Time-Dependent Changes of Urethral Function in Diabetes Mellitus: A Review.
This article reviewed the current knowledge on time-course manifestation of diabetic urethral dysfunction (DUD), and explored an early intervention target to prevent the contribution of DUD to the progression of diabetes-induced impairment of the lower urinary tract (LUT). In the literature search through PubMed, key words used included "diabetes mellitus," "diabetic urethral dysfunction," and "diabetic urethropathy." Polyuria and hyperglycemia induced by diabetes mellitus (DM) can cause the time-dependent changes in functional and morphological manifestations of DUD. In the early stage, it promotes urethral dysfunction characterized by increased urethral pressure during micturition. However, the detrusor muscle of the bladder tries to compensate for inducing complete voiding by increasing the duration and amplitude of bladder contractions. As the disease progresses, it can induce an impairment of coordinated micturition due to dyssynergic activity of external urethra sphincter, leading to detrusor-sphincter dyssynergia. The impairment of relaxation mechanisms of urethral smooth muscles (USMs) may additionally be attributable to decreased responsiveness to nitric oxide, as well as increased USM responsiveness to α1-adrenergic receptor stimulation. In the late stage, diabetic neuropathy may play an important role in inducing LUT dysfunction, showing that the decompensation of the bladder and urethra, which can cause the decrease of voiding efficiency and the reduced thickness of the urothelium and the atrophy of striated muscle bundles, possibly leading to the vicious cycle of the LUT dysfunction. Further studies to increase our understandings of the functional and molecular mechanisms of DUD are warranted to explore potential targets for therapeutic intervention of DM-induced LUT dysfunction.


Aging, changes in the cardiovascular system, and responses to stress.
I have presented a picture of cardiovascular aging that resembles the situation with vision, where in the absence of actual disease, near vision changes with age and cataracts appear with age but after these are corrected, vision remains markedly unchanged with age. For the undiseased heart, intrinsic cardiac muscle function and the inotropic response to nonsympathetic mediators, along with coronary perfusion, are well maintained with age. There are, however, some changes that do occur with age. Cellular hypertrophy occurs, both because of cell drop out and because of some chamber hypertrophy secondary to increased impedance to left ventricular ejection. As a result of the hypertrophy, there is some prolongation of systole secondary to delayed relaxation. This is typical of what occurs in hypertension induced hypertrophy as well. These age-related changes are of critical importance and are the background for the entire discussion of the interplay between hypertension and disease. The large arteries do in fact stiffen with age. Thus, even without hypertension, there is an age-related increased impedance to ejection, a greater systolic load, a lower coronary perfusion pressure, and an increased pulse wave velocity. Added to this is the failure of the entire beta-sympathetic system to respond as well in the elderly as in the younger individuals with a resultant decrease in the vasodilating response. Both the chronotropic and inotropic response to sympathetic mediation is diminished so that states that put sudden loads on the left ventricle, such as accelerated hypertension or myocardial infarction, have more severe results in the elderly. Also acute hypertension may produce less hypertrophy in the elderly and therefore place more hemodynamic stress on the left ventricle than in young adults.


Aspartylglucosaminuria: cDNA encoding human aspartylglucosaminidase and the missense mutation causing the disease.
We have isolated a 2.1 kb cDNA which encodes human aspartylglucosaminidase (AGA, E.C. 188.8.131.52). The activity of this lysosomal enzyme is deficient in aspartylglucosaminuria (AGU), a recessively inherited lysosomal accumulation disease resulting in severe mental retardation. The polypeptide chain deduced from the AGA cDNA consists of 346 amino acids, has two potential N-glycosylation sites and 11 cysteine residues. Transient expression of this cDNA in COS-1 cells resulted in increased expression of immunoprecipitable AGA protein. Direct sequencing of amplified AGA cDNA from an AGU patient revealed a G----C transition resulting in the substitution of cysteine 163 with serine. This mutation was subsequently found in all the 20 analyzed Finnish AGU patients, in the heterozygous form in all 53 carriers and in none of 67 control individuals, suggesting that it represents the major AGU causing mutation enriched in this isolated population. Since the mutation produces a change in the predicted flexibility of the AGA polypeptide chain and removes an intramolecular S-S bridge, it most probably explains the deficient enzyme activity found in cells and tissues of AGU patients.


Predilection of Low Protein C-induced Spontaneous Atherothrombosis for the Right Coronary Sinus in Apolipoprotein E deficient mice.
Silencing of anticoagulant protein C using RNA interference (siProc) evokes low incident but spontaneous atherothrombosis in the aortic root of apolipoprotein E-deficient (Apoe-/-) mice. The aims of the current study were (1) to analyze if plaque characteristics or circulating factors could be linked to atherothrombosis susceptibility, (2) to increase the incidence of atherothrombosis by transiently increasing blood pressure, and (3) to direct atherothrombosis to an additional predefined vascular site by applying a semi-constrictive collar around the carotid artery. siProc-driven spontaneous atherothrombosis in the aortic root of Apoe-/- mice was reproduced and occurred at an incidence of 23% (9 out of 39 mice), while the incidence of collar-induced atherothrombosis in the carotid artery was 2.6% (1 out of 39 mice). Treatment with phenylephrine, to transiently increase blood pressure, did not increase atherothrombosis in the aortic root of the Apoe-/- mice nor in the carotid arteries with collars. Plaques in the aortic root with an associated thrombus were lower in collagen and macrophage content, and mice with atherothrombosis had significantly more circulating platelets. Plasma protein C, white blood cell counts, total cholesterol, fibrinogen, serum amyloid A, and IL-6 were not different amongst siProc treated mice with or without thrombosis. Remarkably, our data revealed that thrombus formation preferably occurred on plaques in the right coronary sinus of the aortic root. In conclusion, there is a predilection of low protein C-induced spontaneous atherothrombosis in Apoe-/- mice for the right coronary sinus, a process that is associated with an increase in platelets and plaques lower in collagen and macrophage content.


A Case of Legionnaires' Disease Manifesting as Heat Exhaustion.
A 69-year-old male with a history of prior admissions of heat exhaustion presented with non-specific symptoms including fatigue, diarrhea, and dehydration. The workup revealed a positive legionella urine antigen. He was treated with levofloxacin with symptom resolution within 48 hours.


Comparison of apolipoprotein B to cholesterol in low density lipoproteins of patients with coronary heart disease.
This study was carried out to determine whether patients with coronary heart disease (CHD) have an unusually high level of apolipoprotein B (apoB) relative to cholesterol (C) in low density lipoproteins (LDL). Seven groups of men were studied. Seventy-two with normolipidemia (NLP) had CHD documented on clinical grounds; another 34 NLP patients had proven coronary artery disease (CAD) by angiography (greater than 50% occlusion of two or three coronary arteries). Another group of 37 with documented CHD had hypertriglyceridemia (HTG), and still another 25 with HTG had proven CAD. Three normolipidemic control groups consisted of 30 healthy young men, 40 healthy middle-aged men, and 35 hypertensive men. In normolipidemic CHD and CAD patients, plasma LDL-C averaged 142 +/- 37 (SD) and 136 +/- 32 mg/dl, respectively; in HTG patients with CHD and CAD, LDL-C levels were 137 +/- 37 and 127 +/- 34 mg/dl, respectively. These values were near those of hypertensive controls (141 +/- 31 mg/dl), but higher than middle-aged and younger healthy controls (118 +/- 32 and 106 +/- 26 mg/dl, respectively). Levels of LDL-apoB followed a similar pattern: CHD-NLP (88 +/- 25 mg/dl), CAD-NLP (83 +/- 25 mg/dl), CHD-HTG (94 +/- 30 mg/dl), CAD-HTG (89 +/- 25 mg/dl), hypertensive controls (89 +/- 24 mg/dl), middle-aged controls (80 +/- 25 mg/dl) and younger controls (58 +/- 14 mg/dl). Normolipidemic patients with CHD and CAD did not have higher LDL-C and LDL-apoB levels than hypertensive and normotensive controls. HTG patients with CHD and CAD however tended to have higher LDL-apoB levels, and their LDL-apoB/C ratios were higher on average than normal. Nevertheless, among all coronary groups, there were no sizable subgroups with elevated LDL-apoB; only about 11% of all coronary patients had LDL-apoB levels over 120 mg/dl (compared to 8% for normo- and hypertensive controls of middle age). The data of this study therefore suggest that LDL-apoB may not prove to be a better indicator of coronary risk in normolipidemic people, but LDL-apoB could be a superior predictor of risk in HTG patients.


Five Challenges When Managing Mass Casualty or Disaster Situations: A Review Study.
Background: Managing mass casualty or disaster incidents is challenging to any person or organisation. Therefore, this paper identifies and describes common challenges to managing such situations, using case and lessons learned reports. It focuses on sudden onset, man-made or technologically caused mass casualty or disaster situations. Methods: A management review was conducted based on a structured search in the PubMed and Web of Science databases. Results: The review included 20 case-and lessons learned reports covering natural disasters, man-made events, and accidents across Europe, the United States of Amerika (USA), Asia and the Middle East. Five common challenges were identified: (1) to identify the situation and deal with uncertainty, (2) to balance the mismatch between the contingency plan and the reality, (3) to establish a functional crisis organization, (4) to adapt the medical response to the actual and overall situation and (5) to ensure a resilient response. Conclusions: The challenges when managing mass casualty or disaster events involved were mainly related to the ability to manage uncertainty and surprising situations, using structured processes to respond. The ability to change mind set, organization and procedures, both from an organizational- and individual perspective, was essential. Non-medical factors and internal factors influenced the medical management. In order to respond in an effective, timely and resilient way, all these factors should be taken into consideration.


Targeting TNF and TNF Receptor Pathway in HIV-1 Infection: from Immune Activation to Viral Reservoirs.
Several cellular functions such as apoptosis, cellular proliferation, inflammation, and immune regulation involve the tumor necrosis factor-α (TNF)/TNF receptor (TNFR) pathway. Human immunodeficiency virus 1 (HIV-1) interacts with the TNF/TNFR pathway. The activation of the TNF/TNFR pathway impacts HIV-1 replication, and the TNF/TNFR pathway is the target of HIV-1 proteins. A hallmark of HIV-1 infection is immune activation and inflammation with increased levels of TNF in the plasma and the tissues. Therefore, the control of the TNF/TNFR pathway by new therapeutic approaches could participate in the control of immune activation and impact both viral replication and viral persistence. In this review, we will describe the intricate interplay between HIV-1 proteins and TNF/TNFR signaling and how TNF/TNFR activation modulates HIV-1 replication and discuss new therapeutic approaches, especially anti-TNF therapy, that could control this pathway and ultimately favor the clearance of infected cells to cure HIV-infected patients.


The Spanish Adaptation of the Sport Motivation Scale-II in Adolescent Athletes.
The aim of this study was to adapt and validate the Spanish version of the Sport Motivation Scale-II (S-SMS-II) in adolescent athletes. The sample included 766 Spanish adolescents (263 females and 503 males; average age = 13.71 ± 1.30 years old). The methodological steps established by the International Test Commission were followed. Four measurement models were compared employing the maximum likelihood estimation (with six, five, three, and two factors). Then, factorial invariance analyses were conducted and the effect sizes were calculated. Finally, the reliability was calculated using Cronbach's alpha, omega, and average variance extracted coefficients. The five-factor S-SMS-II showed the best indices of fit (Cronbach's alpha .64 to .74; goodness of fit index .971, root mean square error of approximation .044, comparative fit index .966). Factorial invariance was also verified across gender and between sport-federated athletes and non-federated athletes. The proposed S-SMS-II is discussed according to previous validated versions (English, Portuguese, and Chinese).


Age‑associated variation in the expression and function of TMEM16A calcium‑activated chloride channels in the cochlear stria vascularis of guinea pigs.
The present study was designed to investigate the expression and function of transmembrane protein 16 (TMEM16A), a calcium‑activated chloride channel (CaCC), in the stria vascularis (SV) of the cochlea of guinea pigs at different ages, and to understand the role of CaCCs in the pathogenesis of presbycusis (age‑related hearing loss), the most common type of sensorineural hearing loss that occurs with natural aging. Guinea pigs were divided into the following groups: 2 weeks (young group), 3 months (youth group), 1 year (adult group), D‑galactose intervention (D‑gal group; aging model induced by subcutaneous injection of D‑galactose) and T16Ainh‑A01 (intraperitoneal injection of 50 µg/kg/day TMEM16A inhibitor T16Ainh‑A01 for 2 weeks). Differences in the hearing of guinea pigs between the various age groups were analyzed using auditory brainstem response (ABR), and immunofluorescence staining was performed to detect TMEM16A expression in the SV and determine the distribution. Reverse transcription‑quantitative PCR and western blot analyses were conducted to detect the mRNA and protein levels of TMEM16A in SV in the different age groups. Morris water maze behavior analysis demonstrated that spatial learning ability and memory were damaged in the D‑gal group. Superoxide dismutase activity and malondialdehyde content assays indicated that there was oxidative stress damage in the D‑gal group. The ABR thresholds gradually increased with age, and the increase in the T16Ainh‑A01 group was pronounced. Immunofluorescence analysis in the cochlear SV of guinea pigs in different groups revealed that expression of TMEM16A increased with increasing age (2 weeks to 1 year); fluorescence intensity was reduced in the D‑gal model of aging. As the guinea pigs continued to mature, the protein and mRNA contents of TMEM16A in the cochlea SV increased gradually, but were decreased in the D‑gal group. The findings indicated that CaCCs in the cochlear SV of guinea pigs were associated with the development of hearing in guinea pigs, and that downregulation of TMEM16A may be associated with age‑associated hearing loss.


Cholera - recommendations for prevention in travellers.
This article about cholera is part of our travel medicine series for 2010, providing a summary of prevention strategies and vaccination for infections that may be acquired by travellers. The series aims to provide practical strategies to assist general practitioners in giving travel advice, as a synthesis of multiple information sources which must otherwise be consulted. Cholera is a severe diarrhoeal disease associated with worldwide pandemics. It affects vulnerable populations who lack adequate quality drinking water and sanitation. Travellers are generally at low risk of contracting cholera, even in endemic areas. It is prevented with general water and food precautions (also advisable for prevention of traveller's diarrhoea). In some situations, the oral killed whole cell B subunit vaccine may be recommended for travellers considered at risk.


[The clinical and immunological manifestations of food intolerance in obese patients].
The clinical and immunological manifestations of food intolerance in obese patients were studied. Food intolerance was diagnosed in 32.6 and 33.4% in obese patients stage 2 and stage 3 respectively, and was basically determined by 13 proteinaceous food products. The changes in immune status in obese patients created conditions for development of food intolerance. The timely diagnose food intolerance allows to personalize the diet therapy.


Statistical methods for HIV dynamic studies in AIDS clinical trials.
Studies of HIV dynamics in AIDS research are very important for understanding pathogenesis of HIV infection and for assessing the potency of antiviral therapies. Since the viral dynamic results from clinical data were first published by Ho et al. and Wei et al., the study of HIV-1 dynamics in vivo has drawn a great attention from AIDS clinicians and researchers. Although the important findings from HIV dynamic studies have been published in many prestigious scientific journals, statistical methods for estimating viral dynamic parameters have not been paid enough attention by HIV dynamic investigators. The estimation methods in many viral dynamic studies are very crude and inefficient. In this paper, we review the statistical methods and mathematical models for HIV dynamic data analysis developed in recent years. We also address some practical issues and share our experiences in the design and analysis of viral dynamic studies. Some principles and guidelines for the design and analysis of viral dynamic studies are provided. The methodologies reviewed in this paper are also applicable to studies of other viruses such as hepatitis B virus or hepatitis C virus. We also pose some challenging statistical problems in this area in order to stimulate further study by the statistical research community.


Isolation and characterization of temperature-sensitive mutants of the Staphylococcus aureus dnaC gene.
A protein encoded by the Staphylococcus aureus dnaC gene has 44% and 58% homology with Escherichia coli DnaB and Bacillus subtilis DnaC replicative DNA helicases, respectively. We identified five mutant strains whose temperature-sensitive colony formation phenotypes were complemented by the dnaC gene. DNA replication in these mutants has a fast-stop phenotype, indicating that the S. aureus dnaC gene encodes the replicative DNA helicase required for the elongation step. These mutants were also sensitive to UV irradiation, suggesting that the dnaC gene is involved in DNA repair. The number of viable mutant cells decreased at a non-permissive temperature, suggesting that S. aureus DnaC helicase is a promising target for antibiotics providing bactericidal effects.


[Prolonged muscle weakness in intensive care patients with special attention to the so-called intensive care polyneuromyopathy].
Generalized muscle weakness in critically ill patients can result in prolonged periods of artificial ventilation and longer stays in the intensive care unit. Both neuropathic (critical illness polyneuropathy) and myopathic (critical illness myopathy) abnormalities seem to play an important role for this prolonged weakness. This article reviews its complex differential diagnosis with special emphasis on the current understanding of the neuromuscular syndromes. An efficient diagnostic plan is necessary for the exclusion of other curable causes of prolonged muscle weakness even in the presence of polyneuromyopathic changes. Psychological support of the patient and prophylaxis of secondary complications of prolonged immobilization are crucial when specific therapy is not possible.


Medical devices for the treatment of obesity.
Obesity is a major public health concern that leads to numerous metabolic, mechanical and psychological complications. Although lifestyle interventions are the cornerstone of obesity management, subsequent physiological neurohormonal adaptations limit weight loss, strongly favour weight regain and counteract sustained weight loss. A range of effective therapies are therefore needed to manage this chronic relapsing disease. Bariatric surgery delivers substantial, durable weight loss but limited access to care, perceived high risks and costs restrict uptake. Medical devices are uniquely positioned to bridge the gap between more conservative lifestyle intervention and weight-loss pharmacotherapy and more disruptive bariatric surgery. In this Review, we examine the range of gastrointestinal medical devices that are available in clinical practice to treat obesity, as well as those that are in advanced stages of development. We focus on the mechanisms of action as well as the efficacy and safety profiles of these devices. Many of these devices are placed endoscopically, which provides gastroenterologists with exciting opportunities for treatment.


Pharmacological effects of a novel isosorbide-based butyrylcholinesterase inhibitor.
Isosorbide-2-benzylcarbamate-5-benzoate, a novel butyrylcholinesterase inhibitor, shows interspecies variation in its inhibitory activity (IC(50) of 4.3 nM for human plasma butyrylcholinesterase, but 1.09 microM for mouse plasma butyrylcholinesterase). Stability studies revealed that this drug is resistant to hydrolysis by human plasma (no degradation in 1 h). However, it was found to undergo rapid degradation when incubated with mouse plasma or mouse liver homogenate, yielding benzyl carbamate and benzoic acid. The addition of the carboxylesterase inhibitor bis-(4-nitrophenyl) phosphate (BNPP) inhibited the degradation of the novel drug, indicating that it may be a substrate for both butyrylcholinesterase and carboxylesterase. The absence of carboxylesterase from human plasma explains the drug's stability in this medium. In vivo, pharmacodynamic studies on single doses of 1 mg/kg to naïve male C57BL/6 mice revealed maximal plasma butyrylcholinesterase inhibition 20 min after intraperitoneal administration (approximately 60% inhibition) and 1 h after administration by gavage (approximately 45% inhibition). While this plasma butyrylcholinesterase inhibition was short-lived, the drug also penetrated the blood-brain barrier resulting in a slight (10-15%) but persistent (> or =72 h) reduction in brain butyrylcholinesterase activity.


Enhanced prostaglandin synthesis after ultraviolet injury is mediated by endogenous histamine stimulation. A mechanism for irradiation erythema.
Acute ultraviolet light B (UVB) injury is associated with dermal mast cell histamine release. The possibility that histamine-stimulated prostaglandin (PG) synthesis could be a mechanism for irradiation erythema was therefore examined using human skin explants. Explants responded to UV irradiation (120 mJ/cm2) with a fivefold increase in synthesis of prostaglandins E2, F2 alpha and 6-keto PGF1 alpha. Incubating explants with the H1 antihistamines brompheniramine (50 microM) or pyrilamine (30 microM) inhibited PG release from irradiated explants 63 +/- 4.9% (mean +/- SEM) 6 h after UV exposure. Antihistamines did not affect PG synthesis in control explants. Irradiation increased the histamine concentration in explant conditioned medium only 50% over basal values, suggesting that irradiation enhanced histamine responsiveness. Explants were therefore incubated with exogenous histamine. In irradiated explants, PG synthesis was stimulated threefold by 3 microM histamine. Unirradiated explants' PG synthesis was unaffected by histamine. Enhanced histamine sensitivity was also examined in epidermal cell cultures. In irradiated cultures, histamine sensitivity was again markedly potentiated: as little as 1 microM histamine stimulated significant PGE2 release and the response to 10-30 microM histamine was increased six to eight times compared with that of unirradiated cultures. These studies demonstrate that endogenous histamine stimulates PG synthesis in human skin after UV injury by potentiation of histamine-induced prostaglandin release. Potentiated agonist responses induced by UV exposure may contribute to the effects of UVB irradiation injury and in particular to irradiation erythema.


Is aliskiren superior to inhibitors of angiotensin-converting enzyme and angiotensin receptor blockers in renin-angiotensin system blockade?
The renin-angiotensin system (RAS) plays a crucial role in development of hypertension, heart failure, as well as in the whole process of nephropathy, particularly of diabetic nephropathy, with or without proteinuria. Blockade of RAS plays the key role in the management of hypertension and other cardiovascular diseases. Angiotensin-converting enzyme (ACE) inhibitors do not provide the full blockade of angiotensin II because it is produced through alternative pathways. Angiotensin receptor blockers (ARBs) also block the negative feedback of angiotensin II upon renin like ACE inhibitors, leading to a several fold increase in angiotensin II levels. Aliskiren is an orally-active, nonpeptidic, direct inhibitor of renin which simultaneously reduces angiotensin I, angiotensin II and plasma renin activity (PRA). This is the main point of action of aliskiren, making it completely different from ACE inhibitors and ARBs. Aliskiren introduces a new concept into the management of hypertension. However, the question concerning its real role in the management of heart failure and its place in the existing therapeutic schemes with ACE inhibitors, ARBs, beta blockers and antagonists of aldosterone receptor, will be answered by numerous ongoing studies and clinical trials. Aliskiren shows renoprotective and antiproteinuric effects similar to those of ACE inhibitors and ARBs. The available results demonstrate that aliskiren provides a new approach to the antagonism of the RAS, offering possibilities of a more efficacious and effective treatment of hypertension, heart failure and proteinuria in diabetic patient.


Effects of training and withdrawal periods on heroin seeking induced by conditioned cue in an animal of model of relapse.
A high incidence of relapse can be triggered by exposure to conditioned cues previously associated with heroin. Extended access to drug and withdrawal are thought to affect the motivation for drug seeking. The present study evaluated how different periods of training to self-administer heroin and different periods of withdrawal affected drug seeking. Following 1 to 14 days of heroin self-administration, rats were left in the home environment for 1 or 14 days. Subsequently, rats were evaluated for extinction of nose poke during the first hour after being returned to the training apparatus. One hour later, a conditioned stimulus was presented to initiate cue-induced reinstatement. Extending the training period from 1 to 14 days caused an escalation of reinstatement of drug seeking induced by conditioned cues. Increasing the withdrawal period from 1 to 14 days produced a similar increase in reinstatement of drug seeking induced by cues. Reinstatement of drug seeking induced by cues was augmented by pretreatment with naltrexone (1, 5 mg/kg) 24 h prior to reinstatement on day 1, but not at 14 days of withdrawal from heroin self-administration. These experiments demonstrate that increasing the duration of either heroin self-administration or the withdrawal periods from heroin self-administration augments the reinstatement induced by cues that were associated previously with heroin reinforcement. Additionally, we provide one of the first demonstrations that opiate withdrawal induces heroin seeking, as assessed in the reinstatement model.


[ATP-synthase--intracellular molecular turbine].
Literature data on molecular and functional organization of ATP synthase as turbine-like rotary motor are reviewed. These data now provide the first experimental evidence that ATP synthases from different sources are able to reversibly couple the proton-motive force (proton electrochemical potential) with the synthesis/hydrolysis of ATP by the mechanical rotation of the rotor component of enzyme relative to the its stator part.


Impact of human leukocyte antigen molecules E, F, and G on the outcome of transplantation.
HLA class I molecules are divided into classic (Ia) and nonclassic (Ib). Nonclassic HLA molecules (E, F, and G) have acquired relevance owing to their immunomodulatory properties and possible repercussions for induction of tolerance in organ transplantation. The objective of this study was to identify the impact of these molecules on transplant success or failure. A systematic review of literature was performed with the use of MeSH terms in Pubmed. Clinical trials, randomized clinical trials, case-control studies, and reviews from the past 15 years were included. HLA-E*0103/E*0103 genotype is associated with lower risk of graft-versus-host disease, decreased mortality, and greater disease-free survival after bone marrow transplantation. There were no significant associations between HLA-F and clinical outcomes in any of the studies. Elevated serum levels of HLA-G were associated with a lower incidence of rejection in hepatic and renal transplantation during the 1st year and lower T-cell response after bone marrow, liver, and kidney transplantation. Detection of mRNA of HLA-G1 was also associated with less graft rejection. Current literature suggests that nonclassic HLA Ib molecules play an important role in immunotolerance in organ transplantation; however, more studies are required to predict outcomes related to specific genotypes.


Recombinant BCG coexpressing Ag85B, ESAT-6 and mouse-IFN-gamma confers effective protection against Mycobacterium tuberculosis in C57BL/6 mice.
In this study, the protective efficacy of a novel recombinant bacille Calmette Géurin (BCG) strain (rBCG-AEI) expressing fusion protein the antigen 85B (Ag85B)- the 6-kDa early secreted antigen target (ESAT-6)-IFN-gamma against Mycobacterium tuberculosis H37Rv in mice was evaluated. The immunogenicity study showed that rBCG-AEI could induce higher specific antibody titers and significantly increase cellular immune response than BCG, or rBCG-A strain (expressing Ag85B), or rBCG-AE strain (expressing fusion protein Ag85B-ESAT-6). The protective experiment demonstrated that rBCG-AEI could confer similar or even better protective efficacy against M. tuberculosis infection compared with others in organ bacterial loads, lung histopathology and net weight gain or loss. The results suggested that rBCG-AEI is a potential candidate for further study.


Comparison of isometric and load moving length-tension models of two bicompartmental muscles.
The length-tension relations of two bicompartmental muscles, including parallel and pennated fibers, were experimentally determined for isometric and load moving contractions. Comparison of the isometric and constant mass load length-tension curves obtained from the same preparations demonstrated significant reductions in force, a shift of the optimal length and increased elongation range for shortening contractions under constant mass load. Pennated muscle demonstrated a larger reduction in force and greater shift in the optimal length relative to the changes in a muscle with parallel fibers. A bicompartmental model was fitted to the experimental data to provide quantitative insight to the changes described above, and for use in mathematical models of other bicompartmental muscles, and for design of optimal electrical stimulation system for restoration of function in spinal cord injury patients.


Studying the "sexuality-health-technology nexus": a new materialist visual methodology.
A school of critical sexual health scholars argues that biomedical and digital technologies need to be understood not as mere objects of use, but as having the agentic capacity to effect new senses of the self and transform social/sexual health relations and outcomes. Such a call to grapple with the multidimensionality of technologies, their affects and effects poses a challenge to current methodological frameworks. To address this challenge, we introduce a novel visual methodology called "embodied mapping" that builds on the arts-based method of body mapping. Drawing from new materialism scholarship, embodied mapping extends the scope of inquiry of sexual-health research and conventional qualitative methods. It does so by interrogating the capacities and properties of sexual agents, technologies and readily available discourses on sexual health and HIV prevention as co-constitutive within the sexual-health-technologies nexus itself. Embodied mapping's research process is collaborative and emergent; researchers, together with an artist and research participants co-create a visual collage tracing the thick moments of sexual/health encounters. Embodied mapping's methodological and analytical capacity to approach sexual health phenomena as performative and immanent to the research process could open new sight lines for comprehending and intervening in this globalised era marked by an increasing technologising of sexual health care.


Urging others to be healthy: "intravention" by injection drug users as a community prevention goal.
"Intravention," prevention activities that are conducted by and sustained through ongoing actions of members of communities-at-risk, is an appropriate goal for HIV intervention activities. Data from 120 injection drug users in a Brooklyn, New York, neighborhood that has seen decreases in HIV prevalence among IDUs and little HIV diffusion to young adults indicate that most of them have recently (3 months) urged other people to engage in one or more self-protective actions. These data suggest that the common image of IDUs as simply being sources of social and medical problems is inaccurate. Research is needed into how to create and diffuse "communities of intravention; " and we suggest that behavioral interventions be evaluated for their success or failure at creating outward-focused health communication by participants as well as for their impact on individual risk behaviors.


Regional immunotherapy for liver and peritoneal metastases.
Pancreatic adenocarcinoma is a biologically aggressive disease, with liver and peritoneal metastases being a frequent cause of death. We examine how the pancreatic carcinoma microenvironment and immunosuppressive landscape favor tumor progression. Immunotherapy has shown promise in select solid tumors, yet challenges remain in applying these gains to stage IV pancreatic adenocarcinoma. We discuss how regional therapy strategies may be leveraged to open new avenues for treating pancreatic carcinoma metastases with immunotherapy.


Nasal IgA Provides Protection against Human Influenza Challenge in Volunteers with Low Serum Influenza Antibody Titre.
In spite of there being a number of vaccines, influenza remains a significant global cause of morbidity and mortality. Understanding more about natural and vaccine induced immune protection against influenza infection would help to develop better vaccines. Virus specific IgG is a known correlate of protection, but other factors may help to reduce viral load or disease severity, for example IgA. In the current study we measured influenza specific responses in a controlled human infection model using influenza A/California/2009 (H1N1) as the challenge agent. Volunteers were pre-selected with low haemagglutination inhibition (HAI) titres in order to ensure a higher proportion of infection; this allowed us to explore the role of other immune correlates. In spite of HAI being uniformly low, there were variable levels of H1N1 specific IgG and IgA prior to infection. There was also a range of disease severity in volunteers allowing us to compare whether differences in systemic and local H1N1 specific IgG and IgA prior to infection affected disease outcome. H1N1 specific IgG level before challenge did not correlate with protection, probably due to the pre-screening for individuals with low HAI. However, the length of time infectious virus was recovered from the nose was reduced in patients with higher pre-existing H1N1 influenza specific nasal IgA or serum IgA. Therefore, IgA contributes to protection against influenza and should be targeted in vaccines.


Assessment of Hearing Impairment in Sick Newborns: A Prospective Observational Study.
Undiagnosed neonatal hearing loss causes severe language, cognitive, and behavioral problems in children. Sick newborns who spend 48 hours in the neonatal intensive care unit (NICU) have a 10- to 20-fold increased risk of permanent hearing loss. The aim of this study is to identify hearing impairment in high-risk sick newborns who spend at least 48 hours in the NICU. The present prospective observational study was conducted at a single center. All sick neonates admitted to the NICU for a minimum of 48 hours at the JK Lon Hospital, Zanana Hospital, and Mahila Chikitsalaya, Sawai Man Singh (SMS) Medical College, Jaipur, Rajasthan, India, from June 2017 to May 2018 were considered eligible for the study. The primary outcome was the assessment of hearing loss of high-risk newborns using otoacoustic emissions at the time of discharge, six weeks of age, and automated auditory brainstem response (AABR) at three months of chronological age. The secondary outcome was to analyze the association of hearing loss with different risk factors in high-risk neonates. A total of 150 infants who had one or more risk factors were studied, 60 were female and 90 were male. No statistically significant difference in hearing loss was observed based on birth weight, sex, and gestational age. The first distortion-product otoacoustic emission (DPOAE) screening was done on infants at the time of discharge from the NICU. Eighty-three infants (55.33%) had "refer" on the first DPOAE and the remaining 67 (44.67%) were passed results at the time of discharge. At six weeks of life, on repeat screening with a second DPOAE test, 36% "refer" on the first screen had a "refer" result on the second DPOAE. However, 4.4% "pass" on the first screen turned out to be "refer" on the second screen. These 33 infants who had "refer" results on the second screen were subjected to testing. At 10 weeks of life, AABR was performed on 33 infants. Eleven infants out of 33 had sensorineural hearing loss (SNHL) on AABR. Hearing impairment with the DPOAE test was observed with risk factors neonatal hyperbilirubinemia (NHH), hypoxic ischemic encephalopathy (HIE), and very low birth weight (VLBW) and was statistically significant among all risk factors. But, no such association (between hearing impairment and risk factors) was observed with the AABR test. In our study, we found that the duration of mechanical ventilation in mean days 7.67±6.24 had statistically significant SNHL compared to the lesser duration of mechanical ventilation (p<0.001). Two-stage DPOAE done prior to AABR is helpful in the early detection of hearing loss.


A high proportion of red snapper sold in North Carolina is mislabeled.
Seafood mislabeling occurs when a market label is inaccurate, primarily in terms of species identity, but also regarding weight, geographic origin, or other characteristics. This widespread problem allows cheaper or illegally-caught species to be marketed as species desirable to consumers. Previous studies have identified red snapper (Lutjanus campechanus) as one of the most frequently mislabeled seafood species in the United States. To quantify how common mislabeling of red snapper is across North Carolina, the Seafood Forensics class at the University of North Carolina at Chapel Hill used DNA barcoding to analyze samples sold as "red snapper" from restaurants, seafood markets, and grocery stores purchased in ten counties. Of 43 samples successfully sequenced and identified, 90.7% were mislabeled. Only one grocery store chain (of four chains tested) accurately labeled red snapper. The mislabeling rate for restaurants and seafood markets was 100%. Vermilion snapper (Rhomboplites aurorubens) and tilapia (Oreochromis aureus and O. niloticus) were the species most frequently substituted for red snapper (13 of 39 mislabeled samples for both taxa, or 26 of 39 mislabeled total). This study builds on previous mislabeling research by collecting samples of a specific species in a confined geographic region, allowing local vendors and policy makers to better understand the scope of red snapper mislabeling in North Carolina. This methodology is also a model for other academic institutions to engage undergraduate researchers in mislabeling data collection, sample processing, and analysis.


Broadband SERS Enhancement by DNA Origami Assembled Bimetallic Nanoantennas with Label-Free Single Protein Sensing.
Engineering hotspots in surface-enhanced Raman spectroscopy (SERS) through precisely controlled assembly of plasmonic nanostructures capable of expanding intense field enhancement are highly desirable to enhance the potentiality of SERS as a label-free optical tool for single molecule detection. Inspired by DNA origami technique, we constructed plasmonic dimer nanoantennas with a tunable gap decorated with Ag-coated Au nanostars on origami. Herein, we demonstrate the single-molecule SERS enhancements of three dyes with emission in different spectral regions after incorporation of single dye molecules in between two nanostars. The enhancement factors (EFs) achieved in the range of 109-1010 for all the single dye molecules, under both resonant and nonresonant excitation conditions, would enable enhanced photostability during time-series measurement. We further successfully explored the potential of our designed nanoantennas to accommodate and detect a single thrombin protein molecule after selective placement in the wide nanogap of 10 nm. Our results suggest that such nanoantennas can serve as a broadband SERS enhancer and enable specific detection of target biological molecules with single-molecule sensitivity.


Influence of Background Noise Produced in University Facilities on the Brain Waves Associated With Attention of Students and Employees.
As a consequence of noise exposure, lack of attention badly affects directly the academic and work performance. The study of the brain and the waves that it produces is the most objective way to evaluate this process. Attentional improvement is associated with increases of the amplitude in both beta and theta bands. The objective of this work is to study the influence of background noise produced inside university facilities on changes in the cerebral waves related to attention processes (beta 13-30 Hz and theta 4-7 Hz). Volunteers were asked to perform a specific task in which attention was involved. This task was performed in both silent and noisy conditions. To evaluate the cerebral activity of volunteers during the development of the test, measurement of spontaneous activity (electroencephalogram) was developed. The results show significant decreases in both beta and theta frequency bands under background noise exposure. Since attentional improvement is related to an increment on amplitude of both beta and theta bands, it is suggested that decreases on amplitude of these frequency bands could directly be related to a lack of attention caused by the exposure to background noise.


Signaling mechanisms involved in crystal-induced tissue damage.
The association of crystal deposition with osteoarthritis and joint destruction is well established. Recent advances in understanding the mechanisms whereby calcium crystals contribute to cartilage damage are highlighted in this review. In vitro studies have shown that when calcium-containing crystals come in contact with cells they cause an influx in Ca 2+ concentration and activation of p42/44 mitogen-activated protein kinases. This is followed by induction of proto-oncogenes (c- fos, c- jun ) and induction of the nuclear transcription factors activator protein-1 and nuclear factor-kappaB, which in turn lead to crystal-induced modulation of normal gene expression. Some of the downstream effects known to date include increased mitogenesis, up-regulation of members of the matrix metalloproteinase family, down-regulation of tissue inhibitor of metalloproteinase-1 and -2 in fibroblasts, induction of neutrophil chemotactic chemokines such as interleukin-8, activation and degranulation of neutrophils, and inhibition of neutrophil apoptosis. Because no known drug prevents or treats the consequences of basic calcium phosphate crystal deposition, an improved understanding of the molecular mechanisms leading to crystal-induced joint degeneration is essential to the development of a rational approach to target the consequences of crystal deposition.


Breaching Subjects' Thoughts Privacy: A Study with Visual Stimuli and Brain-Computer Interfaces.
Brain-computer interfaces (BCIs) started being used in clinical scenarios, reaching nowadays new fields such as entertainment or learning. Using BCIs, neuronal activity can be monitored for various purposes, with the study of the central nervous system response to certain stimuli being one of them, being the case of evoked potentials. However, due to the sensitivity of these data, the transmissions must be protected, with blockchain being an interesting approach to ensure the integrity of the data. This work focuses on the visual sense, and its relationship with the P300 evoked potential, where several open challenges related to the privacy of subjects' information and thoughts appear when using BCI. The first and most important challenge is whether it would be possible to extract sensitive information from evoked potentials. This aspect becomes even more challenging and dangerous if the stimuli are generated when the subject is not aware or conscious that they have occurred. There is an important gap in this regard in the literature, with only one work existing dealing with subliminal stimuli and BCI and having an unclear methodology and experiment setup. As a contribution of this paper, a series of experiments, five in total, have been created to study the impact of visual stimuli on the brain tangibly. These experiments have been applied to a heterogeneous group of ten subjects. The experiments show familiar visual stimuli and gradually reduce the sampling time of known images, from supraliminal to subliminal. The study showed that supraliminal visual stimuli produced P300 potentials about 50% of the time on average across all subjects. Reducing the sample time between images degraded the attack, while the impact of subliminal stimuli was not confirmed. Additionally, younger subjects generally presented a shorter response latency. This work corroborates that subjects' sensitive data can be extracted using visual stimuli and P300.


Simultaneous kissing drug-eluting stent technique for percutaneous treatment of bifurcation lesions in large-size vessels.
Treatment of bifurcation lesions is associated with high procedural complications and restenosis rate due to plaque shift, suboptimal angiographic results, difficulty in crossing the stent struts, and incomplete coverage of the side-branch ostium. The simultaneous kissing stent (SKS) technique involves two stents, one in main vessel (MV) and one in the side branch (SB) with overlapping stents in the MV proximally, extending proximally the carina of bifurcation. We analyzed our first 200 consecutive patients (202 lesions) who underwent SKS technique for true bifurcation lesions using sirolimus eluting stents, with a minimum follow-up of 6 months. Procedural success was 100% for MV and 99% for SB using SKS technique, with clinical success rate of 97%. In-hospital and 30-day major adverse cardiac events were 3% and 5%, respectively, with a procedure time of 36 +/- 14 min. At mean follow-up of 9 +/- 2 months, the incidence of target lesion revascularization was 4% in the entire group. Therefore, SKS technique using sirolimus-eluting stents may become an effective treatment strategy for large-size bifurcation lesions. However, in order to establish its superiority, SKS technique needs to be compared in a randomized manner with conventional stent techniques.


Values of patients and caregivers for donor site scars: an inter-observer analysis between patients and caregivers and prediction of cosmetic satisfaction.
The Patient and Observer Scar Assessment Scale (POSAS) is used to judge scars and involves patients and caregivers. Although the opinions of both are integrated, agreement between them is poorly investigated, especially in donor site scars (DSSs). Furthermore, it is unknown which POSAS-items are mostly associated with overall cosmetic satisfaction with the scar. We included 106 DSS-patients. Twelve weeks after wound healing, patients and caregivers rated the DSS in vivo using the POSAS, comprising seven items. They were unaware of each other's judgment. Inter-observer reliability (IOR) was expressed as intra-class correlation coefficients (ICC). Items of the POSAS that best predicted patients' overall satisfaction were identified using multivariable regression analysis. Eleven caregivers from different medical centers judged the DSSs. IOR for the POSAS items was 'moderate' at best regarding the item 'overall opinion' (ICC 0.44; 95% confidence interval 0.27-0.58). IORs regarding other POSAS-items were 'poor'. Itching and relief best predicted patients' overall satisfaction (total variance explained, R(2)=0.174). For caregivers, pigmentation and pliability were most predictive (R(2)=0.318). Patients and caregivers appreciate different aspects of scar characteristics using the POSAS. This calls for shared decision-making, in which patient opinions are incorporated in the treatment choice.


Caffeine-induced hypokalemia: a case report.
With an increase in the global popularity of coffee, caffeine is one of the most consumed ingredients of modern times. However, the consumption of massive amounts of caffeine can lead to severe hypokalemia. A 29-year-old man without a specific past medical history was admitted to our hospital with recurrent episodes of sudden and severe lower-extremity weakness. Laboratory tests revealed low serum potassium concentration (2.6-2.9 mmol/L) and low urine osmolality (100-130 mOsm/kgH2O) in three such prior episodes. Urinary potassium/urinary creatinine ratio was 12 and 16 mmol/gCr, respectively. The patient was not under medication with laxatives, diuretics, or herbal remedies. Through an in-depth interview, we found that the patient consumed large amounts of caffeine-containing beverages daily, which included > 15 cups of coffee, soda, and various kinds of tea. After the cessation of coffee intake and concomitant intravenous potassium replacement, the symptoms rapidly resolved, and the serum potassium level normalized. An increased intracellular shift of potassium and increased loss of potassium in urine due to the diuretic action have been suggested to be the causes of caffeine-induced hypokalemia. In cases of recurring hypokalemia of unknown cause, high caffeine intake should be considered.


Organocatalytic Enantioselective Michael/Cyclization Domino Reaction between 3-Amideoxindoles and α,β-Unsaturated Aldehydes: One-Pot Preparation of Chiral Spirocyclic Oxindole-γ-lactams.
The first organocatalytic enantioselective Michael/cyclization domino reaction between 3-amideoxindoles and α,β-unsaturated aldehydes is described. After sequential oxidation with pyridinium chlorochromate, a direct and one-pot preparation of highly sterically hindered spirocyclic oxindole-γ-lactams was achieved in 51-81% yields with 75-97% ee and ≤80/20 dr.


The population of the hypogeous fungus Tuber aestivum syn. T. uncinatum on the island of Gotland.
The aim of our study was to examine the genetic variation within Tuber aestivum on the Baltic island of Gotland, Sweden. Variation in such a limited geographical area should help illuminate the dispersal abilities of T. aestivum. Knowledge of the genetic variation in this northern outpost could also be useful in the selection of inoculum for the establishment of truffle orchards. Genetic structure and homogeneity of the population were studied using principal component and parsimony analyses of randomly amplified polymorphic DNA data. Our inventories showed that T. aestivum is abundantly distributed in suitable habitats on Gotland. The genetic variation observed suggests sexual reproduction and slow dispersal on the island. It is possible that the present population was established from one introduction, which may be due to ability to survive in this habitat rather than to rare colonising events. The T. aestivum population on Gotland may be an ecotype adapted to the climate and soil conditions on the island.


Muscle tension and physiologic hyperarousal, performance, and state affectivity: assessing the independence of effects in frequent headache and depression.
Anxiety, depression, and frequent headache are closely associated. The comorbidity may be due to selection bias (such as inherent in treatment seeking), shared environmental or genetic factors, or a common underlying process. In this study, comorbidity is considered an alternative explanation for correlates of frequent headache found in earlier work. This study addressed whether EMG, peripheral temperature, performance measures, and measures of affect were independently attributable to depression or headache proneness, after control of trait anxiety. Headache state was evaluated in parallel analysis. Seventy-two participants, comprising four groups, were tested: depressed/headache-prone depressed/headache-resistant, not depressed/headache-prone, and not depressed/headache-resistant. Participants completed a performance task that allowed assessment of ambition and performance accuracy while measures of affect, headache state, EMG, and peripheral temperature were obtained. Headache proneness, independently of depression and trait anxiety, was related to heightened EMG. Depression was related to EMG, ambition, and performance accuracy independently of headache proneness and trait anxiety. Headache state was associated only with negative affect, independently of depression and anxiety. These results suggest that headache states during assessment, as well as comorbid depression and anxiety, are not primarily responsible for the heightened EMG found in headache-prone individuals. Negative affect often reported in the headache prone, however, may be due to concommitant anxiety. Other analyses address a variety of issues surrounding distinctions among these variables raised in previous research.


Evidence of Biological Self-Organization in Spatial Patterns of a Common Tropical Alga.
AbstractTropical reef communities contain spatial patterns at multiple scales, observable from microscope and satellite alike. Many of the smaller-scale patterns are generated physiologically (e.g., skeletal structures of corals at <1-m scale), while some of the larger patterns have been attributed to scale-dependent feedbacks (e.g., spur and groove reefs at 10-100-m scales). In describing the spatial patterning of reef benthic communities at landscape levels, we uncovered unique spatial patterning among living marine algae. Populations of the calcifying green alga Halimeda were observed to form a consistent polygonal pattern at a characteristic scale of 3-4 m. The pattern showed no clear evidence of having been formed through biologically created shifts in hydrodynamical conditions or related mechanisms. In considering the specifics of Halimeda growth patterns, a model of self-organization involving separation and patterned extension is proposed, a mechanism revealed in some geological pattern formation. This observation reinforces the diversity of pathways by which striking spatial patterns can occur in ecosystems.


The ice-water test--a simple and valuable supplement to routine cystometry.
The results of cystometrograms and ice-water tests (IWTs) were retrospectively evaluated in 557 patients with overactive bladders, lower motor neuron lesions or pure stress incontinence. The IWT was considered positive when, following ice-water instillation, the fluid was expelled from the bladder within 1 min. The test was considered false negative when no fluid escaped despite a sustained detrusor contraction of the same magnitude as the micturition contraction. Ninety-seven percent of patients with complete and 91% of those with incomplete upper motor neuron lesions had a positive or a false negative IWT. About 75% of the patients with multiple sclerosis, Parkinson's disease or previous cerebrovascular accident had a positive IWT. All patients with lower motor neuron lesions or pure stress incontinence had a negative IWT. There was a significant correlation between a positive IWT and an abnormal sensation of bladder filling and inability to inhibit micturition voluntarily, as well as between a negative IWT and the occurrence of phasic detrusor contractions during cystometry. The study shows that the IWT is a sensitive test for differentiating upper from lower motor neuron lesions. It is also a useful parameter for functional subdivision of overactive bladders. In patients with voiding dysfunction in the absence of lower urinary tract inflammation, a positive test is an indicator of a silent or overt neurological disorder.


Effect of paramethasone acetate on ovarian steroids and gonadotropins. I. Normal menstrual cycle.
In an attempt to elucidate the effect of paramethasone acetate on the hormonal profile of the normal menstrual cycle, 5 clinically healthy women, aged 24-36 yr, with ovulatory cycles were studied during a control menstrual cycle and during treatment with paramethasone acetate (6 mg/day). The length of the untreated cycle was 29.2 +/- 2.3 days as compared to 29.0 +/- 3.1 days during the paramethasone-treated cycle. Peak plasma E-2 level was 188.2 +/- 42.1 pg/ml in the control cycle and 74.4 +/- 15.3 pg/ml during paramethasone treatment (P is less than 0.05). Peak plasma 17 OH-P was 4.0 +/- 0.4 ng/ml in the control cycle and 1.6 +/- 0.2 ng/ml during the paramethasone treated cycle (P is less than 0.005). No significant differences in plasma progesterone were observed during the luteal phase of both cycles. Minimal and scattered differences were observed in plasma FSH. However, plasma LH levels were lower in the paramethasone acetate than in the control cycle almost throughout the entire period of study. Furthermore, midcycle LH peak in the control cycle was 958 +/- 104 ng/ml as compared to 283 +/- 24 ng/ml during the paramethasone treatment (P is less than 0.005). Despite these differences, ovulation occurred during paramethasone treatment based upon the observed rise in BBT, the plasma progesterone levels above 6 ng/ml and the secretory changes in the endometrium. These results suggest that: 1) Paramethasone may block E-2 synthesis at the ovarian level and , 2) Ovulation may still occur even in the presence of E-2 and LH plasma concentrations lower than those occurring in the normal menstrual cycle.


CREB-mediated alterations in the amygdala transcriptome: coordinated regulation of immune response genes following cocaine.
The neuronal circuitry underlying stress- and drug-induced reinstatement of cocaine-seeking has been relatively well characterized; however, less is known regarding the long-term molecular changes following cocaine administration that may promote future reinstatement. The transcription factor cAMP response element-binding protein (CREB) is necessary for stress- but not cocaine-induced reinstatement of conditioned reward, suggesting that different molecular mechanisms may underlie these two types of reinstatement. To explore the relationship between this transcription factor and reinstatement, we utilized the place-conditioning paradigm to examine alterations in gene expression in the amygdala, a neural substrate critically involved in stress-induced reinstatement, following the development of cocaine reward and subsequent extinction. Our findings demonstrate that the amygdala transcriptome was altered by CREB deficiency more than by previous cocaine experience, with an over-representation of genes involved in the immune response. However, a subset of genes involved in stress and immune response demonstrated a drug×genotype interaction, indicating that cocaine produces different long-term alterations in gene expression depending on the presence or absence of CREB. This profile of gene expression in the context of addiction enhances our understanding of the long-term molecular changes that occur throughout the addiction cycle and identifies novel genes and pathways that might lead to the creation of better therapeutic agents.


Pistachio (Pistacia vera L.) Detection and Quantification Using a Murine Monoclonal Antibody-Based Direct Sandwich Enzyme-Linked Immunosorbent Assay.
A commercially available direct sandwich enzyme-linked immunosorbent assay (ELISA) (BioFront Technologies, Tallahassee, FL, USA) using murine anti-pistachio monoclonal antibodies (mAbs) as capture and detection antibodies was evaluated. The assay was sensitive (limit of detection = 0.09 ± 0.02 ppm full fat pistachio, linear detection range = 0.5-36 ppm, 50% maximum signal concentration = 7.9 ± 0.7 ppm), reproducible (intra- and inter-assay variability < 24% CV), and rapid (post-extraction testing time ∼ 1.5 h). The target antigen was stable and detectable in whole pistachio seeds subjected to autoclaving (121 °C, 15 psi, 15, 30 min), blanching (100 °C, 5, 10 min), frying (191 °C, 1 min), microwaving (500, 1000 W, 3 min), and dry roasting (140 °C, 30 min; 168 °C, 12 min). No cross-reactivity was observed in 156 food matrices, each tested at 100,000 ppm, suggesting the ELISA to be pistachio specific. The pistachio recovery ranges for spiked (10 ppm) and incurred (10-50000 ppm) food matrices were 93.1-125.6% and 35.7-112.2%, respectively. The assay did not register any false-positive or -negative results among the tested commercial and laboratory prepared samples.


Sociodemographic distributions and molecular characterization of colonized Enterococcus faecium isolates from locality hospitals in Khartoum, Sudan.
Enterococcus faecium is an opportunistic pathogen of humans with diverse hosts, encompassing animals as well as human beings. In the past twenty years, there has been a rise in the instances of nosocomial infections that are linked to antibiotic-resistant Enterococcus faecium. The acquisition of diverse antimicrobial resistance factors has driven the global development of robust and convergent adaptive mechanisms within the healthcare environment. The presence of microorganisms in hospitalized and non-hospitalized patient populations has been significantly aided by the facilitation of various perturbations within their respective microbiomes. This study aimed to determine the antimicrobial profile, demographic and clinical characteristics, along with the detection of virulence encoding genes, and to find out the clonal genetic relationship among colonized E. faecium strains. A hospital-based cross-sectional study was carried out between October 2018 and March 2020 at four Khartoum locality hospitals in Sudan. The study comprised a total of 108 strains of E. faecium isolated from patients admitted to four locality hospitals in Khartoum. A self-structured questionnaire was used to gather information on sociodemographic traits. Data were analyzed using chi-square test. In all cases, P value ≤ 0.05 with a corresponding 95% confidence interval was considered statistically significant. Moreover, enterobacterial repetitive intergenic consensus-polymerase chain reaction (ERIC-PCR) was utilized to assess the prevalence of clonal relationships, and the gel was analyzed using CLIQS software. In this study, the isolation rate of colonized E. faecium strains was 108/170 (63.5%). The colonization of E. faecium and its association with various sociodemographic and clinical features was examined. 73 (67.6%) of patients had multidrug-resistant (MDR), and 22 (20.4%) had extensively drug-resistant (XDR), 73 (67.6%) of patients engaged in self-medication practices. Eighty patients (74.1%) were non-adherence to prescribed antibiotics, while 70 (64.8%) patients reported recent antibiotic usage within the 3 months. The present study suggests that demographic factors may not be significantly associated with the incidence of E. faecium infection except for patients who had a prior history of antibiotic use (P ≤ 0.005). The analysis of virulence genes showed a high prevalence of asa1 gene (22.2%) among strains. In ERIC-PCR the genetic relatedness of E. faecium showed seven identical clusters (A-G) with 100% genetic similarity. This implies clonal propagation in hospitals and communities. This study found that the incidence of E. faecium isolated from locality hospitals in Khartoum was likely due to the spread of E. faecium clones, thereby highlighting the need for intensifying infection control measures to prevent the spreading of nosocomial infection.


Qualitative and event-specific real-time PCR detection methods for Bt brinjal event EE-1.
Bt brinjal event EE-1 with cry1Ac gene, expressing insecticidal protein against fruit and shoot borer, is the first genetically modified food crop in the pipeline for commercialization in India. Qualitative polymerase chain reaction (PCR) along with event-specific conventional as well as real-time PCR methods to characterize the event EE-1 is reported. A multiplex (pentaplex) PCR system simultaneously amplifying cry1Ac transgene, Cauliflower Mosaic Virus (CaMV) 35S promoter, nopaline synthase (nos) terminator, aminoglycoside adenyltransferase (aadA) marker gene, and a taxon-specific beta-fructosidase gene in event EE-1 has been developed. Furthermore, construct-specific PCR, targeting the approximate 1.8 kb region of inserted gene construct comprising the region of CaMV 35S promoter and cry1Ac gene has also been developed. The LOD of developed EE-1 specific conventional PCR assay is 0.01%. The method performance of the reported real-time PCR assay was consistent with the acceptance criteria of Codex Alimentarius Commission ALINORM 10/33/23, with the LOD and LOQ values of 0.05%. The developed detection methods would not only facilitate effective regulatory compliance for identification of genetic traits, risk assessment, management, and postrelease monitoring, but also address consumer concerns and resolution of legal disputes.


Effect of Gutai Decoction on the abortion rate of in vitro fertilization and embryo transfer.
To study the effect of Chinese herbal medicine Gutai Decoction (GTD) on the abortion rate of in vitro fertilization and embryo transfer (IVF-ET). Observed were two hundred and forty-seven women having received IVF-ET and with beta-human chorionic gonadotropin (beta-HCG) > 25 IU/L on the 14th day after transferring. All were treated conventionally with progesterone 20 - 80 mg per day after transferring and if necessary the treatment was supplemented with Progynova 2 - 4 mg per day, with the medication withdrawn gradually from the 9th week of pregnancy till stopped completely. Among them 131 cases received GTD medication additionally, for 109 cases of whom the medication started from the 2nd day of transferring (taken as Group A) and for the other 22 cases from the 14th day after transferring (taken as Group B), the other 116 cases with no additional GTD treatment given were taken as the control group, with the medication lasting to the 12th week. The abortion rate in them was observed. The abortion rate in Group A, Group B and the control group was 12.84%, 13.64% and 23.28%, respectively, the difference between the GTD treated groups and the control group was significant (P < 0.05). Chinese medicine GTD could reduce abortion rate in women receiving IVF-ET.


Evaluation of a live attenuated varicella vaccine in 15- to 18-month-old healthy children.
A clinical trial was conducted in Taiwan in 15- to 18- month-old healthy children to study the reactogenicity and immunogenicity of live varicella vaccine combined with standard measles-mumps-rubella vaccine. A total of 118 varicella antibody-negative children were enrolled. They received one dose of varicella vaccine and one dose of measles-mumps-rubella vaccine at the same time. The vaccines were well tolerated; adverse reactions were mild and infrequent, with 2% of vaccines developed skin rash. No vesicular rash was seen. Concomitant varicella vaccination did not significantly increase the incidences of reactions associated with MMR vaccine. The seroconversion rates to varicella, measles, mumps and rubella all approached 100%. This study confirmed that simultaneous administration of live attenuated varicella vaccine and MMR vaccine was safe and immunogenic in healthy young children in Taiwan.


Paid parental leave supports breastfeeding and mother-infant relationship: a prospective investigation of maternal postpartum employment.
To investigate the association between the mother-infant relationship, defined as maternal-infant emotional attachment, maternal separation anxiety and breastfeeding, and maternal employment status at 10 months following first childbirth. Samples of employed, pregnant women, over 18 years of age and with sufficient English literacy were recruited systematically from one public and one private maternity hospital in Victoria. Data were collected by structured interview and self-report questionnaire in the third trimester, and at 3 and 10 months postpartum. Socio-demographic, employment, and breastfeeding information was collected. Participants completed standardised assessments of maternal separation anxiety and mother-to-infant emotional attachment. Of 205 eligible women, 165 (81%) agreed to participate and 129 (78%) provided complete data. A reduced odds of employment participation was independently associated with continuing to breastfeed at 10 months (OR=0.22, p=0.004) and reporting higher maternal separation anxiety (OR=0.23, p=0.01) when maternal age, education, occupational status and use of paid maternity leave and occupational status were adjusted for in analyses. Employment participation in the first 10 months postpartum is associated with lower maternal separation anxiety, and shorter breastfeeding duration. Paid parental leave has public health implications for mothers and infants. These include permitting sufficient time to protect sustained breastfeeding, and the development of optimal maternal infant attachment, reflected in confidence about separation from her infant.


Probing the mutation independent interaction of DNA probes with SARS-CoV-2 variants through a combination of surface-enhanced Raman scattering and machine learning.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has been characterized by the emergence of sets of mutations impacting the virus characteristics, such as transmissibility and antigenicity, presumably in response to the changing immune profile of the human population. The presence of mutations in the SARS-CoV-2 virus can potentially impact therapeutic and diagnostic test performances. We design and develop here a unique set of DNA probes i.e., antisense oligonucleotides (ASOs) which can interact with genetic sequences of the virus irrespective of its ongoing mutations. The probes, developed herein, target a specific segment of the nucleocapsid phosphoprotein (N) gene of SARS-CoV-2 with high binding efficiency which do not mutate among the known variants. Further probing into the interaction profile of the ASOs reveals that the ASO-RNA hybridization remains unaltered even for a hypothetical single point mutation at the target RNA site and diminished only in case of the hypothetical double or triple point mutations. The mechanism of interaction among the ASOs and SARS-CoV-2 RNA is then explored with a combination of surface-enhanced Raman scattering (SERS) and machine learning techniques. It has been observed that the technique, described herein, could efficiently discriminate between clinically positive and negative samples with ∼100% sensitivity and ∼90% specificity up to 63 copies/mL of SARS-CoV-2 RNA concentration. Thus, this study establishes N gene targeted ASOs as the fundamental machinery to efficiently detect all the current SARS-CoV-2 variants regardless of their mutations.


Microbiological burden on the surfaces of Explorer 33 spacecraft.
The Explorer XXXIII Spacecraft (Anchored Interplanetary Monitoring Platform, or AIMP) was decontaminated to prevent gross contamination of the moon with terrestrial microorganisms. Assay of the total spacecraft surface before and after decontamination showed that the decontamination procedure reduced the viable microbiological burden from 1.40 x 10(6) to 3.60 x 10(4). However, assembly of parts which were not decontaminated for engineering reasons or were not assembled under cleanroom conditions increased the viable microbial burden at the time of launch to 2.62 x 10(5).


Thermal characterization of electrical tracing-assisted dual-microring optical sensors.
In this paper, we study the temperature sensitivity of an electrical tracing-assisted dual-microring optical sensor, which consists of a sensing ring to detect the refractive index change on its surface and a tracing ring to trace the resonance wavelength shift of the sensing ring by the thermo-optic effect with a heating electrode on it. The wavelength shift measurement is therefore changed to electrical power variation measurement. Thanks to the real-time compensation effect of the tracing ring, the temperature dependence of the sensor is found to be intrinsically low. The resonance wavelength temperature sensitivity difference between the two rings is measured to be as low as 10.1 pm/°C, showing that the temperature dependence of the sensor in terms of wavelength per degree is reduced by ~6 times compared to that of a single ring sensor. The temperature sensitivity of the sensor in terms of electrical power per degree is measured to be -0.077 mW/°C. By using tracing ring with enhanced tuning efficiency, this value can be further decreased to -0.0057 W/°C. The experimental results agree well with the expectation. This type of sensors with low temperature dependence has great potential to be deployed in various practical point-of-care diagnostic applications.


Phase-change reconfigurable metasurface for broadband, wide-angle, continuously tunable and switchable cloaking.
Being invisible at will has fascinated humanity for centuries and it has become more tangible with the development of metasurfaces, which have demonstrated the extraordinary ability of wavefront manipulation. However, state-of-the-art invisibility cloaks typically work in a deterministic system with a limited bandwidth and small incident angle ranges. Here, by integrating the phase-change material of Ge2Sb2Te5 and the wavefront tailoring functionality of a reflective metasurface, we have achieved a unique carpet cloak that is endowed with broadband invisibility from 6920 to 8220 nm, fully concealing objects over a wide angular span of ±25° and a prominent radar cross-section reduction. Furthermore, the central cloaking wavelength can be continuously tuned with Ge2Sb2Te5 film under different intermediate phases by precisely controlling external stimuli, which will provide a flexible and encouraging way to achieve active features once fabricated. Simulation results also show that the cloaking bandwidth can be significantly extended by triggering Ge2Sb2Te5 from the amorphous to crystalline states. Importantly, the hybrid metasurface can realize switching of "ON" and "OFF" states in terms of cloaking features by converting Ge2Sb2Te5 from the amorphous to the crystalline state. To the best of our knowledge, this is the first metasurface carpet cloak that utilizes the phase-change material of Ge2Sb2Te5 to achieve ultra-broadband, wide-angle, continuously tunable and switchable cloaking with low profiles, light weights, and easy access. This design of a reconfigurable cloak is expected to find potential applications in various areas such as vehicle cloaking, illusions and so on.


Prognostic impact of cytogenetic aberrations in AL amyloidosis patients after high-dose melphalan: a long-term follow-up study.
Cytogenetic aberrations detected by interphase fluorescence in situ hybridization (iFISH) of plasma cells are routinely evaluated as prognostic markers in multiple myeloma. This long-term follow-up study aimed to assess the prognosis of systemic light chain amyloidosis (AL) patients treated with high-dose melphalan (HDM) chemotherapy and autologous stem cell transplantation, depending on iFISH results. Therefore, we analyzed a consecutive cohort of 123 AL patients recruited from 2003 to 2014. HDM was safe, with only 1 of 123 patients dying as a result of treatment-related mortality, and effective, with a complete remission (CR) rate of 34%. Translocation t(11;14) as the most prevalent aberration (59%) led to an improved CR rate after high-dose therapy (41.2% vs 20.0%; P = .02), translating into a prolonged hematologic event-free survival (hemEFS; median, 46.1 vs 28.1 months; P = .05) and a trend for better overall survival (median, not reached vs 93.7 months; P = .07). In multivariate analysis, t(11;14) was confirmed as a favorable prognostic factor regarding hemEFS along with lower values for the difference between involved and uninvolved free light chains. Conversely, deletion 13q14, gain of 1q21, and hyperdiploidy had no significant prognostic impact. The high-risk cytogenetic aberrations t(4;14), t(14;16), and del(17p13) conferred an unfavorable prognosis, although statistical significance was reached only for univariate CR analysis in this small group of 9 patients. Thus, t(11;14) positivity in HDM-treated AL patients conferred superior CR rates and hemEFS. In view of the reduced response of t(11;14) to bortezomib, this highlights the impact of therapy on the prognostic role of cytogenetic aberrations.


Prevalence of Persistent Renal Dysfunction in Perinatally HIV-infected Thai Adolescents.
Persistent renal dysfunction (PRD) has been reported in up to 22% of perinatally HIV-infected adolescents (PHAs) in the United States and Europe. There are limited data available on PRD among PHAs in resource-limited settings regarding access to antiretroviral therapy (ART) at more advanced HIV stages. We retrospectively described the prevalence of PRD and associated factors in a Thai PHA cohort. Inclusion criteria were current age ≥10 years old and at least 2 serum creatinine (Cr) measurements after ART initiation. Cr and urine examination were performed every 6-12 months. PRD was defined as having ≥2 measurements of low estimated glomerular filtration rate (eGFR); either <60 mL/min/1.73 m2 or elevated Cr for age and eGFR 60-89 mL/min/1.73 m2, or proteinuria (dipstick proteinuria ≥1+). Factors associated with PRD were analyzed using a multivariate logistic regression analysis. This study included 255 PHAs with median (interquartile range) age of 16.7 (14.5-18.8) and ART duration of 10.3 (7.1-12.4) years. Fifty-six percentage used boosted protease inhibitor (bPI)-based regimens, and 63% used tenofovir disoproxil fumarate (TDF). The overall PRD prevalence was 14.1% [95% confidence interval (CI): 10.1-19.0]; low eGFR 6.7%, proteinuria 3.5% and both 3.9%. Among 109 users of TDF with bPI, 22.9% had PRD and 2.8% discontinued/adjusted dosing of TDF because of nephrotoxicity. Factors associated with PRD were age 10-15 years old (adjusted odd ratio (aOR): 10.1, 95% CI: 4.1-25.2), male (aOR: 3.2, 95% CI: 1.4-7.7), CD4 nadir <150 cells/mm (aOR: 2.6, 95% CI: 1.1-6.1) and use of TDF with bPI (aOR: 9.6, 95% CI: 3.2-28.9). PRD is common among PHAs. Almost one-fifth of adolescents using TDF with bPI had PRD. These adolescents should be a priority group for renal monitoring.


Cargo selectivity of the ERGIC-53/MCFD2 transport receptor complex.
Exit of soluble secretory proteins from the endoplasmic reticulum (ER) can occur by receptor-mediated export as exemplified by blood coagulation factors V and VIII. Their efficient secretion requires the membrane lectin ER Golgi intermediate compartment protein-53 (ERGIC-53) and its soluble luminal interaction partner multiple coagulation factor deficiency protein 2 (MCFD2), which form a cargo receptor complex in the early secretory pathway. ERGIC-53 also interacts with the two lysosomal glycoproteins cathepsin Z and cathepsin C. Here, we tested the subunit interdependence and cargo selectivity of ERGIC-53 and MCFD2 by short interference RNA-based knockdown. In the absence of ERGIC-53, MCFD2 was secreted, whereas knocking down MCFD2 had no effect on the localization of ERGIC-53. Cargo binding properties of the ERGIC-53/MCFD2 complex were analyzed in vivo using yellow fluorescent protein fragment complementation. We found that MCFD2 is dispensable for the binding of cathepsin Z and cathepsin C to ERGIC-53. The results indicate that ERGIC-53 can bind cargo glycoproteins in an MCFD2-independent fashion and suggest that MCFD2 is a recruitment factor for blood coagulation factors V and VIII.


Characterization of natural killer cells cultured from human bone marrow cells.
Human bone marrow (BM) cells, depleted of nylon wool-adherent cells, T cells, and natural killer (NK) cells, were cultured in medium containing recombinant interleukin 2 (rIL2). After 21 or 24 days in culture, numerous lymphoid cells with multiple azurophilic granules and a morphology similar to large granular lymphocytes (LGL) were found. Two-color analysis of surface phenotype showed many of these cells to be NKH1-positive and a limited number of cells had other NK markers such as CD16, CD2, or CD8. The CD3 antigen was not coexpressed with NKH1. The cultured BM cells were cytotoxic for K562, Daudi, and Raji cell lines. The NKH1+, CD2-, CD3-, CD16- cells were sorted and, in addition to having the LGL morphology, were found to be cytotoxic for K562 cells (NK [K562]). The generation of NK(K562) activity was significantly suppressed by 5-bromodeoxyuridine plus ultraviolet light treatment, indicating that DNA synthesis is required. These experiments suggest that the described culture conditions allow differentiation of progenitor cells, into immature, but functionally active, NK cells.


The dilated common duct sign. A potential indicator of a sphincter of Oddi dyskinesia.
The cholescintigraphic findings of a Sphincter of Oddi dyskinesia (SOD) in a 45-year-old woman with persistent right upper quadrant pain and biliary colic are reported. After an overnight fast, the patient was injected with 5 mCi of Tc-99 disofenin and .02 micrograms/kg of cholecystokinin (CCK) post maximal gallbladder filling. Pre and postcholescintiscans were obtained and gallbladder ejection fractions determined. The hepatobiliary scan was normal, except for a delay in biliary-bowel transit. The gallbladder responded normally to CCK, however, the Sphincter of Oddi responded abnormally, as there was a paradoxical response to CCK manifested by a marked dilatation of the common bile duct. We postulate that this dilatation (the dilated common duct sign) was due to an inappropriate response of the smooth muscle of the Sphincter of Oddi (contraction vs relaxation) to CCK and was the cause of this patient's biliary colic. The dilated common duct sign should alert the physician to the possibility of a Sphincter of Oddi dyskinesia.


Novel oncogene and tumor suppressor mutations in KIT and PDGFRA wild type gastrointestinal stromal tumors revealed by next generation sequencing.
Among gastrointestinal stromal tumors (GISTs) of 10-15% are negative for KIT and PDGFRA, and most of these cases are SDH deficient. Recent studies have provided data on additional molecular alterations such as KRAS in KIT mutant GISTs. We aimed to assess the frequency and spectrum of somatic mutations in common oncogenes as well as copy number variations in GISTs negative for KIT and PDGFRA mutations. GISTs with wild type KIT/PDGFRA were tested via next generation sequencing for somatic mutations in 341 genes. SDHB immunohistochemistry to evaluate for SDH deficiency was also performed. Of 267 GISTs tested for KIT and PDGFRA mutations, 15 were wild type, of which eight cases had material available for further testing. All eight cases had loss of SDHB expression and had various molecular alterations involving ARID1A, TP53, and other genes. One case had a KRAS G12V (c.35G>T) mutation in both the primary gastric tumor and a post-imatinib recurrence. This tumor had anaplastic features and was resistant to multiple tyrosine kinase inhibitors, ultimately resulting in cancer-related mortality within 2 years of diagnosis. In conclusion, KRAS mutations occur in rare GISTs with wild type KIT and PDGFRA. These tumors may display immunohistochemical positivity for KIT and primary resistance to tyrosine kinase inhibitors.


Progress in understanding the safety and efficacy of Janus kinase inhibitors for treatment of rheumatoid arthritis.
Treatment of rheumatoid arthritis (RA) has improved considerably following the advent of biologic disease-modifying anti-rheumatic drugs (DMARDs). However, these drugs require special storage and transportation. Janus kinase (JAK) inhibitors are oral synthetic DMARDs that inhibit the non-receptor tyrosine kinase family Janus kinase. Recently, many JAK inhibitors are being developed as new therapies for patients with RA. In this article, we mainly review the efficacy and safety of JAK inhibitors currently under investigation. Tofacitinib has already been approved in 43 countries except in the EU. Results of three JAK inhibitors (baricitinib, decernotinib, and peficitinib) in phase III are consistent with that of tofacitinib. Tofacitinib and baricitinib were partially effective in patients who had an inadequate response to biological DMARDs. Expert commentary: JAK kinase inhibitors provide a new therapeutic approach for rheumatoid arthritis. Meanwhile, further studies are needed to determine their risk-benefit ratio and the most appropriate patients suitable for such therapy.


The conversion rate of bipolar hemiarthroplasty after a hip fracture to a total hip arthroplasty.
Bipolar hip hemiarthroplasty is used in the management of fractures of the proximal femur. The dual articulation is cited as advantageous in comparison to unipolar prostheses as it decreases acetabular erosion, has a lower dislocation rates and is easier to convert to a total hip arthroplasty (THA) should the need arise. However, these claims are debatable. Our study examines the rate of conversion of the bipolar hemiarthroplasty to THA and the justification for using it on the basis of future conversion to THA. All cases of bipolar hemiarthroplasty performed in our unit for hip fractures over a 9-year period (1999-2007) were reviewed. Medical notes and radiographs of all patients were reviewed, and all surviving patients that were contactable received a telephone follow-up. Of all 164 patients reviewed with a minimum of 1 year from date of surgery, 4 patients had undergone a conversion of their bipolar prosthesis to THA. Three conversions were performed for infection, dislocation, and fracture. Only one (0.6%) conversion was performed for groin pain. Our study show that bipolar hemiarthroplasties for hip fractures have a low conversion rate to THAs and this is comparable to the published conversion rate of unipolar hemiarthroplasties.


Visible Light-Controlled Inversion of Pickering Emulsions Stabilized by Functional Silica Microspheres.
A new class of donor-acceptor Stenhouse adduct (DASA)-functionalized silica microspheres (SMs) is designed and described to formulate Pickering emulsions with inversion property and large polarity change upon visible light irradiation. By tuning the hydrophilicity of the functional SM particles with visible light, these Pickering emulsions can easily perform inversion from water-in-oil to oil-in-water. The inversion performance of the emulsions is ascribed to DASA photoisomerization from an extended, hydrophobic, and intensely purple-colored triene to a compact, zwitterionic, and colorless cyclopentenone upon irradiation with visible light. This unique inversion behavior has been applied to control encapsulation and the release of fluorescein sodium salt.


"Good annotation practice" for chemical data in biology.
A structural diagram, in the form of a two-dimensional (2-D) sketch, remains the most effective portrait of a "small molecule" or chemical reaction. However, such structural diagrams, as for any other core data, cannot be used in speech (and should not be used in free text). "Good annotation practice" for biological databases is to use either consistent and widely recognised terminology or unique identifiers from a dedicated database to refer to the molecule of interest. Ideally, scientists should use terminology that is both pronounceable and meaningful. Thus, a viable solution for a bioinformatician is to use a definitive controlled vocabulary of biochemical compounds and reactions, which contains both systematic and common names. In addition, chemical ontologies provide a means for placing entities of interest into wider chemical, biological or medical contexts. We present some challenges and achievements in the standardisation of chemical language in biological databases, with emphasis on three aspects of annotation: 1. good drawing practice: how to draw unambiguous 2-D diagrams; 2. good naming practice: how to give most appropriate names; and 3. good ontology practice: how to link the entity of interest by defined logical relationships to other entities.


Prenatal Motherese? Newborn Speech Perception May Be Enhanced by Having a Young Sibling.
Prenatal experience with infant- and child-directed speech (IDS/CDS) may affect newborns' speech perception. We examined this possibility using an existing neonatal database from a recent cross-language study (Moon, Lagercrantz, & Kuhl, 2011). Seventy-three American and Swedish neonates (Mage = 32.58 hr, SD = 13.58 hr) were retrospectively coded as either having High (n = 32) or Low (n = 41) prenatal IDS/CDS exposure based on whether there were any children younger than 4 years old in the household during pregnancy. We compared the mean sucks for contingent presentations of prototypes and nonprototypes of vowel stimuli (native or foreign) among groups. A mixed 3-way ANOVA revealed a significant interaction: Neonates responded to prototypes and nonprototypes differently in the High IDS/CDS group, whereas there was a lack of differential responses in the Low IDS/CDS group. Future research with well-controlled measurement of prenatal speech is warranted.


Peptide antagonists of the calcitonin gene-related peptide (CGRP) receptor with improved pharmacokinetics and pharmacodynamics.
Antagonism of the calcitonin gene-related peptide (CGRP) receptor may be a useful approach for migraine treatment. Selective PEGylated peptide antagonists to the CGRP receptor are described, derived from CGRP(8-37) with polymer derivatization at an engineered lysine-25 residue. Potent PEGylated peptides with improved pharmacokinetics were identified through peptide side-chain modification to mitigate metabolic liabilities. PEGylated Ac-Trp-[Cit(11,18),hArg(24),Lys(25),Asp(31),Pro(34),1-Nal(35)]CGRP(8-37)-NH2, 9, elicits a dose-dependent reduction of intradermal CGRP-induced local blood flow in rodents with an ED50 of 0.52 mg kg(-1) without any overt adverse effects.


Functions of animal microRNA-encoded peptides: the race is on!
Short open reading frame (sORF)-encoded peptides (SEPs) recently emerged as new key players in biology. Pioneering work first established that sORFs encoded by long non-coding RNAs (lncRNAs) are efficiently translated and produce functional peptides. In plants, primary transcripts of microRNAs (pri-miRNAs) also produce sORF-encoded peptides called miPEPs, which are involved in specific transcriptional autoregulatory feedback loops (Lauressergues et al, 2015). To what extend are such mechanisms conserved in other species, especially in animals? In this issue of EMBO reports, Zhou et al show that pri-miR-31 encodes a miPEP promoting Treg differentiation and downregulating pri-miR-31 expression (Zhou et al, 2022).


Studies on the interaction between water and (hydroxypropyl)methylcellulose.
The moisture sorption and desorption profiles of four different viscosity grades of (hydroxypropyl)methylcellulose (HPMC) 2208 (HPMC K100, HPMC K4M, HPMC K15M, and HPMC K100M) of different particle size fractions were analyzed according to the Young and Nelson equations. These equations describe three locations of the sorbed moisture: monolayer adsorption, externally adsorbed moisture, and internally absorbed moisture. The effects of particle size and viscosity grade of HPMC on the three locations of moisture showed that an increase in particle size generally resulted in a reduction in the amount of internal absorption and an increase in the amount of external adsorption. These changes were more apparent for HPMC K100 and HPMC K4M than for the higher viscosity grades. The lowest values of internally absorbed moisture were obtained for HPMC K100M. Changes in tensile strengths, mean yield pressures, and elastic recoveries of HPMC K4M tablets were explained in terms of the changes produced in the internally absorbed moisture and the externally adsorbed moisture. The amounts of nonfreezing and freezing water in samples exposed to moisture were determined from melting endotherms obtained by differential scanning calorimetry. Increases in the water:HPMC ratio resulted in increases in the enthalpies of water melting for the four viscosity grades of HPMC for the < 45 and 250-350 microns particle size fractions. The amount of nonfreezable water was unaffected by change in viscosity grade or particle size.


Practice parameter for telepsychiatry with children and adolescents.
This practice parameter discusses the use of telepsychiatry to provide services to children and adolescents. The parameter defines terms and reviews the status of telepsychiatry as a mode of health service delivery. Because many of the issues addressed are unique to telepsychiatry, the parameter presents principles for establishing a telepsychiatry service and optimizing clinical practice within that service. The principles presented are based on existing scientific evidence and clinical consensus. Telepsychiatry is still evolving, and this parameter represents a first approach to determining "best practices." The parameter emphasizes the integration of telepsychiatry within other practice parameters of the American Academy of Child and Adolescent Psychiatry.


The association of progressive, atrophying, chronic, granulomatous dermohypodermitis with Hodgkin's disease.
The case of a patient with an unusual skin disorder--progressive, atrophying, chronic, granulomatous dermohypodermitis (PACGD)--who developed Hodgkin's disease is reported. A review of the literature revealed only two other cases of PACGD, one of which affected a patient who also was found to have Hodgkin's disease. In an additional report, the diagnosis of Hodgkin's disease was made in a patient who may have had the same dermatologic disorder. The case is reported because the association of these two rare diseases is believed to be more than a chance event.


Characterization of the Coronatine-Like Phytotoxins Produced by the Common Scab Pathogen Streptomyces scabies.
Streptomyces scabies is an important causative agent of common scab disease of potato tubers and other root crops. The primary virulence factor produced by this pathogen is a phytotoxic secondary metabolite called thaxtomin A, which is essential for disease development. In addition, the genome of S. scabies harbors a virulence-associated biosynthetic gene cluster called the coronafacic acid (CFA)-like gene cluster, which was previously predicted to produce metabolites that resemble the Pseudomonas syringae coronatine (COR) phytotoxin. COR consists of CFA linked to an ethylcyclopropyl amino acid called coronamic acid, which is derived from L-allo-isoleucine. Using a combination of genetic and chemical analyses, we show that the S. scabies CFA-like gene cluster is responsible for producing CFA-L-isoleucine as the major product as well as other minor COR-like metabolites. Production of the metabolites was shown to require the cfl gene, which is located within the CFA-like gene cluster and encodes an enzyme involved in ligating CFA to its amino acid partner. CFA-L-isoleucine purified from S. scabies cultures was shown to exhibit bioactivity similar to that of COR, though it was found to be less toxic than COR. This is the first report demonstrating the production of coronafacoyl phytotoxins by S. scabies, which is the most prevalent scab-causing pathogen in North America.


Properties of the PriA helicase domain and its role in binding PriA to specific DNA structures.
Primosome assembly protein PriA functions in the assembly of the replisome at forked DNA structures. Whereas its N-terminal DNA binding domain (DBD) binds independently to DNA, the affinity of DBD protein for forked structures is relatively weak. Although the PriA helicase domain (HD) is required for high affinity fork binding, HD protein had very low affinity for DNA. It had only low levels of ATPase activity, and it hydrolyzed ATP when DNA was absent whereas PriA did not. HD catalyzed unwinding of a minimal substrate composed of a duplex with a 3' single-stranded tail. Single-strand binding protein (SSB) bound to the tail of this substrate inhibited this reaction by full-length PriA but enhanced the reaction by HD. SSB stabilized binding of PriA but not of DBD or HD to duplexes with a 5' or 3' single-stranded tail. On forked substrates SSB enhanced helicase action on the lagging-strand arm by PriA but not by HD. The results indicate that synergy of the DBD and HD allows stable binding at the interface between duplex and single-stranded DNA bound by SSB. This mode of binding may be analogous to fork binding, which orients the helicase to act on the lagging-strand side of the fork.