DM.


Venous thrombosis in older people: prevalence of the factor V gene mutation Q506.
Old age is usually considered to be a risk factor for venous thromboembolism, in conjunction with other factors such as heart failure, major surgery, cancer, long-term immobilization, and antiphospholipid antibodies. Genetic risk factors, especially inherited deficiencies in coagulation inhibitors, also play a role in the pathogenesis of thrombosis, but these are usually diagnosed in thrombophilic patients before the age of 50. The factor V Q506 mutation, responsible for activated protein C resistance, was recently linked to thromboembolic disease. We therefore investigated the prevalence of biological risk factors in older hospital patients with venous thromboembolism. A 2-year study period. Ivry sur Seine (Paris), France. Seventy-nine geriatric patients (60 women and 19 men, mean age 83+/-6.8 years, range 70-102 years) who had had at least one proven episode of venous thromboembolism were enrolled over a 2-year period. Lupus anticoagulant and antithrombin (AT), protein C (PC), and protein S (PS) levels were determined in plasma. The factor V Q506 mutation was detected on genomic DNA. Lupus anticoagulant was detected in two women, one of whom also had a high level of anticardiolipin IgG, leading to the diagnosis of an antiphospholipid syndrome. No hereditary deficiency in AT, PC, or PS was found, but one patient had an acquired AT deficiency. Interestingly, nine of the 79 patients (11.4%, six women and three men) were heterozygous for the factor V Q506 mutation, although none were homozygous. The only major risk factor for thrombosis identified in these patients was prolonged immobilization in four cases. Four of the nine patients who were heterozygous for the factor V Q506 mutation had recurrent thromboembolism, and two of these patients had been immobilized for long periods. This study confirms that hereditary deficiencies in coagulation inhibitors, and the lupus anticoagulant, are rarely involved in the pathogenesis of venous thromboembolism in older subjects. In contrast, the factor V Q506 mutation was frequently associated with thrombosis (11.4% of our patients) and should, therefore, be considered an important risk factor in the older people.


Detection of canine adenoviral infections in urine and faeces by the polymerase chain reaction.
The present study was aimed at developing the polymerase chain reaction (PCR) assay for detection of canine adenoviruses from faecal or urine samples. Urine or faecal samples were treated with chloroform or activated charcoal to eliminate the PCR inhibitory substances and the total DNA was extracted. The PCR was optimized using common set of primers to amplify 508 bp or 1,030 bp DNA sequence within E3 gene of canine adenovirus-1 (CAV-1) and canine adenovirus-2 (CAV-2), respectively. The PCR assay could detect up to 0.016 TCID(50) viruses from CAV-1 infected MDCK cell culture fluid, 1.6 TCID(50) viruses from faeces and 16 TCID(50) viruses from urine. In addition, the PCR assay was validated using clinical samples. Based on the results, it is concluded that, the present PCR assay can be used for rapid detection of canine adenoviral infections.


Injury prevention and emergency medical services: the "Accidents Aren't" program.
This report describes the rationale, purpose, structure, and content of the emergency medical services (EMS) injury prevention program "Accidents Aren't." The program is introduced with a review of injuries' toll professionally, epidemiologically, and economically in terms of the demand on medical care resources and the expense of care. With recognition that most EMS resources are expended on clinical care of non-critical but potentially catastrophic injuries, "Accidents Aren't" was designed to offer a more cost-effective means of care for this population and more efficient utilization of finite resources. The report describes the program's formulation process, its modular design, the instructor guidelines, the core training tool, the STARR mnemonic, and five clinical cases involving a wide array of injury mechanisms to which the mnemonic is applicable. Physician involvement in teaching and implementing the program is discussed. The relationship of the program to the future of EMS concludes the report.


Estrogens: mechanisms of neuroprotective effects.
Within the last few years, there has been a growing interest in the neuroprotective effects of estrogen and the possible beneficial effects of estrogen in neurodegenerative diseases such as stroke, Alzheimer's disease, and Parkinson's disease. The concept of neuroprotective effects of estrogen in women remains controversial because these effects may vary with the timing of treatment. Research increasingly suggests that changes in estrogen levels during aging may increase risk for Alzheimer's disease, the most common type of dementia. This update reviews the newest information about estrogen and cognitive aging, including information regarding the role of bioavailable estrogen in older women and men.


Developmental expression of neurotrophins and their receptors in postnatal rat ventral midbrain.
Neurotrophins are a group of structurally related polypeptides that support the survival, differentiation, and maintenance of neuronal populations that express the appropriate high-affinity neurotrophin receptors. Two members of the neurotrophin family, brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), have been shown to increase the survival of dopaminergic neurons from the ventral midbrain in vitro. Evidence suggests that ventral midbrain neurons might be able to derive support from these trophic factors in vivo through paracrine or autocrine interactions. Both BDNF and NT-3 mRNAs and their receptor mRNAs, trkB and trkC mRNAs, respectively, have been localized to the ventral mesencephalon. However, the relative expression levels of the neurotrophins and their receptor mRNAs throughout ontogeny and in adulthood have not been elucidated. In the present study, the postnatal developmental expression of BDNF, NT-3, trkB, and trkC mRNAs was analyzed via in situ hybridization to gain insight into the possible roles of these factors in vivo. We found that there was a developmental decline in the expression of BDNF and NT-3 mRNAs in the ventral mesencephalon. In contrast, no alterations in the expression of midbrain trkB or trkC mRNAs could be discerned. The present results suggest a role for BDNF and NT-3 in the earlier postnatal developmental events of responsive populations. The continued, albeit lower, expression of the neurotrophins in the ventral mesencephalon in adulthood also suggests a role for these factors in mature neuronal systems.


NADPH- and linoleic acid hydroperoxide-induced lipid peroxidation and destruction of cytochrome P-450 in hepatic microsomes.
Temporal aspects of the effects of inhibitors on hepatic cytochrome P-450 destruction and lipid peroxidation induced by NADPH and linoleic acid hydroperoxide (LAHP) were compared. In the absence of added Fe2+, NADPH-induced lipid peroxidation in hepatic microsomes exhibited a slow phase followed by a fast phase. The addition of Fe2+ eliminated the slow phase, thus demonstrating that iron is a rate-limiting component in the reaction. EDTA, which complexes iron, and p-chloromercurobenzoate (pCMB), which inhibits NADPH-cytochrome P-450 reductase, inhibited both phases of the reaction. Catalase as well as scavengers of hydroxyl radical, inhibited NADPH-induced lipid peroxidation almost completely. GSH also inhibited the NADPH-dependent reaction but only when added at the beginning of the reaction. In contrast with NADPH-dependent lipid peroxidation, the autocatalytic reaction induced by LAHP was not biphasic, NADPH-dependent or iron-dependent, nor was it inhibited by hydroxyl radical scavengers, catalase or GSH. A synergistic effect on lipid peroxidation was observed when both NADPH and LAHP were added to microsomes. It is concluded that both the fast and slow phases of NADPH-dependent microsomal lipid peroxidation are catalyzed enzymatically and are dependent upon Fe2+, whereas LAHP-dependent lipid peroxidation is autocatalytic. Since the fast phase of enzymatic lipid peroxidation occurred during the fast phase of destruction of cytochrome P-450, it is postulated that iron made available from cytochrome P-450 is sufficient to promote optimal lipid peroxidation. Since catalase and hydroxyl radical scavengers inhibited NADPH-dependent but not LAHP-dependent lipid peroxidation, it is concluded that the hydroxyl radical derived from H2O2 is the initiating active-oxygen species in the enzymatic reaction but not in the autocatalytic reaction.


Effects of sodium butyrate nanoparticles on the hemato-immunological indices, hepatic antioxidant capacity, and gene expression responses in Oreochromisniloticus.
Recently, nanotechnology has been greatly developed to provide the aquaculture industry with new beneficial nanomaterials to improve the health and welfare of aquatic animals. Herein, an eight-week experiment was designed to examine the dietary impacts of sodium butyrate nanoparticles (SB-NPs) on the hematological profile, blood proteins, immunological indices, antioxidant capacity, and expression analysis of cytokines and antioxidant-related genes in Oreochromis niloticus. Fish were randomly assigned into 5 experimental groups (3 replicates per group) and were fed diets supplemented with 5 levels of SB-NPs as 0.0 (control), 0.5, 1.0, 1.5, and 2.0 mg kg-1. The results revealed that supplementing diets with SB-NPs (1.0-2.0 mg kg-1) significantly elevated erythrocyte and leukocyte counts, hemoglobin concentrations, hematocrit values, total albumin, globulin, serum lysozyme activities, and total immunoglobulin M values compared with the control group. Notably, the highest levels of the parameters mentioned above were noticed in the group fed diet supplemented with 1.5 mg kg-1 SB-NPs. Moreover, dietary SB-NPs modulated the fish's antioxidant defense mechanisms, whereas there was a significant increase in hepatic superoxide dismutase, catalase, and glutathione peroxidase enzyme activities along with a significant decline in hepatic malondialdehyde concentrations in fish groups fed diets supplemented with SB-NPs (1.0-2.0 mg kg-1). A significant upregulation of antioxidant enzyme genes (gpx and sod), anti-inflammatory cytokine (il-10), and pro-inflammatory cytokines (il-1β and il-8) were noticed in liver tissues of SB-NPs groups (0.5-1.5 mg kg-1). The highest mRNA expression folds of the above genes were recorded in the fish group fed diet supplemented with 1.5 mg kg-1 SB-NPs. In this context, we hypothesized that dietary supplementation with SB-NPs can boost the antioxidant status and immunity of O. niloticus. However, further research studies are still recommended.


High production of 4-hydroxyisoleucine in Corynebacterium glutamicum by multistep metabolic engineering.
4-Hydroxyisoleucine (4-HIL) exhibits a unique glucose-dependent insulinotropic activity and is a promising candidate for the treatment of diabetes. Direct fermentation of 4-HIL has been recently studied; however, the expected titre and yield were not achieved. In this study, we initially developed a pathway for the synthesis of 4-HIL in an L-isoleucine producer, C. glutamicum YI, but insufficient supply of α-ketoglutarate was a bottleneck for a strong production. Six genes involved in oxaloacetate and α-ketoglutarate branches were overexpressed or deleted, which increased the production of 4-HIL to 5.12 g/L but a considerable amount of L-isoleucine still accumulated in the culture. We then dynamically modulated the activity of the α-ketoglutarate dehydrogenase complex (ODHC) by employing L-isoleucine-responsive transcription or attenuation strategies. The best-engineered strain, HIL18, produced 34.21 g/L 4-HIL with a negligible accumulation of byproducts, including approximately 0.6 g/L L-isoleucine. This study achieved the highest production and yield of 4-HIL, and optimizing the TCA cycle by dynamically modulating the activity of ODHA can be a powerful strategy to balance the carbon flux and achieve efficient production of α-ketoglutarate and derivatives.


Cleavage of the MLL gene by activators of apoptosis is independent of topoisomerase II activity.
Exposure to topoisomerase II inhibitors is linked to the generation of leukemia involving translocations of the MLL gene, normally restricted to an 8.3 kbp tract, the breakpoint cluster region (BCR). Using an in vitro assay, apoptotic activators, including radiation and anti-CD95 antibody, trigger site-specific cleavage adjacent to exon 12 within the MLL BCR and promote translocation of the MLL gene in cells that can survive. To explore the mechanism of cleavage and rearrangement in more detail, the entire MLL BCR was placed into the pREP4 episomal vector and transfected into human lymphoblastoid TK6 cells. Episomes containing either the MLL BCR, or deletion constructs of 367 bp or larger, were cleaved at the same position as genomic MLL after exposure to apoptotic stimuli. Further analysis of sequence motifs surrounding the cleaved region of MLL showed the presence of both a predicted nuclear matrix attachment sequence and a potential strong binding site for topoisomerase II, flanking the site of cleavage. Inactivation of topoisomerase II by the catalytic inhibitor merbarone did not inhibit MLL cleavage, suggesting that the initial cleavage step for MLL rearrangement is not mediated by topoisomerase II.


Cortical thickness and trait empathy in patients and people at high risk for alcohol use disorders.
Alcoholism not only affects individuals with alcohol use disorder (AUD) but also their biological relatives. This high-risk (HR) group has a higher probability to develop AUD. The aim of our study was to compare cortical thickness (CT) in AUD patients relative to participants with (HR) and without (non-HR) familial predisposition for AUD. We focused on empathy-related brain areas as sociocognitive impairment represents a known risk factor for AUD. We examined 13 individuals with AUD, 14 HR individuals, and 20 non-HR participants using high-resolution T1-weighted magnetic resonance images (3 Tesla) to investigate differences in CT. CT was correlated with self-reported empathy in empathy-related areas. AUD patients showed decreased CT in the left inferior and superior frontal gyri, the right precuneus and bilaterally in the middle frontal gyri/the insula relative to the HR group, and in the left insula, the right middle frontal gyrus and bilaterally in the superior frontal gyrus/the precuneus relative to the non-HR group (all ps < 0.036, all ƞp2 between 0.161 and 0.375). Reduced CT in inferior, middle, and superior frontal gyri was related to cognitive (all ps < 0.036) and reduced CT in the inferior frontal gyrus to affective (p = 0.031) empathy. We present preliminary evidence of CT reduction in empathy-associated brain regions in patients with AUD relative to healthy participants with and without familial predisposition for AUD. The results have to be interpreted with caution due to low sample sizes and potential confounding effects of medication, gender, and withdrawal.


Upregulation of the let-7 microRNA with precocious development in lin-12/Notch hypermorphic Caenorhabditis elegans mutants.
The lin-12/Notch signaling pathway is conserved from worms to humans and is a master regulator of metazoan development. Here, we demonstrate that lin-12/Notch gain-of-function (gf) animals display precocious alae at the L4 larval stage with a significant increase in let-7 expression levels. Furthermore, lin-12(gf) animals display a precocious and higher level of let-7 gfp transgene expression in seam cells at L3 stage. Interestingly, lin-12(gf) mutant rescued the lethal phenotype of let-7 mutants similar to other known heterochronic mutants. We propose that lin-12/Notch signaling pathway functions in late developmental timing, upstream of or in parallel to the let-7 heterochronic pathway. Importantly, the human microRNA let-7a was also upregulated in various human cell lines in response to Notch 1 activation, suggesting an evolutionarily conserved cross-talk between let-7 and the canonical lin-12/Notch signaling pathway.


Implication of genetic variants in primary microRNA processing sites in the risk of multiple sclerosis.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system with a well-established genetic contribution to susceptibility. Over 200 genetic regions have been linked to the inherited risk of developing MS, but the disease-causing variants and their functional effects at the molecular level are still largely unresolved. We hypothesised that MS-associated single-nucleotide polymorphisms (SNPs) affect the recognition and enzymatic cleavage of primary microRNAs (pri-miRNAs). Our study focused on 11 pri-miRNAs (9 primate-specific) that are encoded in genetic risk loci for MS. The levels of mature miRNAs and potential isoforms (isomiRs) produced from those pri-miRNAs were measured in B cells obtained from the peripheral blood of 63 MS patients and 28 healthy controls. We tested for associations between SNP genotypes and miRNA expression in cis using quantitative trait locus (cis-miR-eQTL) analyses. Genetic effects on miRNA stem-loop processing efficiency were verified using luciferase reporter assays. Potential direct miRNA target genes were identified by transcriptome profiling and computational binding site assessment. Mature miRNAs and isomiRs from hsa-mir-26a-2, hsa-mir-199a-1, hsa-mir-4304, hsa-mir-4423, hsa-mir-4464 and hsa-mir-4492 could be detected in all B-cell samples. When MS patient subgroups were compared with healthy controls, a significant differential expression was observed for miRNAs from the 5' and 3' strands of hsa-mir-26a-2 and hsa-mir-199a-1. The cis-miR-eQTL analyses and reporter assays pointed to a slightly more efficient Drosha-mediated processing of hsa-mir-199a-1 when the MS risk allele T of SNP rs1005039 is present. On the other hand, the MS risk allele A of SNP rs817478, which substitutes the first C in a CNNC sequence motif, was found to cause a markedly lower efficiency in the processing of hsa-mir-4423. Overexpression of hsa-mir-199a-1 inhibited the expression of 60 protein-coding genes, including IRAK2, MIF, TNFRSF12A and TRAF1. The only target gene identified for hsa-mir-4423 was TMEM47. We found that MS-associated SNPs in sequence determinants of pri-miRNA processing can affect the expression of mature miRNAs. Our findings complement the existing literature on the dysregulation of miRNAs in MS. Further studies on the maturation and function of miRNAs in different cell types and tissues may help to gain a more detailed functional understanding of the genetic basis of MS. This study was funded by the Rostock University Medical Center (FORUN program, grant: 889002), Sanofi Genzyme (grant: GZ-2016-11560) and Merck Serono GmbH (Darmstadt, Germany, an affiliate of Merck KGaA, CrossRef Funder ID: 10.13039/100009945, grant: 4501860307). NB was supported by the Stiftung der Deutschen Wirtschaft (sdw) and the FAZIT foundation. EP was supported by the Landesgraduiertenförderung Mecklenburg-Vorpommern.