Misuse of herbal remedies: the case of an outbreak of terminal renal failure in Belgium (Chinese herbs nephropathy)
At least 100 cases of extensive interstitial fibrosis of the kidneys were observed in Belgium in women who had followed a weight-loss regimen that included the use of Chinese herbs. The possible relation between the renal disease and these Chinese herbs was investigated. It was shown that the prescribed Chinese herb called Stephania tetrandra was, in fact, inadvertently replaced by another Chinese herb, namely Aristolochia fangchi in the powdered extracts delivered in Belgium and in France. The development of renal disease in about 100 patients exposed to the so-called Stephania tetrandra stresses the need for more stringent control of herbal medicine.


Cervical cancer screening and prevention in low-resource settings.
Cervical cancer is both preventable and curable, yet it remains one of the leading causes of mortality in women worldwide. Approximately 88% of cervical cancer cases are diagnosed in low-resource countries, yet very few resources are allocated to prevention and treatment programs. In fact, it is estimated that only 5% of women in low-resources countries are screened appropriately for cervical cancer. Cytology-based programs are not feasible because of lack of healthcare infrastructure and cost, thus alternative methods of cancer screening, such as visual inspection with acetic acid and HPV-DNA testing, have been intensively studied and are reviewed in this article.


Dynamics of tissue ubiquitin pools and ubiquitin-proteasome pathway component activities during the systemic response to traumatic shock.
Based on the biological significance of the ubiquitin-proteasome pathway (UPP) and its potential role during sepsis, burns and ischemia-reperfusion injury, we hypothesized that the systemic response to traumatic shock (TS) is accompanied by tissue-specific UPP alterations. Therefore, we studied tissue ubiquitin pools, chymotryptic- and tryptic-like proteasome peptidase activities and ubiquitin-protein ligation (UbPL) rates in skeletal muscle, heart, lung, liver, spleen and kidney using a clinically relevant porcine model (bilateral femur fracture/hemorrhage followed by fluid resuscitation). TS induced a systemic reduction of tissue-specific high molecular mass ubiquitin-protein conjugates (>50 kDa). Free ubiquitin was unaffected. The dynamic organ patterns of ubiquitin pools paralleled the typical physiological response to TS and resuscitation. Reduction of ubiquitin-protein conjugates was most pronounced in heart and lung (p<0.05 vs. control) and accompanied by significant increases in proteasome peptidase and UbPL activities in these organs. Unlike all other tissues, spleen proteasome peptidase and UbPL activities were significantly reduced 10 h after TS. These findings support the concept that the UPP could play an important role in regulation of cell functions during the early whole-body response to TS. The UPP might be a therapeutic target to improve the metabolic care after TS, particularly in the heart, lung, and spleen.


Vitreous involvement in familial amyloidotic neuropathy: a genealogical and genetic study.
Extended genealogical studies stretching back to the 17th century were performed concerning the heredity patterns of vitreous involvement in Swedish patients with familial amyloidotic polyneuropathy (FAP). FAP is an autosomal dominant inherited disorder, characterized by extracellular deposition of amyloid and a clinical syndrome of peripheral and autonomic neuropathy. In addition, some patients show typical vitreous opacities. All patients had their origin in a restricted geographical area. Some main patterns arose from this study: 1) Patients who had vitreous opacities as the first symptom of FAP seem to form a separate group, with a distinct age of onset distribution; 2) The familial occurrence of vitreous opacities raises the possibility that other familial factors modify the expression of the FAP gene; 3) The mean age of onset for vitreous opacities is lower for homozygous than for heterozygous patients.


The "Dead-End Tract" and Its Role in Arrhythmogenesis.
Idiopathic outflow tract ventricular arrhythmias (VAs) represent a significant proportion of all VAs. The mechanism is thought to be catecholamine-mediated delayed after depolarizations and triggered activity, although other etiologies should be considered. In the adult cardiac conduction system it has been demonstrated that sometimes an embryonic branch, the so-called "dead-end tract", persists beyond the bifurcation of the right and left bundle branch (LBB). Several findings suggest an involvement of this tract in idiopathic VAs (IVAs). The aim of this review is to summarize our current knowledge and the possible clinical significance of this tract.


Early upregulation of iNOS mRNA expression and increase in NO metabolites in pressurized renal epithelial cells.
Pressure is an important physiological regulator, but under abnormal conditions it may be a critical factor in the onset and progression of disease in many organs. In vivo, proximal tubular epithelial cells are subjected to pressure as a result of ureteral obstruction, which may influence the production of nitric oxide (NO), a ubiquitous multifunctional cytokine. To directly explore the effect of pressure on the expression and activity of NO synthase (NOS) in cultured proximal tubular epithelial cells, a novel pressure apparatus was developed. Cells were subjected to pressures of 20-120 mmHg over time (5 min-72 h). RT-PCR demonstrated an increase in inducible NOS (iNOS) and sGC, while endothelial NOS remained unchanged. Real-time PCR (qPCR) confirmed an earlier induction of iNOS transcript subjected to 60 mmHg compared with cytokine mix. iNOS protein expression was significantly increased following 60 mmHg of pressure for 24 h. Use of nuclear factor-kappaB inhibitors was shown to prevent the increase in iNOS expression following 60 mmHg for 2 h. NO and cGMP were increased with the application of pressure. The addition of the irreversible iNOS inhibitor (1400W) was shown to prevent this increase. We demonstrate that with the use of a simply designed apparatus, pressure led to an extremely early induction of iNOS and a rapid activation of NOS activity to increase NO and cGMP in proximal tubule epithelial cells. The rapid effects of pressure on iNOS may have important implications in the obstructed kidney.


Interleukin-8 is a powerful prognostic predictor of all-cause and cardiovascular mortality in dialytic patients.
Cohort studies have demonstrated an association between C-reactive protein (CRP) and interleukin-6 (IL-6) and all-cause and cardiovascular mortality in end-stage renal disease (ESRD) patients. Interleukin-8 (IL-8) appears to be not only the plasma expression of the acute-phase response but also a direct pathogenetic mediator of the atherosclerotic process. To evaluate the role of IL-8 in predicting outcome, 76 chronic dialytic patients were prospectively followed for 18 months. At baseline, blood samples were taken for analysis of high-sensitivity CRP, IL-6, IL-8 and other standard laboratory analyses. Median IL-8 was 5.2 mg/l, therefore near half of the patients had IL-8 values within the range of 'normal limits'. IL-6 and CRP were significantly correlated (r = 0.45, p < 0.001) and a positive correlation was also found between IL-6 and IL-8 (r = 0.39, p < 0.001). The correlation coefficient between IL-6 and CRP was 0.43 (p < 0.001) and 0.50 (p < 0.001) in patients without and with history and/or clinical signs of cardiovascular disease, respectively. After a follow-up of 1.5 years, 8 patients had died from cardiovascular causes and another 7 patients for other reasons; furthermore 9 major nonfatal cardiovascular events were recorded. Stepwise regression analysis showed IL-8 as the strongest independent predictor of all-cause and cardiovascular events (p = 0.0025) even after adjustment for age and dialytic age, followed by IL-6 and CRP (p < 0.01). Despite a small population and a relatively short follow-up period, this study firstly demonstrated that IL-8 is a powerful independent predictive factor for cardiovascular and overall mortality cause in ESRD patients.


Importance of mammary gland DNA synthesis on carcinogen-induced mammary tumorigenesis in rats.
DNA synthesis in mammary gland estimated by [3H]thymidine incorporation was significantly higher on the day of proestrus than on the second day of diestrus in 50-day-old female Sprague-Dawley rats. The percentage of progressive mammary tumors, tumor growth rate, and the number and the weight of tumors per tumor-bearing rat were significantly higher in the animals given a single i.v. injection of 5 mg 7,12-dimethylbenz(a)anthracene at proestrus than in the animals given it at diestrus. Inhibition of DNA synthesis at proestrus by 2-bromo-alpha-ergocryptine also suppressed mammary tumorigenesis by the carcinogen. In 90-day-old rats in which little difference was found in mammary gland DNA synthesis between proestrus and diestrus, there was no difference in mammary tumorigenesis between animals given the carcinogen at proestrus and animals given it at diestrus. On the other hand, the prestimulation of mammary gland DNA synthesis by prolactin increased the growth, the number, and the weight of carcinogen-induced mammary tumors. These results demonstrate the importance of mammary DNA synthesis at the time when a carcinogen acts on the glands in mammary tumorigenesis.


Time-course studies of pancreatic exocrine damage induced by excess dietary zinc in the chick.
Experiments were conducted to determine the time course of Zn-induced changes in the exocrine status of the chick pancreas. In experiments 1 and 2, chicks killed at intervals after the addition of excess Zn (500 mg/kg as ZnO) to a purified diet containing 70 mg Zn/kg showed a rapid increase in plasma Zn concentration that reached a plateau within 1 h. The pancreatic soluble Zn level increased linearly for 24 h, but then its rate of accumulation diminished. The same pattern of accumulation was shown by pancreatic metallothionein (MT), which correlated highly with pancreatic Zn; that is, MT-associated Zn consistently accounted for 70 to 80% of pancreatic Zn. Plasma amylase activity started to increase 8-10 h after Zn introduction and reached a maximum by 24 h. Two critical levels of pancreatic soluble Zn (1 and 2.7 micrograms Zn/mg of protein, respectively) were observed at which amylase activities increased in the plasma and decreased in the pancreas. In experiment 3, feeding excess Zn reduced the incorporation of [3H]leucine into pancreatic amylase protein. This was associated with a reduction of tracer incorporation into total pancreatic proteins, that is, the fraction that is precipitable by trichloracetic acid (TCA). In experiment 4, the enzyme (or potential) activities of the exportable Zn-containing enzymes procarboxypeptidases A and B and ribonuclease were not affected by excess Zn intake, indicating the selective nature of the effect of excess Zn on pancreatic function.


Identification of TLE Focus from EEG Signals by Using Deep Learning Approach.
Temporal lobe epilepsy, a neurological disease that causes seizures as a result of excessive neural activities in the brain, is the most common type of focal seizure, accounting for 30-35% of all epilepsies. Detection of epilepsy and localization of epileptic focus are essential for treatment planning and epilepsy surgery. Currently, epileptic focus is decided by expert physician by examining the EEG records and determining EEG channel where epileptic patterns begins and continues intensely during seizure. Examination of long EEG recordings is very time-consuming process, requires attention and decision can vary depending on physician. In this study, to assist physicians in detecting epileptic focus side from EEG recordings, a novel deep learning-based computer-aided diagnosis system is presented. In the proposed framework, ictal epochs are detected using long short-term memory network fed with EEG subband features obtained by discrete wavelet transform, and then, epileptic focus identification is realized by using asymmetry score. This algorithm was tested on EEG database obtained from the Ankara University hospital. Experimental results showed ictal and interictal epochs were classified with accuracy of 86.84%, sensitivity of 86.96% and specificity of 89.68% on Ankara University hospital dataset, and 96.67% success rate was obtained on Bonn EEG dataset. In addition, epileptic focus was identified with accuracy of 96.10%, sensitivity of 100% and specificity of 93.80% by using the proposed deep learning-based algorithm and university hospital dataset. These results showed that proposed method can be used properly in clinical applications, epilepsy treatment and surgical planning as a medical decision support system.


Assessment of estrogenic recruitment before chemotherapy in advanced breast cancer: a double-blind randomized study. European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group.
In the present phase III study, the specific effect of estrogenic recruitment was assessed by comparing two groups of patients with advanced breast cancer receiving either ethinylestradiol (EE2) or placebo (PL) before chemotherapy (CT). The therapeutic regimen consisted of (1) estrogen suppression by aminoglutethimide (AGL) 1 g/d plus hydrocortisone (HC) 40 mg/d, with surgical castration performed on premenopausal patients; (2) fluorouracil (5-FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide (CPA) 500 mg/m2 (FAC) intravenously (IV) every 3 weeks; (3) following randomization, patients were double-blinded to receive either PL or EE2 50 micrograms exactly 24 hours before receiving FAC. All patients had advanced breast cancer presumably sensitive to endocrine therapy (estrogen receptor-positive [ER+] and/or progesterone receptor-positive [PgR+] status) with measurable lesions; none had received prior systemic antineoplastic therapy for metastatic disease; prior adjuvant hormonal therapy (HT) or CT (without anthracyclines) was allowed if interval since completion was longer than 1 year. Among 154 patients treated according to the protocol, tolerance, response rates, time to progression, and median survival duration were identical in the PL and EE2 groups. Only performance status, dominant metastatic site, and menopausal status seemed to influence response (overall response, 64%), with the highest levels of partial remission (PR) and complete remission (CR) being achieved in premenopausal women (CR plus PR, 26% plus 55%) and in those with dominant soft tissue lesions (CR plus PR, 45% plus 28%). We conclude that the validity of the hormonal recruitment concept has not yet been established in clinical practice so that this approach remains experimental. The results achieved by combining (near) complete estrogenic suppression and cyclical FAC chemotherapy are not significantly different from those to be expected with the more conventional use of HT followed by CT in presumably hormone-responsive (ER+) patients.


High-risk behavior during adolescence: comments on part I.
Cardinal and Steinberg provide evidence from both laboratory animal and human studies indicating that behavior is controlled by two distinct brain systems, one activational and the other inhibitory. This conceptual framework continues to be a useful integrative framework in developmental neurobiology and psychology. Despite the conceptual framework that posits a two-system control of high-risk behavior, it is notable that the bulk of research related to this topic has focused on one system in isolation from the other. Since the activational and inhibitory systems are constructs that are amenable to investigation using both laboratory animals and human subjects, it seems that a fruitful avenue for future interdisciplinary research would be to ascertain the interactive effect of these systems across the periadolescent period.


Human trafficking, labor brokering, and mining in southern Africa: responding to a decentralized and hidden public health disaster.
Many southern African economies are dependent on the extractive industries. These industries rely on low-cost labor, often supplied by migrants, typically acquired through labor brokers. Very little attention has so far been paid to trafficking of men into extractive industries or its connection with trafficked women in the region's mining hubs. Recent reports suggest that labor-brokering practices foster human trafficking, both by exposing migrant men to lack of pay and exploitative conditions and by creating male migratory patterns that generate demand for sex workers and associated trafficking of women and girls. While trafficking in persons violates human rights, and thus remains a priority issue globally, there is little or no evidence of an effective political response to mine-related trafficking in southern Africa. This article concludes with recommendations for legal and policy interventions, as well as an enhanced public health response, which if implemented would help reduce human trafficking toward mining sites.


Attomolar Label-Free Detection of DNA Hybridization with Electrolyte-Gated Graphene Field-Effect Transistors.
In this work, we develop a field-effect transistor with a two-dimensional channel made of a single graphene layer to achieve label-free detection of DNA hybridization down to attomolar concentration, while being able to discriminate a single nucleotide polymorphism (SNP). The SNP-level target specificity is achieved by immobilization of probe DNA on the graphene surface through a pyrene-derivative heterobifunctional linker. Biorecognition events result in a positive gate voltage shift of the graphene charge neutrality point. The graphene transistor biosensor displays a sensitivity of 24 mV/dec with a detection limit of 25 aM: the lowest target DNA concentration for which the sensor can discriminate between a perfect-match target sequence and SNP-containing one.


Proliferative nodule in melanocytic nevi mimicking deep penetrating nevus.
Proliferative nodules can occasionally arise on congenital and acquired melanocytic nevi. At first sight their clinical and pathologic features cause alert to both dermatologist and dermatopathologist. However, proliferative nodules are typically benign, regression is common and there is minimum risk of malignization. We present a new case of proliferative nodule in melanocytic nevi with features of deep penetrating nevus.


Effect of intensive glucose control on microvascular events in people with type 2 diabetes.
Effect of intensive glucose control on microvascular events in people with type 2 diabetes ● Febrile seizures in children: benefits and risks of prophylactic drug management More on gastric acid suppression and C difficile risk ● What next for the cardiovascular polypill? ● EMA recommends suspension of some generic drugs ● Phototherapy for vitiligo ● WHO targets medication-related errors.


Impact of chronic liver disease on outcomes of hospitalized patients with COVID-19: A multicentre United States experience.
Liver injury has been described with COVID-19, and early reports suggested 2%-11% of patients had chronic liver disease (CLD). In this multicentre retrospective study, we evaluated hospitalized adults with laboratory-confirmed COVID-19 and the impact of CLD on relevant clinical outcomes. Of 363 patients included, 19% had CLD, including 15.2% with NAFLD. Patients with CLD had longer length of stay. After controlling for age, gender, obesity, cardiac diseases, hypertension, hyperlipidaemia, diabetes and pulmonary disorders, CLD and NAFLD were independently associated with ICU admission ([aOR 1.77, 95% CI 1.03-3.04] and [aOR 2.30, 95% CI 1.27-4.17]) and mechanical ventilation ([aOR 2.08, 95% CI 1.20-3.60] and [aOR 2.15, 95% CI 1.18-3.91]). Presence of cirrhosis was an independent predictor of mortality (aOR 12.5, 95% CI 2.16-72.5). Overall, nearly one-fifth of hospitalized COVID-19 patients had CLD, which was associated with more critical illness. Future studies are needed to identify interventions to improve clinical outcomes.


Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations.
Estimation of mortality and the natural course of a disease is usually based on information of carefully studied individuals with or at risk for a specific disease. Genealogical information has rarely been accurate enough for such studies. With the help of church records and multiple endocrine neoplasia type 1 (MEN1) family information of the two founder MEN1 mutations in Northern Finland (1466del12 and 1657insC), we could trace back common ancestors born in the beginning of the 1700s (1466del12) and approximately 1850 (1657insC) and find 67 probable gene carriers born between 1728 and 1929, which were identified among their offspring. Information was gathered from 34 obligatory MEN1 gene carriers and 31 spouses. The mean age (+/- sd) of death of affected males (n = 16) was 61.1 +/- 12.0 yr vs. 65.8 +/- 15.3 yr for unaffected males (n = 16) and for affected females (n = 16) was 67.2 +/- 10.7 yr vs. 67.7 +/- 14.7 yr for unaffected females (n = 13). The ages of death of the obligatory heterozygotes did not differ from that of the spouses in sex groups or from the sex-matched life expectancy estimates derived from Finnish national statistics. Causes of death differed significantly between female probands and spouses. In conclusion, obligatory MEN1 gene carrier status did not show a harmful effect on survival in this retrospective analysis tracing back to almost 300 yr.


Novel innate immune functions revealed by dynamic, real-time live imaging of bacterial infections.
A bacterial infection is accompanied by dynamic alterations in tissue homeostasis within the infected organ. What starts as a local bacterium-host cell interaction at the site of infection changes over time to include distant signaling and the engagement of multiple cell types in an effort to eradicate the bacteria. Recent advancements in imaging technologies, such as multiphoton microscopy, provide new tools to visualize the realtime dynamics of infection within the living host. The use of live animal models means that all of the interplaying factors, such as the immune, lymphatic, nervous, and vascular systems, are present and can be accounted for. This review describes novel insights of innate immune defense mechanisms obtained using real-time visualization of the infected tissue in a live animal model. This emerging field of "tissue microbiology" will provide data that, when combined with the massive knowledge base generated from research in "cellular microbiology," will provide a more complete picture of the complex infection process.


Mechanical stretch and PI3K signaling link cell migration and proliferation to coordinate epithelial tubule morphogenesis in the zebrafish pronephros.
Organ development leads to the emergence of organ function, which in turn can impact developmental processes. Here we show that fluid flow-induced collective epithelial migration during kidney nephron morphogenesis induces cell stretch that in turn signals epithelial proliferation. Increased cell proliferation was dependent on PI3K signaling. Inhibiting epithelial proliferation by blocking PI3K or CDK4/Cyclin D1 activity arrested cell migration prematurely and caused a marked overstretching of the distal nephron tubule. Computational modeling of the involved cell processes predicted major morphological and kinetic outcomes observed experimentally under a variety of conditions. Overall, our findings suggest that kidney development is a recursive process where emerging organ function "feeds back" to the developmental program to influence fundamental cellular events such as cell migration and proliferation, thus defining final organ morphology.


Free silver nanoparticles doped by potassium: Work-function change in experiment and theory.
The composition-dependent change in the work-function (WF) of binary silver-potassium nanoparticles has been studied experimentally by synchrotron-based x-ray photoelectron spectroscopy (PES) and theoretically using a microscopic jellium model of metals. The Ag-K particles with different K fractions were produced by letting a beam of preformed Ag particles pass through a volume with K vapor. The PES on a beam of individual non-supported Ag-K nanoparticles created in this way allowed a direct absolute measurement of their WF, avoiding several usual shortcomings of the method. Experimentally, the WF has been found to be very sensitive to K concentration: Already at low exposure, it decreased down to ≈2 eV-below the value of pure K. In the jellium modeling, considered for Ag-K nanoparticles, two principally different adsorption patterns were tested: without and with K diffusion. The experimental and calculation results together suggest that only efficient surface alloying of two metals, whose immiscibility was long-term textbook knowledge, could lead to the observed WF values.


Genome-wide screens in yeast models towards understanding chronological lifespan regulation.
Cellular models such as yeasts are a driving force in biogerontology studies. Their simpler genome, short lifespans and vast genetic and genomics resources make them ideal to characterise pro-ageing and anti-ageing genes and signalling pathways. Over the last three decades, yeasts have contributed to the understanding of fundamental aspects of lifespan regulation including the roles of nutrient response, global protein translation rates and quality, DNA damage, oxidative stress, mitochondrial function and dysfunction as well as autophagy. In this short review, we focus on approaches used for competitive and non-competitive cell-based screens using the budding yeast Saccharomyces cerevisiae, and the fission yeast Schizosaccharomyces pombe, for deciphering the molecular mechanisms underlying chronological ageing. Automation accompanied with appropriate computational tools allowed manipulation of hundreds of thousands of colonies, generation, processing and analysis of genome-wide lifespan data. Together with barcoding and modern mutagenesis technologies, these approaches have allowed to take decisive steps towards a global, comprehensive view of cellular ageing.


Implants in regenerated bone: long-term survival.
This retrospective multicenter study analyzed 526 implants placed and loaded in regenerated bone. Both autogenous and allogeneic bone grafts were used in combination with a barrier membrane to reconstruct bone using either a simultaneous or staged approach. Implants were followed from 6 to more than 74 months postloading. Eight of the implants were lost, for a success rate of 97.5%. The type of graft material did not affect the clinical success of the implants, nor did the use of submerged versus nonsubmerged implants or a staged versus a simultaneous approach. In conclusion, regenerated bone reacted to implant placement in a manner that was clinically similar to native bone.


Associations between area-level disadvantage and DMFT among a birth cohort of Indigenous Australians.
Individual-level factors influence DMFT, but little is known about the influence of community environment. This study examined associations between community-level influences and DMFT among a birth cohort of Indigenous Australians aged 16-20 years. Data were collected as part of Wave 3 of the Aboriginal Birth Cohort study. Fifteen community areas were established and the sample comprised 442 individuals. The outcome variable was mean DMFT with explanatory variables including diet and community disadvantage (access to services, infrastructure and communications). Data were analysed using multilevel regression modelling. In a null model, 13.8% of the total variance in mean DMFT was between community areas, which increased to 14.3% after adjusting for gender, age and diet. Addition of the community disadvantage variable decreased the variance between areas by 4.8%, indicating that community disadvantage explained one-third of the area-level variance. Residents of under-resourced communities had significantly higher mean DMFT (β = 3.86, 95% CI 0.02, 7.70) after adjusting for gender, age and diet. Living in under-resourced communities was associated with greater DMFT among this disadvantaged population, indicating that policies aiming to reduce oral health-related inequalities among vulnerable groups may benefit from taking into account factors external to individual-level influences.


Beta-1 and beta-2 adrenoceptors mediate smooth muscle relaxation in bovine isolated mesenteric lymphatics.
The relaxant effects of beta adrenoceptor agonists were investigated in isolated bovine mesenteric lymphatics which had been contracted by 5-hydroxytryptamine. Addition of isoproterenol (a nonselective beta agonist), denopamine (a selective beta-1 agonist) and procaterol (a selective beta-2 agonist) caused concentration-dependent relaxations in the lymphatic preparations. There was no significant difference in the relaxant responses to the beta adrenoceptor agonists between the preparations with and without endothelium. Treatment with 10(-7) to 3 x 10(-6) M metoprolol (a selective beta-1 antagonist) shifted the concentration-response curve for denopamine to the right, whereas 10(-9) to 3 x 10(-8) M ICI 118,551 (a selective beta-2 antagonist) did not affect the relaxant response to denopamine. The relaxations of bovine mesenteric lymphatics induced by isoproterenol were suppressed by both metoprolol and ICI 118,551. The procaterol-induced relaxations were inhibited by 10(-9) to 3 x 10(-8) M ICI 118,551 but not by 10(-7) to 3 x 10(-6) M metoprolol. Schild plot analyses showed that the slope and pA2 values for metoprolol against denopamine were 1.10 and 7.59, respectively, and that those for ICI 118,551 against procaterol were 0.91 and 9.96. These results suggest that both beta-1 and beta-2 adrenoceptors are located on the smooth muscle cells in bovine mesenteric lymphatics and that stimulation of either receptor produces a marked relaxation.


[Innovative therapies in metabolic diseases: ezetimibe (Ezétrol), nicotinic acid (Niaspan), acids omega-3 (Omacor), rimonabant (Acomplia)].
In the field of dyslipidemia and metabolic syndrome, four innovative therapies are reviewed: Ezetimibe (Ezétrol) is a selective cholesterol absorption inhibitor. Co-administration of ezetimibe with low dose of statins shows LDL lowering comparable to that of the highest dose of the respective statin alone. Combination therapy helps more patients in achieving target LDL-cholesterol. Nicotinic acid (Niacin) favourably modifies all lipoprotein level (including Lp(a)). Extended release niacin (Niaspanâ) is a new galenic form, with less side effects (flushing and hepatotoxicity) than the native nicotinic acid. This new preparation represents an effective option in the management of dyslipidemia. The polyunsatured fatty acids (PUFA) omega-3 (Omacor) decreases cardiovascular deaths and mainly fatal arrhythmias after myocardial infarction. Their favourable effects are linked mainly to their anti-inflammatory and antiarrhythmic properties. The PUFA omega-3 could be added to the secondary prevention after myocardial infarction. The blockade of the endocannabinoid system by a specific inhibitor of CB1 receptor (rimonabant or Acomplia) decreases food intake and weight and increases adiponectin and insulin sensitivity. Clinical studies on obesity and tobacco dependence are very encouraging.


Stereoselective Reductive Coupling Reactions Utilizing [1,2]-Phospha-Brook Rearrangement: A Powerful Umpolung Approach.
[1,2]-Phospha-Brook rearrangement entails the generation of α-oxygenated carbanions via the umpolung process. Recently, these anionic species have been widely utilized for several C-C bond forming strategies, providing various useful frameworks that are difficult to access through conventional approaches. However, the application of this powerful methodology in the development of chiral strategies is still at the nascent stage due to challenges involved in controlling chemoselectivity and enantioselectivity. This synopsis provides a detailed summary of diastereo- and/or enantioselective chemical transformations using [1,2]-phospha-Brook rearrangement.


Unique Thermal Stability of Unnatural Hydrophobic Ds Bases in Double-Stranded DNAs.
Genetic alphabet expansion technology, the introduction of unnatural bases or base pairs into replicable DNA, has rapidly advanced as a new synthetic biology area. A hydrophobic unnatural base pair between 7-(2-thienyl)imidazo[4,5-b]pyridine (Ds) and 2-nitro-4-propynylpyrrole (Px) exhibited high fidelity as a third base pair in PCR. SELEX methods using the Ds-Px pair enabled high-affinity DNA aptamer generation, and introducing a few Ds bases into DNA aptamers extremely augmented their affinities and selectivities to target proteins. Here, to further scrutinize the functions of this highly hydrophobic Ds base, the thermal stabilities of double-stranded DNAs (dsDNA) containing a noncognate Ds-Ds or G-Ds pair were examined. The thermal stability of the Ds-Ds self-pair was as high as that of the natural G-C pair, and apart from the generally higher stability of the G-C pair than that of the A-T pair, most of the 5'-pyrimidine-Ds-purine-3' sequences, such as CDsA and TDsA, exhibited higher stability than the 5'-purine-Ds-pyrimidine-3' sequences, such as GDsC and ADsC, in dsDNAs. This trait enabled the GC-content-independent control of the thermal stability of the designed dsDNA fragments. The melting temperatures of dsDNA fragments containing the Ds-Ds pair can be predicted from the nearest-neighbor parameters including the Ds base. In addition, the noncognate G-Ds pair can efficiently distinguish its neighboring cognate natural base pairs from noncognate pairs. We demonstrated that real-time PCR using primers containing Ds accurately detected a single-nucleotide mismatch in target DNAs. These unique properties of the Ds base that affect the stabilities of the neighboring base pairs could impart new functions to DNA molecules and technologies.


Socioeconomic status and health in adolescents: the role of stress interpretations.
The role of psychological interpretations in the relationship between low socioeconomic status (SES) and physiological responses was tested. One hundred high school students (ages 15-19) watched videos of ambiguous and negative life situations, and were interviewed about their interpretations. Lower SES was associated with greater threat interpretations during ambiguous (but not negative) situations and with greater diastolic blood pressure and heart rate reactivity. Threat interpretations partially mediated relationships between SES and reactivity. General life events (e.g., lack of positive life events), rather than specific life events (e.g., exposure to violence), partially explained the relationship between low SES and threat interpretations. Results suggest that the larger social environment helps explain how adolescents approach new social situations, which in turn has implications for adolescent physical health.


Oral human β-defensin 2 in HIV-infected subjects with long-term use of antiretroviral therapy.
The objectives of this study were to determine (i) oral hBD2 expression in HIV-infected subjects compared with non-HIV controls, (ii) the expression of oral hBD2 in HIV-infected subjects with antiretroviral therapy (ART) compared with those without ART, and (iii) factors associated with the expression of oral hBD2. Oral examination and punched biopsy on buccal mucosa were performed in HIV-infected subjects with and without ART, and non-HIV individuals. The expression of hBD2 mRNA was determined by quantitative real-time PCR. Saliva samples of both un-stimulated and stimulated saliva were collected and analyzed for hBD2 levels using ELISA. Student's t-test and nonparametric multi-way ANOVA test were used for comparison of measurements between or among groups. One hundred and fifty-seven HIV-infected subjects were enrolled: 99 on ART (age range, 23-57 years; mean 39 years), 58 not on ART (age range, 20-59 years; mean 34 years), and 50 non-HIV controls (age range, 19-59 years; mean 36 years). The most common ART regimen was two nucleoside reverse transcriptase inhibitors + one non-nucleoside reverse transcriptase inhibitor. Salivary levels of hBD2 were significantly increased in HIV infection (P < 0.001). The levels of hBD2 in stimulated saliva were also found to be significantly different between HIV-infected subjects who were and were not on ART (P < 0.001). No significant difference was observed with the expression of hBD2 mRNA. Oral innate immunity is affected by HIV infection and use of ART. Salivary hBD2 levels may be the useful biomarkers to monitor those on long-term ART who are at risk of developing oral infections and malignant transformation.


[The effect of maxillary and mandibular lip bumper on teeth and dental arch in late mixed dentition].
To study the effect of maxillary and mandibular lip bumper on tooth and dental arch in late mixed dentition. Twelve subjects with mild or moderate crowding were selected. They were treated with maxillary and mandibular lip bumper for eight months. Analysis of cephalometrics and model measurements were done before and after treatment and paired t test were performed respectively for their changes. After treatment, SNA and SNB increased by 1.02 degrees and 0.97 degrees (P<0.05). Upper and lower incisor both had controlled tipping movement. The crown of incisor moved mesially and had root apex were fixed relatively. The center of rotation was close to root apex. The upper and lower molar moved differently. Upper molar was upright distally and the center of rotation was close to the crown. However, the lower molar tipped distally and the center of rotation was close to the center of resistance.The width between the first molars and length of maxillary dental arch increased by 4.12 mm and 5.09 mm (P<0.01). The width between the first molars and length of mandibular dental arch increased by 4.07 mm and 6.86 mm (P<0.01) Clinical application of lip bumper could cause transverse and vertical changes in dental arch ,which help to decrease or remove crowding.


Evaluation of a structured report of functional prostate magnetic resonance imaging in patients with suspicion for prostate cancer or under active surveillance.
Functional magnetic resonance imaging (MRI) seems to be a useful tool for prostate cancer (PCa) detection in patients with a previous negative biopsy but persistently increased prostate-specific antigen (PSA) values. Additionally, it enables correct cancer localization in patients with known PCa under active surveillance to avoid misclassification on repeat biopsies. Nevertheless, suspicious lesions on MRI findings need verification by biopsy. The aim of the present study was to establish a standardized functional prostate MRI reporting scheme. Prostate MRI with T(2)-weighted images, T(1)-weighted images, diffusion-weighted imaging, and dynamic contrast-enhanced MRI of 56 consecutive patients were performed on a 3-T scanner. Patients with prior negative random transrectal ultrasound (TRUS)-guided biopsy and continuous suspicion for PCa as well as patients under active surveillance were included. The MRI localization report of suspicious lesions followed a standardized scheme. TRUS-guided random biopsy with addition of targeted biopsy cores was performed afterwards based on the structured report. Of the 56 patients, 18 had suspicious MRI findings and subsequently underwent repeat biopsy under guidance of the standardized localization scheme. PCa was documented in 72% (13/18). A standardized reporting scheme of suspicious findings on prostate MRI leads to higher success rates as compared to standard random TRUS-guided biopsy.


Generation of induced pluripotent stem cells (IRMBi001-A) from an Alzheimer's disease patient carrying a G217D mutation in the PSEN1 gene.
Induced pluripotent stem cells (iPSC) were generated from skin fibroblasts obtained from a 50 year-old patient suffering from Alzheimer's disease and carrying a G217D causal mutation on presenilin 1 (PSEN1). iPSCs were obtained following reprogramming using the integration-free Sendai Virus system which allows expression of the Yamanaka factors. Verification of their pluripotency was achieved by demonstrating the expression of pluripotency markers and their differentiation potential into the three primary germ layers. iPS cells carry the patient G217D mutation and present a normal karyotype. The reported PS1-G217D iPSC line may be used to model and study human AD pathology in vitro.


Management of lupus erythematosus: recent insights.
This article reviews and cites only publications relating to the management of lupus that have appeared since 1999. The data in these publications demonstrate that preventive and proactive strategies are as important as medication in improving the quality of life and life span of the patient with lupus. The use of lasers and thalidomide represents major advances in cutaneous lupus. The first major study over 25 years using nonsteroidal anti-inflammatory drugs to manage lupus suggests benefits. Further evidence was presented showing that dehydroepiandrosterone, leflunomide, and methotrexate are effective in treating mild to moderate disease. Various iterations and modifications of traditional cyclophosphamide therapy with or without mycophenolate mofetil, cyclosporine, and azathioprine continue to be studied for treating organ-threatening disease. Intravenous gamma globulin and selective apheresis are niche therapies appropriate in a few, highly selected patients. Immunoablative doses of cyclophosphamide appear to be as effective as stem cell transplantation for serious disease resistant to conventional doses of cyclophosphamide. Twelve biologic agents have been studied in lupus since 1999, with only LJP-394 showing clear-cut, convincing efficacy.


Placenta Accreta Spectrum with Ureteral Invasion due to Progression of Cesarean Scar Pregnancy.
Expectant management is not recommended for cesarean scar pregnancies because they are often associated with placenta accreta, cesarean hysterectomy, and massive life-threatening hemorrhages during delivery. Herein, we report a case of placenta accreta spectrum with ureteral invasion due to the progression of a cesarean scar pregnancy. Case. A 41-year-old woman, with a history of three cesarean sections and two miscarriages, was referred to our hospital at 25 weeks of gestation with a diagnosis of placenta accreta spectrum and bladder invasion. Although the gestational sac was located anterior to the lower uterine segment, a cesarean-scar pregnancy was not diagnosed. A cesarean hysterectomy was performed at 31 weeks of gestation with the placement of an aortic balloon. The placenta was found to adhere to the ureter with more than the expected parenchymal tissue displacement (FIGO Classification 3b). The ureter was not obstructed and was preserved by leaving the placenta slightly on the ureteral side. Postoperatively, a ureteral stent was placed because of the ureteral stricture in the area where the placenta had adhered. Two months after surgery, the ureteral stent was removed after observing an improvement in stenosis. An adherent placenta due to continued cesarean scar pregnancy should be managed by assuming placental invasion beyond the parenchyma into the ureter.


Visual Perspective and Feedback Guidance for VR Free-Throw Training.
Accurate distance perception and natural interactions are mandatory conditions when training precision aiming tasks in VR. However, many factors specific to virtual environments (VEs) lead to differences in the way users execute a motor task in VR versus the real world. To investigate these differences, the authors performed a study on basketball beginners' free-throw performance in VEs under different visual conditions. Although the success rate is not statistically different, some adaptations occurred in the way the users performed the task, depending on the visual conditions. In the third-person perspective visual condition, the release parameters indicate that the users more accurately estimated distance to target. Adding visual guidance information (gradual depth information showing the ideal ball trajectory) also led to more natural motor behavior. The final aim of this study was to develop a reliable basketball free-throw training system in VEs, so the authors compared beginners' performances in VR with experts' models of performance. Their results show that most of the performance variables tended to evolve closer to the experts' performance during the training in the VE.


Path integral molecular dynamics for exact quantum statistics of multi-electronic-state systems.
An exact approach to compute physical properties for general multi-electronic-state (MES) systems in thermal equilibrium is presented. The approach is extended from our recent progress on path integral molecular dynamics (PIMD), Liu et al. [J. Chem. Phys. 145, 024103 (2016)] and Zhang et al. [J. Chem. Phys. 147, 034109 (2017)], for quantum statistical mechanics when a single potential energy surface is involved. We first define an effective potential function that is numerically favorable for MES-PIMD and then derive corresponding estimators in MES-PIMD for evaluating various physical properties. Its application to several representative one-dimensional and multi-dimensional models demonstrates that MES-PIMD in principle offers a practical tool in either of the diabatic and adiabatic representations for studying exact quantum statistics of complex/large MES systems when the Born-Oppenheimer approximation, Condon approximation, and harmonic bath approximation are broken.


The capacity and mechanism of bone marrow antibody formation by thymus-independent antigens.
Primary immunization of mice with certain thymus-independent (TI) antigens (i.e., TNP-LPS and DNP-Ficoll) leads to antibody formation in the bone marrow (BM). TNP-Brucella abortus, Pneumococcus pneumoniae organisms, and alpha-(1,6) dextran, on the other hand, do not induce a BM antibody-producing plaque-forming cell (PFC) response. This paper deals with the mechanism underlying antibody formation in the BM to TNP-LPS and DNP-Ficoll. The majority of the BM-localizing PFC induced by TNP-LPS are formed within the BM from the proliferating lymphocyte pool, because this response was found to be resistant to splenectomy and sensitive to treatment with hydroxyurea (HU) before immunization. This local activation of newly formed B cells requires in addition to the antigenic signal of TNP-LPS the mitogenic signal from the lipid A component of LPS. In contrast, the BM PFC response to DNP-ficoll was reduced in splenectomized mice and resistant to HU treatment before the primary immunization. Thus, antibody formation in the BM to DNP-Ficoll is mainly dependent on long-lived B cells that migrate from the peripheral lymphoid organs into the BM.


Quazepam in the short-term treatment of insomnia in outpatients.
The safety and hypnotic efficacy of quazepam 30 mg vs placebo in 57 insomniac outpatients were assessed in a randomized, controlled comparison. Patients received placebo during a 3-night, single-blind baseline period, and then quazepam 30 mg or placebo during a 5-night, double-blind treatment period. Quazepam-treated patients reported significantly better sleep quantity and quality on the first treatment night and for the overall treatment period than did placebo patients. No clinically significant change was seen in pre- and posttreatment physical examinations, electrocardiograms, or routine laboratory tests. Of the 57 subjects, 20 (16 quazepam, 4 placebo) reported adverse experiences. All 20 reported daytime somnolence (drowsiness, lethargy, or sleepiness), and one quazepam-treated patient also had hypokinesia. Overall, quazepam 30 mg was a safe and effective hypnotic, with significant hypnotic activity on the first night of administration.


Properties of crude Campylobacter jejuni heat-labile enterotoxin.
The amount of crude Campylobacter jejuni enterotoxin present in culture products was quantitated by comparing the response of these preparations with that of pure Escherichia coli heat-labile toxin (LT) in the Chinese hamster ovary assay and in enzyme-linked immunosorbent assays that used GM ganglioside or antisera to LT or both. Maximum C. jejuni enterotoxin production was achieved by growth at 42 degrees C for 24 h under agitation in supplemented GC medium. Adding polymyxin separately to either the broth supernatant or the cells enhanced the recovery of toxin; the yield from cell lysates was much lower. The quantity of C. jejuni enterotoxin produced by clinical isolates obtained locally or provided from Mexico varied widely, over a spectrum from none to large amounts; quantitative values for the amount of C. jejuni enterotoxin determined by the Chinese hamster ovary and enzyme-linked immunosorbent assays correlated with the degree of secretory potency of this material in ligated rat ileal loops. The cytotonic activity of C. jejuni enterotoxin in Chinese hamster ovary cells was abolished by heating at 96 degrees C for 10 min and by preincubation either with GM ganglioside or with LT or cholera toxin antisera. The secretory activity of C. jejuni enterotoxin in ligated rat ileal loops was passively neutralized by antiserum to LT, and immunizing rats with either LT or its B subunit significantly (P less than 0.001) reduced fluid response to active challenge with C. jejuni enterotoxin in ligated ileal loops. These observations indicate that strains of C. jejuni vary in their capacity to elaborate a heat-labile enterotoxin that has close immunological homology with LT and cholera toxin.


Glass-liquid and glass-gel transitions of soft-shell particles.
We study the structure and dynamics of colloidal particles with a spherical hard core and a thermo-responsive soft shell over the whole phase diagram by means of small-angle x-ray scattering and x-ray photon correlation spectroscopy. By changing the effective volume fraction by temperature and particle concentration, liquid, repulsive glass. and attractive gel phases are observed. The dynamics slow down with increasing volume fraction in the liquid phase and reflect a Vogel-Fulcher-Tamann behavior known for fragile glass formers. We find a liquid-glass transition above 50 vol.% that is independent of the particles' concentration and temperature. In an overpacked state at effective volume fractions above 1, the dispersion does not show a liquid phase but undergoes a gel-glass transition at an effective volume fraction of 34 vol.%. At the same concentration, extrema of subdiffusive dynamics are found in the liquid phase at lower weight fractions. We interpret this as dynamic precursors of the glass-gel transition.


Narrative, written sign-outs and interns' and senior medical students' confidence: a randomized, controlled crossover trial.
Failures of communication during the transfer of patient care errors. We created a new format for written sign-out material, based on aviation industry practice and cognitive psychology theory, designed to improve interns' and senior medical students' communication during transfers of patient care responsibility. We carried out a randomized, blinded, crossover trial, comparing a new, narrative, written sign-out report to a usual written sign-out. Thirty-two interns and fourth-year medical students rated their confidence across various clinical tasks and answered clinical questions regarding hypothetical patients presented to them in written, new, narrative sign-out compared with the customary format. There was no statistical difference in confidence when interns and senior medical students received usual versus narrative sign-outs. Although a limited measure suggested some improvement in competence, the narrative format did not improve participants' self-rated confidence during patient-care transfer.


Structural characteristics of the Corynebacterium lilium bacteriophage CL31.
Bacteriophage CL31 was isolated on a Corynebacterium lilium strain. Out of 30 strains tested, only CL31 was able to form plaques on Corynebacterium glutamicum ATCC 13287, Brevibacterium lactofermentum ATCC 21086, and Arthrobacter sp. strain SI55, but at a very low frequency. This phage belongs to group B of Bradley's classification (D. E. Bradley, Bacteriol. Rev. 31:230-314; 1967). Its head is 53 nm in diameter, and its tail is 396 nm in length. The phage capsid contains three major proteins, of 12.5, 29.0, and 37.0 kilodaltons, and five minor ones (23.9, 26.0, 27.0, 40.0, and 55.4 kilodaltons). CL31 DNA is a linear molecule of 48 kilobases with cohesive ends. Restriction mapping was performed for endonucleases BglII, EcoRI, SalI, and KpnI. The expression of CL31 genes in Escherichia coli was studied by the maxicell technique; 12 different proteins were detected.


Modeling framework unifying contact and social networks.
Temporal networks of face-to-face interactions between individuals are useful proxies of the dynamics of social systems on fast timescales. Several empirical statistical properties of these networks have been shown to be robust across a large variety of contexts. To better grasp the role of various mechanisms of social interactions in the emergence of these properties, models in which schematic implementations of such mechanisms can be carried out have proven useful. Here, we put forward a framework to model temporal networks of human interactions based on the idea of a coevolution and feedback between (i) an observed network of instantaneous interactions and (ii) an underlying unobserved social bond network: Social bonds partially drive interaction opportunities and in turn are reinforced by interactions and weakened or even removed by the lack of interactions. Through this coevolution, we also integrate in the model well-known mechanisms such as triadic closure, but also the impact of shared social context and nonintentional (casual) interactions, with several tunable parameters. We then propose a method to compare the statistical properties of each version of the model with empirical face-to-face interaction data sets to determine which sets of mechanisms lead to realistic social temporal networks within this modeling framework.


Multiple Spatial Coordinates Influence the Prediction of Tactile Events Facilitated by Approaching Visual Stimuli.
Interaction with other sensory information is important for prediction of tactile events. Recent studies have reported that the approach of visual information toward the body facilitates prediction of subsequent tactile events. However, the processing of tactile events is influenced by multiple spatial coordinates, and it remains unclear how this approach effect influences tactile events in different spatial coordinates, i.e., spatial reference frames. We investigated the relationship between the prediction of a tactile stimulus via this approach effect and spatial coordinates by comparing ERPs. Participants were asked to place their arms on a desk and required to respond tactile stimuli which were presented to the left (or right) index finger with a high probability (80%) or to the opposite index finger with a low probability (20%). Before the presentation of each tactile stimulus, visual stimuli approached sequentially toward the hand to which the high-probability tactile stimulus was presented. In the uncrossed condition, each hand was placed on the corresponding side. In the crossed condition, each hand was crossed and placed on the opposite side, i.e., left (right) hand placed on the right (left) side. Thus, the spatial location of the tactile stimulus and hand was consistent in the uncrossed condition and inconsistent in the crossed condition. The results showed that N1 amplitudes elicited by high-probability tactile stimuli only decreased in the uncrossed condition. These results suggest that the prediction of a tactile stimulus facilitated by approaching visual information is influenced by multiple spatial coordinates.


The association of eicosanoids and eicosanoid-related metabolites with pulmonary hypertension.
Eicosanoids are bioactive lipids that regulate systemic inflammation and exert vasoactive effects. Specific eicosanoid metabolites have previously been associated with pulmonary hypertension (PH), yet their role remains incompletely understood. We studied 482 participants with chronic dyspnoea who underwent clinically indicated cardiopulmonary exercise testing (CPET) with invasive haemodynamic monitoring. We performed comprehensive profiling of 888 eicosanoids and eicosanoid-related metabolites using directed non-targeted mass spectrometry, and examined associations with PH (mean pulmonary arterial pressure (mPAP) >20 mmHg), PH subtypes and physiological correlates, including transpulmonary metabolite gradients. Among 482 participants (mean±sd age 56±16 years, 62% women), 200 had rest PH. We found 48 eicosanoids and eicosanoid-related metabolites that were associated with PH. Specifically, prostaglandin (11β-dhk-PGF2α), linoleic acid (12,13-EpOME) and arachidonic acid derivatives (11,12-DiHETrE) were associated with higher odds of PH (false discovery rate q<0.05 for all). By contrast, epoxide (8(9)-EpETE), α-linolenic acid (13(S)-HOTrE(γ)) and lipokine derivatives (12,13-DiHOME) were associated with lower odds. Among PH-related eicosanoids, 14 showed differential transpulmonary metabolite gradients, with directionality suggesting that metabolites associated with lower odds of PH also displayed pulmonary artery uptake. In individuals with exercise PH, eicosanoid profiles were intermediate between no PH and rest PH, with six metabolites that differed between rest and exercise PH. Our findings highlight the role of specific eicosanoids, including linoleic acid and epoxide derivatives, as potential regulators of inflammation in PH. Of note, physiological correlates, including transpulmonary metabolite gradients, may prioritise future studies focused on eicosanoid-related pathways as important contributors to PH pathogenesis.


Mitigation of augmented extrasynaptic NMDAR signaling and apoptosis in cortico-striatal co-cultures from Huntington's disease mice.
We recently reported evidence for disturbed synaptic versus extrasynaptic NMDAR transmission in the early pathogenesis of Huntington's disease (HD), a late-onset neurodegenerative disorder caused by CAG repeat expansion in the gene encoding huntingtin. Studies in glutamatergic cells indicate that synaptic NMDAR transmission increases phosphorylated cyclic-AMP response element binding protein (pCREB) levels and drives neuroprotective gene transcription, whereas extrasynaptic NMDAR activation reduces pCREB and promotes cell death. By generating striatal and cortical neuronal co-cultures to investigate the glutamatergic innervation of striatal neurons, we demonstrate that dichotomous synaptic and extrasynaptic NMDAR signaling also occurs in GABAergic striatal medium-sized spiny neurons (MSNs), which are acutely vulnerable in HD. Further, we show that wild-type (WT) and HD transgenic YAC128 MSNs co-cultured with cortical cells have similar levels of glutamatergic synapses, synaptic NMDAR currents and synaptic GluN2B and GluN2A subunit-containing NMDARs. However, NMDAR whole-cell, and especially extrasynaptic, current is elevated in YAC128 MSNs. Moreover, GluN2B subunit-containing NMDAR surface expression is markedly increased, irrespective of whether or not the co-cultured cortical cells express mutant huntingtin. The data suggest that MSN cell-autonomous increases in extrasynaptic NMDARs are driven by the HD mutation. Consistent with these results, we find that extrasynaptic NMDAR-induced pCREB reductions and apoptosis are also augmented in YAC128 MSNs. Moreover, both NMDAR-mediated apoptosis and CREB-off signaling are blocked by co-application of either memantine or the GluN2B subunit-selective antagonist ifenprodil in YAC128 MSNs. GluN2A-subunit-selective concentrations of the antagonist NVP-AAM077 did not reduce cell death in either genotype. Cortico-striatal co-cultures provide an in vitro model system in which to better investigate striatal neuronal dysfunction in disease than mono-cultured striatal cells. Results from the use of this system, which partially recapitulates the cortico-striatal circuit and is amenable to acute genetic and pharmacological manipulations, suggest that pathophysiological NMDAR signaling is an intrinsic frailty in HD MSNs that can be successfully targeted by pharmacological interventions.


Mandibular Second Molars and Their Pathologies Related to the Position of the Mandibular Third Molar: A Radiographic Study.
The aim of this study was to determine the prevalence of mandibular third molar malposition and its impact in relation to the lower second molar using panoramic radiography. This was a cross-sectional descriptive study of 353 panoramic images of patients who visited the Dental Clinic of the International University of Rabat. Panoramic images were analyzed in order to determine the number of second molar pathologies associated with the positions of third molars. The following radiographic lesions on the second molar were recorded: caries, root resorption and distal alveolysis. The Chi-square test was used to assess the association between different variables. Of these 353 radiographies, 169 were males, ie, 48%, and 184 were females, ie, 52%. The age range was from 18 to 63 years. The prevalence of the impacted position of the lower third molar was noted in 60%. Distal caries on the second mandibular molar was present in 47.5% of instances having an impacted third molar. Caries was present in 65.5% of wisdom teeth in a normal position and was also present in 79.6% of the impacted teeth. This difference was statistically significant with p = 0.01. The angulation of the third molar is a factor of caries of the second molar: 58.56% of them were carious. Of all the teeth in association with an angulation, 72.03% showed distal alveolysis in the second molar. In addition, root resorption was found in 20.4% of second molars linked to a wisdom tooth in all angulation occurrences. It has been noted that among the pathologies seen on the mandibular second molar, distal alveolysis accounts for the majority of cases (58%), followed by caries (47.5%) and root resorption (13.3%). This study illustrated the importance of performing Orthopantomogram X-rays at each new consultation in patients over the age of 18.


Alloantigen Infusion Activates the Transcriptome of Type 2 Conventional Dendritic Cells.
Recent studies have revealed novel molecular mechanisms by which innate monocytic cells acutely recognize and respond to alloantigen with significance to allograft rejection and tolerance. What remains unclear is the single-cell heterogeneity of the innate alloresponse, particularly the contribution of dendritic cell (DC) subsets. To investigate the response of these cells to exposure of alloantigen, C57BL/6J mice were administered live allogenic BALB/cJ splenic murine cells versus isogenic cells. In parallel, we infused apoptotic allogenic and isogenic cells, which have been reported to modulate immunity. Forty-eight hours after injection, recipient spleens were harvested, enriched for DCs, and subjected to single-cell mRNA sequencing. Injection of live cells induced a greater transcriptional change across DC subsets compared with apoptotic cells. In the setting of live cell infusion, type 2 conventional DCs (cDC2s) were most transcriptionally responsive with a Ccr2+ cDC2 subcluster uniquely responding to the presence of alloantigen compared with the isogenic control. In vitro experimentation confirmed unique activation of CCR2+ cDC2s following alloantigen exposure. Candidate receptors of allorecognition in other innate populations were interrogated and A type paired Ig-like receptors were found to be increased in the cDC2 population following alloexposure. These results illuminate previously unclear distinctions between therapeutic infusions of live versus apoptotic allogenic cells and suggest a role for cDC2s in innate allorecognition. More critically, these studies allow for future interrogation of the transcriptional response of immune cells in the setting of alloantigen exposure in vivo, encouraging assessment of novel pathways and previously unexamined receptors in this setting.


Heteroaryl-Heteroaryl, Suzuki-Miyaura, Anhydrous Cross-Coupling Reactions Enabled by Trimethyl Borate.
Reaction conditions have been developed for refractory heteroaryl-heteroaryl Suzuki-Miyaura cross-couplings. The reported method employs neopentyl heteroarylboronic esters as nucleophiles, heteroaryl bromides and chlorides as the electrophiles, and the soluble base potassium trimethylsilanolate (TMSOK) under anhydrous conditions. The addition of trimethyl borate enhances reaction rates by several mechanisms, including (1) solubilization of in situ-generated boronate complexes, (2) preventing catalyst poisoning by the heteroatomic units, and (3) buffering the inhibitory effect of excess TMSOK. The use of this method enables cross-coupling of diverse reaction partners including a broad range of π-rich and π-deficient heteroaryl boronic esters and heteroaryl bromides. Reactions proceed in good yields and short reaction times (3 h or less).


ALDH2 Gene rs671 Polymorphism May Decrease the Risk of Essential Hypertension.
Aldehyde dehydrogenase-2 (ALDH2) rs671 G>A polymorphism can influence the activity of ALDH2 and may be associated with the risk of essential hypertension (EH). Although many previous studies have explored such a relationship, the conclusion is still controversial.The PubMed, Embase, and China National Knowledge Infrastructure databases were searched on the ALDH2 gene and EH. We used the Newcastle-Ottawa Scale to evaluate the quality of the study. Then we calculated the strength of relationship between ALDH2 rs671 mutation and EH by utilizing odds ratios and 95% confidence intervals. Besides, subgroup analysis and sensitivity analysis were performed and the publication bias was assessed.There were 12 studies containing 8153 cases and 10,162 controls. Our meta-analysis showed significant association between ALDH2 rs671 polymorphism and EH in four genetic models (the allele model, the homozygote model, the heterozygote model, and the dominant model), whereas it did not indicate this connection in the recessive model. However, a trend of decreased risk still could be seen. Furthermore, we also found an obvious association between rs671 mutation and the risk of EH in the male group than in the female group in all five genetic models.We concluded that ALDH2 rs671 G>A polymorphism may decrease the risk of EH. Furthermore, susceptibility to EH reduced in males but not in females. As a variant in ALDH2, rs671 G>A could be an attractive candidate for genetic therapy of EH. In addition, more case-control studies should be conducted to strengthen our conclusion and evaluate the gene-gene and gene-environment interactions between the ALDH2 gene and EH.


Ambulatory blood pressure monitoring in Uygur centenarians.
Cross-sectional surveillance was carried out in long-lived Uygur in China to investigate blood pressure (BP) and pulse rate (PR) variation in centenarians. The study group comprised 33 centenarians (age > or = 100 years), 103 longevous subjects (age 90-99 years) and 100 elderly (age 65-70 years) subjects. Office BP was measured, and 24-h noninvasive ambulatory blood pressure monitoring (ABPM) was performed. The office BP was higher and hypertension occurred more frequently in the centenarians than in either the longevous or elderly subjects. Mean 24-h systolic and diastolic BP was higher in the centenarians than in the other 2 groups. However, mean 24-h PR did not differ between them. Day-night differences in systolic BP decreased, and the non-dipper-type BP pattern was common in the centenarians (79.1% vs 68% and 63.6% in longevous and elderly subjects, respectively). Circadian BP was characterized by 3 peaks in longevous subjects and multiple peaks in centenarians. Morning rising and nocturnal dipping of BP were observed in both longevous and elderly subjects. In conclusion, BP in longevous and elderly Uygur was characterized by circadian rhythmicity, but the nocturnal fall in BP was not seen in centenarians. Differences in day-night BP and circadian rhythmicity may decrease with advancing age, especially in centenarians.


Athletes with Eating Disorders: Analysis of Their Clinical Characteristics, Psychopathology and Response to Treatment.
Eating disorders (ED) have frequently been described among athletes. However, their specific features and therapy responses are lacking in the literature. The aims of this article were to compare clinical, psychopathological and personality traits between ED patients who were professional athletes (ED-A) with those who were not (ED-NA) and to explore differences in response to treatment. The sample comprised n = 104 patients with ED (n = 52 ED-A and n = 52 matched ED-NA) diagnosed according to DSM-5 criteria. Evaluation consisted of a semi-structured face-to-face clinical interview conducted by expert clinicians and a psychometric battery. Treatment outcome was evaluated when the treatment program ended. ED-A patients showed less body dissatisfaction and psychological distress. No differences were found in treatment outcome among the groups. Within the ED-A group, those participants who performed individual sport activities and aesthetic sports presented higher eating psychopathology, more general psychopathology, differential personality traits and poor therapy outcome. Individual and aesthetic sports presented more severity and worse prognosis. Although usual treatment for ED might be similarly effective in ED-A and ED-NA, it might be important to develop preventive and early detection programs involving sports physicians and psychologists, coaches and family throughout the entire athletic career and afterwards.


Mapping suitable habitats for globally endangered raptors in Kenya: Integrating climate factors and conservation planning.
Raptors face global threats like electrocution, collisions, and habitat fragmentation. Many species remain understudied, and their distribution patterns are unknown. Understanding their current and future distribution is crucial for conservation. Protecting these top predators requires knowledge of their spatial distribution and environmental influences. This study addresses knowledge gaps in raptor habitats and distributions in Kenya, considering current and future climate changes. Using species distribution models and occurrence data from the Global Biodiversity Information Facility, we evaluated suitable habitats for four endangered Kenyan raptor species: Martial eagle, Secretarybird, Bateleur, and Steppe Eagle. We assessed the impact of climatic predictors on their distribution, considering two climate change scenarios for 2020-2040. Our findings reveal that raptor distribution in Kenya is predominantly concentrated in the southwestern region, extending into the central region of the country. The most significant predictors of raptor species distribution varied for each species, with Steppe eagle and Secretarybird being highly influenced by precipitation during the warmest quarter, Martial eagle being influenced by mean temperature during the driest quarter, and Bateleur being primarily influenced by precipitation during the coldest quarter. When projecting our model into the climate change scenarios for 2020-2040, all species except the Bateleur exhibited a negative range shift. The results of our study suggest that climate change may have adverse impacts on the raptor species examined. In light of these findings, we recommend implementing targeted monitoring and conducting surveys in accordance with our current model predictions. Specifically, our focus should be on monitoring areas that exhibit the highest climate suitability, as these areas are likely to undergo significant shifts in the near future. By conducting regular monitoring and engaging in further research, we can enhance our understanding of these raptor species and gather valuable data to improve the accuracy and reliability of our model predictions.


Brk/PTK6 and Involucrin Expression May Predict Breast Cancer Cell Responses to Vitamin D3.
The process of human embryonic mammary development gives rise to the structures in which mammary cells share a developmental lineage with skin epithelial cells such as keratinocytes. As some breast carcinomas have previously been shown to express high levels of involucrin, a marker of keratinocyte differentiation, we hypothesised that some breast tumours may de-differentiate to a keratinocyte-derived 'evolutionary history'. To confirm our hypothesis, we investigated the frequency of involucrin expression along with that of Brk, a tyrosine kinase expressed in up to 86% of breast carcinomas whose normal expression patterns are restricted to differentiating epithelial cells, most notably those in the skin (keratinocytes) and the gastrointestinal tract. We found that involucrin, a keratinocyte differentiation marker, was expressed in a high proportion (78%) of breast carcinoma samples and cell lines. Interestingly, tumour samples found to express high levels of involucrin were also shown to express Brk. 1,25-dihydroxyvitamin D3, a known differentiation agent and potential anti-cancer agent, decreased proliferation in the breast cancer cell lines that expressed both involucrin and Brk, whereas the Brk/involucrin negative cell lines tested were less susceptible. In addition, responses to 1,25-dihydroxyvitamin D3 were not correlated with vitamin D receptor expression. These data contribute to the growing body of evidence suggesting that cellular responses to 1,25-dihydroxyvitamin D3 are potentially independent of vitamin D receptor status and provide an insight into potential markers, such as Brk and/or involucrin that could predict therapeutic responses to 1,25-dihydroxyvitamin D3.


Environmental effects on resistance gene expression in milk stage popcorn kernels and associations with mycotoxin production.
Like other forms of maize, popcorn is subject to increased levels of contamination by a variety of different mycotoxins under stress conditions, although levels generally are less than dent maize under comparable stress. Gene array analysis was used to determine expression differences of disease resistance-associated genes in milk stage kernels from commercial popcorn fields over 3 years. Relatively lower expression of resistance gene types was noted in years with higher temperatures and lower rainfall, which was consistent with prior results for many previously identified resistance response-associated genes. The lower rates of expression occurred for genes such as chitinases, protease inhibitors, and peroxidases; enzymes involved in the synthesis of cell wall barriers and secondary metabolites; and regulatory proteins. However, expression of several specific resistance genes previously associated with mycotoxins, such as aflatoxin in dent maize, was not affected. Insect damage altered the spectrum of resistance gene expression differences compared to undamaged ears. Correlation analyses showed expression differences of some previously reported resistance genes that were highly associated with mycotoxin levels and included glucanases, protease inhibitors, peroxidases, and thionins.


[Long-term surgical results for congenital aural atresia and hearing reconstruction].
To evaluate the stability of hearing results and complications in long-term following-up who underwent reconstruction surgery. Six hundreds and seventy five cases (700 ears) of congenital aural atresia were reviewed from January 1984 to January 2001 at the Department of Otorhinolaryngology Head and Neck Surgery, Tongren hospital. Except 40 ears undone hearing reconstruction, 635 cases (660 ears) underwent long-term following-up for 3 to 19 years, with an average of 7.9 years. Stenosis and recurrent infection of the external auditory canal (EAC) were the most frequent complications. Stenosis was seen in 120 ears, and 2 ears re-atresia, with an incidence of 18.48% (122/660). Recurrent infection of the cavity and canal skin happened in 6 ears. Closure of the air-bone gap (ABG) post-operation were gained in all cases, and ABG gains 20 dB or more occurred in 512 ears (77.57%), but 30 dB or more in 231 ears (35%). Following-up results: Stable hearing results gained in 450 ears over the length of following-up; the hearing worsened than that of 3 weeks postoperatively occurred in 160 ears, including 2 ears with sensorineural hearing loss. Hearing deteriorated more than 20 dB happened in 35 ears, and 10-15 dB in others cases but still be improved compared with that of preoperation. Atresiaplasty surgery in individuals with congenital aural atresia can yield reliable, lasting hearing results in 68.2% (450/660), with a low incidence of complications; the initial improved hearing deteriorated gradually over the first 6 months post-operation, which are related with the stenosis and infection of canal. Cavity adhesion, bony EAC re-growth, ossicular chain re-fixation or displace may affect the hearing results in some cases. Even unilateral aural atresia may benefit from the reconstruction surgery and achieve serviceable hearing results.


The development of trait inference.
This study charted the increase with age in trait inference and examined the accompanying organizational processes. The Ss, eight males and eight females at each grade level from kindergarten through sixth, were read descriptions of other children. These served as the basis for "spontaneous" and "suggested" inferences which they were then asked to justify. Trait inference appeared as early as kindergarten and increased in frequency up to sixth grade. This increase was explained as evidence of a greater capacity for hierarchical organization. The justifications were classified into five reasoning categories which were interpreted in terms of the social psychological literature and Piaget's (16, 17) "mother structures."


Predicting disease trait with genomic data: a composite kernel approach.
With the advancement of biotechniques, a vast amount of genomic data is generated with no limit. Predicting a disease trait based on these data offers a cost-effective and time-efficient way for early disease screening. Here we proposed a composite kernel partial least squares (CKPLS) regression model for quantitative disease trait prediction focusing on genomic data. It can efficiently capture nonlinear relationships among features compared with linear learning algorithms such as Least Absolute Shrinkage and Selection Operator or ridge regression. We proposed to optimize the kernel parameters and kernel weights with the genetic algorithm (GA). In addition to improved performance for parameter optimization, the proposed GA-CKPLS approach also has better learning capacity and generalization ability compared with single kernel-based KPLS method as well as other nonlinear prediction models such as the support vector regression. Extensive simulation studies demonstrated that GA-CKPLS had better prediction performance than its counterparts under different scenarios. The utility of the method was further demonstrated through two case studies. Our method provides an efficient quantitative platform for disease trait prediction based on increasing volume of omics data.


Chronic depression.
Chronic depression has not been appreciated or studied as well as episodic mood disorders or other chronic psychiatric disorders. This review provides an overview of the clinical features, biology, and treatment of chronic depression and suggests additional areas for research. The English-language literature was searched using MEDLINE. Additional references were selected from the bibliographies of recent publications. Studies of chronic nonbipolar depressed patients were selected; chronicity was defined as the persistence of depressive symptoms for at least two years or as a diagnosis of DSM-III or DSM-III-R dysthymia, "double depression," or chronic major depression. Reported prevalence rates of chronic depression range from 3 to 5 percent in community samples and from 9 to 31 percent in clinical samples. Compared with patients with major depression, those with chronic depression have increased neurotic personality traits, adverse life events, health care utilization, and comorbid psychiatric and medical conditions, especially thyroid dysfunction. Biological and family studies support the relationship of chronic depression to the major mood disorders. Chronicity is also associated with inadequate treatment with anti-depressant drugs. Serotonergic or monoamine oxidase inhibitors may be more effective in treating chronic depression than tricyclic antidepressants. Psychosocial therapies need further study but may be especially useful in combination with drug treatment. Future research should investigate the clinical and biological correlates of subtypes of chronic depression, the response of the subtypes to different antidepressants, and the relative efficacy of combined antidepressant-psychosocial treatment.


Simultaneous determination of flavonoids, isochlorogenic acids and triterpenoids in Ilex hainanensis Using high performance liquid chromatography coupled with diode array and evaporative light scattering detection.
A high performance liquid chromatography coupled with diode array and evaporative light scattering detection (HPLC-DAD-ELSD) method for simultaneous determination of eight major bioactive compounds including two flavonoids (rutin and eriodictyol-7-O-β-D-glucopyranoside), two isochlorogenic acids (isochlorogenic acid A and isochlorogenic acid C) and four triterpenoids (ilexhainanoside D, ilexsaponin A1, ilexgenin A and ursolic acid) in Ilex hainanensis has been developed for the first time. The 283 nm wavelength was chosen for determination of two flavonoids and two isochlorogenic acids. ELSD was applied to determine four triterpenoids. The analysis was performed on an Agilent Zorbax SB-C18 column (250 × 4.6 mm i.d., 5 µm) with gradient elution of 0.2% formic acid in water and acetonitrile. The method was validated for linearity, limit of detection, limit of quantification, precision, repeatability and accuracy. The proposed method has been successfully applied for simultaneous quantification of the analytes in four samples of Ilex hainanensis, which is helpful for quality control of this plant.


Effects of phenothiazine drugs on serum levels of apolipoproteins and lipoproteins in schizophrenic subjects.
To investigate the risk factors and clinical significance of blood-lipid metabolic disorder in schizophrenic patients caused by phenothiazine treatment for long term (from 1 month to 25 years). Serum levels of apolipoprotein AI (apoAI), apolipoprotein B (apoB), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and total cholesterol (TC) were measured in 120 chronic schizophrenia patients, 50 vascular dementia, and 100 normal controls by the enzyme method and immune fluoroscopy turbidimetric method. The patients with schizophrenia and vascular dementia had significantly lower content of apoAI, HDL-C, and apoAI/apoB than those in normal control (P<0.01). Their apoB and TG levels were higher than the healthy control group (P<0.01). The TG contents in the negative group and the vascular dementia group were obviously higher than the positive group (P<0.01) while there was no marked difference between the TC levels in the three groups and the normal control group (P>0.05). The chronic schizophrenic patients have a blood-lipid metabolic disorder by long-term intake of phenothiazine drugs. It is suggested that the traditional treatment with antipsychotic should reformed, and that drugs of degrading lipid and coagulation should be used to prevent and reduce the risk factors causing the onset of cardiovascular and cerebrovascular diseases and delay the development of the disturbance of intelligence and dementia.


Deaza analogs of folic acid as antitumor agents.
Derivatives of the vitamin folic acid function in the body for the synthesis of thymidylate, purines and amino acids and are necessary for normal metabolism and growth. Methotrexate (MTX), an inhibitor of dihydrofolate reductase (DHFR) is the outstanding example of an antitumor antifolate. MTX is clinically useful in the treatment of childhood leukemia, choriocarcinoma and psoriasis, where it corrects abnormal growth, and in rheumatoid arthritis and other autoimmune diseases where it corrects abnormal immune function. Since 1949, when the chemical synthesis of MTX was reported by workers at the Lederle Laboratories of the American Cyanamid Company, much has been learned about the basis of antifolate cytotoxicity and selectivity. This review will focus on deaza antifolates which are: 1). presently under clinical development and 2). less developed compounds which represent novel approaches. Compounds will be grouped according to their enzyme targets; DHFR, thymidylate synthase (TS) and glycinamide ribonucleotide formyltransferase (GARFT). In addition to inhibition of target enzymes, antifolate membrane transport into cells and conversion to poly-L-gamma-glutamate forms are important considerations in drug design along with the reverse processes, cellular hydrolysis of antifolate poly-L-gamma-glutamates to monoglutamates and the extrusion of the monoglutamates through the cell membrane. These processes can be modulated by competition with folates.


Gastrointestinal blood flow and oxygen consumption in the newborn lamb: effect of chronic anemia and acute hypoxia.
The purpose of this study was to investigate the compensatory change in circulation and oxygenation of the newborn lamb gastrointestinal (GI) tract in response to anemic and hypoxic hypoxemia. Radiolabeled microspheres were used to measure blood flow. We subjected the newborn lamb to a 30-35% reduction in hematocrit 4 d before study and to a 10% oxygen environment for 30 min during the study to induce chronic anemic and acute hypoxic hypoxemia, respectively. The circulatory and oxygenation responses were measured 1 h after a standard milk feeding in all cases. During the experimental periods, no change in total GI blood flow was observed. Because of a failure to augment blood flow during hypoxemia, O2 delivery to the GI tract decreased significantly. Despite this, GI O2 consumption was not compromised because tissue O2 extraction by the GI tract rose significantly. The response of the newborn lamb GI tract to hypoxemia after feeding is augmentation of O2 extraction. The newborn's GI tract did not regulate local GI blood flow.


Immunoradiometric assay of thyrotropin in plasma: its value in predicting response to thyroliberin stimulation and assessing thyroid function in amiodarone-treated patients.
We measured thyrotropin in plasma by an ultrasensitive immunoradiometric assay (TSH-IRMA, "Sucrosep," Boots-Celltech), before and after thyroliberin (TRH) stimulation, in 71 patients with suspected thyroid-function disorders. Thirty-three were taking amiodarone; none was receiving (anti)thyroid drugs. The patients were divided into four groups, according to their TSH response to TRH (as measured previously by conventional TSH-RIA) and the concentrations of thyroxin (T4) and triiodothyronine (T3) in their plasma. Observed ranges of plasma TSH-IRMA (milli-int. units/L) before and after TRH were: euthyroid (n = 20), 0.2-3.0 and 1.7-15.5; subclinically hypothyroid (n = 14), 4.3-18.5 and 20-75; hyperthyroid (n = 17), less than 0.09 and less than 0.09-0.4; and subclinically hyperthyroid (n = 20), less than 0.09-1.1 and less than 0.09-2.6. Evidently TSH-IRMA results for a single sample completely distinguish hyperthyroidism from euthyroidism. However, TSH-IRMA values may also be undetectable in subclinical hyperthyroidism. The TSH response to TRH can be predicted from basal TSH-IRMA results less than 0.09 or greater than or equal to 0.8 milli-int. unit/L, intermediate values can be associated with either a normal TSH response (euthyroidism) or a decreased TSH response (subclinical hyperthyroidism only). We advocate TSH-IRMA as the first diagnostic test of thyroid function for amiodarone-treated patients.


Navicular bone disease: results of treatment using egg-bar shoeing technique.
Although the diagnostic criteria of navicular disease are generally accepted in practice, their limitations are recognised. However, the authors believe that navicular disease per se is reversible and that only secondary changes like adhesions to the deep flexor tendon or spur formations are irreversible. This hypothesis is supported by the results presented of the effect of the application of an egg-bar shoe, which caused permanent cessation of signs of navicular disease in more than 50 per cent of treated cases. The egg-bar shoeing technique can be usefully applied in practice.


[Paget's coxarthrosis. Implantation of a modular tumor reconstruction system. Case report].
A male patient aged 69 years suffering from Paget-coxarthrosis with a large distension of the proximal femur was implanted a cementless tumor reconstruction system. The surgical procedure consisted of opening of the femoral shaft with a special drill, insertion of the prosthesis and its anchorage within the healthy distal bone. By this method we were able to save the femoral muscle insertion planes. Twenty-eight months postoperatively the patient is pain-free and very satisfied with the outcome. The X-rays show a good fit of the prosthesis. The Harris Hip Score is now 90.1 points as compared to 46.4 points preoperatively.


Ultra-rapid access to words in chronic aphasia: the effects of intensive language action therapy (ILAT).
Effects of intensive language action therapy (ILAT) on automatic language processing were assessed using Magnetoencephalography (MEG). Auditory magnetic mismatch negativity (MMNm) responses to words and pseudowords were recorded in twelve patients with chronic aphasia before and immediately after two weeks of ILAT. Following therapy, Patients showed significant clinical improvements of auditory comprehension as measured by the Token Test and in word retrieval and naming as measured by the Boston Naming Test. Neuromagnetic responses dissociated between meaningful words and meaningless word-like stimuli ultra-rapidly, approximately 50 ms after acoustic information first allowed for stimulus identification. Over treatment, there was a significant increase in the left-lateralisation of this early word-elicited activation, observed in perilesional fronto-temporal regions. No comparable change was seen for pseudowords. The results may reflect successful, therapy-induced, language restitution in the left hemisphere.


Design, synthesis, and cytotoxicity of novel 3-arylidenones derived from alicyclic ketones.
Forty-four novel chalcone-inspired analogs having a 3-aryl-2-propenoyl moiety derived from alicyclic ketones were designed, synthesized, and investigated for cytotoxicity against murine B16 and L1210 cancer cell lines. The analogs belong to four structurally divergent series, three of which (series g, h, and i) contain differently substituted cyclopentanone units and the fourth (series j) contains a 3,3-dimethyl-4-piperidinone moiety. Of these, the analogs in series j showed potential cytotoxic activity against murine B16 (melanoma) and L1210 (lymphoma) cells. The most active compounds 5j, 11j, 15j, and 12h produced IC(50) values from 4.4 to 15 μm against both cell lines. A single-crystal X-ray structure analysis and molecular modeling studies confirmed that these chalcones have an E-geometry about the alkene bond and possess a slightly 'twisted' conformation similar to that of combretastatin A-4. At a concentration of 30 μm, compounds 5j, 11j, and 15j did not cause microtubule depolymerization in cells, suggesting that they have a different mechanism of action.


Frequent recombination in telomeric DNA may extend the proliferative life of telomerase-negative cells.
For cells on the path to carcinogenesis, the key to unlimited growth potential lies in overcoming the steady loss of telomeric sequence commonly referred to as the 'end-replication problem' that occurs with each cell division. Most human tumors have reactivated telomerase, a specialized reverse transcriptase that directs RNA-templated addition of telomeric repeats on to chromosomal termini. However, approximately 10% of tumors maintain their telomeres through a recombination-based mechanism, termed alternative lengthening of telomeres or ALT. Here we demonstrate that telomeric DNA undergoes a high rate of a particular type of recombination visualized cytogenetically as sister chromatid exchange (SCE), and that this rate is dependent on genotype. A novel model of ALT is presented in which it is argued that telomeric exchanges, if they are unequal and occur at a sufficiently high frequency, will allow cells to proliferate indefinitely without polymerase-mediated extension of telomeric sequence.


Minisci C-H Alkylation of Heteroarenes Enabled by Dual Photoredox/Bromide Catalysis in Micellar Solutions*.
Aromatic heterocycles are omnipresent structural motifs in various natural products, pharmaceuticals and agrochemicals. This work describes a photocatalytic Minisci-type C-H functionalization of heteroarenes with non-activated alkyl bromides. The reaction avoids stoichiometric radical-promoters, oxidants, or acids, and is conducted using blue LEDs as the light source. The reactive carbon-centered alkyl radicals are generated by merging the photoredox approach with bromide anion co-catalysis and spatial pre-aggregation of reacting species in the micellar aqueous solutions. The obtained data highlight the critical importance of microstructuring and organization of the components in the reaction mixture.


[The anti-arrhythmia effect of carbamazepine in chagasic patients with advanced myocardial damage].
Oral administration of 600 mg/day of carbamazepine to 14 arrhythmic chagasic patients with advanced myocardial damage and no signs of congestive heart failure did not alter the frequency of ventricular extrasystoles, but reduced the total number of supraventricular ectopic beats in 7/14 patients and the episodes of complex ventricular arrhythmias in up to 43% of patients. This assessment was made from 24 hour continuous Holter recording during the course of this double-blind, placebo controlled, randomized crossover study. Serum levels of carbamazepine were also determined and found within therapeutic limits. Six patients complained of minor side effects. One patient presented with iatrogenic complete AV block, another case had proarrhythmic effect and one patient had to be withdrawn from the study because of gastric irritation. No instance of contractile depression was observed. Accordingly, carbamazepine is a therapeutic alternative for treatment of symptomatic complex ventricular or supraventricular arrhythmias in chronic chagasic patients without evidence of conduction system involvement or with intolerance to other antiarrhythmic drugs.


High-resolution mapping of resistance to cassava mosaic geminiviruses in cassava using genotyping-by-sequencing and its implications for breeding.
Cassava mosaic disease (CMD), caused by different species of cassava mosaic geminiviruses (CMGs), is the most important disease of cassava in Africa and the Indian sub-continent. The cultivated cassava species is protected from CMD by polygenic resistance introgressed from the wild species Manihot glaziovii and a dominant monogenic type of resistance, named CMD2, discovered in African landraces. The ability of the monogenic resistance to confer high levels of resistance in different genetic backgrounds has led recently to its extensive usage in breeding across Africa as well as pre-emptive breeding in Latin America. However, most of the landraces carrying the monogenic resistance are morphologically very similar and come from a geographically restricted area of West Africa, raising the possibility that the diversity of the single-gene resistance could be very limited, or even located at a single locus. Several mapping studies, employing bulk segregant analysis, in different genetic backgrounds have reported additional molecular markers linked to supposedly new resistance genes. However, it is not possible to tell if these are indeed new genes in the absence adequate genetic map framework or allelism tests. To address this important question, a high-density single nucleotide polymorphism (SNP) map of cassava was developed through genotyping-by-sequencing a bi-parental mapping population (N=180) that segregates for the dominant monogenic resistance to CMD. Virus screening using PCR showed that CMD symptoms and presence of virus were strongly correlated (r=0.98). Genome-wide scan and high-resolution composite interval mapping using 6756 SNPs uncovered a single locus with large effect (R(2)=0.74). Projection of the previously published resistance-linked microsatellite markers showed that they co-occurred in the same chromosomal location surrounding the presently mapped resistance locus. Moreover, their relative distance to the mapped resistance locus correlated with the reported degree of linkage with the resistance phenotype. Cluster analysis of the landraces first shown to have this type of resistance revealed that they are very closely related, if not identical. These findings suggest that there is a single source of monogenic resistance in the crop's genepool tracing back to a common ancestral clone. In the absence of further resistance diversification, the long-term effectiveness of the single gene resistance is known to be precarious, given the potential to be overcome by CMGs due to their fast-paced evolutionary rate. However, combining the quantitative with the qualitative type of resistance may ensure that this resistance gene continues to offer protection to cassava, a crop that is depended upon by millions of people in Africa against the devastating onslaught of CMGs.