Peptic esophageal stricture: a report from Argentina.
Peptic esophageal stricture (PES) is a major complication of gastroesophageal reflux disease. The aims of this paper were to determine the characteristics of these patients with regard to demography, morphology, functional status and results of therapy. The charts of the patients treated at our service who underwent esophageal dilatation for PES between 1971 and 1998 were reviewed. Statistical analyses were performed by means of chi2, Mann-Whitney and Student's t-tests. One hundred and thirty-five patients with PES were dilated by various means. The mean age was 61.1 +/- 16.3 years, the ratio of men to women was 2.75/1 and mean duration of symptoms was 44.4 +/- 74.6 months. Their symptoms were dysphagia in 100%, pyrosis in 70%, and regurgitation in 40% of the cases. There was an average weight loss of 3.3 +/- 6 kg. The upper gastro-intestinal series showed pre- and post-dilatation diameters at the stricture of 8 +/- 2.5 mm and 15.9 +/- 1.2 mm, respectively. The stricture was located at the lower third of the esophagus in 97% and at the middle third in 3% of the cases. We found PES endoscopically in all instances, with different degrees of erosions in 64%, ulcers in 20% and Barrett's esophagus in 16% of the cases. The biopsy samples showed intestinal metaplasia in 16% and esophagitis in 75.5%, being normal in the remaining 8.5%. Brush cytology was negative for malignancy in 100% of the cases. Esophageal manometry showed peristaltic wave amplitude of 40 +/- 3 mmHg and presence of peristaltic waves of 62 +/- 38.6%. LES pressure was 8.6 +/- 6.3 mmHg (NV 24.2 +/- 6.3 mmHg). Measurement of pH showed 15% of patients had pH < 4. Patients needed a mean of 4.7 +/- 1.6 dilations per case, with successful results in 87.2% of cases. The perforation rate was 0.1% of the total number of procedures and 0.7%, of patients. The mortality rate was 0.7% (one case). We observed PES relapse in 32% of the cases. There was no correlation between relapse, age, duration of the stenosis or pharmacological treatment with H2 blockers or proton pump inhibitors. We conclude that in Argentina, demography, morphology, functional status and results of dilatation of PES patients are similar to those reported in the Western world, with the exception of the different behavior seen after treatment with H2 blockers or proton pump inhibitors.


Cost of employee assistance programs: comparison of national estimates from 1993 and 1995.
The cost and financing of mental health services is gaining increasing importance with the spread of managed care and cost-cutting measures throughout the health care system. The delivery of mental health services through structured employee assistance programs (EAPs) could be undermined by revised health insurance contracts and cutbacks in employer-provided benefits at the workplace. This study uses two recently completed national surveys of EAPs to estimate the costs of providing EAP services during 1993 and 1995. EAP costs are determined by program type, worksite size, industry, and region. In addition, information on program services is reported to determine the most common types and categories of services and whether service delivery changes have occurred between 1993 and 1995. The results of this study will be useful to EAP managers, mental health administrators, and mental health services researchers who are interested in the delivery and costs of EAP services.


Toxic effects of different-sized graphene oxide particles on zebrafish embryonic development.
Graphene oxide (GO) has broad application potential in many fields, such as biomedicine and energy. Due to the wide-ranging GO applications, its entry into the environment is inevitable along with the potential for ecological and environmental risks. In the present study, we systematically investigated the dose-dependent effects of three different-sized GO particles (50-200 nm, <500 nm, and >500 nm) on zebrafish during the very early developmental stages (4-124 h post-fertilization). The results showed that GOs could accumulate in the eyes, heart, yolk sac, and blood vessels of fish larvae. Consequently, their effects on multiple toxic endpoints were observed, including delayed hatching times, shortened body lengths, alterations in heart rate and blood flow, changes in swimming activity and responses to photoperiod stimulation, and the enhanced activity of total superoxide dismutase, inducible nitric oxide synthase, acetylcholinesterase, caspase-3, and induction of apoptosis-related gene expression. As a result, the occurrence of oxidative stress and the induction of apoptosis are suggested in fish larvae exposed to all three different-sized GO particles. In addition, our results highlight the impacts of waterborne-GO exposure on zebrafish during early development, which were not merely dependent on GO concentration but also on the associated GO sizes. This study hereby provides a basis for the potential ecological and health risks of GO exposure.


A communication standards ontology using basic formal ontologies.
Working interoperability not only requires harmonized system's architectures, but also the same interpretation of technical specifications in order to guide the development process. This paper analyses the commonly used structures of communication standards elaborated with HL7 Version 3 and proposes an ontological structure resulting in the so-called Communication Standards Ontology (CSO). As such a solution has to be developed within an architectural framework, the approach is aligned with the Generic Component Model (GCM).


Blockade of D-2 dopamine receptors strongly enhances the potency of enkephalins to inhibit dopamine-sensitive adenylate cyclase in rat neostriatum: involvement of delta- and mu-opioid receptors.
The interactions between dopamine receptors and opioid receptors coupled to adenylate cyclase in rat neostriatum were investigated. cAMP efflux from neostriatal slices induced by simultaneous activation of (stimulatory) D-1 and (inhibitory) D-2 dopamine receptors with 30 microM dopamine was inhibited by the preferential delta-opioid receptor agonist [D-Ala2-D-Leu5] enkephalin (DADLE) and the mu-opioid receptor agonist morphine with an EC50 of 100 and 800 nM, respectively. On selective D-1 receptor activation (i.e., with D-2 receptors blocked by 10 microM (-)sulpiride), the EC50 of DADLE was strongly reduced to 3 nM, whereas that of morphine was unaffected. When D-1 and D-2 receptors were activated simultaneously, the inhibitory effects of DADLE (0.3 microM) and morphine (3 microM) on cAMP efflux were antagonized equally well by naloxone, a mu-opioid receptor antagonist. In contrast, on selective D-1 receptor activation, naloxone was about 20 times more potent in antagonizing the inhibitory effect of morphine than DADLE. Moreover, the delta-opioid receptor antagonist ICI 174864 (0.75 microM) did not affect the inhibitory effect of morphine but antagonized that of DADLE, provided that D-2 receptors were blocked. The highly selective delta-opioid receptor agonist [D-Pen2-D-Pen5] enkephalin (DPDPE) inhibited dopamine-stimulated cAMP efflux only when D-2 receptors were blocked. Similar results were obtained when the agonists SKF 38393 and LY 141865 were used to activate D-1 and D-2 receptors, respectively. These data indicate that blockade of D-2 receptors in the neostriatum elicits the coupling of delta-opioid receptors to dopamine-sensitive adenylate cyclase, thereby making it considerably more sensitive to inhibition by the enkephalins.


Fuzzy Approximate Entropy of Extrema Based on Multiple Moving Averages as a Novel Approach in Obstructive Sleep Apnea Screening.
Obstructive sleep apnea (OSA) is a respiratory disease associated with autonomic nervous system dysfunction. As a novel method for analyzing OSA depending on heart rate variability, fuzzy approximate entropy of extrema based on multiple moving averages (Emma-fApEn) can effectively assess the sympathetic tension limits, thereby realizing a good performance in the disease severity screening. Sixty 6-h electrocardiogram recordings (20 healthy, 16 mild/moderate OSA and 34 severe OSA) from the PhysioNet database were used in this study. The performances of minima of Emma-fApEn (fApEn-minima), maxima of Emma-fApEn (fApEn-maxima) and classic time-frequency domain indices for each recording were assessed by significance analysis, correlation analysis, parameter optimization and OSA screening. fApEn-minima and fApEn-maxima had significant differences between the severe OSA group and the other two groups, while the mean value (Mean) and the ratio of low-frequency power and high-frequency power (LH) could significantly differentiate OSA recordings from healthy recordings. The correlation coefficient between fApEn-minima and apnea-hypopnea index was the highest (|R| = 0.705). Machine learning methods were used to evaluate the performances of the above four indices. Random forest (RF) achieved the highest accuracy of 96.67% in OSA screening and 91.67% in severe OSA screening, with a good balance in both. Emma-fApEn may be used as a simple preliminary detection tool to assess the severity of OSA prior to polysomnography analysis.


A murine transmembrane tumor necrosis factor (TNF) transgene induces arthritis by cooperative p55/p75 TNF receptor signaling.
The arthritogenic activities of tumor necrosis factor (TNF) and its p55TNF-receptor (R) have been well documented in experimental animal models of arthritis, and in transgenic mice expressing wild-type or mutant transmembrane human TNF proteins in their joints. In this study we show that chronic inflammatory arthritis also develops in transgenic mice made to overexpress a mutant transmembrane from of the murine TNF protein (muTNF delta 1-12) which is known to utilize efficiently both the p55 and the p75TNFR. Cross-breeding of the transgene into a TNF knockout background did not alter development of disease. Analysis of TNF bioactivity in sera from lipopolysaccharide-stimulated mice or ex vivo macrophage cultures demonstrated that the muTNF delta 1-12 protein accumulates on the cell surface and is not processed to bioactive soluble TNF, indicating that transmembrane TNF is by itself sufficient to mediate pathogenesis of arthritis. Furthermore, using TNFR knockout mice, it is shown that development of transmembrane TNF-mediated arthritis requires the presence of the p55TNFR but is significantly delayed in the absence of the p75TNFR, suggesting a positive cooperation between the two TNFR in the arthritogenic process. These results indicate that blocking the activities of both soluble and transmembrane TNF may be required to effectively neutralize the pathogenic potential of this cytokine in arthritis.


Differential Impact of Clinical Factors for Predicting High Platelet Reactivity on Clinical Outcomes in Acute Myocardial Infarction Patients Treated With Clopidogrel and Prasugrel.
Several scoring systems, including the ABCD-GENE and HHD-GENE scores incorporating clinical and genetic factors, have been developed to identify patients likely to have high platelet reactivity on P2Y12 inhibitors, leading to increased risks of ischemic events. However, genetic testing is not widely available in daily practice. We aimed to evaluate the differential impact of clinical factors in the scores on ischemic outcomes in patients treated with clopidogrel and prasugrel. This bi-center registry included 789 patients with acute myocardial infarction (MI) undergoing percutaneous coronary intervention and treated with either clopidogrel or prasugrel at discharge. The relations of the number of clinical factors included in the ABCD-GENE (age ≥ 75 years, body mass index >30 kg/m2, chronic kidney disease, and diabetes) and HHD-GENE (hypertension, hemodialysis, and diabetes) scores to the primary endpoint of major cardiovascular events after discharge, a composite of death, recurrent MI, and ischemic stroke, were evaluated. The number of clinical factors in the ABCD-GENE score was not predictive of ischemic outcomes after discharge in patients treated with clopidogrel and/or prasugrel, while the increase in the number of clinical factors of the HHD-GENE score was associated with an increased risk of the primary endpoint in a stepwise manner in patients on a P2Y12 inhibitor. Clinical factors listed in the HHD-GENE score may help stratify ischemic risks in patients with acute MI treated with clopidogrel and prasugrel, whereas risk stratification without genetic testing in patients treated with clopidogrel may be challenging.


MiR-193a-5p suppresses cell proliferation and induces cell apoptosis by regulating HOXA7 in human ovarian cancer.
Ovarian cancer is one of the most common malignancies in women in the world. MicroRNAs (miRNAs) were identified as a group of regulators that played important roles in the progression of cancer development. The main purpose of this study was to investigate the functional mechanism of microRNA-193a-5p (miR-193a-5p) in human ovarian cancer. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the RNA levels of miR-193a-5p and homeobox genes A7 (HOXA7). Western blot assay was performed to determine the protein level of HOXA7. The interaction between miR-193a-5p and HOXA7 was predicted by online software starBase v3.0, and then verified by the dual luciferase reporter assay. The cell proliferation and apoptosis rate were examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and colony formation assay as well as flow cytometry analysis. We found out that the expression level of miR-193a-5p was decreased in human ovarian cancer tissues and cells. The overexpression of miR-193a-5p inhibited cell proliferation and induced apoptosis in human ovarian cancer. Interestingly, miR-193a-5p reduced the expression of HOXA7 by binding to 3'-untranslated region (3'-UTR) of HOXA7 mRNA. As expected, the knockdown of HOXA7 also suppressed cell proliferation and promoted apoptosis in human ovarian cancer. Besides, the upregulation of HOXA7 reversed the effect of miR-193a-5p on human ovarian cell proliferation and apoptosis. Our findings confirmed that miR-193a-5p inhibited cell proliferation and induced apoptosis through the downregulation of HOXA7 in human ovarian cancer, providing a theoretical value for the therapy of human ovarian cancer.


The Cultural Fabric of Human Causal Cognition.
Causal cognition emerges early in development and confers an important advantage for survival. But does this mean that it is universal in humans? Our cross-disciplinary review suggests a broad evolutionary basis for core components of causal cognition but also underlines the essential role of culturally transmitted content as being uniquely human. The multiple ways in which both content and the key mechanisms of cultural transmission generate cultural diversity suggest that causal cognition in humans is not only colored by their specific cultural background but also shaped more fundamentally by the very fact that humans are a cultural species.


Regulation of alternative macrophage activation by galectin-3.
Alternative macrophage activation is implicated in diverse disease pathologies such as asthma, organ fibrosis, and granulomatous diseases, but the mechanisms underlying macrophage programming are not fully understood. Galectin-3 is a carbohydrate-binding lectin present on macrophages. We show that disruption of the galectin-3 gene in 129sv mice specifically restrains IL-4/IL-13-induced alternative macrophage activation in bone marrow-derived macrophages in vitro and in resident lung and recruited peritoneal macrophages in vivo without affecting IFN-gamma/LPS-induced classical activation or IL-10-induced deactivation. IL-4-mediated alternative macrophage activation is inhibited by siRNA-targeted deletion of galectin-3 or its membrane receptor CD98 and by inhibition of PI3K. Increased galectin-3 expression and secretion is a feature of alternative macrophage activation. IL-4 stimulates galectin-3 expression and release in parallel with other phenotypic markers of alternative macrophage activation. By contrast, classical macrophage activation with LPS inhibits galectin-3 expression and release. Galectin-3 binds to CD98, and exogenous galectin-3 or cross-linking CD98 with the mAb 4F2 stimulates PI3K activation and alternative activation. IL-4-induced alternative activation is blocked by bis-(3-deoxy-3-(3-methoxybenzamido)-beta-D-galactopyranosyl) sulfane, a specific inhibitor of extracellular galectin-3 carbohydrate binding. These results demonstrate that a galectin-3 feedback loop drives alternative macrophage activation. Pharmacological modulation of galectin-3 function represents a novel therapeutic strategy in pathologies associated with alternatively activated macrophages.


Oral care practices of intensive care nurses: a descriptive study.
The aim of this study was to investigate intensive care unit (ICU) nurses' views and practices on oral care and to define the factors related to oral care measures. A study was carried out in eight ICUs of a teaching hospital in 2008. One hundred one nurses constituted the study sample. The data were collected using 'Oral Care Practices Survey' which included demographic characteristics (5 items) and current oral care practices (13 items). Oral care was given the highest priority by nearly 60% of the nurses. The most commonly used solution was sodium bicarbonate (79.2%), and the most frequently used equipment was foam swab (82.2%). Oral care was carried out less than every 4 h per day by 44.5% of the nurses. The oral care products and solutions were reported to be different in almost every unit. The relationship between the use of toothpaste and the place of employment was statistically significant (x(2) = 24.566, d.f. = 6, P = 0.000). There was a statistical significance between the clinics and frequency of oral care (x(2) = 81.486, d.f. = 42, P = 0.000). This study suggests that there is a wide variety of type and frequency of oral care measures among ICU nurses. Optimal oral care supported by evidence is an effective prevention method for eliminating oral complications.


Virtual Reality Model of the Three-Dimensional Anatomy of the Cavernous Sinus Based on a Cadaveric Image and Dissection.
Studying the three-dimensional (3D) anatomy of the cavernous sinus is essential for treating lesions in this region with skull base surgeries. Cadaver dissection is a conventional method that has insurmountable flaws with regard to understanding spatial anatomy. The authors' research aimed to build an image model of the cavernous sinus region in a virtual reality system to precisely, individually and objectively elucidate the complete and local stereo-anatomy. Computed tomography and magnetic resonance imaging scans were performed on 5 adult cadaver heads. Latex mixed with contrast agent was injected into the arterial system and then into the venous system. Computed tomography scans were performed again following the 2 injections. Magnetic resonance imaging scans were performed again after the cranial nerves were exposed. Image data were input into a virtual reality system to establish a model of the cavernous sinus. Observation results of the image models were compared with those of the cadaver heads. Visualization of the cavernous sinus region models built using the virtual reality system was good for all the cadavers. High resolutions were achieved for the images of different tissues. The observed results were consistent with those of the cadaver head. The spatial architecture and modality of the cavernous sinus were clearly displayed in the 3D model by rotating the model and conveniently changing its transparency. A 3D virtual reality model of the cavernous sinus region is helpful for globally and objectively understanding anatomy. The observation procedure was accurate, convenient, noninvasive, and time and specimen saving.


The effect of green tea extract and EGCG on the signaling network in squamous cell carcinoma.
Green tea and its major active component, epigallocatechin-3-gallate (EGCG), have been reported to have anticancer activity on various cancers. However, the exact molecular mechanism of its anticancer activity is still not well understood. We investigated the anticancer activity of green tea extract (GTE) and EGCG on 3 human squamous carcinoma cell lines (CAL-27, SCC-25, and KB) in vitro. We also examined the effects of GTE and EGCG on cell signaling networks using our newly developed Pathway Array technology, which is an innovative proteomic assay to globally screen changes in protein expression and phosphorylation. Our results demonstrated that GTE and EGCG inhibited all 3 squamous carcinoma cells' growth via S and G(2)/M phase arrest, but different sensitivities to GTE and EGCG in different cell lines were observed: CAL-27 cells were more sensitive to the both agents than SCC-25 and KB cells, and GTE at an EGCG equivalent concentration displayed a stronger inhibition than EGCG alone. The Pathway Array assessment of 107 proteins indicated that different signaling pathways were activated in different cell lines, suggesting heterogeneity at the signaling network level. After treatment with GTE or EGCG, a total of 21 proteins and phosphorylations altered significantly in all 3 cell lines based on analysis of variance (ANOVA) (P < 0.05). The major signaling pathways affected by GTE and EGCG were EGFR and Notch pathways, which, in turn, affected cell cycle-related networks. These results suggested that GTE and EGCG target multiple pathways or global networks in cancer cells, which resulted in collective inhibition of cancer cell growth. The finding pointed out the future direction to study the underlying mechanism of the chemotherapeutic and chemopreventive activities of EGCG and GTE.


M-SAKHI-Mobile health solutions to help community providers promote maternal and infant nutrition and health using a community-based cluster randomized controlled trial in rural India: A study protocol.
Reduction of childhood stunting is difficult to achieve by interventions that focus only on improving nutrition during infancy. Comprehensive interventions that extend through the continuum of care from pregnancy to infancy are needed. Mobile phones are now successfully being used for behaviour change communication to improve health. We present the methodology of an mHealth intervention "Mobile Solutions Aiding Knowledge for Health Improvement" (M-SAKHI) to be delivered by rural community health workers or Accredited Social Health Activists (ASHAs) for rural women, below or up to 20 weeks of pregnancy through delivery until their infant is 12 months of age. This protocol paper describes the cluster randomized controlled trial to evaluate the effectiveness of M-SAKHI. The primary objective of the trial is to reduce the prevalence of stunting (height-for-age < -2 z-score) in children at 18 months of age by 8% in the intervention as compared with control. The secondary objectives include evaluating the impact on maternal dietary diversity, birth weight, infant and young child feeding practices, infant development, and child morbidity, along with a range of intermediate outcomes for maternal, neonatal, and infant health. A total of 297 ASHAs, five trained counsellors, and 2,501 participants from 244 villages are participating in this study. The outcome data are being collected by 51 field research officers. This study will provide evidence regarding the efficacy of M-SAKHI to reduce stunting in young children in rural India, and if effective, the cost-effectiveness of M-SAKHI.


Extended action of MKC-242, a selective 5-HT(1A) receptor agonist, on light-induced Per gene expression in the suprachiasmatic nucleus in mice.
We reported previously that (S)-5-[3-[(1,4-benzodioxan-2-ylmethyl)amino]propoxy]-1,3-benzodioxole hydrochloride (MKC-242) (3 mg kg(-1), i.p.), a selective 5-HT(1A) receptor agonist, accelerated the re-entrainment of hamster wheel-running rhythms to a new 8 hr delayed or advanced light-dark cycle, and also potentiated the phase advance of the wheel-running rhythm produced by light pulses. The molecular mechanism underlying MKC-242-induced potentiation of this phase shift, however, has not yet been elucidated. We examined the effects of MKC-242 on light-induced mPer1 and mPer2 mRNA expression in the suprachiasmatic nucleus (SCN) of mice. MKC-242 (5 mg kg(-1), i.p.) potentiated light-induced mPer1 and mPer2 expression in the SCN of mice housed in constant darkness for 2 days, when mRNA levels were observed 3 hr after light-exposure. More potentiating action of MKC-242 on mPer2 expression in the SCN was observed in mice housed in constant darkness for 9-10 days. This facilitatory action of MKC-242 on mPer1 expression was antagonized by WAY100635, a selective 5-HT(1A) receptor blocker, indicating that MKC-242 activated 5-HT(1A) receptors. Other drugs such as 8-hydroxy-dipropylaminotetralin (10 mg kg(-1), i.p.), paroxetine (10 mg kg(-1), i.p.), buspirone (10 mg kg(-1), i.p.), and diazepam (10 mg kg(-1), i.p.) did not display a potentiating action on light-induced mPer1 and mPer2 expression in the SCN. In the behavioral experiments, we found that MKC-242 (5 mg kg(-1), i.p.) potentiated light-induced phase delays of free-running rhythm in mice. The present results suggest that prolonged increase of mPer1 or mPer2 expression in the SCN by MKC-242 may be involved in the potentiation of photic entrainment by MKC-242 in mice.


High-resolution analysis of gene activity during the Xenopus mid-blastula transition.
The Xenopus mid-blastula transition (MBT) marks the onset of large-scale zygotic transcription, as well as an increase in cell cycle length and a loss of synchronous cell divisions. Little is known about what triggers the activation of transcription or how newly expressed genes interact with each other. Here, we use high-resolution expression profiling to identify three waves of gene activity: a post-fertilisation wave involving polyadenylation of maternal transcripts; a broad wave of zygotic transcription detectable as early as the seventh cleavage and extending beyond the MBT at the twelfth cleavage; and a shorter post-MBT wave of transcription that becomes apparent as development proceeds. Our studies have also allowed us to define a set of maternal mRNAs that are deadenylated shortly after fertilisation, and are likely to be degraded thereafter. Experimental analysis indicates that the polyadenylation of maternal transcripts is necessary for the establishment of proper levels of zygotic transcription at the MBT, and that genes activated in the second wave of expression, including Brachyury and Mixer, contribute to the regulation of genes expressed in the third. Together, our high-resolution time series and experimental studies have yielded a deeper understanding of the temporal organisation of gene regulatory networks in the early Xenopus embryo.


Patterns and prognosis of all components of the J-wave pattern in multiethnic athletes and ambulatory patients.
Despite recent concern about the significance of the J-wave pattern (also often referred to as early repolarization) and the importance of screening in athletes, there are limited rigorous prognostic data characterizing the 3 components of the J-wave pattern (ST elevation, J waves, and QRS slurs). We aim to assess the prevalence, patterns, and prognosis of the J-wave pattern among both stable clinical and athlete populations. We retrospectively studied 4,041 electrocardiograms from a multiethnic clinical population from 1997 to 1999 at the Veterans Affairs Palo Alto Health Care System. We also examined preparticipation electrocardiograms of 1,114 Stanford University varsity athletes from 2007 to 2008. Strictly defined criteria for components of the J-wave pattern were examined. In clinical subjects, prognosis was assessed using the end point of cardiovascular death after 7 years of follow-up. Components of the J-wave pattern were most prevalent in males; African Americans; and, particularly, athletes, with the greatest variations demonstrated in the lateral leads. ST elevation was the most common. Inferior J waves and slurs, previously linked to cardiovascular risk, were observed in 9.6% of clinical subjects and 12.3% of athletes. J waves, slurs, or ST elevation was not associated with time to cardiovascular death in clinical subjects, and ST-segment slope abnormalities were not prevalent enough in conjunction with them to reach significance. J waves, slurs, or ST elevation was not associated with increased hazard of cardiovascular death in our large multiethnic, ambulatory population. Even subsets of J-wave patterns, recently proposed to pose a risk of arrhythmic death, occurred at such a high prevalence as to negate their utility in screening.


Experimental AA amyloidosis in mice is inhibited by treatment with triptolide, a purified traditional Chinese medicine.
The effect of triptolide, which is isolated from Tripterygium Wilfordii, on induction and development of murine AA amyloidosis was studied. In the first experiment, we examined the ability of triptolide to inhibit initiation of amyloidosis. Oral or intraperitoneal administration of 480 microg/kg/day triptolide inhibited splenic amyloid deposition in both rapid and chronic induction models of mouse AA amyloidosis. Moreover, serum amyloid A (SAA) and interleukin (IL)-6 levels were also suppressed remarkably. Triptolide also immediately decreased SAA levels and reduced the incidence of amyloidosis even under conditions of high SAA levels. In the second experiment, we evaluated the influence of triptolide on development and resorption of amyloid deposition. Amyloid deposition was induced in mice by 28 daily injections of casein. After splenic and hepatic biopsies to confirm the presence of amyloid deposits, the mice immediately started to receive daily injections of 480 microg/kg/day triptolide with or without casein. Treatment with triptolide for 35 days and 105 days prevented deposition of amyloid and promoted resorption of splenic amyloid deposits. In conclusion, we show for the first time that triptolide inhibits induction and development of experimental murine amyloidosis. These results suggest that through suppression of IL-6, triptolide can reduce production of SAA. Amyloid deposition is prevented when levels of the amyloid-forming precursor protein SAA are decreased significantly.


[Status of knowledge regarding various aspects of tuberculosis among industrial workers].
The level of awareness of some aspects of tuberculosis by the workers of two industrial enterprises was analysed on the basis of 1700 anonymous questionnaires by them. Questions found the most difficult by the respondents were singled out. The necessity to restructure antituberculosis education activities with regard to the priorities in this matter was substantiated.


Mechanisms of high-order photobleaching and its relationship to intracellular ablation.
In two-photon laser-scanning microscopy using femtosecond laser pulses, the dependence of the photobleaching rate on excitation power may have a quadratic, cubic or even biquadratic order. To date, there are still many open questions concerning this so-called high-order photobleaching. We studied the photobleaching kinetics of an intrinsic (enhanced Green Fluorescent Protein (eGFP)) and an extrinsic (Hoechst 33342) fluorophore in a cellular environment in two-photon microscopy. Furthermore, we examined the correlation between bleaching and the formation of reactive oxygen species. We observed bleaching-orders of three and four for eGFP and two and three for Hoechst increasing step-wise at a certain wavelength. An increase of reactive oxygen species correlating with the bleaching over time was recognized. Comparing our results to the mechanisms involved in intracellular ablation with respect to the amount of interacting photons and involved energetic states, we found that a low-density plasma is formed in both cases with a smooth transition in between. Photobleaching, however, is mediated by sequential-absorption and multiphoton-ionization, while ablation is dominated by the latter and cascade-ionization processes.


Effects of Breast-Conserving Surgery and Mastectomy on the Survival of Patients with Early-stage (T1-2N0-1M0) HER2-Positive Breast Cancer: A Propensity Score-Matched Analysis.
Although breast-conserving therapy (BCT) promises at least a similar survival rate for patients with early breast cancer compared with mastectomy, its efficacy in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors remains unclear. Therefore, we conducted this study to explore differential effects of BCT and mastectomy on survival outcomes of patients with early-stage HER2-positive breast cancer. Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, and basic characteristics of patients who received either BCT or mastectomy were balanced using propensity score matching (PSM). Kaplan-Meier analysis, log-rank testing, and Cox proportional hazards regression were performed. In total, 20,277 patients were diagnosed with T1-2N0-1M0 HER2-positive breast cancer between 2010 and 2015. After PSM, 6,185 pairs of patients were enrolled for further analysis. Compared with those undergoing mastectomy, patients receiving BCT had superior overall survival (OS) (hazard ratio [HR], 0.63; 95% confidence interval [CI]: 0.55-0.73; P < 0.001) and breast cancer-specific survival (BCSS) (HR: 0.59; 95% CI: 0.48-0.71; P < 0.001). The subgroup analyses revealed that survival outcomes (OS and BCSS) of BCT were better than that of mastectomy among estrogen receptor (ER)+/progesterone receptor (PR)+/HER2+, ER+/PR-/HER2+, and ER-/PR-/HER2+subtypes (P < 0.05 for all); however, patients with ER-/PR+/HER2+ subtypes who underwent BCT had similar OS and BCSS (P > 0.05 for both) to those treated with mastectomy. Despite the aggressiveness of the disease, we found that BCT may confer a better long-term survival than mastectomy for patients with T1-2N0-1M0 HER2-positive breast cancer, particularly for those with ER+/PR+/HER2+, ER+/PR-/HER2+, and ER-/PR-/HER2+ subtypes. In addition, our study provided insights into the clinical applications of BCT. However, this retrospective study has introduced several inevitable limitations, and further prospective research is warranted to verify these conclusions.


Guided care for multimorbid older adults.
The purpose of this study was to test the feasibility of a new model of health care designed to improve the quality of life and the efficiency of resource use for older adults with multimorbidity. Guided Care enhances primary care by infusing the operative principles of seven chronic care innovations: disease management, self-management, case management, lifestyle modification, transitional care, caregiver education and support, and geriatric evaluation and management. To practice Guided Care, a registered nurse completes an educational program and uses a customized electronic health record in working with two to five primary care physicians to meet the health care needs of 50 to 60 older patients with multimorbidity. For each patient, the nurse performs a standardized comprehensive home assessment and then collaborates with the physician, the patient, and the caregiver to create two comprehensive, evidence-based management plans: a Care Guide for health care professionals, and an Action Plan for the patient and caregiver. Based in the primary care office, the nurse then regularly monitors the patient's chronic conditions, coaches the patient in self-management, coordinates the efforts of all involved health care professionals, smoothes the patient's transitions between sites of care, provides education and support for family caregivers, and facilitates access to community resources. A 1-year pilot test in a community-based primary care practice suggested that Guided Care is feasible and acceptable to physicians, patients, and caregivers. If successful in a controlled trial, Guided Care could improve the quality of life and efficiency of health care for older adults with multimorbidity.


Patient-provider communication, self-reported medication adherence, and race in a postmyocardial infarction population.
Our objectives were to: 1) describe patient-reported communication with their provider and explore differences in perceptions of racially diverse adherent versus nonadherent patients; and 2) examine whether the association between unanswered questions and patient-reported medication nonadherence varied as a function of patients' race. We conducted a cross-sectional analysis of baseline in-person survey data from a trial designed to improve postmyocardial infarction management of cardiovascular disease risk factors. Overall, 298 patients (74%) reported never leaving their doctor's office with unanswered questions. Among those who were adherent and nonadherent with their medications, 183 (79%) and 115 (67%) patients, respectively, never left their doctor's office with unanswered questions. In multivariable logistic regression, although the simple effects of the interaction term were different for patients of nonminority race (odds ratio [OR]: 2.16; 95% confidence interval [CI]: 1.19-3.92) and those of minority race (OR: 1.19; 95% CI: 0.54-2.66), the overall interaction effect was not statistically significant (P=0.24). The quality of patient-provider communication is critical for cardiovascular disease medication adherence. In this study, however, having unanswered questions did not impact medication adherence differently as a function of patients' race. Nevertheless, there were racial differences in medication adherence that may need to be addressed to ensure optimal adherence and health outcomes. Effort should be made to provide training opportunities for both patients and their providers to ensure strong communication skills and to address potential differences in medication adherence in patients of diverse backgrounds.


Biochemical properties of MutT2 proteins from Mycobacterium tuberculosis and M. smegmatis and their contrasting antimutator roles in Escherichia coli.
Mycobacterium tuberculosis, the causative agent of tuberculosis, is at increased risk of accumulating damaged guanine nucleotides such as 8-oxo-dGTP and 8-oxo-GTP because of its residency in the oxidative environment of the host macrophages. By hydrolyzing the oxidized guanine nucleotides before their incorporation into nucleic acids, MutT proteins play a critical role in allowing organisms to avoid their deleterious effects. Mycobacteria possess several MutT proteins. Here, we purified recombinant M. tuberculosis MutT2 (MtuMutT2) and M. smegmatis MutT2 (MsmMutT2) proteins from M. tuberculosis (a slow grower) and M. smegmatis (fast growing model mycobacteria), respectively, for their biochemical characterization. Distinct from the Escherichia coli MutT, which hydrolyzes 8-oxo-dGTP and 8-oxo-GTP, the mycobacterial proteins hydrolyze not only 8-oxo-dGTP and 8-oxo-GTP but also dCTP and 5-methyl-dCTP. Determination of kinetic parameters (Km and Vmax) revealed that while MtuMutT2 hydrolyzes dCTP nearly four times better than it does 8-oxo-dGTP, MsmMutT2 hydrolyzes them nearly equally. Also, MsmMutT2 is about 14 times more efficient than MtuMutT2 in its catalytic activity of hydrolyzing 8-oxo-dGTP. Consistent with these observations, MsmMutT2 but not MtuMutT2 rescues E. coli for MutT deficiency by decreasing both the mutation frequency and A-to-C mutations (a hallmark of MutT deficiency). We discuss these findings in the context of the physiological significance of MutT proteins.


Effect of aging on microRNAs and regulation of pathogen recognition receptors.
Immunosenescence is the multifactorial age-associated immune deteriorization that leads to increased susceptibility to infections and decreased responses to vaccines. Recent studies have shown a fundamental role for microRNAs (miRNAs) in regulating immune responses, and nearly all the miRNAs involved in immune regulation show modulation during aging. Aging-associated miRNAs are largely negative regulators of the immune innate response and target central nodes of aging-associated networks, in particular, NF-κB, the downstream effector of TLR signals that leads to induction of proinflammatory responses. Multiple miRNAs have been reported to share similar regulatory activity. Here we review miRNA regulation of human innate immune recognition in aging, including both activation and resolution of inflammation, critical issues in detection, and areas of active investigation into our understanding of immunosenescence.


Water Production Activity of Nine Long-Period Comets from SOHO/SWAN Observations of Hydrogen Lyman-alpha: 2013-2016.
Nine recently discovered long-period comets were observed by the Solar Wind Anisotropies (SWAN) Lyman-alpha all-sky camera on board the Solar and Heliosphere Observatory (SOHO) satellite during the period of 2013 to 2016. These were C/2012 K1 (PanSTARRS), C/2013 US10 (Catalina), C/2013 V5 (Oukaimeden), C/2013 R1 (Lovejoy), C/2014 E2 (Jacques), C/2014 Q2 (Lovejoy), C/2015 G2 (MASTER), C/2014 Q1 (PanSTARRS) and C/2013 X1 (PanSTARRS). Of these 9 comets 6 were long-period comets and 3 were possibly dynamically new. Water production rates were calculated from each of the 885 images using our standard time-resolved model that accounts for the whole water photodissociation chain, exothermic velocities and collisional escape of H atoms. For most of these comets there were enough observations over a broad enough range of heliocentric distances to calculate power-law fits to the variation of production rate with heliocentric distances for pre- and post-perihelion portions of the orbits. Comet C/2014 Q1 (PanSTARRS), with a perihelion distance of only ~0.3 AU, showed the most unusual variation of water production rate with heliocentric distance and the resulting active area variation, indicating that when the comet was within 0.7 AU its activity was dominated by the continuous release of icy grains and chunks, greatly increasing the active sublimation area by more than a factor of 10 beyond what it had at larger heliocentric distances. A possible interpretation suggests that a large fraction of the comet's mass was lost during the apparition.


Clinical practice in the management of ulcerative colitis--an Italian survey.
To investigate the concordance of medical care of ulcerative colitis (UC) patients in Italy. Interviews with responsible physicians in referral centres for inflammatory bowel disease (IBD) regarding the management (e.g. time to referral, time to diagnosis, disease activity at the first visit and after 1 year, treatment algorithm, treatment goals, follow up, etc) of patients with UC. The obtained data showed a correct diagnostic approach, once the patient reached the referral centre, and similar figures for disease activity as reported in studies on epidemiology or on the natural history of UC. Treatment goals for the acute phase of disease and for maintenance therapy were mainly clinically oriented and include only in a minority parameters like quality of life or the regulation of the immune response. The treatment algorithms were consistent with the established guidelines for the treatment of UC. Major disparity was found for the endoscopic control of treatment success.


Ion Concentration-Dependent Surface Charge Density Inside a Nanopore.
Surface charges shape the electrical double layer (EDL) structure at solid-liquid interfaces, critically influencing the performance of energy storage and micro/nanofluidic devices. However, accurately measuring surface charge density in nanoconfined spaces continues to be a challenge. Here, we introduce a methodology via solid-state nanopores that can investigate the dependence of surface charge density on salt concentrations and nanopore diameters. Measurements, complemented by a theoretical model, reveal that the surface charge density decreases as both the salt concentration in bulk solutions and the nanopore sizes are reduced. Notably, when the salt concentration in the bulk solution drops below 10-3 M, protons dominate ion conductance in a nanopore, resulting in a constant surface charge density. This study introduces an effective approach to surface charge characterization and may serve in the design of electrokinetically driven nanofluidic systems.


MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18.
Signaling through the adaptor protein myeloid differentiation factor 88 (MyD88) promotes carcinogenesis in several cancer models. In contrast, MyD88 signaling has a protective role in the development of azoxymethane (AOM)/dextran sodium sulfate (DSS) colitis-associated cancer (CAC). The inability of Myd88(-/-) mice to heal ulcers generated upon injury creates an altered inflammatory environment that induces early alterations in expression of genes encoding proinflammatory factors, as well as pathways regulating cell proliferation, apoptosis, and DNA repair, resulting in a dramatic increase in adenoma formation and progression to infiltrating adenocarcinomas with frequent clonal mutations in the beta-catenin gene. Others have reported that toll-like receptor (Tlr) 4-deficient mice have a similar susceptibility to colitis to Myd88-deficient mice but, unlike the latter, are resistant to CAC. We have observed that mice deficient for Tlr2 or Il1r do not show a differential susceptibility to colitis or CAC. However, upon AOM/DSS treatment Il18(-/-) and Il18r1(-/-) mice were more susceptible to colitis and polyp formation than wild-type mice, suggesting that the phenotype of Myd88(-/-) mice is, in part, a result of their inability to signal through the IL-18 receptor. This study revealed a previously unknown level of complexity surrounding MyD88 activities downstream of different receptors that impact tissue homeostasis and carcinogenesis.


Does constant photoperiod inhibit the onset of the reproductive cycle in northern pike (Esox lucius) males?
For most temperate and arctic fish species, photoperiod is the key abiotic factor determining the onset of the reproductive cycle, and, for many species, constant long photoperiod seems to have an inhibitory effect. Yet, there is no knowledge about the effect of photoperiod on the onset of the reproductive cycle in northern pike males. The aim of this work was to investigate the potential inhibitory effect of constant long photoperiod on pike males. Batches of fish were reared in triplicate under natural simulated photoperiod (NSP) or constant long photoperiod (CP; 16L:8D) from 14 October 2013 to 14 March 2014. Fish were sampled three times (at the beginning of the photoperiod decrease, at the beginning of the temperature decrease and at the end of the temperature decrease). Morphological parameters, sexual steroid levels and spermatogenetic stages were investigated. Our results showed that CP partially inhibited gonadal development (gonado-somatic index or GSI, %; 2.5% under NSP and 1.2% under CP at day 152), spermatic development (96.2% of spermatozoa under NSP and 69.3% under CP at day 152) and the plasmatic levels of testosterone (7.20 ng/mL under NSP and 2.37 ng/mL under CP at day 152). In conclusion, photoperiod may be one of the determinant factors that control the onset of the reproductive cycle in pike males, but temperature and endogenous rhythms also need to be investigated.


Epidemiology of Type 3 Poliovirus AFP Cases in Israel between 1973 and 1988: Whole Genome Sequencing of RNA Extracted Directly from Archived Stocks to Avoid Re-Culturing Neurovirulent Wild Poliovirus.
Poliovirus post-eradication containment of wild-type 2 poliovirus (PV2) requires the destruction of all materials containing, or potentially containing, PV2. Acute flaccid paralysis (AFP) cases in Israel between 1973 and 1988 were caused by all three serotypes; thus, isolates from cases and case-contacts were either PV2 or potentially contaminated with PV2. To provide a proof-of-concept that whole genome sequences (WGS) of wild-type 3 poliovirus (PV3s) could be salvaged from the RNA extracted directly from archived poliovirus stocks avoiding re-amplification of neurovirulent viruses, we link WGSs to case histories and determine the phylogenetic relationships among the PV3s. Data retrieved from 427 poliovirus-positive cases reported between 1973 and 1988 identified 85 PV3-associated cases. A total of 71 archived PV3 isolates were available from PV3-positive cases and contacts. WGSs were obtained by NGS from cDNA libraries constructed from RNA extracted directly from archived viral stocks. Sequences were subjected to phylogenetic analysis and linked to case data. WGSs were successfully constructed for 55 isolates. Phylogenetic analysis revealed the circulation of seven lineages of PV3. One lineage, with 23 isolates, presented as an outbreak of six-year duration. Isolates from six other lineages were consistent with subsequent separate introductions, sporadic cases, and limited transmission. Recombinant vaccine-like PV3 recombinants were isolated from some cases. Whole or near-whole genome sequence information, obtained from RNA extracted directly from the archived material, safely provided detailed genetic information linked to patient data from a time when limited sequence information was previously available and revealed the pattern of transmission of wild PV3 in Israel.


Rates of Positive Findings on Positron Emission Tomography and Bone Marrow Biopsy in Patients With Ocular Adnexal Lymphoma.
The aim of this study was to determine rates of positive findings on positron emission tomography (PET) and bone marrow biopsy performed during staging workup for ocular adnexal lymphoma (OAL). A retrospective review of OAL patients was conducted. Demographics, primary versus secondary OAL, histologic subtype, and findings on PET and bone marrow biopsy performed as part of the initial staging workup for OAL were recorded. The study included 119 patients with OAL. There were 85 primary and 34 secondary OALs. The main histologic subtypes of lymphoma were mucosa-associated lymphoid tissue (n = 61), follicular (n = 26), diffuse large B-cell (n = 17), and mantle cell (n = 10). Positive PET findings were seen in 42 of 68 patients (62%) with primary OAL and 19 of 24 (79%) with secondary OAL. Positive PET findings were seen in 24 of 47 patients (51%) with mucosa-associated lymphoid tissue, 13 of 17 (76%) with follicular, 14 of 15 (93%) with diffuse large B-cell, and 9 of 10 (90%) with mantle cell lymphoma. Positive findings on bone marrow biopsy were seen in 7 of 59 patients (12%) with mucosa-associated lymphoid tissue, 4 of 23 (17%) with follicular, 1 of 17 (6%) with diffuse large B-cell, and 2 of 9 (22%) with mantle cell lymphoma. Our findings suggest that a significant proportion of patients with primary and secondary OAL have positive findings on PET and bone marrow biopsy at initial diagnosis, suggesting a reasonable yield for these tests as part of the initial staging workup in patients with a new diagnosis of OAL.


Oligomerization of G protein-coupled receptors: computational methods.
Recent research has unveiled the complexity of mechanisms involved in G protein-coupled receptor (GPCR) functioning in which receptor dimerization/oligomerization may play an important role. Although the first high-resolution X-ray structure for a likely functional chemokine receptor dimer has been deposited in the Protein Data Bank, the interactions and mechanisms of dimer formation are not yet fully understood. In this respect, computational methods play a key role for predicting accurate GPCR complexes. This review outlines computational approaches focusing on sequence- and structure-based methodologies as well as discusses their advantages and limitations. Sequence-based approaches that search for possible protein-protein interfaces in GPCR complexes have been applied with success in several studies, but did not yield always consistent results. Structure-based methodologies are a potent complement to sequence-based approaches. For instance, protein-protein docking is a valuable method especially when guided by experimental constraints. Some disadvantages like limited receptor flexibility and non-consideration of the membrane environment have to be taken into account. Molecular dynamics simulation can overcome these drawbacks giving a detailed description of conformational changes in a native-like membrane. Successful prediction of GPCR complexes using computational approaches combined with experimental efforts may help to understand the role of dimeric/oligomeric GPCR complexes for fine-tuning receptor signaling. Moreover, since such GPCR complexes have attracted interest as potential drug target for diverse diseases, unveiling molecular determinants of dimerization/oligomerization can provide important implications for drug discovery.


Contemporary Diagnostic Imaging of Oral Squamous Cell Carcinoma - A Review of Literature.
Oral squamous cell carcinoma (OSCC) is the most common cancer of the oral cavity and constitutes 95% of all cancers of this area. Men are affected twice as commonly as women, primarily if they are over 50 years of age. Forty percent of the lesions are localized in the tongue and 30% in the floor of the oral cavity. OSCC often affects upper and lower gingiva, buccal mucous membrane, the retromolar triangle and the palate. The prognosis is poor and the five-year survival rate ranges from 20% (OSCC in the floor of the mouth) to 60% (OSCC in the alveolar part of the mandible). Treatment is difficult, because of the localization and the invasiveness of the available methods. The diagnosis is made based on a histopathological examination of a biopsy sample. The low detection rate of early oral SCC is a considerable clinical issue. Although the oral cavity can be easily examined, in the majority of cases oral SCC is diagnosed in its late stages. It is difficult to diagnose metastases in local lymph nodes and distant organs, which is important for planning the scope of resection and further treatment, graft implantation, and differentiation between reactive and metastatic lymph nodes as well as between disease recurrence and scars or adverse reactions after surgery or radiation therapy. Imaging studies are performed as part of the routine work-up in oral SCC. However, it is difficult to interpret the results at the early stages of the disease. The following imaging methods are used - dental radiographs, panoramic radiographs, magnetic resonance imaging with diffusion-weighted and dynamic sequences, perfusion computed tomography, cone beam computed tomography, single-photon emission computed tomography, hybrid methods (PET/CT, PET/MRI, SPECT/CT) and ultrasound. Some important clinical problems can be resolved with the use of novel modalities such as MRI with ADC sequences and PET. The aim of this article is to describe oral squamous cell carcinoma as it appears in different imaging methods considering both their advantages and limitations.


The SaeR/S gene regulatory system induces a pro-inflammatory cytokine response during Staphylococcus aureus infection.
Community-associated methicillin-resistant Staphylococcus aureus accounts for a large portion of the increased staphylococcal disease incidence and can cause illness ranging from mild skin infections to rapidly fatal sepsis syndromes. Currently, we have limited understanding of S. aureus-derived mechanisms contributing to bacterial pathogenesis and host inflammation during staphylococcal disease. Herein, we characterize an influential role for the saeR/S two-component gene regulatory system in mediating cytokine induction using mouse models of S. aureus pathogenesis. Invasive S. aureus infection induced the production of localized and systemic pro-inflammatory cytokines, including tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interleukin (IL)-6 and IL-2. In contrast, mice infected with an isogenic saeR/S deletion mutant demonstrated significantly reduced pro-inflammatory cytokine levels. Additionally, secreted factors influenced by saeR/S elicited pro-inflammatory cytokines in human blood ex vivo. Our study further demonstrated robust saeR/S-mediated IFN-γ production during both invasive and subcutaneous skin infections. Results also indicated a critical role for saeR/S in promoting bacterial survival and enhancing host mortality during S. aureus peritonitis. Taken together, this study provides insight into specific mechanisms used by S. aureus during staphylococcal disease and characterizes a relationship between a bacterial global regulator of virulence and the production of pro-inflammatory mediators.


Metabolism of designer drugs of abuse: an updated review.
This paper reviews the metabolism of new designer drugs of abuse that have emerged on the black market during the last years and is an update of a review published in 2005. The presented review contains data concerning the so-called 2C compounds (phenethylamine type) such as 4-bromo-2,5-dimethoxy-beta-phenethylamine (2C-B), 4-iodo-2,5-dimethoxy-beta-phenethylamine (2C-I), 2,5-dimethoxy-4-methyl-beta-phenethylamine (2C-D), 4-ethyl-2,5-dimethoxy-beta-phenethylamine (2C-E), 4-ethylthio-2,5-dimethoxy-beta-phenethylamine (2C-T-2), and 2,5-dimethoxy-4-propylthio-beta-phenethylamine (2C-T-7), beta-keto designer drugs such as 2-methylamino-1-(3,4-methylenedioxyphenyl)butan-1-one (butylone, bk-MBDB), 2-ethylamino-1-(3,4-methylenedioxyphenyl)propan-1-one (ethylone, bk-MDEA), 2-methylamino-1-(3,4-methylene notdioxy notphenyl)propan-1-one (methylone, bk-MDMA), and 2-methylamino-1-p-tolylpropane-1-one (mephedrone, 4-methyl-methcathinone), pyrrolidino notphenones such as 4-methyl-pyrrolidinobutyrophenone (MPBP) and alpha-pyrrolidinovalerophenone (PVP), phencyclidine-derived drugs such as N (1 phenylcyclohexyl) propanamine (PCPr), N-(1-phenylcyclohexyl)-2-ethoxyethanamine (PCEEA), N-(1-phenylcyclohexyl)-3-methoxypropanamine (PCMPA), and N-(1-phenylcyclohexyl)-2-methoxyethanamine (PCMEA), tryptamines such as 5-methoxy-N,N-diisopropyl nottryptamine (5-MeO-DIPT), and finally alpha-methylfentanyl (alpha-MF) and 3-methylfentanyl (3-MF). Papers have been considered and reviewed on the identification of in vivo or in vitro human or animal metabolites and the cytochrome P450 or monoamineoxidase isoenzyme-dependent metabolism.


The nuclear lamina and its functions in the nucleus.
The nuclear lamina is a structure near the inner nuclear membrane and the peripheral chromatin. It is composed of lamins, which are also present in the nuclear interior, and lamin-associated proteins. The increasing number of proteins that interact with lamins and the compound interactions between these proteins and chromatin-associated proteins make the nuclear lamina a highly complex but also a very exciting structure. The nuclear lamina is an essential component of metazoan cells. It is involved in most nuclear activities including DNA replication, RNA transcription, nuclear and chromatin organization, cell cycle regulation, cell development and differentiation, nuclear migration, and apoptosis. Specific mutations in nuclear lamina genes cause a wide range of heritable human diseases. These diseases include Emery-Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy (DCM) with conduction system disease, familial partial lipodystrophy (FPLD), autosomal recessive axonal neuropathy (Charcot-Marie-Tooth disorder type 2, CMT2), mandibuloacral dysplasia (MAD), Hutchison Gilford Progeria syndrome (HGS), Greenberg Skeletal Dysplasia, and Pelger-Huet anomaly (PHA). Genetic analyses in Caenorhabditis elegans, Drosophila, and mice show new insights into the functions of the nuclear lamina, and recent structural analyses have begun to unravel the molecular structure and assembly of lamins and their associated proteins.


Home delivery of medication during Coronavirus disease 2019, Cape Town, South Africa: Short report.
The public sector primary care facilities in Cape Town serve a large number of patients with chronic diseases such as human immunodeficiency virus, tuberculosis, diabetes, hypertension, asthma and chronic obstructive pulmonary disease. Prior to the Coronavirus disease 2019 (COVID-19) epidemic, stable patients with chronic conditions attended the facility or support groups to obtain their medication. During the COVID-19 epidemic, these patients would be put at risk if they had to travel and gather in groups to receive medication. The Metropolitan Health Services, therefore, decided to offer home delivery of medication. A system of home delivery was rapidly established by linking the existing chronic dispensing unit system with the emerging approach to community-orientated primary care in the Metro. Medication was delivered as usual to primary care pharmacies, but then a variety of means were used to disseminate the parcels to local non-profit organisations, where they could be delivered by a city-wide network of community health workers (CHWs). Innovations included various ways of delivering the parcels, including via Uber, bicycles and electric scooters, as well as Google forms to monitor the success of the initiative. It was estimated that up to 200 000 parcels per month could be delivered in this way via 2500 CHWs. The new system was established throughout the Metropole, and its strengths, weaknesses, opportunities and threats are further discussed. The initiative may prevent COVID-19 amongst people with comorbidities who would be at risk of more severe diseases. It may also have de-congested primary care facilities ahead of the expected surge in COVID-19 cases.


Some insights into X chromosome inactivation from studies of human cells.
The inactivation of all but one X chromosome in the somatic cells of mammalian females in an important mechanism for regulating X chromosomal genes. Although the molecular basis for the single active X remains to be elucidated, recent studies have provided some insights. Inactivation occurs about the time of implantation, at least in mouse embryos. On the other hand, germ cells from human embryos have two active X chromosomes and may never be subjected to inactivation. As a consequence of X inactivation, one X chromosome becomes the sole determinant of X specified characteristics of the cell, resulting in cellular mosaicism. Transfer of gene products between cells occurs via gap junctions and by pinocytosis so that in heterozygotes carrying X linked mutations, the mutant phenotype may be masked by the presence of cells or normal type. There is considerable evidence that inactivation in the embryo is random with respect to parental origin of the X chromosome, but that selection occurs subsequently, and may lead to elimination of a whole population of cells in the female. Although there is evidence for preferential inactivation of the paternal X in extra-embryonic membranes of rodents, studies in human embryos have not been confirmatory. Analysis of clonal populations from heterozygotes for X chromosome mutations have been used to determine whether a whole X chromosome is inactive or only parts thereof. Individuals with multiple X chromosomes often manifest somatic abnormalities as well as gonadal ones. There is recent evidence that some loci on the short arm may escape inactivation. X inactivation in diploid human cells has been shown to be a very stable process. The silent X, once inactivated, maintains inactivity despite attempts to turn it on. Our recent studies of enzyme activity in cells from a human triploid abortus (69, XXY) with two active chromosomes indicates that the "active chromosomes" are also stably maintained. The presence of two active chromosomes in triploid cells implicates the autosomes in the regulation of X chromosome activity.


Dynamic Control over the Optical Transmission of Nanoscale Dielectric Metasurface by Alkali Vapors.
In recent years, dielectric and metallic nanoscale metasurfaces are attracting growing attention and are being used for variety of applications. Resulting from the ability to introduce abrupt changes in optical properties at nanoscale dimensions, metasurfaces enable unprecedented control over light's different degrees of freedom, in an essentially two-dimensional configuration. Yet, the dynamic control over metasurface properties still remains one of the ultimate goals of this field. Here, we demonstrate the optical resonant interaction between a form birefringent dielectric metasurface made of silicon and alkali atomic vapor to control and effectively tune the optical transmission pattern initially generated by the nanoscale dielectric metasurface. By doing so, we present a controllable metasurface system, the output of which may be altered by applying magnetic fields, changing input polarization, or shifting the optical frequency. Furthermore, we also demonstrate the nonlinear behavior of our system taking advantage of the saturation effect of atomic transition. The demonstrated approach paves the way for using metasurfaces in applications where dynamic tunability of the metasurface is in need, for example, for scanning systems, tunable focusing, real time displays, and more.


Heavy metals, hematology, plasma chemistry, and parasites in adult hellbenders (Cryptobranchus alleganiensis).
Ozark (Cryptobranchus alleganiensis bishopi) and eastern hellbenders (C. a. alleganiensis) from seven rivers in Missouri, USA, were collected to investigate essential information on hematology, parasites, and plasma chemistry and levels of select heavy metals (Hg, Pb, Cd, Cr, and Co) in the animals' blood. The body masses of Ozark hellbenders were much smaller than those of eastern hellbenders. Blood parasites were detected in Ozark hellbenders, but not eastern hellbenders. The higher frequency in occurrence of eosinophils in Ozark hellbenders (8.8-16.8%) than in eastern hellbenders (highest at 6.6%) might result from the infection of parasites. Seven of the 18 hematology and plasma parameters (hematocrit, basophils, eosinophils, K, P, Ca, and chloride) showed significant differences between subspecies. The blood levels of heavy metals Co, Hg, and Pb differed significantly between subspecies. Ozark hellbenders had higher blood levels of Co (p<0.001), while blood levels of Hg and Pb were higher in eastern hellbenders. The levels of chromium (Cr) and cadmium (Cd) were not different between subspecies and among rivers. The eastern hellbenders at Niangua River and the Ozark hellbenders at the North Fork of the White River had lower Hg levels compared to eastern and Ozark hellbenders at other sites. All together, our findings provide important baseline information for managing this endangered species.


QseA directly activates transcription of LEE1 in enterohemorrhagic Escherichia coli.
Quorum sensing (QS) in enterohemorrhagic Escherichia coli (EHEC) regulates the expression of the locus of enterocyte effacement (LEE). The LEE contains five major operons named LEE1 through LEE5. QseA was previously shown to be activated through QS and to activate the transcription of LEE1. The LEE1 operon encodes Ler, the transcription activator of all other LEE genes, and has two promoters: a distal promoter (P1) and a proximal promoter (P2). We have previously reported that QseA acts on P1 and not P2. To identify the minimal region of LEE1 that is necessary for QseA-mediated activation, a series of nested-deletion constructs of the LEE1 promoter fused to a lacZ reporter were constructed in both the EHEC and E. coli K-12 backgrounds. In an EHEC background, QseA-dependent activation of LEE1 can be observed for the entire regulatory region (beginning at nucleotide -393 and ending at nucleotide -123). In contrast to what occurred in EHEC, in K-12 there was no QseA-dependent activation of LEE1 transcription between base pairs -393 and -343. These data indicate that a QseA-dependent EHEC-specific regulator is required for the activation of transcription in this region. We also observed QseA-dependent LEE1 activation from nucleotides -218 to -123 in K-12, similar to results of the nested-deletion analysis performed with EHEC. Electrophoretic mobility shift assays established that QseA directly binds to the region of LEE1 from bp -173 to -42 and not to the region from bp -393 to -343. These studies suggest that QseA activates the transcription of LEE1 by directly binding upstream of its P1 promoter region.


Patients admitted to hospital with chest pain--changes in a 20-year perspective.
To describe the differences in characteristics and outcome between two consecutive series of patients admitted to hospital with chest pain in a 20-year perspective. Particular emphasis is placed on changes in outcome in relation to the initial electrocardiogram (ECG). In the two periods, 1986-1987 and 2008, all patients with chest pain admitted to the study hospitals in Gothenburg, Sweden, were included. Five thousand and sixteen patients were registered in a period of 21 months in 1986-1987 and 2287 patients were registered during 3 months in 2008. In a comparison of the two time periods, the age of chest pain patients was not significantly different (mean age 60.1 ± 17.8 years in 1986-1987 and 59.8 ± 19.1 years in 2008, p=0.50). There was a lower prevalence of previous angina pectoris, congestive heart failure and current smoking in the second period, whereas a history of acute myocardial infarction, hypertension and diabetes mellitus had become more prevalent. The use of cardio-protective drugs increased and ECG changes indicating acute myocardial ischemia on admission to hospital decreased. Length of hospitalisation was reduced from a median of 5 days to 3 days (p<0.0001). A significant decrease in 30-day and 1-year mortality was found (3.8% in 1986-1987 vs 2.0% in 2008 and 9.9% vs 6.3% respectively, p<0.0001 for both comparisons). During a period of 20 years, the characteristics and outcome of patients admitted to hospital with chest pain changed. The most important changes were a lower prevalence of ECG signs indicating acute myocardial ischemia on admission, shorter hospitalisation time and a lower 30-day and 1-year mortality.


INVOLVEMENT OF MULTIPLE MOLECULAR PATHWAYS IN THE GENETICS OF OCULAR REFRACTION AND MYOPIA.
The prevalence of myopia has increased dramatically worldwide within the last three decades. Recent studies have shown that refractive development is influenced by environmental, behavioral, and inherited factors. This review aims to analyze recent progress in the genetics of refractive error and myopia. A comprehensive literature search of PubMed and OMIM was conducted to identify relevant articles in the genetics of refractive error. Genome-wide association and sequencing studies have increased our understanding of the genetics involved in refractive error. These studies have identified interesting candidate genes. All genetic loci discovered to date indicate that refractive development is a heterogeneous process mediated by a number of overlapping biological processes. The exact mechanisms by which these biological networks regulate eye growth are poorly understood. Although several individual genes and/or molecular pathways have been investigated in animal models, a systematic network-based approach in modeling human refractive development is necessary to understand the complex interplay between genes and environment in refractive error. New biomedical technologies and better-designed studies will continue to refine our understanding of the genetics and molecular pathways of refractive error, and may lead to preventative and therapeutic measures to combat the myopia epidemic.


Differential stability of antigenic MHC class I-restricted synthetic peptides.
Various synthetic peptides recognized as Ag by CTL in the context of MHC class I molecules were tested for stability in vitro and in vivo. Peptide inactivation in vitro was quantitated by titrating the amount of peptide required to sensitize target cells for lysis by specific CTL clones. The degree of inactivation after overnight incubation at 37 degrees C varied widely among a series of antigenic peptides. Some were nearly unaffected, whereas others lost activity by more than 100-fold or even 10,000-fold. However, no correlation was found between susceptibility to serum inactivation and antigenic potency as measured in short term cytolytic assays. No inactivation occurred at 4 degrees C, or at 37 degrees C in the absence of serum, under the conditions used. Serum inactivation most likely involved proteolysis because it could be inhibited by protease inhibitors. Moreover, presumed cleavage products of a radiolabeled susceptible peptide could be visualized by TLC. In vivo, the persistence of the antigenic activity of the injected peptides, either in extracellular fluids or on tumor target cells growing in an ascites form, correlated with the degree of stability found for the peptides in vitro. The differential stability of synthetic peptides may have important consequences for attempts to manipulate the development of an immune response in vivo.


How should we manage heart failure developing in patients already treated with angiotensin-converting enzyme inhibitors and beta-blockers for hypertension, diabetes or coronary disease?
An increasing number of patients in the community are being treated with angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and beta-blockers for hypertension, coronary disease or diabetic renal and vascular complications. Some of these patients will develop heart failure despite such treatment. Based on data from hypertension trials it can be estimated that approximately 5% of treated patients will develop heart failure over 5 years. It is unclear whether patients developing heart failure on and off ACE-inhibitors or beta-blockers, respectively, at the time of heart failure diagnosis have similar prognosis.Treatment options for patients developing heart failure while already treated with ACE inhibitors/ARBs and beta-blockers are very limited if current heart failure guidelines are followed. In this review possible strategies are outlined and important areas for research are identified. It is suggested that trials are designed specifically to address prognosis and treatment in this growing population.


Dipyridamole-atropine stress echocardiography versus exercise SPECT scintigraphy for detection of coronary artery disease in hypertensives with positive exercise test.
Many different stress echocardiographic and radionuclide perfusion imaging tests have been proposed for detecting epicardial coronary artery disease (CAD) in hypertensive patients. Their relative diagnostic and prognostic value has not been exactly established. A positive exercise electrocardiography test has a low diagnostic specificity in hypertensive patients and warrants for a complementary imaging test to confirm the diagnosis of coronary artery disease. Hypertensive patients (n = 53), (29 males, aged 58 +/- 10 years) with normal left ventricular function detected by echocardiography and previous positive exercise test ( > or = 0.15 mV of ST segment depression on 12 lead electrocardiogram) underwent dipyridamole-atropine stress echocardiography (DASE) and thallium-201 stress/ rest myocardial single-photon emission computed tomography (SPECT). All patients had coronary angiography within 15 days and independently of imaging test results. Coronary angiogram showed significant ( > or = 50% qualitatively assessed diameter reduction) epicardial coronary artery disease in 23 (43%) patients. Sensitivity for detection of coronary artery disease was significantly higher for scintigraphy (DASE = 78% versus SPECT = 100%, P < 0.05) while specificity was higher for echo (DASE = 100% versus SPECT = 47%, P < 0.00001). Diagnostic accuracy was also higher for echo (DASE = 91% versus SPECT = 70%, P < 0.01). In patients with exercise-nduced ST segment depression, dipyridamole stress echo and SPECT perfusion scintigraphy are both good diagnostic options, with DASE characterized by higher specificity, lower sensitivity, and at least comparable diagnostic accuracy than SPECT.


Prevention of depression and sleep disturbances in elderly with memory-problems by activation of the biological clock with light--a randomized clinical trial.
Depression frequently occurs in the elderly and in patients suffering from dementia. Its cause is largely unknown, but several studies point to a possible contribution of circadian rhythm disturbances. Post-mortem studies on aging, dementia and depression show impaired functioning of the suprachiasmatic nucleus (SCN) which is thought to be involved in the increased prevalence of day-night rhythm perturbations in these conditions. Bright light enhances neuronal activity in the SCN. Bright light therapy has beneficial effects on rhythms and mood in institutionalized moderate to advanced demented elderly. In spite of the fact that this is a potentially safe and inexpensive treatment option, no previous clinical trial evaluated the use of long-term daily light therapy to prevent worsening of sleep-wake rhythms and depressive symptoms in early to moderately demented home-dwelling elderly. This study investigates whether long-term daily bright light prevents worsening of sleep-wake rhythms and depressive symptoms in elderly people with memory complaints. Patients with early Alzheimer's Disease (AD), Mild Cognitive Impairment (MCI) and Subjective Memory Complaints (SMC), between the ages of 50 and 75, are included in a randomized double-blind placebo-controlled trial. For the duration of two years, patients are exposed to approximately 10,000 lux in the active condition or approximately 300 lux in the placebo condition, daily, for two half-hour sessions at fixed times in the morning and evening. Neuropsychological, behavioral, physiological and endocrine measures are assessed at baseline and follow-up every five to six months. If bright light therapy attenuates the worsening of sleep-wake rhythms and depressive symptoms, it will provide a measure that is easy to implement in the homes of elderly people with memory complaints, to complement treatments with cholinesterase inhibitors, sleep medication or anti-depressants or as a stand-alone treatment. ISRCTN29863753.


Searching for a technology-driven acute rheumatic fever test: the START study protocol.
The absence of a diagnostic test for acute rheumatic fever (ARF) is a major impediment in managing this serious childhood condition. ARF is an autoimmune condition triggered by infection with group A Streptococcus. It is the precursor to rheumatic heart disease (RHD), a leading cause of health inequity and premature mortality for Indigenous peoples of Australia, New Zealand and internationally. METHODS AND ANALYSIS: 'Searching for a Technology-Driven Acute Rheumatic Fever Test' (START) is a biomarker discovery study that aims to detect and test a biomarker signature that distinguishes ARF cases from non-ARF, and use systems biology and serology to better understand ARF pathogenesis. Eligible participants with ARF diagnosed by an expert clinical panel according to the 2015 Revised Jones Criteria, aged 5-30 years, will be recruited from three hospitals in Australia and New Zealand. Age, sex and ethnicity-matched individuals who are healthy or have non-ARF acute diagnoses or RHD, will be recruited as controls. In the discovery cohort, blood samples collected at baseline, and during convalescence in a subset, will be interrogated by comprehensive profiling to generate possible diagnostic biomarker signatures. A biomarker validation cohort will subsequently be used to test promising combinations of biomarkers. By defining the first biomarker signatures able to discriminate between ARF and other clinical conditions, the START study has the potential to transform the approach to ARF diagnosis and RHD prevention. The study has approval from the Northern Territory Department of Health and Menzies School of Health Research ethics committee and the New Zealand Health and Disability Ethics Committee. It will be conducted according to ethical standards for research involving Indigenous Australians and New Zealand Māori and Pacific Peoples. Indigenous investigators and governance groups will provide oversight of study processes and advise on cultural matters.


Iodoform gauze removes necrotic tissue from pressure ulcer wounds by fibrinolytic activity.
Iodoform gauze is used in clinical practice for treatment of infected wounds. However, effectiveness and action mechanism of iodoform gauze for removal of necrotic tissue are unknown. We therefore employed case control and biochemical studies in order to clarify the pharmacological activity of iodoform gauze. A clinical study demonstrated that treatment with iodoform gauze removed necrotic tissue more effectively than treatment with conventional ointments. More than 60% of iodoform gauze-treated wounds were completely debrided within 2 weeks. Consistent with the clinical observation, biochemical analyses revealed clear differences in wound fluid proteins after treatment with iodoform gauze or conventional gauze. The amount of macroaggregates of type I collagen from wounds were remarkably decreased in iodoform gauze. Moreover, iodoform gauze and iodoform itself released non-aggregative type I collagen from necrotic debris in vitro. Taken together, we conclude that iodoform gauze efficiently removes necrotic tissue by its lytic activity for collagen fibers.


Improving Contrast and Detectability: Imaging with [55Co]Co-DOTATATE in Comparison with [64Cu]Cu-DOTATATE and [68Ga]Ga-DOTATATE.
PET imaging at late time points after injection may allow tracer clearance from normal tissue and hence improve image contrast and detectability. 55Co is a promising isotope with high positron yield and a long half-life suitable for imaging at delayed time points. Here, we compared the 3 radioconjugates [68Ga]Ga-DOTATATE, [64Cu]Cu-DOTATATE, and [55Co]Co-DOTATATE by PET/CT imaging in NOD-SCID mice bearing subcutaneous somatostatin receptor-expressing AR42J tumors. Methods:55Co and 64Cu were produced by the 54Fe(d,n)55Co and 64Ni(p,n)64Cu nuclear reactions, whereas 68Ga was obtained from a 68Ge/68Ga generator. 55Co and 64Cu were labeled with DOTATATE by heating in a sodium acetate buffer and 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid buffer, respectively. AR42J tumor-bearing mice were dynamically scanned 0-1 h after injection. For 64Cu and 55Co, additional imaging was also performed at late time points after 4 and 24 h. Dose calculations were based on a known biodistribution. The cumulated disintegrations in each organ were calculated by integration of a fitted exponential function to the biodistribution of each respective organ. Equivalent doses were calculated by OLINDA/EXM using the MIRD formalism. Results: Tumor uptake was rapid from 0 to 1 h after injection for all 3 radioconjugates. Normal-tissue ratios as represented by tumor-to-liver, tumor-to-kidney, and tumor-to-muscle ratios increased significantly over time, with [55Co]Co-DOTATATE reaching the highest ratio of all radioconjugates. For [55Co]Co-DOTATATE, the tumor-to-liver ratio increased to 65 ± 16 at 4 h and 50 ± 6 at 24 h, which were 15 (P < 0.001) and 30 (P < 0.001) times higher, respectively, than the corresponding ratios for [64Cu]Cu-DOTATATE and 5 (P < 0.001) times higher than that of [68Ga]Ga-DOTATATE at 1 h. Correspondingly, tumor-to-kidney and tumor-to-muscle ratios for [55Co]Co-DOTATATE were 4 (P < 0.001) and 11 (P < 0.001) times higher than that of [64Cu]Cu-DOTATATE at 24 h. An equivalent dose was calculated as 9.6E-02 mSv/MBq for [55Co]Co-DOTATATE. Conclusion: [55Co]Co-DOTATATE demonstrated superior image contrast compared with [64Cu]Cu-DOTATATE and [68Ga]Ga-DOTATATE for PET imaging of somatostatin receptor-expressing tumors, warranting translation into clinical trials. Dosimetry calculations found that effective doses for [55Co]Co-DOTATATE were comparable to those for both [64Cu]Cu-DOTATATE and [68Ga]Ga-DOTATATE.


Impaired heteronymous somatosensory motor cortical inhibition in dystonia.
A typical pathophysiological abnormality in dystonia is cocontraction of antagonist muscles, with impaired reciprocal inhibitory mechanisms in the spinal cord. Recent experimental data have shown that inhibitory interactions between antagonist muscles have also a parallel control at the level of the sensorimotor cortex. The aim of this work was to study heteronymous effects of a median nerve stimulus on the corticospinal projections to forearm muscles in dystonia. We used the technique of antagonist cortical inhibition, which assesses the conditioning effect of median nerve afferent input on motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) in ipsilateral forearm extensor muscles at rest. Nine healthy subjects and 10 patients with torsion dystonia participated in the study. MEPs and somatosensory evoked potentials were normal in patients. In healthy subjects, median nerve stimulation at 15- to 18-msec intervals inhibited the test MEPs in forearm extensors. In dystonic patients, median nerve stimulation delivered at the same conditioning-test intervals elicited significantly less inhibition of the test MEP. On the whole, these data suggest an impaired sensory-motor integration in dystonia and, more specifically, the decreased antagonistic cortical inhibition could suggest that functional interactions between antagonist muscles are primarily impaired at the cortical level.


US Preventive Services Task Force. Screening for breast cancer with breast self-examination. A critical review.
We reviewed evidence regarding breast self-examination (BSE) and screening for breast cancer. To our knowledge, no controlled prospective trial links BSE to lives saved from breast cancer. Compared with clinical breast examination and mammography, the estimated sensitivity of BSE is low (20% to 30%) and is lower among older women. The potential sensitivity of BSE should be higher because women can detect small lumps (0.3 cm) in silicone models. Instruction increases BSE frequency over the short term. Sensitivity also increases, but specificity decreases. The psychological effects of teaching and performing BSE are not yet clear. The cost of screening by BSE is unknown but depends on the accuracy of the test as well as the training method used. Breast self-examination has potential as a screening test for breast cancer, but many questions require scientific examination before this procedure can be advocated as a screening test for breast cancer.


Re-emergence of interferon-α in the treatment of chronic myeloid leukemia.
Treatment for chronic myeloid leukemia (CML) has evolved from chemotherapy (busulfan, hydroxyurea) to interferon-α (IFNα), and finally to tyrosine kinase inhibitors such as imatinib. Although imatinib has profoundly improved outcomes for patients with CML, it has limitations. Most significantly, imatinib cannot eradicate CML primitive progenitors, which likely accounts for the high relapse rate when imatinib is discontinued. IFNα, unlike imatinib, preferentially targets CML stem cells. Early studies with IFNα in CML demonstrated its ability to induce cytogenetic remission. Moreover, a small percentage of patients treated with IFNα were able to sustain durable remissions after discontinuing therapy and were probably cured. The mechanisms by which IFNα exerts its antitumor activity in CML are not well understood; however, activation of leukemia-specific immunity may have a role. Some clinical studies have demonstrated that the combination of imatinib and IFNα is superior to either therapy alone, perhaps because of their different mechanisms of action. Nonetheless, the side effects of IFNα often impede its administration, especially in combination therapy. Here, we review the role of IFNα in CML treatment and the recent developments that have renewed interest in this once standard therapy for patients with CML.


Disparities in Breast Cancer Screening Rates Among Adults With and Without Intellectual and Developmental Disabilities.
Individuals with intellectual and developmental disabilities may face barriers in accessing healthcare, including cancer screening and detection services. We sought to assess the association of intellectual and developmental disabilities (IDD) with breast cancer screening rates. Data from 2018 to 2020 was used to identify screening-eligible individuals from Medicare Standard Analytic Files. Adults aged 65-79 years who did not have a previous diagnosis of breast cancer were included. Multivariable regression was used to analyze the differences in breast cancer screening rates among individuals with and without IDD. Among 9,383,349 Medicare beneficiaries, 11,265 (0.1%) individuals met the criteria for IDD. Of note, individuals with IDD were more likely to be non-Hispanic White (90.5% vs. 87.3%), have a Charlson Comorbidity Index score ≤ 2 (66.2% vs. 85.5%), and reside in a low social vulnerability index neighborhood (35.7% vs. 34.4%). IDD was associated with reduced odds of undergoing breast cancer screening (odds ratio (OR) 0.77, 95% confidence interval (CI) 0.74-0.80; p < 0.001). Breast cancer screening rates in individuals with IDD were further influenced by social vulnerability and belonging to a racial/ethnic minority. Individuals with IDD may face additional barriers to breast cancer screening. The combination of IDD and social vulnerability placed patients at particularly high risk of not being screened for breast cancer.


Myocyte/capillary mismatch in the heart of uremic patients.
Experiments indicate that capillary density is reduced in the hypertrophied left ventricle of rats with subtotal nephrectomy compared to control rats with similar BP and left ventricular hypertrophy, suggesting that in uremia, hypertrophying cardiomyocytes outgrow their capillary supply. No information on myocardial capillary supply in humans is currently available. The hearts of nine dialyzed patients, nine patients with essential hypertension, and 10 normotensive control subjects at postmortem were obtained. Subjects with stenosing coronary lesions and left ventricular pump failure were excluded. Special sampling procedures were used to exclude stereologic artefacts. Capillaries were specifically stained with ulex lectin and analyzed by stereologic techniques. Length density of myocardial capillaries (Lv; mm/mm3) was significantly (P < 0.001) lower in dialyzed patients (1483 +/- 238) than in patients with essential hypertension (1872 +/- 243) or in normotensive control patients (2898 +/- 456). In parallel, myocyte diameter and volume density of myocardial interstitial tissue were significantly (P < 0.001) increased in uremic patients compared to patients with essential hypertension and control patients, respectively. Diminished left ventricular capillary supply in renal failure must increase critical oxygen diffusion distance in the myocardium, thus exposing cardiomyocytes to the risk of hypoxia. It is unknown whether such reduced ischemia tolerance can be reversed by increasing oxygen supply (e.g., by reversing anemia).


One-pot bioinspired synthesis of fluorescent metal chalcogenide and carbon quantum dots: Applications and potential biotoxicity.
Quantum dots (QDs) are promising nanoscale materials with sizes ranging from 1 to 10 nm, and have exponentially triggered scientific interest worldwide during the past decade. They exhibit size-tunable optical features, zero-dimensional structures, and quantum confinement effects. Moreover, they can be tailored to suit various applications. Phyto-synthesis of fluorescent metal chalcogenide QDs and carbon dots (CDs) is a green, feasible, low-cost, and environmentally safe approach to overcome the limitations of chemical and physical synthesis techniques. Different plant extracts provide several phytochemical constituents with numerous functional moieties for natural capping and stabilization of the synthesized metal chalcogenide QDs and CDs. Therefore, the green synthesis of metal chalcogenide QDs and CDs, their optical and structural properties, and applications such as diagnostics, biosensing, heavy metal detection, and photocatalytic degradation are comprehensively summarized in this review. Furthermore, the biovalorization of agricultural wastes, such as fruit and vegetable peels, is addressed to produce high-value metal chalcogenide QDs and CDs. In addition, the toxicity issues associated with these particles are described for the safe usage of QDs. Challenges that restrict the widespread application of QD particles are discussed along with future perspectives for their commercial, safe, and upscale production.


Lycorine hydrochloride inhibits metastatic melanoma cell-dominant vasculogenic mimicry.
Melanoma cells actively participate in tumor angiogenesis and vasculogenic mimicry. However, anti-angiogenic therapy in patients with melanoma has not shown a significant survival gain. Thus, new anti-melanoma angiogenic and vasculogenic drugs are highly desired. Using the metastatic melanoma cell line C8161 as a model, we explored melanoma vasculogenic inhibitors and found that lycorine hydrochloride (LH) effectively suppressed C8161 cell-dominant formation of capillary-like tubes in vitro and generation of tumor blood vessels in vivo with low toxicity. Mechanistic studies revealed that LH markedly hindered expression of VE-cadherin in C8161 cells, but did not affect expression of six other important angiogenic and vasculogenic genes. Luciferase assays showed that LH significantly impeded promoter activity of the VE-cadherin gene in a dose-dependent manner. Together, these data suggest that LH inhibits melanoma C8161 cell-dominant vasculogenic mimicry by reducing VE-cadherin gene expression and diminishing cell surface exposure of the protein.


Childhood developmental disorders: an academic and clinical convergence point for psychiatry, neurology, psychology and pediatrics.
Significant advances in understanding brain development and behavior have not been accompanied by revisions of traditional academic structure. Disciplinary isolation and a lack of meaningful interdisciplinary opportunities are persistent barriers in academic medicine. To enhance clinical practice, research, and training for the next generation, academic centers will need to take bold steps that challenge traditional departmental boundaries. Such change is not only desirable but, in fact, necessary to bring about a truly innovative and more effective approach to treating disorders of the developing brain. I focus on developmental disorders as a convergence point for transcending traditional academic boundaries. First, the current taxonomy of developmental disorders is described with emphasis on how current diagnostic systems inadvertently hinder research progress. Second, I describe the clinical features of autism, a phenomenologically defined condition, and Rett and fragile X syndromes, neurogenetic diseases that are risk factors for autism. Finally, I describe how the fields of psychiatry, psychology, neurology, and pediatrics now have an unprecedented opportunity to promote an interdisciplinary approach to training, research, and clinical practice and, thus, advance a deeper understanding of developmental disorders. Research focused on autism is increasingly demonstrating the heterogeneity of individuals diagnosed by DSM criteria. This heterogeneity hinders the ability of investigators to replicate research results as well as progress towards more effective, etiology-specific interventions. In contrast, fragile X and Rett syndromes are 'real' diseases for which advances in research are rapidly accelerating towards more disease-specific human treatment trials. A major paradigm shift is required to improve our ability to diagnose and treat individuals with developmental disorders. This paradigm shift must take place at all levels - training, research and clinical activity. As clinicians and scientists who are currently constrained by disciplinary-specific history and training, we must move towards redefining ourselves as clinical neuroscientists with shared interests and expertise that permit a more cohesive and effective approach to improving the lives of patients.


Low revascularization of human islets when experimentally transplanted into the liver.
Previously, we have found that human islets experimentally transplanted beneath the kidney capsule have lower vascular density than native islets. This study aimed to investigate whether human islets experimentally transplanted into the liver are also poorly revascularized in the same manner as islets at the renal subcapsular site. Human islets were transplanted to nude mice. One month posttransplantation, the islet graft-bearing livers or kidneys were removed, formalin-fixed, and stained with the lectin Bandeiraea (Griffonia) simplicifolia (BS-1) to visualize endothelium. The vascular density in the intraportally transplanted human islets was found to be similarly low as in human islets transplanted beneath the kidney capsule. The intrahepatic human islets were coated with numerous vessels, but few vessels could be seen within the islets. Human islets transplanted intraportally into the liver become poorly revascularized. This could contribute to the loss of function in human islets transplanted into the liver over time.