Ventricular premature contractions. Which should be treated?
The treatment of ventricular premature contractions (VPCs) is based on two factors: bothersome symptoms from which the patient desires relief and the association of ectopic ventricular beats with sudden cardiac death. The sudden death risk related to ventricular ectopic beats is real, but appears to be a function of the frequency or pattern in which they occur plus the presence of underlying heart disease. A serious risk exists when frequent, multifocal, successive, or R-on-T-type VPCs occur in a patient monitored late after a fresh myocardial infarction, particularly if left ventricular failure is also present. Current data have been used to formulate levels of risk for sudden cardiac death on the basis of ventricular ectopic beats, which in turn provides a reasonable basis for the treatment of asymptomatic ventricular ectopy.


National survey on the non-pharmacological modalities prescribed by French general practitioners in the treatment of lower limb (knee and hip) osteoarthritis. Adherence to the EULAR recommendations and factors influencing adherence.
Guidelines for the treatment of lower limb osteoarthritis (LLOA) include non-pharmacological (NPM) and pharmacological modalities (PM). In France, general practitioners (GPs) are the main prescribers of pharmacological treatment for LLOA but little is known about the non-pharmacological modalities they usually prescribe. To determine how French GPs prescribe non-pharmacological modalities of LLOA treatment in daily practice. A four-point questionnaire (systematically, frequently, rarely, never) was built to assess the French GPs' opinion regarding the NPM of LLOA treatment (10 questions). The questionnaire was given between April and June 2005 to 3000 GPs, all over the French regions. The percentage reported in this abstract are those of the systematic and frequent responses. 59.2% of the questionnaires (n=1775) could be retrieved. Weight reduction recommendations (76%), joint sparing (71.7%), physical activity development (61.7%), rehabilitation (57.8%), self-exercise (46%) were the more frequently prescribed NPM. Sticks (36%), insoles (35.6%), bed relief (25.4%) and knee bracing (10.5%) were far less regularly proposed. However weight reduction and physical activity development appeared to be the patients less-well observed NPM. The main means used to improve the efficacy of the diet were the support of a nutritionist (74.5%) and the support of the GPs (70.7%) far beyond the support group and familial intervention (both 36,6%). The large majority of GPs considered that a good physical activity was essential (51.7%) or useful (43.3%) to the success of the weight reduction programme. The main recommended physical activities were walking (84.3%), swimming (74.3%), cycling (47%) and water-gymnastics (40.4%). To improve the success of the physical activity development, analgesics were recommended by 93% of GPs, settling up through rehabilitation by 57.4%, support through GPs appointments by 50%. Lastly, 68.4% of GPs recommended a systematic analgesic consumption, since a non-steroidal anti-infammatory drug (NSAID) prescription was proposed by only 30.5%, and NSAID treatment before or after physical activities by 19% and 9.3% respectively. This large survey shows that non-pharmacological modalities are frequently prescribed by French GPs in the treatment of LLOA, in addition to analgesic therapy. However, most GPs consider that some of them are difficult to follow in the long term.


Initial treatment with amphotericin B plus rifampin in the acute treatment of cryptococcal meningitis in aids.
The result of initial treatment with amphotericin B (0.7 mg/kg/day) plus rifampin (600 mg/day) for 2 weeks, followed by fluconazole (400 mg/day) for 8 weeks in the acute treatment of cryptococcal meningitis in AIDS is reported. There were 10 patients in the study: at 2 weeks, all had made a clinical response and cerebrospinal fluid was sterile in 4 patients; at 10 weeks, all had negative cerebrospinal fluid cultures. Serious side effects were not detected.


Bilirubin impacts microglial autophagy via the Akt-mTOR signaling pathway.
Bilirubin encephalopathy is a severe complication of neonatal hyperbilirubinemia. With elevation of serum unconjugated bilirubin (UCB) levels, UCB crosses the blood-brain barrier and possibly leads to neurological dysfunction. Neuroinflammation is recognized as a prominent pathological feature in bilirubin encephalopathy. Recent studies have suggested that autophagy plays a crucial role in the inflammatory response. However, the potential effect of microglial autophagy in the pathogenesis of bilirubin encephalopathy remains uncertain. The in vitro findings verified that in primary cultured microglia, UCB significantly reduced the ratio of LC3B-II to LC3B-I and downregulated the expression of ATG5, Beclin-1, and ATG7, while increasing the expression of p62/SQSTM1. The results showed that UCB could decrease the number of mCherry-EGFP-LC3 positive puncta, even when chloroquine (CQ) was applied to block the microglial autophagy flux. Mechanistically, UCB was found to upregulate the expression of TLR4 and increase the phosphorylation levels of Akt and mammalian target of rapamycin (mTOR). Promoting microglial autophagy by treatment with Rapamycin (RAPA), an mTOR inhibitor, decreased the levels of NOD-like receptor protein 3 (NLRP3) inflammasome components and IL-1β, rescued microglial overactivation, and improved neurological functions. These data indicated that UCB could impact microglial autophagy via the Akt-mTOR signaling pathway and synergistically promote neuroinflammatory responses. Enhancing autophagy might disrupt the assembly of NLRP3 inflammasome, attenuate UCB-induced neuroinflammation, and improve the prognosis of model rats with bilirubin encephalopathy. In conclusion, this study implies that regulating microglial autophagy might be a promising therapeutic strategy for bilirubin encephalopathy.


TIRAP, TRAM, and Toll-Like Receptors: The Untold Story.
Toll-like receptors (TLRs) are the most studied receptors among the pattern recognition receptors (PRRs). They act as microbial sensors, playing major roles in the regulation of the innate immune system. TLRs mediate their cellular functions through the activation of MyD88-dependent or MyD88-independent signaling pathways. Myd88, or myeloid differentiation primary response 88, is a cytosolic adaptor protein essential for the induction of proinflammatory cytokines by all TLRs except TLR3. While the crucial role of Myd88 is well described, the contribution of other adaptors in mediating TLR signaling and function has been underestimated. In this review, we highlight important results demonstrating that TIRAP and TRAM adaptors are also required for full signaling activity and responses induced by most TLRs.


Glucose signalling positively regulates aliphatic glucosinolate biosynthesis.
The effects of glucose on aliphatic glucosinolate biosynthesis in Arabidopsis thaliana were investigated in this study by using mutants related to aliphatic glucosinolate biosynthesis and regulation, as well as glucose signalling. The results showed that glucose significantly increased the contents of individual and total aliphatic glucosinolates. Expression of MYB28 and MYB29, two key transcription factors in aliphatic glucosinolate biosynthesis, was also induced by glucose. Consistently, the increased accumulation of aliphatic glucosinolates and the up-regulated expression of CYP79F1 and CYP79F2 induced by glucose disappeared in the double mutant myb28myb29. MYB28 and MYB29 synergistically functioned in the glucose-induced biosynthesis of aliphatic glucosinolates, but MYB28 was predominant over MYB29. Interestingly, the content of total aliphatic glucosinolates and the expression level of MYB28 and MYB29 were substantially reduced in the glucose insensitive mutant gin2-1 and the ABA insensitive 5 (abi5-7) mutant compared with the wild type. In addition, total aliphatic glucosinolates accumulated much less in another sugar-insensitive RGS1 (regulator of G-protein signaling 1) mutant (rgs1-2) than in the wild type. These results suggest that glucose-promoted aliphatic glucosinolate biosynthesis is regulated by HXK1- and/or RGS1-mediated signalling via transcription factors, MYB28, MYB29, and ABI5.


Economic evaluation of etoricoxib versus non-selective NSAIDs in the treatment of osteoarthritis and rheumatoid arthritis patients in the UK.
The objective of this study was to evaluate the potential economic implications of using etoricoxib versus non-selective NSAID alternatives in the treatment of patients with osteoarthritis (OA) or rheumatoid arthritis (RA) in the UK. Decision-analytical modelling was used to calculate the expected costs and consequences of the use of etoricoxib compared with non-selective NSAIDs alone, NSAIDs plus proton pump inhibitors (PPIs), NSAIDs plus histamine H2 receptor antagonists and NSAIDs plus misoprostol over a continuous treatment period of 1 year. The model considered direct medical costs from the perspective of the UK National Health Service (NHS) and used data from phase IIb and III clinical trials of etoricoxib to determine probabilities of gastrointestinal (GI) events. Model outcomes were defined as resource-consuming GI-related events, including clinically evident gastroduodenal perforations, symptomatic gastroduodenal ulcers, or upper GI bleeding (collectively, PUBs ['perforation, ulcers and/or bleeding']). Resource utilisation and costs (2002 values) for the treatment of OA and RA as well as GI events were based on published literature and information available from UK-specific sources. The model suggests that etoricoxib is cost saving compared with non-selective NSAIDs plus PPIs or non-selective NSAIDs plus misoprostol. The model also suggests that etoricoxib is cost effective in terms of the incremental cost per QALY gained for non-selective NSAIDs alone (pound 19,766) and for non-selective NSAIDs plus H2 antagonists (pound 9350). The incremental cost of etoricoxib per PUB avoided was pound 12,446 versus non-selective NSAIDs alone and pound 6438 versus NSAIDs co-prescribed with H2 antagonists. For patients without the presence of specific GI risk factors (history of GI event, corticosteroid use or disability), etoricoxib may be cost effective for patients over age 56 years, assuming a cost-effectiveness threshold of pound 30,000 per QALY gained. Etoricoxib may also be cost effective in patients of all ages who had at least one specific GI risk factor. The model suggests, with its underlying assumptions and data, that etoricoxib is a cost-effective alternative to therapeutic regimens involving non-selective NSAIDs for OA or RA, from the UK NHS perspective. Etoricoxib may be cost saving and dominant over non-selective NSAIDs used together with a PPI or misoprostol. When compared with non-selective NSAIDs alone or non-selective NSAIDs co-prescribed with H2 antagonists, the incremental cost per QALY gained with use of etoricoxib was within the generally accepted threshold for cost effectiveness (less than pound 30,000 per QALY gained).


Identification of the nature of modification that causes the shift of DNA topoisomerase II beta to apparent higher molecular weight forms in the M phase.
Human cell lines express two genetically distinct isoforms of DNA topoisomerase (topo II) II: topo II alpha (p170) and topo II beta (p180). We detected a higher molecular weight form with an apparent molecular mass of about 190 kDa in M phase-arrested HeLa cells (Kimura, K., Saijo, M., Ui, M., and Enomoto, T. (1994) J. Biol. Chem. 269, 1173-1176). In this study we confirmed, using anti-topo II alpha and topo II beta monoclonal antibodies, that this higher molecular weight form is topo II beta and consists of doublet bands around 190 kDa. We confirmed that the doublet bands constituted an M phase-specific phenomenon and were not an artifact of the procedure used to accumulate mitotic cells. Digesting the immunoprecipitated materials from mitotic cell extracts with alkaline phosphatase resulted in the disappearance of the doublet bands and the appearance of the 180-kDa band with the concomitant disappearance of 32P label in the region of the doublet bands. Neither heat-inactivated alkaline phosphatase nor phosphodiesterase affected the doublet bands and the 32P label. Topo II beta in interphase cells was also phosphorylated, but the shift in apparent molecular weight was very slight after alkaline phosphatase digestion. Analysis of the labeled phosphoamino acids present in topo II beta from M phase and logarithmically growing cells indicated that phosphorylation occurred mainly on serine and fairly on threonine residues in both topo II beta isoforms. These results indicated that topo II beta is phosphorylated at specific sites in M phase, resulting in the formation of the doublet bands.


[A proposed new target for deep brain stimulation in obsessive-compulsive disorder].
The obsessive-compulsive disorder (OCD) has an incidence in general population of 1.5-3%. If we consider as a positive respond a diminution of the 25-35% in the symptoms of OCD according to the Y-BOCS, and we add the cognitive-behavioral therapy to the pharmacological treatment, only a 40-60% of treated patients would have significant improvement and a 10% of patients with OCD, would be refractory to all type of medical treatment. Current neurosurgical techniques for resistant cases of OCD interrupt the connections between the frontal lobes and subcortical structures (cingulotomy, capsulotomy). These techniques are ablative and irreversible. It shows the importance of finding a less aggressive technique with better clinical results. Deep brain stimulation (DBS) is an alternative to traditional neurosurgery based in neuromodulation methods. It's considered that the physiopathology of the OCD consists of a dysfunction of the direct and indirect vias that control the extrapiramidal limbic circuit. On the other hand, it had been obtained positive results after DBS of the subthalamic nucleus of three patients with Parkinson's disease and OCD. This article has as target the demonstration that bilateral DBS of the limbic part of the subthalamic nucleus is an alternative for the treatment of refractory OCD.


Is admission hyperglycaemia in non-diabetic patients with acute myocardial infarction a surrogate for previously undiagnosed abnormal glucose tolerance?
To investigate whether admission hyperglycaemia in non-diabetic patients with acute myocardial infarction (AMI) is a surrogate for previously undiagnosed abnormal glucose tolerance. Two hundred non-diabetic patients with AMI were divided into three groups: 81 patients with admission glucose < 7.8 mmol/L (group 1), 83 patients with admission glucose > or = 7.8 mmol/L and < 11.1 mmol/L (group 2), and 36 patients with admission glucose > or = 11.1 mmol/L (group 3). Abnormal glucose tolerance, diabetes, or impaired glucose tolerance (IGT) was diagnosed by oral glucose tolerance test (OGTT). OGTT identified diabetes in 53 patients (27%) and IGT in 78 patients (39%). When the fasting glucose criteria were applied, however, only 14 patients (7%) were diagnosed as having diabetes. The prevalence of abnormal glucose tolerance was similar among the three groups: 67% in group 1, 63% in group 2, and 69% in group 3 (P = 0.74). The relation of fasting glucose (r2 = 0.50, P < 0.001) and HbA1c (r2 = 0.34, P < 0.001) to 2-h post-load glucose was significant, but the relation of admission glucose to 2-h post-load glucose was not significant (r2 = 0.02, P = 0.08). Multivariable analysis showed that fasting glucose and HbA1c were independent predictors of abnormal glucose tolerance, but admission glucose was not. Admission hyperglycaemia in non-diabetic patients with AMI does not represent previously undiagnosed abnormal glucose tolerance. Fasting glucose and HbA1c, rather than admission glucose, may be useful to predict abnormal glucose tolerance. However, these parameters lacked sensitivity. OGTT should be considered in all non-diabetic patients with AMI.


[Repair and suture of cutaneous wounds].
Suturing is the preferred method for closing a simple wound. The procedure should be preceded by surgical debridement of the wound and carefully done level by level. A number of topographical characteristics should be known and kept in mind. The best technique, in the best possible environment, is a necessary condition, not always sufficient, to reduce the importance of sequelae.


[Prevention and treatment of influenza].
Influenza is a familiar disease responsible for an important morbidity and mortality and a medical over consumption. The management of influenza should be optimized by a wide use of vaccine which is the cornerstone of prevention. Neuraminidase inhibitors are specific antiviral drugs with activity on both typesA and B Influenzavirus. Clinical efficacy has been demonstrated on duration of disease, intensity of symptoms, reduction of complications including those increasing antibiotic use. Moreover, limited studies have demonstrated a positive effect on hospitalizations and mortality risk in some populations. Neuraminidase inhibitors exhibit also a protective effect when administered as prophylaxis (post-exposure prophylaxis, seasonal prophylaxis, or prophylaxis during institution epidemic). For these reasons, neuraminidase inhibitors should not be considered as symptomatic treatment of influenza, but as specific antiviral drugs and play an important role (especially oseltamivir) in the French pandemic plan. Hygienic rules play also a fundamental role for prevention of transmission; neglected for many decades, they have been rehabilitated by the pandemic threat.


Diabetes Is Not Associated With Increased 90-Day Mortality Risk in Critically Ill Patients With Sepsis.
To determine the association of pre-existing diabetes, hyperglycemia, and hypoglycemia during the first 24 hours of ICU admissions with 90-day mortality in patients with sepsis admitted to the ICU. We used mixed effects logistic regression to analyze the association of diabetes, hyperglycemia, and hypoglycemia with 90-day mortality (n = 128,222). All ICUs in the Netherlands between January 2009 and 2014 that participated in the Dutch National Intensive Care Evaluation registry. All unplanned ICU admissions in patients with sepsis. The association between 90-day mortality and pre-existing diabetes, hyperglycemia, and hypoglycemia, corrected for other factors, was analyzed using a generalized linear mixed effect model. In a multivariable analysis, diabetes was not associated with increased 90-day mortality. In diabetes patients, only severe hypoglycemia in the absence of hyperglycemia was associated with increased 90-day mortality (odds ratio, 2.95; 95% CI, 1.19-7.32), whereas in patients without pre-existing diabetes, several combinations of abnormal glucose levels were associated with increased 90-day mortality. In the current retrospective large database review, diabetes was not associated with adjusted 90-day mortality risk in critically ill patients admitted with sepsis.


Sickness at high altitude: a literature review.
When some individuals spend just a few hours at low atmospheric pressure above 1,500 m (5,000 ft)--such as when climbing a mountain or flying in a plane at high altitude--they become ill. Altitude sickness studies originally concentrated on life-threatening illnesses which beset determined and athletic climbers at extreme altitudes. In recent years, however, research attention is moving towards milder forms of sickness reported by a significant proportion of the growing number of visitors to mountain and ski resorts at more moderate altitude. Some of this research is also relevant in understanding the problems experienced by passengers in newer planes that fly at a significantly higher equivalent cabin altitude, i.e. 2,440 m (8,000 ft), than earlier designs. Engineering solutions--such as enriched oxygen in enclosed spaces at altitude, or in the case of aircraft, lower cabin altitudes--are possible, but for an economic assessment to be realistic an engineer needs to identify the scale of the problem and to understand the factors determining susceptibility. This review concentrates on the problems of mountain sickness in the ordinary population at altitudes of around 3,000 m (10,000 ft); this is a problem of growing concern as ski resorts develop, mountain trekking increases in popularity, and as higher altitude cabin pressures are achieved in aircraft.


Effect of electro-acupuncture therapy on limb spasm and excitability of motor neurons in stroke rats.
To investigate the effect of electro-acupuncture therapy on limb spasm and excitability of motor neurons in stroke rats. Ischemic stroke model was induced with middle cerebral artery embolization in SD rats. Thirty-three modeled rats were randomly divided into model group, electro-acupuncture group, and baclofen group with 11 rats in each group, and another 10 rats were taken as sham operation group. The electro-acupuncture group and the baclofen group were treated with electro-acupuncture and baclofen tablets respectively. The model group and the sham operation group had no intervention. The neural function was evaluated with Bederson's scale and balance beam test; the muscle tension was measured with electrophysiography; the pathological changes of brain tissue was examined with HE staining; the content of glutamic acid (Glu) and γ-aminobutyric acid (GABA) in rat cerebral cortex was analyze with enzyme linked immunosorbent assay (ELISA) method, the expression of metabotropic glutamate receptor 1a () and γ-aminobutyric acid type B receptor subunit 1 () mRNA were detected with RT-qPCR. Compared with the model group, the neurological function scores of the electro-acupuncture group and the baclofen group showed a downward trend at d7 after operation (all >0.05), and the neurological function scores of the electro-acupuncture group and the baclofen group were significantly decreased at d12 after the operation (all <0.05). Compared with sham operation group, the electrophysiological results of model group, electro-acupuncture group and baclofen group were significantly lower (all <0.05), and there was no statistical difference in the electrophysiological results of the model group, electro-acupuncture group and baclofen group at d7 after operation (all >0.05). Compared with the model group, the electrophysiological results of the electro-acupuncture group and baclofen group were significantly increased after operation (all <0.05). The results of HE staining showed that there was no cell edema and degeneration in the sham operation group, no pyknosis of the nucleus, and no bleeding in the interstitium. Cell edema and degeneration and mesenchymal congestion appeared in the model group. Compared with the model group, the cytoplasmic edema and degeneration and the interstitial bleeding in the electroacupuncture group and the baclofen group were reduced. Compared with sham operation group, the Glu content and the relative expression of mRNA was increased in the model group, electro-acupuncture group and baclofen group, while the GABA content and the relative expression of mRNA decreased (all <0.05). Compared with model group, the Glu content and the relative expression of mRNA in the electro-acupuncture group and baclofen group decreased, and the GABA content and relative expression of mRNA increased (all <0.05). Electro-acupuncture may improve limb spasm after stroke through regulating the expression of Glu and GABA in the cerebral cortex and the excitability of motor neurons in rats.


The validation and evaluation of anti-HIV testing algorithm used in mobile clinic setting for men who have sex with men in metropolitan Bangkok, Thailand.
Same-day anti-HIV testing algorithm is recommended by Thai National Guidelines. We compared performance characteristics of algorithms used in a mobile clinic and a facility-based clinic for men who have sex with men (MSM) in Bangkok. Mobile clinic samples collected from 4 saunas and 2 spa venues were tested by Alere DetermineTM HIV 1/2, followed by DoubleCheck GoldTM Ultra HIV 1/2 and SD Bioline HIV 1/2 3.0. All samples were re-tested at the Thai Red Cross Anonymous Clinic (TRCAC) by Architect HIV Ag/Ab or Elecsys HIV combi PT, followed by Alere DetermineTM HIV 1/2 and Serodia HIV 1/2. Non-reactive samples were tested by Aptima nucleic acid amplification test (NAAT) and reactive/inconclusive samples were tested by less-sensitive immunoassays (IA) and HIV-1 RNA to detect acute HIV infection (positive NAAT or non-reactive IA/positive HIV-1 RNA). Of 233 MSM, 36 (15.5%) had HIV infection diagnosed using mobile clinic algorithm. Two additional acute HIV cases (1 positive NAAT and 1 reactive Architect with detectable HIV-1 RNA) were diagnosed using TRCAC algorithm. The mobile clinic algorithm had a sensitivity of 94.9% (95% CI: 82.7, 99.4) and a specificity of 100% (95% CI: 98.1, 100). Use of whole blood on rapid test kits demonstrated satisfactory performance and allowed same-day HIV test result through a mobile clinic model. For populations with high HIV incidence, careful history taking to define the window period is crucial and repeat testing must be encouraged if the testing algorithm does not include 4th generation anti-HIV assay or NAAT.


Two new compounds from the seeds of Descurainia sophia.
Two new compounds, descurainin A (1) and descurainoside B (2), were isolated from the seeds of Descurainia sophia (L.) Webb ex Prantl. Their structures were elucidated by spectroscopic methods (MS, 1H, 13C and 2D NMR).


[Experience with the treatment of acute hepatic coma using extracorporeal perfusion of heterologous liver and exchange transfusion].
Extracorporeal pig liver perfusion was adopted in 2 patients with acute hepatic coma due to fulminant hepatitis. Exchange transfusion was used in a third patient, while a fourth was subjected to both procedures. A marked haematological improvement was noted in all cases. Yet, three patients died without showing any clinical benefit. In the fourth case, coma regressed and gradual improvement to the point of complete recovery was achieved. Liver perfusion and exchange transfusion in the same patient were attended by very different clinical effects, though each procedure produced a comparable improvement at the blood chemistry data. Careful analysis of the data suggests that the difference was attributable to discrepancies between the degree of tissue purification achieved.


Technical Note: Enhancing the surface dose using a weak longitudinal magnetic field.
The surface dose in radiotherapy is subject to the physical properties of the radiation beam and collimator. The purpose of this work is to investigate the manipulation of surface dose using magnetic fields produced with a resistive magnet. Better understanding of the feasibility and mechanisms of altered surface dose could have important clinical applications where the surface dose must be increased for therapeutic goals, or reduced to enhance the therapeutic benefit. A resistive magnet capable of generating a peak magnetic field up to 0.24 T was integrated with a cobalt treatment unit. The magnetic fringe field of the magnet was small due to the self-shielding built within the magnet. The magnetic field at the beam collimation jaws of the cobalt irradiator was less than 10 G. The surface dose and depth dose were measured for varying magnetic field strengths. The resistive magnet was able to alter the dose in the buildup region of the (60)Co depth dose significantly, and the magnitude of dose enhancement was directly related to the strength of the longitudinal magnetic field. Peak magnetic fields as low as 0.08 T were able to affect the surface dose. At a peak field of 0.24 T, the authors measured a surface dose enhancement of 2.8-fold. Surface dose enhancement using resistive magnets is feasible. Further experimental study is needed to understand the origin of the scattered electrons that contribute to the increase in surface dose.


Planning for Older Adult Day Programs in an Arab American Community: Perceptions From Older Adults, Caregivers, and Professional Providers.
Background and Objective: This study explored Arab American stakeholders' perceptions about potential future adult day programming to inform geriatric service providers about relevant services for culturally diverse older adults. Research Design and Method: Participants (N = 28) in five focus groups were recruited through a social service provider in Metropolitan Detroit, Michigan. Results were analyzed using thematic analysis. Results: Themes included basic requirements, promoting clear and transparent understanding of adult day programs (ADPs), respecting the person, social engagement and activities, explaining complex ethnic and geographic identities, and implementing diversity. Discussion and Implications: ADP service providers can enhance services by drawing on the life experiences, resilience, and creativity of older Arab Americans. Person-focused policies and programs that draw on the strengths of the diverse local community should be developed and communicated clearly for potential participants, family members, and service providers.


The Dynamic Duo: Combining noninvasive brain stimulation with cognitive interventions.
Pharmacotherapy, psychotherapy, and non-invasive brain stimulation (NIBS)1 each show efficacy in the treatment of psychiatric disorders; however, more efficacious interventions are needed as reflected by an overall unmet need in mental health care. While each modality has typically been studied and developed as a monotherapy, in practice they are typically used in combination. Research has begun to emerge studying the potential synergistic actions of multi-modal, combination therapies. For example, NIBS combined with rehabilitation strategies have demonstrated some success for speech and motor rehabilitation in stroke patients. In this review we present evidence suggesting that combining NIBS with targeted, cognitive interventions offers a potentially powerful new approach to treating neuropsychiatric disorders. Here we focus on NIBS studies using transcranial direct current stimulation (tDCS)2 and transcranial magnetic stimulation (TMS)3 given that these modalities are relatively safe, noninvasive, and can be performed simultaneously with neurocognitive interventions. We review the concept of "state dependent" effects of NIBS and highlight how simultaneous or sequential cognitive interventions could help optimize NIBS therapy by providing further control of ongoing neural activity in targeted neural networks. This review spans a range of neuropsychiatric disorders including major depressive disorder, schizophrenia, generalized anxiety, and autism. For each disorder, we emphasize neuroanatomical circuitry that could be engaged with combination therapy and critically discuss the literature that has begun to emerge. Finally, we present possible underlying mechanisms and propose future research strategies that may further refine the potential of combination therapies.


Nitration of H2B histone elicits an immune response in experimental animals.
Histone H2B is an autoantigen that appears in circulation due to altered apoptosis/or insufficient clearance and is likely to be involved in the induction and progression of autoimmune diseases since modified-H2B is immunogenic. Our studies demonstrate that tyrosines of H2B histone spontaneously converts to free and nitrotyrosine bound protein in vivo. Commercially available H2B histone was modified with peroxynitrite in vitro. Modified H2B was found to be more immunogenic than native form in experimental animals. Furthermore, the sera of rabbits were analyzed for the native and modified forms of the H2B histone. The binding specificity of autoantibodies was characterized by competitive enzyme-linked immunosorbent assay (ELISA) and band shift assay. The free 3-nitrotyrosine in systemic lupus erythematosus sera was quantified by high-performance liquid chromatography. Peroxynitrite-modified H2B induced high titre antibodies as compared to native form which were directly proportional to the nitrotyrosine content. Furthermore, the induced antibodies showed specificity towards the immunogen and cross-reacted with tyrosine-nitrated proteins. ELISA showed preferential binding of induced anti-peroxynitrite modified H2B antibodies to modified H2B as compared to native H2B. The present study shows that peroxynitrite modification of self-antigen(s) generates neoepitopes capable of inducing modified-H2B autoantibodies in experimental animals.


Clinical use of deslorelin (GnRH agonist) in companion animals: a review.
Over the years, many contraceptive medications have been developed for companion animals, but many secondary adverse effects have limited their use. A major advancement was achieved with the use of gonadotropin-releasing hormone (GnRH) analogues, mainly GnRH agonists, which mimic the effects of native GnRH. The development of effective low-dose, slow-release implants with potent agonists such as deslorelin (Suprelorin®, Virbac) have allowed their use to become widespread in recent years, with many potential benefits in companion animals. While the major application of deslorelin was initially male contraception, due to its two differing actions, either the stimulation of oestrus or the sterilization of fertility, its use has been increasing in the bitch as well. The aim of this study is to review the applications of deslorelin GnRH agonist implants in companion animal, such as dogs, cats and some exotic pets.


Achieving quality older person care.
Perhaps the most important consideration when looking at the standards of care given to older people is to make sure that we listen to their opinions and incorporate their wishes into our plans for improving care.


Options for the modified radiation weighting factor of neutrons.
The recent ICRP Report 92 has noted that the current radiation weighting factor, wR, depends on the energy of the incident neutrons in a manner that differs substantially from the dependence, which results from the current convention, QL. At all neutron energies, but most conspicuously below 1 MeV, the values of wR exceed those of the effective quality factor, qE. The discrepancy is largely due to the fact that--in the absence of computed values of the effective quality factor for neutrons--wR has been patterned after the values of the ambient quality factor, which accounts insufficiently for the low-linear energy transfer (LET) gamma ray component from neutron capture in the human body. There are different options to remove the discrepancy. Option 1 is to reduce wR substantially at all neutron energies to make it equal to qE for a standard condition, such as isotropic incidence of the neutrons. Since such a reduction may cause problems in those countries where the current wR values are already legally implemented, ICRP 92 has proposed what is here termed Option 2. It recommended to replace QL by the increased value 1.6 QL - 0.6 and, accordingly, to make the radiation weighting factor equal to 1.6 qE - 0.6. With Option 2 the radiation weighting factor needs to be decreased appreciably at low neutron energies, but for fission neutron spectra the overall changes are minor. To guide--regardless which option is chosen--the selection of the numerical values, the effective quality factor, qE, is computed here for different directional distributions of neutrons incident on the anthropomorphic phantoms ADAM and EVA. None of the sex averaged numerical values is found to deviate much from those for isotropic incidence. Isotropic incidence can, thus, be used as an adequate standard condition. A numerical approximation is proposed for the standard qE that is nearly equivalent to a formula invoked by ICRP 92, but is somewhat simpler and provides realistic values of qE even for the extremely high neutron energies in space. In line with ICRP 92, it is emphasised that wR needs to be seen as a derived quantity related to the LET-dependent weighting factor.


ASSOCIATION OF INTERLEUKIN-10 -1082 A/G (RS1800896) POLYMORPHISM WITH SUSCEPTIBILITY TO GASTRIC CANCER: META-ANALYSIS OF 6,101 CASES AND 8,557 CONTROLS.
The promoter -1082 A/G (rs1800896) polymorphism of Interleukin-10 (IL-10) gene have been widely reported and considered to have a significant role on gastric cancer risk, but the results are inconsistent. To clarify the association, we conducted a meta-analysis to investigate the associations IL-10 -1082 A/G polymorphism with gastric cancer. Eligible articles were identified by searching databases including PubMed, Web of Science, and Google Scholar up to August 03, 2017. Odds ratios (OR) with corresponding 95% confidence intervals (CIs) were used to assess the association. A total of 30 case-control studies with 6,101 cases and 8,557 controls were included in this meta-analysis. Overall, a significant association between IL-10 -1082 A/G polymorphism and gastric cancer risk was observed under the allele model (G vs A: OR=1.305, 95% CI=1.076-1.584; P=0.007), heterozygote model and (GA vs AA: OR=1.252, 95% CI=1.252-1.054; P=0.011) and dominant model (GG+GA vs AA: OR=1.264, 95% CI=1.053-1.516; P=0.012). In the subgroup analysis by ethnicity, increased gastric cancer risk were found in Asians under the allele model (G vs A: OR=1.520, 95% CI=1.172-1.973; P=0.002), homozygote model (GG+GA vs AA: OR=1.571, 95% CI=1.023-2.414; P= 0.039), heterozygote model (GA vs AA: OR=1.465, 95% CI=1.192-1.801; P≤0.001) and dominant model (GG+GA vs AA: OR=1.448, 95% CI=1.152-1.821; P=0.002), but not among Caucasian and Latinos populations. These results suggested that the IL-10 -1082 A/G (rs1800896) polymorphism might contribute to the gastric cancer susceptibility, especially among Asians.


Chronic injury of human renal microvessels with low-dose cyclosporine therapy.
Physiologic and morphologic techniques were used to study kidneys of cardiac transplant recipients treated with either low-dose (low-CsA) or high-dose (high-CsA) cyclosporine. After 12 months both low-CsA (4.6 +/- 0.4) and high-CsA (6.3 +/- 0.3 mg/Kg/24 hr, p less than 0.01) were associated with azotemia and hypertension; GFR with each regimen was depressed below values in a third group treated without CsA (no-CsA) by 40-47%, while corresponding renal vascular resistance was elevated greater than 2-fold (P less than 0.01). Morphologic changes in both CsA groups included an obliterative arteriolopathy with downstream collapse or sclerosis of glomeruli. Determination of renal arcuate vein occlusion pressure revealed an increasing renal artery-to-peritubular capillary pressure gradient between 1 and 12 months of CsA therapy. Fractional clearances of dextrans of graded size were elevated at each time compared with the no-CsA group. Analysis of dextran transport with an isoporous membrane model indicates that transglomerular hydraulic pressure difference (delta P) approximated 39 with no-CsA, but was reduced with low-CsA therapy to about 30 at 1 month, and about 34 mmHg after 12 months. We conclude that chronic CsA therapy induces constriction and eventual occlusion of afferent arterioles, causing downstream glomerular damage that is irreversible. Low versus high dosage of CsA confers only marginal protection against this serious microvascular injury.


Busulfan and subsequent malignancy: An evidence-based risk assessment.
The incidence of secondary malignancies associated with busulfan exposure is considered low, but has been poorly characterized. Because this alkylating agent is increasingly utilized as conditioning prior to gene therapy in nonmalignant hematologic and related disorders, more precise characterization of busulfan's potential contribution to subsequent malignant risk is warranted. We conducted a literature-based assessment of busulfan and subsequent late effects, with emphasis on secondary malignancies, identifying publications via PubMed searches, and selecting those reporting at least 3 years of follow-up. We identified eight pediatric and 13 adult publications describing long-term follow-up in 570 pediatric and 2076 adult hematopoietic cell transplant (HCT) recipients. Secondary malignancies were reported in 0.5% of pediatric HCT recipients, with no cases of myelodysplastic syndrome (MDS) or acute myelocytic leukemia (AML). Fatal secondary malignancies were reported in 0.8% of 1887 evaluable adult HCT recipients, and an overall incidence of secondary malignancies of 4.8% was reported in a subset of 389 evaluable adult patients. We also reviewed long-term results from eight publications evaluating lentiviral- and human promotor-based HSC-targeted gene therapy in 215 patients with nonmalignant conditions, in which busulfan/treosulfan monotherapy or busulfan/fludarabine was the only conditioning. Two malignancies were reported in patients with sickle cell disease (SCD), one of which was potentially busulfan-related. No additional malignancies were reported in 173 patients with follow-up of 5-12 years. The incidence of busulfan-related secondary malignancies is low, and likely to be substantially less than 1% in pediatric transplant recipients, especially those receiving busulfan monotherapy for nonmalignant conditions other than SCD.


Water network-mediated, electron-induced proton transfer in [C5H5N ⋅ (H2O)n](-) clusters.
The role of proton-assisted charge accommodation in electron capture by a heterocyclic electron scavenger is investigated through theoretical analysis of the vibrational spectra of cold, gas phase [Py ⋅ (H2O)n=3-5](-) clusters. These radical anions are formed when an excess electron is attached to water clusters containing a single pyridine (Py) molecule in a supersonic jet ion source. Under these conditions, the cluster ion distribution starts promptly at n = 3, and the photoelectron spectra, combined with vibrational predissociation spectra of the Ar-tagged anions, establish that for n > 3, these species are best described as hydrated hydroxide ions with the neutral pyridinium radical, PyH((0)), occupying one of the primary solvation sites of the OH(-). The n = 3 cluster appears to be a special case where charge localization on Py and hydroxide is nearly isoenergetic, and the nature of this species is explored with ab initio molecular dynamics calculations of the trajectories that start from metastable arrangements of the anion based on a diffuse, essentially dipole-bound electron. These calculations indicate that the reaction proceeds via a relatively slow rearrangement of the water network to create a favorable hydration configuration around the water molecule that eventually donates a proton to the Py nitrogen atom to yield the product hydroxide ion. The correlation between the degree of excess charge localization and the evolving shape of the water network revealed by this approach thus provides a microscopic picture of the "solvent coordinate" at the heart of a prototypical proton-coupled electron transfer reaction.


Association of street connectivity and road traffic speed with park usage and park-based physical activity.
The purpose of this study was to examine associations between street connectivity and road traffic speed and neighborhood residents' use of parks and park-based physical activity. Cross-sectional. Kansas City, Missouri. Participants were 893 adults from randomly selected households. Both self-reported park use and park-based physical activity were dichotomized as some versus none. Intersection density was calculated around each participant, and network analysis was used to determine whether participants had to travel on or cross a road with traffic speed greater than 35 miles per hour (mph) to reach the closest park. Multilevel logistic regression examined the association between intersection density and traffic speed wit park use and park-based physical activity. Compared to those in the lowest intersection density quartile, participants in the third and fourth quartiles were more likely to use parks and to engage in physical activity in parks (odds ratio [OR] = 1.76-2.34; all p < .05). Likewise, compared to those who had a high-speed road on their way to the closest park, participants with slower traffic routes to parks were more likely to use the parks (OR = 1.47; 95% confidence interval [CI] = 1.05-1.92). In addition to park proximity and the design of park features, ensuring direct and safe access to parks through street network design and traffic speed reduction strategies may be key to facilitating park-related physical activity.


A short, rigid linker between pyrene and guanidiniocarbonyl-pyrrole induced a new set of spectroscopic responses to the ds-DNA secondary structure.
A novel pyrene-guanidiniocarbonyl-pyrrole dye, characterised by a short, rigid linker between the two chromophores, interacts strongly with ds-DNA but only negligibly with ds-RNA. Under neutral conditions the dye shows strong selectivity toward AT-DNA (with respect to GC-DNA). Binding is accompanied by a specific ICD band at 350 nm and fluorescence quenching for all DNAs/RNAs studied. At pH 5 the affinity of the dye is reversed, now favouring GC-DNA over AT-DNA. A strong emission increase for AT-DNA is observed but with quenching for GC-DNA.


NMR spectroscopy in drug discovery and development: Evaluation of physico-chemical properties.
Determination of physico-chemical properties of compounds is one of the corner-stones in selection of hit molecules for further progression into lead development in the modern drug discovery process. The speed of traditional analyses and limited quantities of hit molecules are obstacles for efficient acquisition of experimental data. Herein, the range of applications of quantitative nuclear magnetic resonance (NMR) spectroscopy as a fast technique used to evaluate solubility, log P and pKa are discussed.


Multiband vector lattice solitons.
We predict multiband vector solitons in nonlinear periodic systems, using photonic lattices as a prime example. The solitons consist of two optical fields arising from different bands of the transmission spectrum, which involve both bound state and radiation mode components.


Trends in Imaging Utilization Among United States Medicare Beneficiaries and the Impact of the COVID-19 Pandemic.
This study characterizes trends in ophthalmic imaging volume and utilization in the United States among and assesses the potential impact of the COVID-19 pandemic using data from the Centers for Medicare and Medicaid Services. Utilization of macular optical coherence tomography (OCT), optic nerve OCT, and fundus photography steadily increased from 2013 to 2020 and was not impacted by the COVID-19 pandemic. At the same time, there was minimal adoption of anterior segment OCT and a decline in the utilization of dye-based angiography. Utilization patterns may be impacted by the advent of new technologies, role of the clinician, and alignment with treatment paradigms. [Ophthalmic Surg Lasers Imaging Retina 2023;54:661-665.].


Immune Modulation of Asian Folk Herbal Medicines and Related Chemical Components for Cancer Management.
Various exciting immunotherapies aiming to address immune deficiency induced by tumor and treatment hold promise in improving the quality of life and survival rate of cancer patients. It is thus becoming an important and rewarding arena to develop some appropriate immune modulators for cancer prevention and/or treatment. Exploitation of natural products-based immune modulators is of particular imperative because the potential of numerous traditional herbal medicines and edible mushrooms in boosting human immune system has long been verified by folklore practices. This review summarizes the immune modulations of various herbal medicines and edible mushrooms, their crude extracts, and/or key chemical components that have been, at least partly, associated with their cancer management. This article also tabulates the origin of species, key chemical components, and clinical studies of these herbal medicines and edible mushrooms.


Sex-specific effects of relaxin-3 on food intake and brain expression of corticotropin-releasing factor in rats.
This study compared the effects of relaxin-3 (RLN3) on food intake, plasma corticosterone, and the expression of corticotropin-releasing factor (CRF) in male and female rats. RLN3 was injected into the lateral ventricle at 25, 200, and 800 pmol concentrations. RLN3 at 25 pmol increased food intake (grams) at 30 and 60 minutes after injection in female but not male rats. Female rats also showed higher increase in relative to body weight (BW) food intake (mg/g BW) for all RLN3 concentrations at 30 minutes and for 800 pmol of RLN3 at 60 minutes. Moreover, RLN3 at 800 pmol significantly increased 24-hour BW gain in female but not male rats. At 60 minutes after administration, 800 pmol of RLN3 produced a significant increase in plasma corticosterone and in the expression of CRF and c-fos mRNAs in the parvocellular paraventricular hypothalamic nucleus (PVN) in male but not female rats. The levels of c-fos mRNA in the magnocellular PVN were increased by RLN3 but did not differ between the sexes. Conversely, expression of CRF mRNA in the medial preoptic area was increased in female rats but was not sensitive to 800 pmol of RLN3. In the bed nucleus of the stria terminalis, 800 pmol of RLN3 significantly increased CRF mRNA expression in female but not male rats. Therefore, female rats showed more sensitivity and stronger food intake increase in response to RLN3. The differential effects of RLN3 on CRF expression in the PVN and bed nucleus of the stria terminalis may contribute to the sex-specific difference in the behavioral response.


Experimental formulation of a kinetic model describing the nitrification process in biological aerated filters filled with plastic elements.
The present work reports the results of a series of experimental tests performed on cylindrically shaped biological aerated filters (BAFs) to define a new model for reactors design. The nitrification performance was analysed by monitoring a laboratory pilot plant over a six-month period; the dependence of the nitrification rate from the biomass surface density, from ammonia nitrogen concentration and dissolved oxygen concentration was determined using kinetic batch tests. The controls performed on the pilot plant exhibited a nitrification efficiency of approximately 98% at loadings up to [Formula: see text]. Over this value, the pilot plant performance decreased without a correlation with the applied loads. In response to the inlet ammonia loading increase, the bacterial surface density showed a logistic growing trend. The results of kinetic tests proved that the nitrification rate was not affected by the ammonia nitrogen concentration; instead, a first-order kinetic with respect to the dissolved oxygen concentration was detected. Moreover, it was observed that a minimum oxygen concentration, which was proportional to the bacterial surface density, was necessary to initiate the nitrification process. The reaction rate related to bacterial surface density exhibited an increasing trend that was followed by a subsequent decreasing behaviour. The results of kinetic tests and the identification of the relationship between bacterial surface density and ammonia loading permitted the formulation of a mathematical model to predict BAFs' nitrification efficiency.


Hyperuricemia is an independent risk factor for psoriatic arthritis in psoriatic patients.
Psoriatic arthritis (PsA) is a spondyloarthritic condition mainly seen in patients with psoriasis. Psoriatic patients with plaques on the scalp, gluteal fold or nail lesions are known to develop PsA more frequently, but other markers for PsA have not yet been identified. To determine which psoriatic patients are at greatest risk of developing PsA, psoriasis vulgaris (PsV) patients who visited the Department of Dermatology, Fukuoka University Hospital in 2015 were enrolled. Patients with and without PsA were statistically compared with respect to age, sex, age at onset, body mass index (BMI), smoking and drinking habits, familial history of psoriasis and comorbidities. Of 331 patients (237 men, 94 women), 55 had PsA (17%; 39 men, 16 women). PsA patients had significantly higher frequencies of nail lesions (PsA vs PsV-only, 62% vs 29%; P < 0.0001) and hyperuricemia (PsA vs PsV-only, 22% vs 9%; P = 0.01). These were confirmed as independent risk factors for PsA by logistic regression analysis, with odds ratios of 5.05 for nail lesions (P < 0.0001) and 4.18 for hyperuricemia (P < 0.01). There was no difference in age at onset, sex, BMI and incidence of diabetes mellitus, hypertension or dyslipidemia. Hyperuricemia is also known to be more frequent in psoriatic subjects than the normal population. Uric acid crystals are a strong stimulator of innate immunity. Considering that none of our cohort had gouty arthritis, hyperuricemia may increase uric acid crystallization in and around joints, thereby inducing PsA in psoriatic subjects. Hyperuricemia appears to be an independent risk factor for PsA.


Infection Control for CT Equipment and Radiographers' Personal Protection During the Coronavirus Disease (COVID-19) Outbreak in China.
OBJECTIVE. Because CT plays an important role in diagnosis, isolation, treatment, and effective evaluation of coronavirus disease (COVID-19), infection prevention and control management of CT examination rooms is important. CONCLUSION. We describe modifications to the CT examination process, strict disinfection of examination rooms, arrangement of waiting areas, and efforts to increase radiographers' awareness of personal protection made at our institution during the COVID-19 outbreak. In addition, we discuss the potential of using artificial intelligence in imaging patients with contagious diseases.


Expression of a Secreted Fibroblast Growth Factor Binding Protein-1 (FGFBP1) in Angioproliferative Kaposi Sarcoma.
Kaposi's sarcoma (KS) is an angioproliferative disease frequently seen in patients with the acquired immunodeficiency syndrome (AIDS). Previous studies suggest that the HIV-1 protein Tat and Fibroblast Growth Factor 2 (FGF-2) have synergistic angiogenic effects in AIDS-KS tumors. However, the mechanisms by which FGF-2 is released and activated in KS tumors are not clearly defined. We carried out this study to determine whether an FGF-binding protein (FGFBP1 or BP1) that enhances the angiogenic activity of FGF-2 is expressed in AIDS-KS tumors, and to define whether BP1, FGF-2, and HIV-Tat protein-protein interactions could play a potential clinically role in the pathogenesis of AIDS-KS. BP1 was localized in AIDS-KS lesions by immunohistochemistry and in situ hybridization studies. The binding of radiolabeled FGF-2 to His-tagged BP1 or the FGF-receptor 1 was assessed in the presence and absence of HIV-Tat and other viral proteins. Mice carrying tetracycline-regulated BP1 transgene mice were used to determine whether activation of BP1 during wound healing induces KS-like lesions. BP1 expression was detected in AIDS-KS tumor keratinocytes, spindle cells, and infiltrating mononuclear cells. In addition, HIV-Tat competed for the binding of FGF-2 to immobilized BP1, but does not affect the interactions of FGF-2 with its high affinity receptor (FGFR-1). In contrast, two other HIV-proteins, Nef and gp120, did not affect the binding of FGF-2 to BP1 or to FGFR-1. Finally, up-regulation of BP1 expression in tetracycline-regulated -conditional BP1 transgenic mice subjected to skin wounds, induced KS-like skin lesions. Taking into consideration the results of previous studies showing that both HIV-Tat and BP1 enhance the mitogenic and angiogenic activity of locally-stored FGF-2, both in vitro and in vivo, our findings suggest a novel mechanism by which the release and activity of FGFs can be modulated in AIDS-KS tumors by HIV-Tat as well as BP1.


Isolation and characterization of fission yeast sns mutants defective at the mitosis-to-interphase transition.
pim1-d1ts was previously identified in a visual screen for fission yeast mutants unable to complete the mitosis-to-interphase transition. pim1+ encodes the guanine nucleotide exchange factor (GEF) for the spi1 GTPase. Perturbations of this GTPase system by either mutation or overproduction of its regulatory proteins cause cells to arrest with postmitotic condensed chromosomes, an unreplicated genome, and a wide medial septum. The septation phenotype of pim1-d1ts was used as the basis for a more extensive screen for this novel class of sns (septated, not in S-phase) mutants. Seventeen mutants representing 14 complementation groups were isolated. Three strains, sns-A3, sns-A5, and sns-A6, representing two different alleles, are mutated in the pim1+ gene. Of the 13 non-pim1ts sns complementation groups, 11 showed genetic interactions with the spi1 GTPase system. The genes mutated in 10 sns strains were synthetically lethal with pim1-d1, and six sns strains were hypersensitive to overexpression of one or more of the known components of the spil GTPase system. Epistasis analysis places the action of the genes mutated in nine of these strains downstream of pim1+ and the action of one gene upstream of pim1+. Three strains, sns-A2, sns-B1, and sns-B9, showed genetic interaction with the spil GTPase system in every test performed. sns-B1 and sns-B9 are likely to identify downstream targets, whereas sns-A2 is likely to identify upstream regulators of the spi1 GTPase system that are required for the mitosis-to-interphase transition.


Attention and multisensory modulation argue against total encapsulation.
Firestone & Scholl (F&S) postulate that vision proceeds without any direct interference from cognition. We argue that this view is extreme and not in line with the available evidence. Specifically, we discuss two well-established counterexamples: Attention directly affects core aspects of visual processing, and multisensory modulations of vision originate on multiple levels, some of which are unlikely to fall "within perception."


Rapid Communication: Plasma Interleukin-35 in Children with Autism.
In autism spectrum disorders (ASD) many individuals have co-morbid immune dysregulation that can lead to inflammation in the brain and periphery. The novel cytokine interleukin (IL)-35 has described anti-inflammatory properties; however, the plasma levels of IL-35 in children with ASD have never been investigated. The plasma levels of IL-35 were measured by an enzyme-linked immunosorbent assay in 30 children with ASD and 39 typically developing (TD) controls. In the current study, we found that plasma IL-35 levels were significantly decreased in children with ASD compared with TD children. Furthermore, lower IL-35 levels were associated with worse behaviors as assessed using the aberrant behavior checklist. These findings are in line with other observations of decreased regulatory cytokines such as transforming growth factor beta and IL-10 in ASD, and associations with severity of behaviors. In conclusion, regulating the expression of IL-35 may provide a new possible target for the treatment of immune issues in ASD to address an imbalance between pro- and anti-inflammatory signals that alter the behavioral phenotype.


Management of hemopoietic neoplasias during pregnancy.
Hemopoietic neoplasias are unique cancers generally affecting bone marrow, and requires a special attention for disease control and also their complications. When these neoplastic disorders accompany to pregnancy there are many risks both for mother and foetus. Diagnostic difficulties due to the limited use of imaging modalities is essential in pregnant women. On the other hand suboptimal using of the anti-neoplastic drugs and their higher toxicity in mother and foetus must be considered in the management of these neoplastic disorders. Due to the lack of therapeutic guidelines in these cases, team approach is essential and therapy requires to the use the art of medicine.


[Brazilian Protocol for Sexually Transmitted Infections 2020: approaching sexually active individuals].
This article aims to present concepts and clinical practices recommended to approach people with an active sex life. These concepts are an integral part of the recommendations of the Clinical Protocol and Therapeutic Guidelines for Comprehensive Care for People with Sexually Transmitted Infections (STI), published by the Ministry of Health of Brazil in 2020.The article proposes a comprehensive approach to sexuality for health promotion and presents important aspects of the communication process that must develop clearly, without prejudice and judgment, with a focus on sexual and reproductive health. It also highlights relevant points about the exercise of sexuality at specific stages of life, recommending assessment of risks and vulnerabilities, as well as screening for STI and condom use. In this way, it is possible to contribute so that people can exercise their sexuality fully, responsibly and safely.


Electroreduction of the muscle relaxant drug dantrolene sodium at the mercury electrode and its determination in bulk form and pharmaceutical formulation.
The electroreduction of the muscle relaxant drug dantrolene sodium at the mercury electrode has been studied in the Britton-Robinson universal buffer of pH 2.5-11.5 containing 20% (v/v) methanol by means of dc-polarography, cyclic voltammetry and controlled-potential coulometry. Its reduction took place via three irreversible cathodic steps in solutions of pH < or =6, two steps in solutions of 6<pH<10 and a single step at pH values > or =10 through the consumption of 10, 8 or 4 electrons, respectively. This behavior was attributed to the reduction of NO(2) group (1st and 2nd steps at pH < or =6 or the single step at pH > or =10) and the -CH=N- double bond (3rd step at pH <10). Two polarographic procedures (direct current and differential-pulse modes) and three adsorptive cathodic stripping voltammetric procedures (linear-sweep, differential-pulse and square-wave modes) were described and successfully applied for quantification of dantrolene sodium in its bulk form and in pharmaceutical formulation (Dantrolex tablets).


Identification of potential serum biomarkers for breast cancer using a functional proteomics technology.
Cancer is a genetic disease; its development and metastasis depend on the function of many proteins. Human serum contains thousands of proteins; it is a window for the homeostasis of individual's health. Many of the proteins found in the human serum could be potential biomarkers for cancer early detection and drug efficacy evaluation. In this study, a functional proteomics technology was used to systematically monitor metabolic enzyme and protease activities from resolved serum proteins produced by a modified 2-D gel separation and subsequent Protein Elution Plate, a method collectively called PEP. All the experiments were repeated at least twice to ensure the validity of the findings. For the first time, significant differences were found between breast cancer patient serum and normal serum in two families of enzymes known to be involved in cancer development and metastasis: metabolic enzymes and proteases. Multiple enzyme species were identified in the serum assayed directly or after enrichment. Both qualitative and quantitative differences in the metabolic enzyme and protease activity were detected between breast cancer patient and control group, providing excellent biomarker candidates for breast cancer diagnosis and drug development. This study identified several potential functional protein biomarkers from breast cancer patient serum. It also demonstrated that the functional proteomics technology, PEP, can be applied to the analysis of any functional proteins in human serum which contains thousands of proteins. The study indicated that the functional domain of the human serum could be unlocked with the PEP technology, pointing to a novel alternative for the development of diagnosis biomarkers for breast cancer and other diseases.


Increased A-ring reduction of glucocorticoids in obese Zucker rats: effects of insulin sensitization.
Obesity is associated with altered glucocorticoid metabolism, which may impact on hypothalamic-pituitary-adrenal axis activity. Here we characterize hepatic 5alpha- and 5beta-reductase in obese rats and their responses to insulin sensitization. Hepatic A-ring reductase protein and mRNA were assessed in lean and obese Zucker rats after insulin sensitization with metformin or rosiglitazone (n = 7 to 8/group). Hepatic 5alpha-reductase 1 and 5beta-reductase mRNA and protein (p < 0.01) were increased in obese rats. Insulin sensitization ameliorated increased 5alpha-reductase 1 mRNA in obese rats (p < 0.01) and partially reversed increased 5beta-reductase activity. Hepatic clearance of glucocorticoids by 5alpha- and 5beta-reductase is increased in obese Zucker rats, and this increase in clearance is attenuated by insulin sensitization. This increased hepatic clearance may underpin compensatory activation of the hypothalamic-pituitary-adrenal axis in obesity.


Macrocycle breathing in [2]rotaxanes with tetralactam macrocycles.
The structural dynamics of two pairs of [2]rotaxanes were compared using variable-temperature NMR. Each rotaxane had a surrounding tetralactam macrocycle with either 2,6-pyridine dicarboxamide or isophthalamide bridging units. Differences were observed in two types of rotational processes: spinning of the phenylene wall units in the surrounding macrocycle of squaraine rotaxanes and macrocycle pirouetting in xanthone rotaxanes. The rotaxanes with macrocycles containing 2,6-pyridine dicarboxamide bridges exhibited higher rotational barriers due to a cavity contraction effect, which disfavored macrocycle breathing.


Higher efficacy of nevirapine than efavirenz to achieve HIV-1 plasma viral load below 1 copy/ml.
To compare the level of HIV-1 residual viremia, defined by a viral load below 50 copies/ml in patients receiving a tenofovir/emtricitabine and nevirapine (NVP) or efavirenz (EFV)-containing regimen. One hundred and sixty-five HIV-1-infected patients were retrospectively included since they achieved virological suppression (viral load <50 copies/ml) for at least 6 months with a tenofovir/emtricitabine and non-nucleoside reverse transcriptase inhibitor-containing regimen (NVP, n = 75 and EFV, n = 90). Residual plasma viremia was measured using an ultrasensitive assay with a limit of quantification of 1 copy/ml. A Fisher's exact test was used to compare the percentage of patients with HIV-1 RNA below 1 copy/ml between the two treatment groups. Logistic regression was used to search for factors associated with a viral load below 1 copy/ml among the different patient characteristics. Patients in the NVP group had more frequently a viral load below 1 copy/ml than patients in the EFV group (81.3 vs. 55.6%, P < 0.001). In multivariate analysis, only NVP vs EFV (P = 0.005) and duration of viral suppression under antiretroviral treatment (P = 0.005) were independently associated with viral load below 1 copy/ml. It is well known that NVP has a good penetration in anatomic compartments that could explain a deep control of virus replication in some compartments and consequently decrease the residual level of viral load. The clinical relevance of having a viral load below 1 copy/ml has now to be studied for example on systemic inflammatory or immune activation markers.


Prior iodine exposure and impact on thyroid function during controlled ovarian hyperstimulation: A prospective study.
Iodine supplements are recommended for women planning pregnancy, but their impact on thyroid function during controlled ovarian hyperstimulation (COH) and into pregnancy is unknown. The aim of this study was to assess the impact of iodine supplementation on thyroid function during COH. One-hundred and six euthyroid women (thyroid stimulating hormone (TSH) 0.4-2.5 mIU/L) planning their first COH cycle were subdivided according to iodine supplementation (nil, <6 months, ≥6 months) and compared to levothyroxine (LT4)-treated controls. Serial TSH, free thyroxine, free triiodothyronine and thyroglobulin (Tg) levels were recorded at four time points: (i) baseline, (ii) day 7 ovarian stimulation, (iii) ovulation trigger and (iv) two weeks post oocyte retrieval. Oocyte numbers, fertilisation rates and pregnancy outcome were recorded. TSH increased during COH for those women taking iodine supplements for ≥6 months (P = 0.025). One quarter recorded a TSH level >2.5 mIU/L before embryo transfer. A similar increase in TSH was demonstrated by LT4-dependent controls (P = 0.024) but not the remaining subgroups. Tg levels did not change during COH in any group but decreased significantly post oocyte retrieval if nil iodine (P < 0.0001) or supplemented for ≥6 months (P < 0.005). Iodine supplementation did not influence oocyte count, fertilisation or implantation rates. Women taking iodine for <6 months were four times more likely to achieve a live birth than women taking iodine for longer. Women taking iodine supplements for ≥6 months are less able to adapt to the thyroidal demands of COH, with responses comparable to LT4-dependent patients.


PKC zeta-mediated phosphorylation controls budding of the pre-chylomicron transport vesicle.
Dietary triacylglycerols are absorbed by enterocytes and packaged in the endoplasmic reticulum (ER) in the intestinal specific lipoprotein, the chylomicron, for export into mesenteric lymph. Chylomicrons exit the ER in an ER-to-Golgi transport vesicle, the pre-chylomicron transport vesicle (PCTV), which is the rate-limiting step in the transit of chylomicrons across the cell. Here, we focus on potential mechanisms of control of the PCTV-budding step from the intestinal ER. We incubated intestinal ER with intestinal cytosol and ATP to cause PCTV budding. The budding reaction was inhibited by 60 nM of the PKC inhibitor Gö 6983, suggesting the importance of PKCzeta in the generation of PCTV. Immunodepletion of PKCzeta from the cytosol and the use of washed ER greatly inhibited the generation of PCTVs, but was restored following the addition of recombinant PKCzeta. Intestinal ER incubated with intestinal cytosol and [gamma-(32)P]ATP under conditions supporting the generation of PCTVs showed the phosphorylation of a 9-kDa band following autoradiography. The phosphorylation of this protein correlated with the generation of PCTVs but not the formation of protein vesicles and was inhibited by depletion of PKCzeta. Phosphorylation of the 9-kDa protein was restored following the addition of recombinant PKCzeta. The association of the 9-kDa protein with proteins that are important for PCTV budding was phosphorylation dependent. We conclude that PKCzeta activity is required for PCTV budding from intestinal ER, and is associated with phosphorylation of a 9-kDa protein that might regulate PCTV budding.


[Endobronchial lipomas].
The authors report three cases of endobronchial lipoma, and study the etiopathogenesis and the main clinical and therapeutical aspects of such neoplasiae. Both diagnosis and treatment should be timely, in order to prevent irreversible damages to lung parenchyma, compelling surgeons to mutilating operations making the function of the apparatus heavier.


Covalent binding of the natural antimicrobial peptide indolicidin to DNA abasic sites.
Indolicidin is a host defense tridecapeptide that inhibits the catalytic activity of HIV-1 integrase in vitro. Here we have elucidated its mechanism of integrase inhibition. Using crosslinking and mass spectrometric footprinting approaches, we found that indolicidin interferes with formation of the catalytic integrase-DNA complex by directly binding DNA. Further characterization revealed that the peptide forms covalent links with abasic sites. Indolicidin crosslinks single- or double-stranded DNAs and various positions of the viral cDNA with comparable efficiency. Using truncated and chemically modified peptides, we show that abasic site crosslinking is independent of the PWWP motif but involves the indolicidin unique lysine residue and the N- and C- terminal NH2 groups. Because indolicidin can also inhibit topoisomerase I, we believe that multiple actions at the level of DNA might be a common property of antimicrobial peptides.


Optical alignment of an x-ray collimator.
The hard x-ray imaging spectrometer (HXIS) is one of the instruments aboard the NASA Solar Maximum Mission satellite. For the imaging of solar flares in hard x rays HXIS employs a grid collimator with an 8-sec of arc FWHM angular resolution. The collimator consists of ten grid plates in a sequence. The position accuracy of the grids in their planes must be better than a few microns. This paper describes a simple optical alignment method developed to perform measurements of the grid positions with a precision of 1 microm.


[The clinical characteristics of stroke in young patients with cardiac myxoma].
Objective: To investigate the clinical characteristics of stroke in young patients with cardiac myxoma. Methods: Medical records of young patients (aged between 18-44 years) diagnosed with cardiac myxoma in Beijing Anzhen Hospital affiliated to Capital Medical University from January 2005 to March 2016 were retrospective reviewed. Results: A total of 117 cases were included (85 female and 32 male)with the average age (36±7)years old. Most myxomas (83.8%) were located in the left atrium, 7.7% were in the right atrium, 3.5% were in the both atriums, 2.6% were in the left ventricle, and a few were in the left atrium plus left ventricle and in the right ventricle. Of all the patients, 24 (20.5%) (16 women and 8 men) were complicated with cerebral infarction. Among them, 3 patients were with lower extremity arterial embolisms. Two patients were with cerebral hemorrhage. The cerebral infarction mainly involved in the distribution area of the internal carotid artery. Infarctions involving 2 or more cerebral vessels were found in 4 cases. Most subjects (58.3%) manifested with hemiplegia, and some (18.2%) with syncope. The proportion of the left atrial myxoma in patients with cerebral infarction (100.0%) was significantly higher than those in patients without cerebral infarction (85.1%, P=0.044). Subjects with tumor diameter less than 3 cm were more frequently complicated with cerebral infarction (37.5% vs 13.8%, P= 0.009). A logistic analysis showed that the odds ratio of myxoma with tumor diameter less than 3 cm for cerebral infarction was 3.750(95%CI 1.343-10.470). Conclusions: Cardiac myxoma is more common in young women, and often complicated with cerebral infarction. The infarctions are mainly distributed in internal carotid artery system, and some are involved in multiple vascular systems. The incidence of stroke is associated with the position of the myxoma. Smail-size myxoma cannot be ignored for its risk of stroke.


A serology-based approach combined with clinical examination of 125 Ro/SSA-positive patients to define incidence and prevalence of subacute cutaneous lupus erythematosus.
To estimate the incidence and prevalence of Ro/SSA-positive subacute cutaneous lupus erythematosus (SCLE) in Stockholm County, Sweden (1.8 million inhabitants) and to investigate the frequency of photosensitivity and other clinical manifestations associated with Ro/SSA autoantibodies. Ro/SSA-positive patients in Stockholm were identified via registry-based searches. All patients who tested positive for the presence of Ro/SSA autoantibodies during 1996-2002 (n = 1,323; 85% women) were identified. A questionnaire was sent to all patients still living in Stockholm in 2003 (n = 1,048). Patients who reported having skin symptoms and photosensitivity (n = 125) underwent a clinical examination. Of the 741 (71%) of 1,048 Ro/SSA-positive patients who responded to the questionnaire, 400 (54%) reported having photosensitivity, and of these patients, 125 agreed to be clinically examined. A diagnosis of LE was confirmed in 59 of the 125 patients (SCLE in 20, systemic LE [SLE] in 33, and chronic CLE in 6). Eighty-six patients reported experiencing symptoms consistent with polymorphous light eruption (PLE). Comorbidities such as cardiovascular disease, autoimmune disease, and other skin diseases were common. The incidence of Ro/SSA-positive SCLE during the study period was estimated to be 0.7 cases per 100,000 persons per year and the prevalence was approximately 6.2-14 in 100,000 persons. The incidence of Ro/SSA-positive SCLE in Stockholm County, Sweden is estimated to be 0.7 per 100,000 persons per year as compared with an incidence of SLE in Sweden of 4.8 per 100,000 persons per year. The prevalence is estimated to be 6.2-14 in 100,000 persons. Self-reported photosensitivity commonly corresponds to a history of PLE in Ro/SSA-positive patients, even when the clinical profile of SCLE is absent. Photoprotection should therefore be included in the treatment recommendations for these patients.


Seeking the Value in Value-Based Care.
The market forces pushing health care to evolve from volume to value are intensifying. At the same time, the culture change, capabilities, assets, methods, and mindset required to redefine the health care paradigm are staggering. Unlike corporate initiatives, we simply can't get there thinking quarter to quarter. But we will get there.


Using FTIR-photoacoustic spectroscopy for phosphorus speciation analysis of biochars.
In the last decade, numerous studies have evaluated the benefits of biochar for improving soil quality. The purposes of the current study were to use Fourier transform infrared-photoacoustic spectroscopy (FTIR-PAS) to analyse P species in biochar and to determine the effect of pyrolysis temperature on P speciation. The photoacoustic detector has a range of advantages for the very dark biochar samples in comparison to more traditional reflectance or transmission FTIR detectors. The spectra turned out to be more informative in the regions with P vibrations for biochar produced at temperatures above 400°C, where most of the remaining organic compounds were aromatic and therefore not overlapping with the P vibrations. For biochars produced from the solid fraction of digestate from biogas production, an increase in the pyrolysis temperature led to the formation of a large variety of P species. Hydroxylapatite and tricalcium phosphate were the most dominant P species in the mid to high temperature range (600-900°C), while at 1050°C apatite, iron phosphates, variscite and calcium phosphates were identified. However, the changes in P speciation in biochars produced from bone meal at different temperatures were smaller than in the biochars from digestate. Hydroxylapatite and calcium phosphates were identified in biochar produced at all temperatures, while there was some indication of struvite formation.


Predicting potential survival benefit of renal transplantation in patients with chronic kidney disease.
To facilitate decision-making about treatment options for patients with end-stage renal disease considering kidney transplantation, we sought to develop an index for clinical prediction of risk for death. We derived and validated a multivariable survival model predicting time to death in 169,393 patients with end-stage renal disease who were eligible for transplantation. We modified the model into a simple point-system index. Deaths occurred in 23.5% of the cohort. Twelve variables independently predicted death: age, race, cause of kidney failure, body mass index, comorbid disease, smoking, employment status, serum albumin level, year of first renal replacement therapy, kidney transplantation, time to transplant wait-listing and time on the wait list. The index separated patients into 26 groups having significantly unique five-year survival, ranging from 97.8% in the lowest-risk group to 24.7% in the highest-risk group. The index score was discriminative, with a concordance probability of 0.746 (95% CI 0.741-0.751). Observed survival in the derivation and validation cohorts was similar for each level of index score in 93.9% of patients. Our prognostic index uses commonly available information to predict mortality accurately in patients with end-stage renal disease. This index could provide valuable quantitative data on survival for clinicians and patients to use when deciding whether to pursue transplantation or remain on dialysis.


Metabolic Engineering of Escherichia coli for para-Amino-Phenylethanol and para-Amino-Phenylacetic Acid Biosynthesis.
Aromatic amines are an important class of chemicals which are used as building blocks for the synthesis of polymers and pharmaceuticals. In this study we establish a de novo pathway for the biosynthesis of the aromatic amines para-amino-phenylethanol (PAPE) and para-amino-phenylacetic acid (4-APA) in Escherichia coli. We combined a synthetic para-amino-l-phenylalanine pathway with the fungal Ehrlich pathway. Therefore, we overexpressed the heterologous genes encoding 4-amino-4-deoxychorismate synthase (pabAB from Corynebacterium glutamicum), 4-amino-4-deoxychorismate mutase and 4-amino-4-deoxyprephenate dehydrogenase (papB and papC from Streptomyces venezuelae) and ThDP-dependent keto-acid decarboxylase (aro10 from Saccharomyces cerevisiae) in E. coli. The resulting para-amino-phenylacetaldehyde either was reduced to PAPE or oxidized to 4-APA. The wild type strain E. coli LJ110 with a plasmid carrying these four genes produced (in shake flask cultures) 11 ± 1.5 mg l-1 of PAPE from glucose (4.5 g l-1). By the additional cloning and expression of feaB (phenylacetaldehyde dehydrogenase from E. coli) 36 ± 5 mg l-1 of 4-APA were obtained from 4.5 g l-1 glucose. Competing reactions, such as the genes for aminotransferases (aspC and tyrB) or for biosynthesis of L-phenylalanine and L-tyrosine (pheA, tyrA) and for the regulator TyrR were removed. Additionally, the E. coli genes aroFBL were cloned and expressed from a second plasmid. The best producer strains of E. coli showed improved formation of PAPE and 4-APA, respectively. Plasmid-borne expression of an aldehyde reductase (yahK from E. coli) gave best values for PAPE production, whereas feaB-overexpression led to best values for 4-APA. In fed-batch cultivation, the best producer strains achieved 2.5 ± 0.15 g l-1 of PAPE from glucose (11% C mol mol-1 glucose) and 3.4 ± 0.3 g l-1 of 4-APA (17% C mol mol-1 glucose), respectively which are the highest values for recombinant strains reported so far.


Hydration and cognition: a critical review and recommendations for future research.
The limited literature on the effects of dehydration on human cognitive function is contradictory and inconsistent. Although it has been suggested that decrements in cognitive performance are present in the range of a 2 to 3% reduction in body weight, several dose-response studies indicate dehydration levels of 1% may adversely affect cognitive performance. When a 2% or more reduction in body weight is induced by heat and exercise exposure, decrements in visual-motor tracking, short-term memory and attention are reported, but not all studies find behavioral effects in this range. Future research should be conducted using dose-response designs and state-of-the-art behavioral methods to determine the lowest levels of dehydration that produce substantive effects on cognitive performance and mood. Confounding factors, such as caffeine intake and the methods used to produce dehydration, need to be considered in the design and conduct of such studies. Inclusion of a positive control condition, such as alcohol intake, a hypnotic drug, or other treatments known to produce adverse changes in cognitive performance should be included in such studies. To the extent possible, efforts to blind both volunteers and investigators should be an important consideration in study design.


In Vitro Activity of Miltefosine against Candida albicans under Planktonic and Biofilm Growth Conditions and In Vivo Efficacy in a Murine Model of Oral Candidiasis.
The generation of a new antifungal against Candida albicans biofilms has become a major priority, since biofilm formation by this opportunistic pathogenic fungus is usually associated with an increased resistance to azole antifungal drugs and treatment failures. Miltefosine is an alkyl phospholipid with promising antifungal activity. Here, we report that, when tested under planktonic conditions, miltefosine displays potent in vitro activity against multiple fluconazole-susceptible and -resistant C. albicans clinical isolates, including isolates overexpressing efflux pumps and/or with well-characterized Erg11 mutations. Moreover, miltefosine inhibits C. albicans biofilm formation and displays activity against preformed biofilms. Serial passage experiments confirmed that miltefosine has a reduced potential to elicit resistance, and screening of a library of C. albicans transcription factor mutants provided additional insight into the activity of miltefosine against C. albicans growing under planktonic and biofilm conditions. Finally, we demonstrate the in vivo efficacy of topical treatment with miltefosine in the murine model of oropharyngeal candidiasis. Overall, our results confirm the potential of miltefosine as a promising antifungal drug candidate, in particular for the treatment of azole-resistant and biofilm-associated superficial candidiasis.


Biological Nanopores: Confined Spaces for Electrochemical Single-Molecule Analysis.
Nanopore sensing is developing into a powerful single-molecule approach to investigate the features of biomolecules that are not accessible by studying ensemble systems. When a target molecule is transported through a nanopore, the ions occupying the pore are excluded, resulting in an electrical signal from the intermittent ionic blockade event. By statistical analysis of the amplitudes, duration, frequencies, and shapes of the blockade events, many properties of the target molecule can be obtained in real time at the single-molecule level, including its size, conformation, structure, charge, geometry, and interactions with other molecules. With the development of the use of α-hemolysin to characterize individual polynucleotides, nanopore technology has attracted a wide range of research interest in the fields of biology, physics, chemistry, and nanoscience. As a powerful single-molecule analytical method, nanopore technology has been applied for the detection of various biomolecules, including oligonucleotides, peptides, oligosaccharides, organic molecules, and disease-related proteins. In this Account, we highlight recent developments of biological nanopores in DNA-based sensing and in studying the conformational structures of DNA and RNA. Furthermore, we introduce the application of biological nanopores to investigate the conformations of peptides affected by charge, length, and dipole moment and to study disease-related proteins' structures and aggregation transitions influenced by an inhibitor, a promoter, or an applied voltage. To improve the sensing ability of biological nanopores and further extend their application to a wider range of molecular sensing, we focus on exploring novel biological nanopores, such as aerolysin and Stable Protein 1. Aerolysin exhibits an especially high sensitivity for the detection of single oligonucleotides both in current separation and duration. Finally, to facilitate the use of nanopore measurements and statistical analysis, we develop an integrated current measurement system and an accurate data processing method for nanopore sensing. The unique geometric structure of a biological nanopore offers a distinct advantage as a nanosensor for single-molecule sensing. The construction of the pore entrance is responsible for capturing the target molecule, while the lumen region determines the translocation process of the single molecule. Since the capture of the target molecule is predominantly diffusion-limited, it is expected that the capture ability of the nanopore toward the target analyte could be effectively enhanced by site-directed mutations of key amino acids with desirable groups. Additionally, changing the side chains inside the wall of the biological nanopore could optimize the geometry of the pore and realize an optimal interaction between the single-molecule interface and the analyte. These improvements would allow for high spatial and current resolution of nanopore sensors, which would ensure the possibility of dynamic study of single biomolecules, including their metastable conformations, charge distributions, and interactions. In the future, data analysis with powerful algorithms will make it possible to automatically and statistically extract detailed information while an analyte translocates through the pore. We conclude that these improvements could have tremendous potential applications for nanopore sensing in the near future.


A unified powerful set-based test for sequencing data analysis of GxE interactions.
The development of next-generation sequencing technologies has allowed researchers to study comprehensively the contribution of genetic variation particularly rare variants to complex diseases. To date many sequencing analyses of rare variants have focused on marginal genetic effects and have not explored the potential role environmental factors play in modifying genetic risk. Analysis of gene-environment interaction (GxE) for rare variants poses considerable challenges because of variant rarity and paucity of subjects who carry the variants while being exposed. To tackle this challenge, we propose a hierarchical model to jointly assess the GxE effects of a set of rare variants for example, in a gene or regulatory region, leveraging the information across the variants. Under this model, GxE is modeled by two components. The first component incorporates variant functional information as weights to calculate the weighted burden of variant alleles across variants, and then assess their GxE interaction with the environmental factor. Since this information is a priori known, this component is fixed effects in the model. The second component involves residual GxE effects that have not been accounted for by the fixed effects. In this component, the residual GxE effects are postulated to follow an unspecified distribution with mean 0 and variance [Formula: see text] We develop a novel testing procedure by deriving two independent score statistics for the fixed effects and the variance component separately. We propose two data-adaptive combination approaches for combining these two score statistics and establish the asymptotic distributions. An extensive simulation study shows that the proposed approaches maintain the correct type I error and the power is comparable to or better than existing methods under a wide range of scenarios. Finally we illustrate the proposed methods by a exome-wide GxE analysis with NSAIDs use in colorectal cancer.


Farnesoid X receptor contributes to oleanolic acid-induced cholestatic liver injury in mice.
Farnesoid X receptor (FXR) is a nuclear receptor involved in the metabolism of bile acid. However, the molecular signaling of FXR in bile acid homeostasis in cholestatic drug-induced liver injury remains unclear. Oleanolic acid (OA), a natural triterpenoid, has been reported to produce evident cholestatic liver injury in mice after a long-term use. The present study aimed to investigate the role of FXR in OA-induced cholestatic liver injury in mice using C57BL/6J (WT) mice and FXR knockout (FXR-/- ) mice. The results showed that a significant alleviation in OA-induced cholestatic liver injury was observed in FXR-/- mice as evidenced by decreases in serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase as well as reduced hepatocyte necrosis. UPLC-MS analysis of bile acids revealed that the contents of bile acids decreased significantly in liver and serum, while increased in the bile in FXR-/- mice compared with in WT mice. In addition, the mRNA expressions of hepatic transporter Bsep, bile acid synthesis enzymes Bacs and Baat, and bile acids detoxifying enzymes Cyp3a11, Cyp2b10, Ephx1, Ugt1a1, and Ugt2b5 were increased in liver tissues of FXR-/- mice treated with OA. Furthermore, the expression of membrane protein BSEP was significantly higher in livers of FXR-/- mice compared with WT mice treated with OA. These results demonstrate that knockout of FXR may alleviate OA-induced cholestatic liver injury in mice by decreasing accumulation of bile acids both in the liver and serum, increasing the export of bile acids via the bile, and by upregulation of bile acids detoxification enzymes.


Implications of Th1 and Th17 cells in pathogenesis of oral lichen planus.
Oral lichen planus (OLP) is considered a T cell-mediated autoimmune disease with unknown aetiology. T helper cells appear to play an important role in the pathogenesis of OLP. We investigated the possible role of T helper cells, Th1 and Th17, in the lesions and circulation of patients with OLP. Forty patients with OLP and 15 healthy volunteers were recruited. Double immunofluorescence staining was used to detect Th1 and Th17 cells in the OLP lesions, and intracellular cytokine staining and flow cytometry to evaluate the proportion of Th1 and Th17 cells in peripheral blood. The levels of serum interferon (IFN)-γ and interleukin (IL)-17 were assessed by using an enzyme-linked immunosorbent assay. It was found that Th17 cells, as well as Th1 cells, were present in OLP lesions. The proportion of peripheral Th1 and Th17 cells was significantly increased in patients with OLP. The proportion of Th17 cells in atrophic-erosive OLP was elevated as compared with that in reticular OLP. Serum IL-17 levels in OLP patients were significantly higher than in controls, and those in the atrophic-erosive OLP group were increased as compared with the reticular OLP group. However, the levels of serum IFN-γ were slightly decreased in OLP patients. Our data suggested that Th1 and Th17 cells in the local lesions and peripheral blood may be associated with the pathogenesis of OLP, and that IL-17 may be an important proinflammatory cytokine in OLP. These findings enhance our understanding of OLP pathogenesis.


Photodynamic Therapy for the Treatment and Diagnosis of Cancer-A Review of the Current Clinical Status.
Photodynamic therapy (PDT) has been used as an anti-tumor treatment method for a long time and photosensitizers (PS) can be used in various types of tumors. Originally, light is an effective tool that has been used in the treatment of diseases for ages. The effects of combination of specific dyes with light illumination was demonstrated at the beginning of 20th century and novel PDT approaches have been developed ever since. Main strategies of current studies are to reduce off-target effects and improve pharmacokinetic properties. Given the high interest and vast literature about the topic, approval of PDT as the first drug/device combination by the FDA should come as no surprise. PDT consists of two stages of treatment, combining light energy with a PS in order to destruct tumor cells after activation by light. In general, PDT has fewer side effects and toxicity than chemotherapy and/or radiotherapy. In addition to the purpose of treatment, several types of PSs can be used for diagnostic purposes for tumors. Such approaches are called photodynamic diagnosis (PDD). In this Review, we provide a general overview of the clinical applications of PDT in cancer, including the diagnostic and therapeutic approaches. Assessment of PDT therapeutic efficacy in the clinic will be discussed, since identifying predictors to determine the response to treatment is crucial. In addition, examples of PDT in various types of tumors will be discussed. Furthermore, combination of PDT with other therapy modalities such as chemotherapy, radiotherapy, surgery and immunotherapy will be emphasized, since such approaches seem to be promising in terms of enhancing effectiveness against tumor. The combination of PDT with other treatments may yield better results than by single treatments. Moreover, the utilization of lower doses in a combination therapy setting may cause less side effects and better results than single therapy. A better understanding of the effectiveness of PDT in a combination setting in the clinic as well as the optimization of such complex multimodal treatments may expand the clinical applications of PDT.


[Effects of Podoplanin on cell proliferation and cell cycle in oral leukoplakia cells].
To investigate the effects of Podoplanin on cell proliferation and cell cycle in oral leukoplakia cells. Oral leukoplakia cell line (Leuk-1) transfected with pCMV-Podoplanin (A4-1) or pCMV (B4-1) was used in this study. The levels of mRNA and protein of Podoplanin were detected by real-time PCR and Western boltting in A4-1, B4-1 and Leuk-1 cells. The localization of Podoplanin was detected by confocal microscope. Cell growth and proliferation was examined by methyl thiazolyl tetrazolium (MTT) assay and cell cycle was detected by flow cytometry (FCM). The value of Podoplanin mRNA level in A4-1 cells was 0.022, which was significantly higher than the values in B4-1 (0.001) and Leuk-1 cells (0.002), P < 0.05. The gray scale of Podoplanin protein in A4-1 cells was significantly higher than in the control groups (P < 0.05). The expression of Podoplanin was observed in cell plasm and membrane of A4-1, B4-1 and Leuk-1 cells. But the expression level of Podoplanin in A4-1 cells was higher than in control groups. A4-1 cells grew faster than Leuk-1 cells. The proliferation rate after 3 days of culture in A4-1 cells was 40.4% higher than that in B4-1 cells (P < 0.05). The G₂-M phase (24.89 +/- 4.55)% and PI (0.57 +/- 0.06) of A4-1 cells were significantly higher than that in B4-1 cells [(4.13 +/- 5.24)%, (0.41 +/- 0.04)] and Leuk-1 cells [(4.69 +/- 7.42)%, (0.40 +/- 0.02)], P < 0.05. Over expression of Podoplanin accelerated the growth and proliferation of oral leukoplakia cells. Podoplanin may be one of key genes in the malignant transformation of oral leukoplakia.