The 5-HT1B serotonin receptor regulates methylphenidate-induced gene expression in the striatum: Differential effects on immediate-early genes.
Drug combinations that include a psychostimulant such as methylphenidate (Ritalin) and a selective serotonin reuptake inhibitor such as fluoxetine are indicated in several medical conditions. Co-exposure to these drugs also occurs with "cognitive enhancer" use by individuals treated with selective serotonin reuptake inhibitors. Methylphenidate, a dopamine reuptake inhibitor, by itself produces some addiction-related gene regulation in the striatum. We have demonstrated that co-administration of selective serotonin reuptake inhibitors potentiates these methylphenidate-induced molecular effects, thus producing a more "cocaine-like" profile. There is evidence that the 5-HT1B serotonin receptor subtype mediates some of the cocaine-induced gene regulation. We thus investigated whether the 5-HT1B receptor also modifies methylphenidate-induced gene regulation, by assessing effects of a selective 5-HT1B receptor agonist (CP94253) on immediate-early gene markers ( Zif268, c- Fos, Homer1a) in adolescent male rats. Gene expression was measured by in situ hybridization histochemistry. Our results show that CP94253 (3, 10 mg/kg) produced a dose-dependent potentiation of methylphenidate (5 mg/kg)-induced expression of Zif268 and c- Fos. This potentiation was widespread in the striatum and was maximal in lateral (sensorimotor) sectors, thus mimicking the effects seen after cocaine alone, or co-administration of fluoxetine. However, in contrast to fluoxetine, this 5-HT1B agonist did not influence methylphenidate-induced expression of Homer1a. CP94253 also potentiated methylphenidate-induced locomotor activity. These findings indicate that stimulation of the 5-HT1B receptor can enhance methylphenidate (dopamine)-induced gene regulation. This receptor may thus participate in the potentiation induced by fluoxetine (serotonin) and may serve as a pharmacological target to attenuate methylphenidate + selective serotonin reuptake inhibitor-induced "cocaine-like" effects.


Analyses of macrolide antibiotic residues in eggs, raw milk, and honey using both ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry and high-performance liquid chromatography/tandem mass spectrometry.
Two liquid chromatography mass spectrometric techniques, i.e. ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-Tof MS) and high-performance liquid chromatography/tandem mass spectrometry (LC/MS/MS), were used for quantification, confirmation or identification of six macrolide antibiotic residues and/or their degradation products in eggs, raw milk, and/or honey. Macrolides were extracted from food samples by acetonitrile or phosphate buffer (0.1 M, pH 8.0), and sample extracts were further cleaned up using solid-phase extraction cartridges. UPLC/Q-Tof data were acquired in Tof MS full scan mode that allowed both quantification and confirmation of macrolides, and identification of their degradation products. LC/MS/MS data acquisition was achieved using multiple reaction monitoring (MRM), i.e. two transitions, to provide a high degree of sensitivity and repeatability. Matrix-matched standard calibration curves with the use of roxithromycin as an internal standard were utilized to achieve the best accuracy of the method. Both techniques demonstrated good quantitative performance in terms of accuracy and repeatability. LC/MS/MS had advantages over UPLC/Q-Tof MS in that its limits of detection were lower and repeatability was somewhat better. UPLC/Q-Tof provided ultimate and unequivocal confirmation of positive findings, and allowed degradation product identification based on accurate mass. The combination of the two techniques can be very beneficial or complementary in routine analysis of macrolide antibiotic residues and their degradation products in food matrices to ensure the safety of food supply.


Characterization of Fusobacterium necrophorum isolated from llama and alpaca.
Fusobacterium necrophorum, a Gram-negative, anaerobic bacterium, is an opportunistic animal and human pathogen that causes a variety of infections termed necrobacillosis. There are 2 subspecies of F. necrophorum (subsp. necrophorum and subsp. funduliforme) that differ morphologically and biochemically and in virulence. Leukotoxin, a secreted protein, is considered to be the major virulence factor. In camelids, F. necrophorum causes a variety of infections, generally involving the lips, tongue, pharynx, interdigital spaces, foot pad, larynx, mandible, or maxillary bones. The objective of the current study was to characterize the presumptive Fusobacterium isolates from a variety of necrotic infections in llama (Lama glama) and alpaca (Vicugna pacos) and determine whether the strains possess leukotoxin activities. A total of 7 isolates from alpaca and 2 isolates from llama were characterized. Based on growth characteristics in broth culture, and biochemical and polymerase chain reaction analyses, all 9 isolates belonged to subsp. necrophorum and possessed the putative hemagglutinin gene. Western blot analysis with antileukotoxin antibodies raised in rabbit showed the presence of leukotoxin protein in the culture supernatant of all isolates. Furthermore, flow cytometry of the culture supernatants demonstrated cytotoxicity to bovine and alpaca polymorphonuclear leukocytes (PMNs). The extent of cytotoxicity to either alpaca or bovine PMNs differed among camelid strains. The cytotoxicity of many of the camelid strains was higher (P < 0.05) toward alpaca PMNs compared to bovine PMNs. Fusobacterium necrophorum isolates from llama and alpaca are similar to bovine isolates, and leukotoxin may be a major virulence factor.


Surgical treatment of liver metastasis from breast cancer.
We report five patients who underwent laparotomy for liver metastasis from breast cancer without extrahepatic spread, with the intention to perform liver resection. All these patients had been subjected to modified radical mastectomy following systemic chemotherapy and periodical consecutive investigations to detect distant spreading. After laparotomy, patients have been regularly followed. Case 1, right trisegmentectomy in a 53-year-old woman, 36.5 months after the mastectomy. In the 17th postoperative month she continues without relapse. Case 2, hepatic artery ligature in a 41-year-old woman, 15 months after the mastectomy. In the 17th postoperative month she died. Case 3, bisegmentectomy (VI-VII) in a 51-year-old woman, 24 months after the mastectomy. In the 17th postoperative month she died. Case 4, exploratory laparotomy in a 51-year-old woman, 91 months after the mastectomy. In the 31th postoperative month she remains alive. Case 5, segmentectomy (IV) in a 59-year-old woman, 112 months after the mastectomy. In the 33th postoperative month she continues without relapse. As a conclusion, the surgical resection of liver metastasis from breast tumors after chemotherapy must be used in selected cases.


Leadership During the Boston Marathon Bombings: A Qualitative After-Action Review.
On April 15, 2013, two improvised explosive devices (IEDs) exploded at the Boston Marathon and 264 patients were treated at 26 hospitals in the aftermath. Despite the extent of injuries sustained by victims, there was no subsequent mortality for those treated in hospitals. Leadership decisions and actions in major trauma centers were a critical factor in this response. The objective of this investigation was to describe and characterize organizational dynamics and leadership themes immediately after the bombings by utilizing a novel structured sequential qualitative approach consisting of a focus group followed by subsequent detailed interviews and combined expert analysis. Across physician leaders representing 7 hospitals, several leadership and management themes emerged from our analysis: communications and volunteer surges, flexibility, the challenge of technology, and command versus collaboration. Disasters provide a distinctive context in which to study the robustness and resilience of response systems. Therefore, in the aftermath of a large-scale crisis, every effort should be invested in forming a coalition and collecting critical lessons so they can be shared and incorporated into best practices and preparations. Novel communication strategies, flexible leadership structures, and improved information systems will be necessary to reduce morbidity and mortality during future events.


Computer-aided analysis of structural properties and epitopes of Iranian HPV-16 E7 oncoprotein.
Infection by human papillomavirus type 16 (HPV-16) is the cause of 50% or more of cervical cancers in women. The E7 oncoprotein of HPV-16 has long been known as a potent immortalizing and transforming agent. We used different servers like PseAAC, MHC_binding, MHC_II_binding and Expasy for the present computational prediction. The results for T cell epitopes showed that B1501, A0203, A0201, A0202, A6801 and DRB0405 alleles had lower IC50 than other alleles. We also predicted several peptides with the best binding affinities for alleles of the most frequent MHC class I and II alleles of the various ethnic groups living in the different region of Iran. Two peptides (26-35) and (44-52) were predicted as B-cell epitopes. According to this analysis 1 N-glycosylation site, 2 PKC sites, 4 CK2 sites and 3 disulfide sites were predicted. Our computational study predicted that B cell epitope 1 was Casein kinase II phosphorylated (site No. 31) and glycosylated (site No. 29). Putative MHC-I epitopes 3 and 5 and MHC-II epitopes 19, 21 and 26 were predicted to be casein kinase II phosphorylated. MHC-II epitopes 19 and 21 was predicted to be glycosylated. T cell epitopes 1, 13, 16 and 24 were demonstrated to be kinase C phosphorylated. The result of this analysis for Iranian HPV-16 E7 also indicated that 21.43%, 18.37% and 60.20% of the protein were in the α-helix, extended strand and random coil respectively.


Do home visiting services received during pregnancy improve birth outcomes? Findings from Virginia PRAMS 2007-2008.
Reducing poor birth outcomes are national and state priorities. At the national level participation in home visiting services has gained momentum with the recent appropriation of federal funds for states to implement evidence-based maternal and child health home visiting programs. The effects of having a home visit are unknown at the state level. Using cross-sectional data from 2007 to 2008 Virginia Pregnancy Risk Assessment and Monitoring System (PRAMS), maternal and infant outcomes were examined. Women who had a home visit during pregnancy were assigned into the home visiting (HV) participation group and those who did not were assigned to the HV Comparison group and used for the analysis. Bivariate analyses, Rao-Scott chi square tests, and multivariate logistic regression measured and quantified the association between HV participation and outcomes. The HV Participation group were 87.5% less likely to have a low birth weight infant (0.13, 95% CI: 0.020, 0.78), 4.5 times more likely to initiate breastfeeding (aOR: 4.5, 95% CI: 1.05, 19.54), and 39 times more likely to use contraceptives postpartum (aOR: 38.55, 95% CI: 3.14, 473.21). Receiving home visiting services during pregnancy increased breastfeeding initiation and postpartum contraceptive use while reducing the risk of low birth weight.


Conjugated linolenic acids and their bioactivities: a review.
Conjugated linolenic acid (CLNA) is a mixture of positional and geometric isomers of octadecatrienoic acid (α-linolenic acid, cis9,cis12,cis15-18:3 n-3) found in plant seeds. Three 8,10,12-18:3 isomers and four 9,11,13-18:3 isomers have been reported to occur naturally. CLNA isomers such as punicic acid, α-eleostearic acid and jacaric acid have been attributed to exhibit several health benefits that are largely based on animal and in vitro studies. This review has summarized and updated the evidence regarding the metabolism and bioactivities of CLNA isomers, and comprehensively discussed the recent studies on the effects of anti-carcinogenic, lipid metabolism regulation, anti-inflammatory, anti-obese and antioxidant activities of CLNA isomers. The available results may provide a potential application for CLNA isomers from natural sources, especially edible plant seeds, as effective functional food ingredients and dietary supplements for the above mentioned disease management. Further research, especially human randomized clinical trials, is warranted to investigate the detailed physiological effects, bioactivity and molecular mechanism of CLNA.


Effect of essential oil supplementation to diet on meat quality, fatty acid composition, performance parameters and intestinal microbiota of Japanese quails.
The effect of essential oil (EO) supplementation on carcass characteristics of Japanese quails and interactions between ingredients and intestinal morphology were investigated in this study. A total of 250 quails were fed different diet: D1, basal diet (BD); D2, BD plus palmarosa oil (PO; 100 µg/kg diet); D3, BD plus lemon myrtle oil (LMO; 100 µg/kg diet); D4, BD plus α-Tops (mixture of α-terpineol, cineole and terpinene-4-ol; 100 µg/kg diet); and D5, BD plus cyclodextrin. Overall growth performance was determined at multiple time points during 35 days of experiment. Carcass characteristics (fatty acid, pH and colour), intestinal morphology and the expression levels of meat quality-related genes including the insulin-like growth factor (IGF-1), myogenin and avian uncoupling protein (avUCP) were examined at the end of the trial. Additionally, intestinal microbiome of quails was studied by next-generation sequencing-based culture-independent analysis. Although the inclusion of EOs into the diet had no effect on the growth performance of quails and the microbial profile, the significant changes in pH24 and colour (a*) of the quail's breast muscle (p < .05) in the group receiving PO were observed. Additionally, oleic acid content in the breast muscle was significantly higher in the EOs supplemented groups (p < .01). Quails fed the PO supplemented diet had higher villus and relatively rich in oleic acid. The expression levels of IGF-1 and myogenin genes in quail's muscle were not affected, but the expression of avUCP gene was significantly lower in quails fed with LMO and α-Tops (p < .05). The results demonstrated variable effects of these treatments on intestinal morphology. Taken together, dietary inclusion of EOs is found to be beneficial and hence can be recommended for improving the quality of poultry meat.


Paediatric Virology: A rapidly increasing educational challenge.
The '2nd Workshop on Paediatric Virology', which took place on Saturday the 8th of October 2016 in Athens, Greece, provided an overview on recent views and advances on Paediatric Virology. Emphasis was given to HIV-1 management in Greece, a country under continuous financial crisis, hepatitis B vaccination in Africa, treatment options for hepatitis C virus in childhood, Zika virus in pregnancy and infancy, the burden of influenza on childhood, hand-foot-mouth disease and myocarditis associated with Coxsackie viruses. Other general topics covered included a critical evaluation of Paediatric Accident and Emergency viral infections, multimodality imaging of viral infections in children, surgical approaches of otolaryngologists to complex viral infections, new advances in the diagnosis and treatment of viral conjunctivitis and novel molecular diagnostic methods for HPV in childhood. A brief historical overview of the anti-vaccination movement was also provided, as well as presentations on the educational challenge of Paediatric Virology as a new subspecialty of Paediatrics. This review highlights selected lectures and discussions of the workshop.


Plant virus movement proteins originated from jelly-roll capsid proteins.
Numerous, diverse plant viruses encode movement proteins (MPs) that aid the virus movement through plasmodesmata, the plant intercellular channels. MPs are essential for virus spread and propagation in distal tissues, and several unrelated MPs have been identified. The 30K superfamily of MPs (named after the molecular mass of tobacco mosaic virus MP, the classical model of plant virology) is the largest and most diverse MP variety, represented in 16 virus families, but its evolutionary origin remained obscure. Here, we show that the core structural domain of the 30K MPs is homologous to the jelly-roll domain of the capsid proteins (CPs) of small RNA and DNA viruses, in particular, those infecting plants. The closest similarity was observed between the 30K MPs and the CPs of the viruses in the families Bromoviridae and Geminiviridae. We hypothesize that the MPs evolved via duplication or horizontal acquisition of the CP gene in a virus that infected an ancestor of vascular plants, followed by neofunctionalization of one of the paralogous CPs, potentially through the acquisition of unique N- and C-terminal regions. During the subsequent coevolution of viruses with diversifying vascular plants, the 30K MP genes underwent explosive horizontal spread among emergent RNA and DNA viruses, likely permitting viruses of insects and fungi that coinfected plants to expand their host ranges, molding the contemporary plant virome.


Evidence of a transcriptional co-activator function of cohesin STAG/SA/Scc3.
Cohesins hold sister chromatids together from DNA replication until they are segregated. Although cohesins Smc1, Smc3, and Scc1/Rad21 are involved in chromatid cohesion and other cellular processes, little is known about the other mitotic cohesin subunit, Scc3/STAG. Here we describe STAG/Scc3, which may act as a transcriptional co-activator. STAG2 is able to enhance the activity of the tumor necrosis factor alpha, the CD69, and the human immunodeficiency virus long terminal repeat promoters in a NF-kappaB-dependent manner. In addition, STAG2 interacts with the viral transactivator Tat and enhances the Tat-mediated activation of the human immunodeficiency virus long terminal repeat promoter. Moreover, STAG2 co-activates a multimeric NF-kappaB reporter construct and enhances the activity of the transactivation domain of p65/RelA in a Gal4 system. This function is dependent on one of the LXXLL co-activation motives present in this cohesin and is substantiated by the interaction of STAG2 with the p65 subunit of NF-kappaB. These results describe a novel activity for cohesins, suggesting a role for STAG/Scc3 in transcriptional regulation.


Mutation of the surface valine residues 8 and 44 in the rubredoxin from Clostridium pasteurianum: solvent access versus structural changes as determinants of reversible potential.
The Pr(i) sidechains of two adjacent valine residues, V8 and V44, define the surface of the rubredoxin from Clostridium pasteurianum and control access to its Fe(S-Cys)4 active site. To assess the effect of systematic change of the steric bulk of the alkyl sidechains, eight single and three double mutant proteins have been isolated which vary G (H), A (Me), V (Pr(i)), L (Bu(i)) and I (Bu(s)) at those positions. X-ray crystal structures of the Fe(III) forms of the V44A and V44I proteins are reported. Positive shifts in reversible potential of up to 116 mV are observed and attributed to increased polarity around the Fe(S-Cys)4 site induced by (1) changes in protein backbone conformation driven by variation of the steric demands of the sidechain substituents and (2) changes in solvent access to the side-chains of ligands C9 and C42. Data for the V44A mutant show that a minor change in the steric requirements of a surface residue can introduce a NH...Sgamma hydrogen bond at the active site and lead to a shift in potential of + 50 mV.


[Swine-spread severe influenza-associated pneumonia: A case report and literature review].
We report and analyze the clinical data of the first case of severe pneumonia caused by influenza B virus from swine. The patient, a 62 year-old male domestic pig breeder, was admitted to hospital because of fever and muscle pain for 5 days, and anhelation for 3 days. One week before the onset of disease, the patient kept close contact with pigs. CT scan of the chest showed diffuse infiltration in both lungs. Influenza B virus antigen detection (colloidal gold method) was repeatedly positive. These all confirmed influenza B virus infection. Poor appetite, weight loss, cough, poor spirit of pigs, positive influenza B virus antigen test occurred in the pig, while the patient had no history of exposure to influenza B-infected patients. It was likely that influenza B virus was transmitted from domestic pigs to the patient by droplets or close contact. Influenza B virus epidemics always occur every five or six years a time, and patients and carriers are the main source of infection. After searching the Pubmed, Web of science, Elsevier, Wanfang, and CNKI databases, it was found that although there were many studies on influenza B virus infecting seals, ferret, domestic pigs, guinea pigs, and other animals, there was no case report for animal-to-human infection. It is the first case report of type B influenza virus transmission from domestic pigs to people in the world, which provides a new direction for the research and prevention of influenza B virus.


Micro fluorescent analysis system integrating GaN-light-emitting-diode on a silicon platform.
A micro fluorescent analysis system is proposed using silicon micromachining. GaN blue light-emitting diode (LED) monolithically integrated on a silicon substrate is used as a light source for the fluorescent analysis system. The blue light suits the excitation of several dyes used commonly in fluorescent analysis. Silicon photodiode (Si-PD) that matches the visible and near infrared fluorescent wavelengths of dyes is integrated on a silicon substrate. Polydimethylsiloxane (PDMS) micro-channels are also stacked for flowing dye-sensitized liquid. Therefore, the proposed system is an integrated system that can be composed on a silicon platform, i.e. a bottom layer of Si-PD, a middle layer of GaN-LED on silicon substrate and a top layer of micro PDMS channel. An aperture is opened into the GaN-LED layer by deep reactive ion etching to create a ring-shaped GaN-LED and a through-hole for detection. The light from the ring-shaped GaN-LED in the middle layer excites the dye-sensitized liquid in the top micro-channel layer. The fluorescence emitted from dye is detected by the Si-PD on the bottom layer at an angle larger than 90 degrees from the direction of excitation. Therefore, the detection optics consist basically of a dark-field illumination optical system. In order to evaluate the performance of the integrated system, fluorescence of fluorescein isothiocyanate (FITC) solution flowing in the micro channel is measured. From the measurement, the noise, sensitivity and limit of detection in the fabricated system are evaluated for FITC dye to be 0.57 pA, 1.21 pA μM(-1) and 469 nM, respectively. From these results, a compact fluorescence analysis system is demonstrated.


Formulation of Deformable Liponiosomal Hybrid of Repaglinide: In vitro Characterization and Evaluation of the Anti-Diabetic Effect.
The current study sought to create novel deformable liponiosomal hybrids (LNHs) as a viable RPG delivery system. Repaglinide (RPG) is an effective anti-hyperglycemic drug. However, its limited solubility may limit its therapeutic applicability. LNHs are a potential liposome-niosome combination. Using phospholipids and non-ionic surfactants together improves their functionality in regulating drug release and increasing their permeability and stability. The development of RPG-loaded LNHs was performed using the reverse ethanol injection method based on the 23 factorial design to explore the potential of various variables on the encapsulation efficiency (EE%) and % RPG released after 12 h (Q12h). Further in vitro characterization tests and in vivo study were also performed on the optimal RPG-loaded LNHs. After investigating how the examined independent factors could affect significantly both the EE % and Q12h, F7 was selected as the optimal liponiosomal formulation. F7 showed 87.07 ± 2.27 EE% and 94.32 ± 1.25 Q12h. F7 demonstrated higher permeability and stability than the corresponding liposomes and niosomes. Furthermore, F7 demonstrated greater hypoglycemic efficacy and bioavailability than pure RPG. The combination of liponiosomes and niosomes in the form of LNHs has the potential to be an effective nano-drug delivery vehicle for RPG.


Keeping cancer guidelines current: results of a comprehensive prospective literature monitoring strategy for twenty clinical practice guidelines.
To describe a methodology used to keep practice guidelines up to date and to summarize data collected during the first year of implementing this plan with a cancer practice guidelines program. The updating strategy includes regular searches of peer-reviewed literature and meeting proceedings, review and interpretation of new evidence, review and revision of clinical recommendations, and notification to practitioners and policy makers about new evidence and its impact on recommendations. Eighty pieces of new evidence were found relating to seventeen of the twenty guidelines included in this study. On average, four pieces of new evidence were found per guideline, but there was considerable variation across the guidelines. Of the eighty pieces, nineteen contributed to modifications of clinical recommendations in six practice guidelines, whereas the remaining evidence served to support the original recommendations. None of the modifications led to changes that advised against original recommendations. MEDLINE, the Cochrane Library, and meeting proceedings yielded many pieces of evidence, whereas CancerLit and HealthStar did not contribute significantly to the overall yield. Furthermore, key pieces of evidence that led to modifications to the recommendations were often identified by members of the disease site groups before appearing in electronic databases. The updating process is resource intensive but yields important findings. In response to this evaluation, the updating protocol has been revised such that literature searches are conducted quarterly and the scope of sources searched routinely is restricted to MEDLINE, the Cochrane Library, and meeting proceedings.


Relation of automatic postural responses and reaction-time voluntary movements of human leg muscles.
This study contrasts the properties of compensatory postural adjustments in response to movements of the support surface with those of reaction-time voluntary movements in human subjects. Subjects stood upon a six degrees-of-freedom movable platform and performed tone and movement-triggered voluntary sways about the ankle joints both under conditions of postural stability and instability. These triggered movements could be executed as rapidly as postural adjustments to support surface perturbations (80-120 ms), but only when the former were well practiced, single-choice (direction) and were performed under conditions of postural stability. Evaluation of the properties of postural adjustments and reaction-time voluntary movements revealed a number of clear organizational differences between the two categories of movement, but most interesting was the finding that, when reaction-time movements were triggered by or at the onset of platform movement, the postural adjustments always occurred first. Only when subjects were given a tone trigger 50 ms in advance of platform movement were they able to execute the reaction-time movement first. We found that the dichotomous voluntary/reflexive classification of movements was not consistent with all of the identified properties of postural adjustments and reaction-time movements. Instead, we find a system which classifies movements by function, as either stabilizating or orientational adjustments, to be more useful. In the context of whole-body movement then, intentional focal components would be closely associated with others directed towards postural stabilization.


Plasma lipoprotein and apolipoprotein distribution as a function of density in the rainbow trout (Salmo gairdneri).
I have previously described [Babin (1987) J. Biol. Chem. 262, 4290-4296] the apolipoprotein composition of the major classes of trout plasma lipoproteins. The present work describes the use of an isopycnic density gradient centrifugation procedure and sequential flotation ultracentrifugation to show: (1) the presence of intermediate density lipoproteins (IDL) in the plasma, between 1.015 and 1.040 g/ml; (2) the existence of a single type of Mr 240,000 apoB-like in the low density lipoproteins (LDL, 1.040 less than p less than 1.085 g/ml); (3) the presence of apoA-I-like (Mr 25,000) in the densest LDL; (4) the adequacy of 1.085 g/ml as a cutoff between the LDL and high density lipoproteins (HDL); (5) the accumulation of Mr 55,000 and 76,000 apolipoproteins and apoA-like apolipoproteins in the 1.21 g/ml infranatant. The fractionation of trout lipoprotein spectrum thus furnishes the distribution of the different lipoprotein classes and leads to the description of the constituent apolipoproteins, which account for about 36% of circulating plasma proteins in this species.


Functional asymmetry of left and right avian piriform cortex in homing pigeons' navigation.
It has been shown that homing pigeons rely on olfactory cues to navigate over unfamiliar areas and that any kind of olfactory impairment produces a dramatic reduction of navigational performance from unfamiliar sites. The avian piriform cortex is the main projection field of olfactory bulbs and it is supposed to process olfactory information; not surprisingly bilateral lesions to this telencephalic region disrupt homing pigeon navigation. In the present study, we attempted to assess whether the left and right piriform cortex are differentially involved in the use of the olfactory navigational map. Therefore, we released from unfamiliar locations pigeons subjected, when adult, to unilateral ablation of the piriform cortex. After being released, the pigeons lesioned to the right piriform cortex orientated similarly to the intact controls. On the contrary, the left lesioned birds were significantly more scattered than controls, showing a crucial role of the left piriform cortex in processing the olfactory cues needed for determining the direction of displacement. However, both lesioned groups were significantly slower than controls in flying back to the home loft, showing that the integrity of both sides of the piriform cortex is necessary to accomplish the whole homing process.


Safe disconnection of 5-fluorouracil elastomeric pumps: The benefit of a closed-system-transfer device designed for cytotoxic drug administration/perfusion.
Occupational exposure to cytotoxic drugs can lead to significant health problems. This study was designed to evaluate the risk of 5-fluorouracil (5-FU) contamination for nurses when disconnecting the infusion line of an elastomeric pump from a non-coring needle, by comparing three configurations: the first one using standard Male and Female Luer lock (Group 1), the second one using a needle-free connector (NFC) and a Male Luer lock (Group 2) and the third one using a closed-system transfer device (CSTD), Qimono® (Group 3). In this in vitro study, 10 elastomeric pumps for each of the three groups were filled with 5-FU and a tissue mimicking the patient's arm was placed below the connection between the infusion line and the tubing of non-coring needle. After 48 h of infusion, disconnection was performed by a nurse with a wipe soaked in a mix of chlorhexidine and isopropyl alcohol in order to mimic care practices. For each pump, the tissue, the pair of gloves and the wipes used during the disconnection were collected for analysis. Median level of overall 5-FU contamination (gloves + wipes + tissues) in group 3 was significantly lower than in group 1 (p = 0.018) and group 2 (p = 0.036). There was no difference between groups 1 and 2. Results per sample type showed no difference in contamination between the three configurations for the gloves as well as for the tissues. Concerning the wipes, the lowest contamination was observed in group 3, representing a mean reduction of 61% compared to group 1 and a mean reduction of 43% compared to group 2. The use of Qimono® appears to significantly reduce 5-FU contamination when disconnecting infusion lines of an elastomeric pump unlike NFC and standard Luer lock.


A route to nanoscopic materials via sequential infiltration synthesis on block copolymer templates.
Sequential infiltration synthesis (SIS), combining stepwise molecular assembly reactions with self-assembled block copolymer (BCP) substrates, provides a new strategy to pattern nanoscopic materials in a controllable way. The selective reaction of a metal precursor with one of the pristine BCP domains is the key step in the SIS process. Here we present a straightforward strategy to selectively modify self-assembled polystyrene-block-poly(methyl methacrylate) (PS-b-PMMA) BCP thin films to enable the SIS of a variety of materials including SiO(2), ZnO, and W. The selective and controlled interaction of trimethyl aluminum with carbonyl groups in the PMMA polymer domains generates Al-CH(3)/Al-OH sites inside the BCP scaffold which can seed the subsequent growth of a diverse range of materials without requiring complex block copolymer design and synthesis.


Interest in paromomycin for the treatment of visceral leishmaniasis (kala-azar).
Leishmaniasis is an important vector-borne disease, and it is classified as one of the most important tropical fly-borne infections. This disease can cause two types of clinical manifestations: cutaneous forms and visceral forms. Visceral leishmaniasis, which is also called kala-azar, is a very serious infection that can be fatal. The management of visceral leishmaniasis requires informed diagnostic and therapeutic approaches. Continuous research and development regarding the treatment of visceral leishmaniasis had led to many improvements. Paromomycin is a relatively new antibiotic drug that has been used for the treatment of visceral leishmaniasis for several years. This article reviews and discusses the use of paromomycin for visceral leishmaniasis therapy.


Restoration of stamp marks on steel components.
Stamp marks are used as a unique identification for a range of items, but these can be erased for criminal activities. Erased marks can sometimes be recovered by etching or magnetic means. The present study looked at the application of Fry's reagent to recover erased marks from steel. The investigation also demonstrated that Fry's reagent can deteriorate on storing and will require a longer etching time. The effect of different applied forces of stamping was investigated, and the depth of the underlying deformation was determined by etching after varying degrees of metal removal. The amount of metal needing to be removed depends on the force applied to the die. Metal removal also affects the time needed for recovery. The underlying structural change remains as a hidden identification mark, and could potentially be used by manufacturers as an unseen identifier. A model for the underlying deformation is proposed.


Phenotypic effects of the "mini-muscle" allele in a large HR x C57BL/6J mouse backcross.
From outbred Hsd:ICR mice, we selectively bred 4 replicate lines for high running (High-Runner [HR] lines) on wheels while maintaining 4 nonselected lines as controls (C lines). An apparent Mendelian recessive, the "mini-muscle" (MM) allele, whose main phenotypic effect is to reduce hindlimb muscle mass by 50%, was discovered in 2 HR lines and 1 C line. This gene of major effect has gone to fixation in one selected line, remains polymorphic in another, and is now undetectable in the one C line. Homozygotes exhibit various pleiotropic effects, including a doubling of mass-specific muscle aerobic capacity, and larger hearts, livers, and spleens. To create a population suitable for mapping the genomic location of the MM allele and to better characterize its pleiotropic effects, we crossed females fixed for the MM allele with male C57BL/6J. F(1) males were then backcrossed to the MM parent females. Backcross (BC) mice (N = 404) were dissected, and a 50:50 ratio of normal to MM phenotype was observed with no overlap in relative muscle mass. In the BC, analysis of covariance revealed that MM individuals ran significantly more on days 5 and 6 of a 6-day exposure to running wheels (as in the routine selective-breeding protocol), were smaller in body mass, and had larger ventricles and spleens.


Clinical pharmacology, biomarkers and personalized medicine: education please.
Over the past decades, the scope of clinical pharmacology within the pharmaceutical industry has widened considerably. Key growth has been in the area of translational science and exploratory medicine, where clinical pharmacologists are nowadays the mediator between basic research and establishment of clinical usefulness. This role has led to and is supported by the rapid developments in pharmacokinetic-pharmacodynamic modeling and simulation, a strong focus on biomarkers for early informed decision-making, and the advent of pharmacogenomics into safety and efficacy predictions and evaluations. The ultimate goal--safer, more efficacious drug prescription--is shared with that of today's drive for more personalized medicine. This article reviews the evolution of clinical pharmacology within the industry, the regulatory, clinical and societal drivers for this evolution, and the analogy with the establishment of personalized medicine in clinical practice. Special attention is given to the integration of biomarkers into clinical practice and the concurrent need for education of clinicians, pharmacists, payers and patients.


Novel type I restriction specificities through domain shuffling of HsdS subunits in Lactococcus lactis.
This study identifies a natural system in Lactococcus lactis, in which a restriction modification specificity subunit resident on a 6159 bp plasmid (pAH33) alters the specificity of a functional R/M mechanism encoded by a 20.3 kb plasmid, pAH82. The new specificity was identified after phenotypic and molecular analysis of a 26.5 kb co-integrate plasmid (pAH90), which was detected after bacteriophage challenge of the parent strain. Analysis of the regions involved in the co-integration revealed that two novel hybrid hsdS genes had been formed during the co-integration event. The HsdS chimeras had interchanged the C- and N-terminal variable domains of the parent subunits, generating two new restriction specificities. Comparison of the parent hsdS genes with other type I specificity determinants revealed that the region of the hsdS genes responsible for the co-integration event is highly conserved among lactococcal type I hsdS determinants. Thus, as hsdS determinants are widespread in the genus Lactococcus, new restriction specificities may evolve rapidly after homologous recombination between these genes. This study demonstrates that, similar to previous observations in Gram-negative bacteria, a Gram-positive bacterium can acquire novel restriction specificities naturally through domain shuffling of resident HsdS subunits.


High accumulation of platinum-DNA adducts in strial marginal cells of the cochlea is an early event in cisplatin but not carboplatin ototoxicity.
Ototoxicity is a typical dose-limiting side effect of cancer chemotherapy with cisplatin but much less so with carboplatin. To elucidate the underlying molecular pathological mechanisms, we have measured the formation and persistence of drug-induced DNA adducts in the nuclei of inner ear cells of guinea pigs after short-term exposure to either cisplatin or carboplatin using immunofluorescence staining and quantitative image analysis. After application of carboplatin, all cells of the cochlea exhibited a similar burden of guanine-guanine intrastrand cross-links in DNA. In contrast, we observed a pronounced 3- to 5-fold accumulation of this cytotoxic adduct exclusively in the marginal cells of the stria vascularis between 8 and 48 h after treatment with cisplatin. In the kidney, the other critical target tissue of cisplatin toxicity, a similar high preferential formation of cytotoxic DNA adducts was measured in the tubular epithelial cells but not in other renal cell types. As for the ear, this excessive formation of DNA damage in a particular cell type was seen in animals treated with cisplatin but not those treated with carboplatin. Because cisplatin ototoxicity is often attributed to oxidative stress mediated by the generation of radical oxygen species (ROS), we have measured in parallel the levels of the lead DNA oxidation product 8-oxoguanine (8-oxoG) in cochlear cryosections. Compared with basal levels in untreated control cochleas, no additional formation of 8-oxoG was detectable up to 48 h after cisplatin treatment in the DNA of either inner-ear cell type. This suggests that the generation of ROS may be a secondary event in cisplatin ototoxicity.


Dynamics and Structure-Function Relationships of the Lamin B Receptor (LBR).
The lamin B receptor (LBR) is a multi-spanning membrane protein of the inner nuclear membrane that is often employed as a "reporter" of nuclear envelope dynamics. We show here that the diffusional mobility of full-length LBR exhibits significant regional variation along the nuclear envelope, consistent with the existence of discrete LBR microdomains and the occurrence of multiple, asymmetrically-spaced anastomoses along the nuclear envelope-endoplasmic reticulum interface. Interestingly, a commonly used fusion protein that contains the amino-terminal region and the first transmembrane domain of LBR exhibits reduced mobility at the nuclear envelope, but behaves similarly to full-length LBR in the endoplasmic reticulum. On the other hand, carboxy-terminally truncated mutants that retain the first four transmembrane domains and a part or the whole of the amino-terminal region of LBR are generally hyper-mobile. These results suggest that LBR dynamics is structure and compartment specific. They also indicate that native LBR is probably "configured" by long-range interactions that involve the loops between adjacent transmembrane domains and parts of the amino-terminal region.


Thermal injury model in the rabbit ear with quantifiable burn progression and hypertrophic scar.
Hypertrophic scar is a major clinical outcome of deep-partial thickness to full thickness thermal burn injury. Appropriate animal models are a limitation to burn research due to the lack of, or access to, animal models which address the endpoint of hypertrophic scar. Lower species, such as rodents, heal mainly by contracture, which limits the duration of study. Higher species, such as pigs, heal more similarly to humans, but are associated with high cost, long duration for scar development, challenges in quantifying scar hypertrophy, and poor manageability. Here, we present a quantifiable deep-partial thickness burn model in the rabbit ear. Burns were created using a dry-heated brass rod for 10 and 20 seconds at 90 °C. At the time of eschar excision on day 3, excisional wounds were made on the contralateral ear for comparison. Burn wound progression, in which the wound size expands over time is a major distinction between excisional and thermal injuries, was quantified at 1 hour and 3 days after the injuries using calibrated photographs and histology and the size of the wounds was found to be unchanged from the initial wound size at 1 hour, but 10% in the 20 seconds burn wounds at 3 days. A quantifiable hypertrophic scar, measured by histology as the scar elevation index, was present in both 20 seconds burn wounds and excisional wounds at day 35. ImageJ measurements revealed that the 20 seconds burn wound scars were 22% larger than the excisional wound scars and the 20 seconds burn scar area measurements from histology were 26% greater than in the excisional wound scar. The ability to measure both burn progression and scar hypertrophy over a 35-day time frame suits this model to screening early intervention burn wound therapeutics or scar treatments in a burn-specific scar model.


MK-801 neurotoxicity in the guinea pig cerebral cortex: susceptibility and regional differences compared with the rat.
N-methyl-D-aspartate (NMDA) receptor antagonists induce transient vacuole formation in neurons of the retrosplenial cortex and, after higher doses, necrosis in the same region. To our knowledge, all studies demonstrating these effects have been carried out in rats or mice. The present study investigated whether vacuolization occurs in the guinea pig, rats being used as controls. Female Dunkin-Hartley guinea pigs (age 15-18 weeks) were given a single subcutaneous injection of saline or the non-competitive NMDA antagonist dizocilpine maleate [(+)-MK-801; 1, 4, or 12 mg/kg]. Female Sprague-Dawley rats (age 16 weeks) received saline or MK-801 (1 mg/kg). Whatever the dose of MK-801, guinea pigs showed only occasional vacuolated neurons in the retrosplenial cortex. However, affected neurons (mainly large pyramidal cells of layer V) were found in the frontoparietal neocortex. The reaction was limited after 1 mg/kg, and seemed to reach a maximum at 4 mg/kg. Rats injected with 1 mg/kg MK-801 showed an intense vacuole reaction in neurons from layers III-IV of the retrosplenial cortex, but no affected neurons were noted in neocortical areas. We conclude that there are significant species differences in susceptibility to, and location of, vacuolization induced by NMDA receptor antagonists.


Disruption of the blood-aqueous barrier and lens abnormalities in mice lacking lysyl oxidase-like 1 (LOXL1).
Exfoliation syndrome (ES) is commonly associated with glaucoma, premature cataracts, and other ocular and systemic pathologies. LOXL1 gene variants are significantly associated with ES; however, the role of the protein in ES development remains unclear. The purpose of this study was to characterize the ocular phenotype in Loxl1(-/-) (null) mice. Loxl1 null mice and strain-matched controls (C57BL) were evaluated by clinical and histologic analyses. Anterior segment histology showed a pronounced vesiculation of the anterior lens in the null mice. The lesions were subcapsular and in direct apposition with the posterior iris surface. Fluorescein angiography showed increased diffusion of fluorescein into the anterior chamber of the null mice compared with age-matched controls (P = 0.003, two-tailed, unequal variance t-test), suggesting compromise of the blood-aqueous barrier. Intraocular pressure measurements were within the normal range (16.5 ± 2.0 mm Hg) in null mice up to 1 year of age. Immunohistochemistry showed decreased elastin in the iris and ciliary body in the null mouse compared with controls. Elimination of LOXL1 in mice impairs the blood-aqueous humor barrier in the ocular anterior segment and causes lens abnormalities consistent with cataract formation, but does not result in deposition of macromolecular material or glaucoma. These results show that mice lacking LOXL1 have some ES features but that complete disease manifestation requires other factors that could be genetic and/or environmental.


Two classes of single-input X-cells in cat lateral geniculate nucleus. II. Retinal inputs and the generation of receptive-field properties.
The retinal inputs to cells in the cat's lateral geniculate nucleus (LGN) were directly recorded to study the basis for the properties of two classes of LGN X-cells: Xs (single) and XL (lagged). The presence of excitatory or inhibitory input to an LGN cell from a particular simultaneously recorded ganglion cell was assessed with cross-correlograms during unstimulated activity. Because neighboring ganglion cells do not fire independently, features in a retinogeniculate correlogram can arise in two ways that must be distinguished by a direct effect of the ganglion cell on the LGN cell, or by correlated firing between that ganglion cell and some other ganglion cell that is an excitatory or inhibitory input to the LGN cell. It was possible to determine the origin of correlogram features because features indicating a retinogeniculate effect were distinctly different in timing and strength from features arising solely from correlated firing in the retina. The characteristic feature in a correlogram between an LGN cell and an excitatory retinal input was a sharp peak in LGN cell firing rate at the appropriate latency after the firing of the ganglion cell. The characteristic feature for an inhibitory input was a dip in LGN cell firing rate after the firing of the ganglion cell. Typically, this dip lasted 10-40 ms and was followed by a prolonged enhancement in LGN cell firing rate, which may reflect a postinhibitory rebound. XS-cells had a single retinal X input whose excitatory effect caused most of the LGN cell's spikes during stimulated and unstimulated activity. There was no conclusive evidence that any XS-cell received excitatory retinal input from either Y-cells or other X-cells of the same center sign. There was usually evidence for inhibition of XS-cells by retinal X-cells of opposite center sign with receptive fields highly overlapping that of the XS-cell, but rarely evidence for inhibition by Y-cells. XL-cells also had only a single excitatory input, but this X input had a relatively weak effect that caused only a minority of the LGN cell's spikes, typically 17% during maintained activity and 29% during visual stimulation. The input's excitatory effect was immediately followed by strong inhibition of the XL-cell. XL-cells were also inhibited by retinal X-cells of the same center sign that were adjacent (nearest neighbors) to the excitatory input. The strength and latency of both of these inhibitory effects indicate that the inhibition was disynaptic.(ABSTRACT TRUNCATED AT 400 WORDS)


Cross-linking of integrins induces tyrosine phosphorylation of the proto-oncogene product Vav and the protein tyrosine kinase Syk in human factor-dependent myeloid cells.
Attachment to extracellular matrix is important in the regulation of proliferation and differentiation of hematopoietic stem and progenitor cells. Post-ligand occupancy events of integrin receptors in myeloid cells are largely unknown. We examined early signaling events after stimulation of integrin receptors (outside-in signal) using a cross-linking system in a growth factor-dependent myeloid cell line, M07e, alpha 4, alpha 5, and beta 1 integrin cross-linking induced a similar pattern of transient tyrosine phosphorylation of cellular proteins. The approximate molecular weights of these phosphoproteins were M(r) 150,000, M(r) 120,000-125,000, M(r) 95,000, M(r) 70,000, M(r) 60,000, and M(r) 40,000-50,000. Vav, Syk, and Erk2 were identified as some of the tyrosine-phosphorylated proteins, and their weights were M(r) 95,000, M(r) 70,000, and M(r) 40,000-50,000, respectively. Erk2 and Vav were also tyrosine-phosphorylated by stimulation with Steel factor (SLF) and granulocyte macrophage colony-stimulating factor, whereas tyrosine phosphorylation of Syk was not induced by stimulation with these cytokines. The degree of tyrosine phosphorylation of Vav through integrin engagement was almost equal to that by SLF stimulation, whereas that of Erk2 was much weaker than with SLF stimulation. Upon integrin engagement, antibodies raised against Syk coprecipitated several tyrosine-phosphorylated proteins. In vitro binding assays demonstrated that, among these Syk-associated proteins, pp40, which differed from Erks, Crk, and Crkl, binds Syk through SH2 domains of Syk and is a prominent tyrosine-phosphorylated protein in integrin cross-linked cells. These results suggest that tyrosine phosphorylation of Vav and Erk2 in myeloid cells might be regulated by both integrins and cytokines in the bone marrow microenvironment, whereas Syk might be involved in a distinct pathway from the shared between integrins and cytokines in myeloid cells.


Species-specific and mutant MWFE proteins. Their effect on the assembly of a functional mammalian mitochondrial complex I.
The MWFE protein (70 amino acids) is highly conserved in evolution, but the human protein (80% identical to hamster) does not complement a null mutation in Chinese hamster cells. We have identified a small protein segment where significant differences exist between rodents and primates, illustrating very specifically the need for compatibility of the nuclear and mitochondrial genomes in the assembly of complex I. The segment between amino acids 39 and 46 appears to be critical for species-specific compatibility. Amino acid substitutions in this region were tested that caused a reduction of activity of the hamster protein or converted the inactive human protein into a partially active one. Such mutations could be useful in making mice with partial complex I activity as models for mitochondrial diseases. Their potential as dominant negative mutants was explored. More deleterious mutations in the NDUFA1 gene were also characterized. A conservative substitution, R50K, or a short C-terminal deletion makes the protein completely inactive. In the absence of MWFE, no high molecular weight complex was detectable by Blue Native-gel electrophoresis. The MWFE protein itself is unstable in the absence of assembled mitochondrially encoded integral membrane proteins of complex I.


The reliability and validity of self-reported puffing behavior: evidence from a cross-national study.
Self-reported puffing behavior has considerable potential as an indicator of smoking intensity, particularly in survey research evaluating population-based changes in smoking patterns. However, little is known about the reliability and validity of self-reported puffing behavior. This study compared smokers' perceptions of their puffing behavior with measures of both machine-determined puffing behavior and nicotine uptake to assess the utility of self-report. We assessed self-reported puffing behavior as well as demographic and smoking characteristics of 118 smokers from Australia, Canada, the United Kingdom, and the United States. At two visits, participants were asked to provide a saliva sample and to smoke a cigarette through a portable smoking topography device, the CReSSmicro, to measure puffing behavior. Saliva samples were assayed for cotinine, a measure of nicotine uptake, to provide estimates of smoke exposure. Intraclass coefficients for all measures of self-reported general puffing behavior were above .6, indicating that self-reported measures had fair-to-good test-retest reliability. Self-report, in particular of interpuff interval and number of cigarette puffs, was correlated only moderately with machine-determined puffing measures (.2<r<.4), and no self-report measure related to smoke exposure as measured by cotinine. Self-reported measures of puffing behavior appear to be fairly reliable but are correlated only weakly with objective measures of smoking topography. Results suggest that smokers have a better perception of the time spent between puffs and of the number of puffs taken than of the intensity and depth of each puff or their actual smoke exposure.


Chemistry of nucleic acids: impacts in multiple fields.
Research in nucleic acids has made major advances in the past decade in multiple fields of science and technology. Here we discuss some of the most important findings in DNA and RNA research in the fields of biology, chemistry, biotechnology, synthetic biology, nanostructures and optical materials, with emphasis on how chemistry has impacted, and is impacted by, these developments. Major challenges ahead include the development of new chemical strategies that allow synthetically modified nucleic acids to enter into, and function in, living systems.


High inflammatory activity related to the number of metabolic syndrome components.
It has been known that each component of the metabolic syndrome (MS) has an atherogenic potential and increases the risk of cardiovascular events. Therefore, patients who have MS are candidates for the development of atherosclerosis and accompanying complications. In this study, the authors assessed the levels of acute phase reactants as an indicator of inflammation in patients with MS. Twenty-five patients with recently diagnosed MS and not treated before who had at least 3 of 5 diagnostic criteria of MS listed in the Third Report of the Adult Treatment Panel National Cholesterol Education Program (NCEP-ATP III) guidelines were included in the study. Twenty healthy patients constituted the control group. Inflammatory parameters were compared between the groups. There was no significant difference between the MS and control group with regard to age and sex. White blood cell count (/mm(3)), high-sensitivity C-reactive protein (hs-CRP), uric acid, interleukin (IL) 6, and fibrinogen levels were found to be significantly higher in the MS group. Number of MS components was strongly correlated with serum levels of hs-CRP (r=0.688, P=.0001), IL-6 (r=0.546, P=.0001), fibrinogen (r=0.551, P=.0001), uric acid (r=0.517, P=.0001), and leucocyte count (/mm(3)) (r=0.456, P=.002). Inflammation plays an important role in atherosclerotic complications, which is activated in MS. Increased number of MS components are strongly associated with elevated inflammatory and metabolic markers. Measurement of serum inflammatory parameters in patients with MS may be beneficial in detection and management of cardiovascular events and in the assessment of efficacy of treatment.


Vasopressin receptor blockade in the anterior hypothalamus suppresses aggression in hamsters.
Although the anterior hypothalamus has been implicated in the control of aggression in various rodent species, little is known about the neurochemical mechanisms mediating this control. It has been established that flank marking, which occurs with high frequency during agonistic encounters in hamsters, is dependent upon vasopressin-sensitive neurons in the anterior hypothalamus. The present study was undertaken to determine whether intraspecific aggression in this species is similarly influenced by vasopressin in this area of the hypothalamus. Adult male hamsters, surgically implanted with guide cannulae aimed at the anterior hypothalamus, were microinjected with three different concentrations of the V1-receptor antagonist d(CH2)5Tyr(Me)AVP or a vehicle control of 0.9% NaCl. Sixty minutes after each microinjection a smaller male hamster was introduced into the home cage of the treated hamster. The resident hamsters showed a significant dose-dependent reduction in the number of biting attacks on the intruders over the 10 minute test period. The V1-receptor antagonist also caused a significant increase in the resident hamster's latencies to attack the intruder. However, the resident hamsters' total contact time with the intruder was unaffected by drug treatment suggesting that the reduction of aggression was not due to a generalized effect upon social behavior. The specificity of the drug treatment was further supported by the observation that it did not affect resident hamsters' sexual motivation or ability to mount a receptive female. These data suggest that vasopressin-sensitive neurons in the anterior hypothalamus are involved in the control of intraspecific aggression in male hamsters.


Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens.
Numerous research has pointed out that serotonin2c (5-HT2C) receptor, a subtype of 5-HT receptors belonging to the G-protein-coupled receptor superfamily, modulates the activity of mesencephalic dopamine (DA) neurons, the dysfunction of which is involved in devastating diseases such as schizophrenia, Parkinson's disease, and drug addiction. In the present study, using in vivo intracerebral microdialysis and Chinese hamster ovary (CHO) cells expressing 5-HT2C receptors to identify appropriate 5-HT2C receptor ligands, we sought to determine whether the property of 5-HT2C receptors to spontaneously activate intracellular signaling pathways in vitro (constitutive activity) participates in the tonic inhibitory control that they exert on DA release in the rat striatum and nucleus accumbens in vivo. In CHO cells, the purported antagonist 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f] indole hydrochloride (SB 206553), but not 6-chloro-5-methyl-1-[6-(2-methylpiridin-3-yloxy)pyridin-3-yl carbamoyl] indoline (SB 242084), decreased basal inositol phosphate accumulation, thus behaving as a 5-HT2C inverse agonist. Its effect was prevented by SB 242084. In vivo, SB 206553 (1-10 mg/kg) elicited a dose-dependent and clear-cut increase in accumbal and striatal DA release compared with SB 242084 (1-10 mg/kg), and the 5-HT2C agonist S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine hydrochloride (Ro-60-0175) (0.3-3 mg/kg) inhibited DA release. Pretreatment by SB 242084 reversed the change in DA release elicited by Ro-60-0175 and SB 206553. Furthermore, SB 206553-stimulated DA release was insensitive to reduction of 5-HT neuronal function induced by the 5-HT1A agonist (+/-)-8-hydroxy-2-dipropylaminotetralin or intra-raphe injections of 5,7-dihydroxytryptamine neurotoxin. The obtained results provide the first in vivo evidence that constitutive activity of the 5-HT2C receptor tonically inhibits mesencephalic DA neurons and underscore the need for a better understanding of the pathophysiological role of constitutive receptor activity.


Apoptosis and histopathological lesions in parasite-infected species of bivalve molluscs.
Apoptosis (programmed cell death) is an important mechanism for preservation of a healthy and balanced immune system in vertebrates. Little is known, however, about how apoptosis processes regulate invertebrate immune system. Thus, the present histopathological study was performed to search for the level of apoptosis on hemocytes of three bivalve species namely, Macoma edentula, Hiatula rupelliana and Gastrana fraglis in the Timsah Lake infected with branchial Rickettsia-like parasites and ciliated parasites in the digestive gland. Microscopically, special to elongated intracytoplasmic Rickettsia-like colonies were observed in the base of gill filaments of the clams. Histologically, the distribution and shapes of apoptotic cells were classified into three main types. The aggregation of apoptotic cells were observed in the apical and the basal parts of the ciliated cells lining the gill epithelium. These results provide a first insight into apoptotic processes in mollusc immune cells.


In vitro osmoregulation of taurine in fetal mouse hearts.
Regulation of taurine transport and accumulation in explanted fetal mouse hearts is shown to be under osmotic control. All osmotic agents studied, both ionic (NaCl, LiCl, choline Cl) and nonionic (sucrose, glucose) stimulated [3H]-taurine transport during an incubation of 19 h. Hyperosmotic stimulation of transport achieved statistical significance by 3 h in the presence of sucrose (P less than 0.05). After 1 h, 40 mM NaCl engendered a 56% increase in [3H]-taurine transport (P less than 0.01). The NaCl stimulation at 1 h may relate more to the transport system's absolute sodium ion requirement than hyperosmotic stimulation. Incremental addition of NaCl or sucrose linearly stimulates [3H]-taurine transport in an incubation of 19 h. Total taurine, measured by HPLC, increased 25% with addition of either 40 mM NaCl or 80 mM sucrose. Hyperosmotic stimulation of transport was not blocked with propranolol but was additive to beta-adrenergic stimulation of transport. Osmotic stimulation occurred with a large increase in Vmax (0.41----0.81 nmol/mg tissue/h) but only a small change in Km (0.51----0.43 mM). After 1 h preincubation with a hyperosmotic addition phenylalanine transport was measured, but was not different from control. Phenylalanine accumulation measured during 19 h incubation similarly was not altered. Streptozotocin induced diabetic rats had elevated plasma osmolarities (295 +/- 2.1----322 +/- 1.3 mosmol) and cardiac taurine (24.3 +/- 1.2----36 +/- 1.0 mumol/g wet wt.). The data presented demonstrates that mammalian cardiac taurine is regulated by the osmotic environment of the heart, suggesting an osmoregulatory function for intracellular taurine and physiological relevance in disease states such as diabetes.


Seasonal and perennial allergic conjunctivitis.
Seasonal and perennial allergic conjunctivitis are IgE-mediated, hypersensitivity ophthalmic conditions characterized by ocular pruritus, epiphora, and hyperemia. Proper diagnosis is usually made clinically based on history and physical examination. Diagnostic procedures are rarely necessary. Non-pharmacological measures, such as environmental modification and proper eye care, should be considered for all patients with allergic conjunctivitis. Pharmacological interventions may also be required. Milder cases can be treated with short-term topical ophthalmic therapy such as a decongestant/antihistamine combination, a mast cell stabilizer, or a multi-action agent. Moderate to severe cases may require longer usage of the above agents or the addition of an oral antihistamine. Refractory cases may necessitate the use of topical ophthalmic corticosteroids and/or immunotherapy. Despite all the available therapeutic agents, there continues to be a constant need to discover more effective ways to treat seasonal and perennial allergic conjunctivitis. This review article also discusses recent patents related to the field.


The herpes simplex virus 1 gene encoding a protease also contains within its coding domain the gene encoding the more abundant substrate.
The herpes simplex virus 1 open reading frames UL26 and UL26.5 are 3' coterminal. The larger, UL26 open reading frame encodes a protein approximately 80,000 in apparent molecular weight and contains the promoter and coding sequence of the UL26.5 gene, which specifies a capsid protein designated infected cell protein 35. The larger product contains in its entirety the amino acid sequence of the smaller protein. We report that the UL26 gene encodes a protease which catalyzes its own cleavage and that of the more abundant product of UL26.5. By inserting the coding sequence of an epitope to a cytomegalovirus monoclonal antibody and homologs of the immunoglobulin G binding domain of staphylococcal protein A into the 3' termini of the coding domains of the two open reading frames, we identified both products of the cleavage and determined that the cleavage site is approximately 20 amino acids from the carboxyl termini of both proteins.


Neutral mutations and repetitive DNA.
We have previously shown that computer simulations of processes that generate selectively advantageous changes together with random duplications and deletions give rise to genomes with many different genes embedded in a large amount of dispensable DNA sequence. We now explore the consequences of neutral changes on the evolution of genomes. We follow the consequences of sequence divergences that are neutral when they occur in dispensable sequences or extra copies of genes present in multigene families. We find that when divergence occurs at about the same frequency as duplication/deletion events, genomes carry repetitive sequences in proportion to their size. Inspection of the genomes as they evolved showed that multigene families were generated by relatively recent duplications of single genes and so would be expected to be highly homogeneous.


[Independence of the processes of transposition and genome rearrangements induced by transposons].
The data on the influence of the tnm mutations affecting transposition process on the deletion formation promoted by Tn and IS elements are presented. It was shown that the tnm mutations did not affect the frequency of deletion formation. The results of genetic analysis of the tnm mutant deficient in both transposition and genomic rearrangements induced by Tn9 inserted into lambda prophage, indicated that the mutant phenotype was caused by two different but linked mutations. A mutation affecting the process of genomic rearrangements was designated gerA2. The gerA2 mutation decreased sharply the frequency of rearrangements promoted by Tn9, Tn10 or Tn601 inserted into lambda prophage. However, this mutation had no influence upon transposition of the same Tn elements. The data obtained could be interpreted as indicating the independence of the processes of transposition and genomic rearrangements or as indication of the existence of specific steps of these processes.


Binding of [(3)H]lysergic acid diethylamide to serotonin 5-HT(2A) receptors and of [(3)H]paroxetine to serotonin uptake sites in platelets from healthy children, adolescents and adults.
Possible age effects on binding of [(3)H]lysergic acid diethylamide ([(3)H]LSD) to serotonin 5-HT(2A) receptors and of [(3)H]paroxetine to serotonin uptake sites were studied in platelets from healthy children (11-12 years of age), adolescents (16-17 years of age) and adults. Significant overall age effects were found both for the number of binding sites (B(max)) for [(3)H]LSD binding (p < 0.001), the affinity constant (K(d)) for [(3)H]LSD binding (p < 0.001), B(max) for [(3)H]paroxetine binding (p < 0.001) and K(d) for [(3)H] paroxetine binding (p = 0.006). In general, there was a decrease in B(max) with increasing age, which predominantly occurred between the ages 11-12 years and 16-17 years for the 5-HT(2A) receptor, and after 16-17 years of age for the serotonin uptake site. These developmental changes might have an impact on the effect of treatment with serotonergic drugs in children and adolescents. When the platelet serotonin variables investigated are employed in studies in children or adolescents, age matching or, alternatively, introduction of age control in the statistical analysis should be performed.


Failure to downregulate the epithelial sodium channel causes salt sensitivity in Hsd11b2 heterozygote mice.
In vivo, the enzyme 11β-hydroxysteroid dehydrogenase type 2 influences ligand access to the mineralocorticoid receptor. Ablation of the encoding gene, HSD11B2, causes the hypertensive syndrome of apparent mineralocorticoid excess. Studies in humans and experimental animals have linked reduced 11β-hydroxysteroid dehydrogenase type 2 activity and salt sensitivity of blood pressure. In the present study, renal mechanisms underpinning salt sensitivity were investigated in Hsd11b2(+/-) mice fed low-, standard-, and high-sodium diets. In wild-type mice, there was a strong correlation between dietary sodium content and fractional sodium excretion but not blood pressure. High sodium feeding abolished amiloride-sensitive sodium reabsorption, consistent with downregulation of the epithelial sodium channel. In Hsd11b2(+/-) mice, the natriuretic response to increased dietary sodium content was blunted, and epithelial sodium channel activity persisted. High-sodium diet also reduced renal blood flow and increased blood pressure in Hsd11b2(+/-) mice. Aldosterone was modulated by dietary sodium in both genotypes, and salt sensitivity in Hsd11b2(+/-) mice was associated with increased plasma corticosterone levels. Chronic administration of an epithelial sodium channel blocker or a glucocorticoid receptor antagonist prevented salt sensitivity in Hsd11b2(+/-) mice, whereas mineralocorticoid receptor blockade with spironolactone did not. This study shows that reduced 11β-hydroxysteroid dehydrogenase type 2 causes salt sensitivity of blood pressure because of impaired renal natriuretic capacity. This reflects deregulation of epithelial sodium channels and increased renal vascular resistance. The phenotype is not caused by illicit activation of mineralocorticoid receptors by glucocorticoids but by direct activation of glucocorticoid receptors.


Stability of warfarin sodium flavoured preservative-free oral liquid formulations.
This study was designed to assess the physicochemical stability of warfarin sodium liquid formulations stored at room temperature and under refrigeration. Formulations of warfarin sodium 1mg/mL were prepared from either powder or tablets dispersed in mixture containing deionised water, glycerin, sodium phosphate and strawberry alcohol-free concentrate flavour and stored in amber glass bottles at 25°C and 4°C. Stability indicating high-performance liquid chromatography assay procedure was used to analyse the concentration of the drug at the time of preparation and on days 7, 14, 21, 30, 45, 60 and 90. Changes in colour, taste and pH, as well as visual evidence of precipitation, were assessed for physicochemical instability. Between day 0 and day 90, the pH of the powder and tablet formulations stored at 25°C decreased by -1.40 units and -1.16 units, respectively. There were minor changes in pH for both formulations stored at 4°C. The formulation from powder stored at 25°C and 4°C maintained at least 90% of the initial warfarin concentration for 30 days and 45 days, respectively. The formulation from tablets stored at 25°C and 4°C maintained at least 90% of initial warfarin concentration for 21 days and 30 days, respectively. Warfarin sodium in flavoured preservative-free formulation from powder is recommended and stable in amber glass bottles for at least 30 days stored at 25°C and 45 days stored at 4°C.


Efficacy of fluoroscopically guided steroid injections in the management of coccydynia.
Coccydynia is a rare but painful disorder characterized by axial coccygeal pain which is typically exacerbated by pressure. Management includes physical therapy/rectal manipulation, use of anti-inflammatory medications, modality use, coccygectomy, and fluoroscopically guided steroid injections. There are no studies documenting the efficacy of fluoroscopically guided coccygeal steroid injections in patients with coccydynia. Retrospective chart review was used to collect data on 14 consecutive patients diagnosed with coccydynia who underwent a fluoroscopically guided coccygeal injection of 80 mg triamcinolone acetate and 2mg of 1% lidocaine over a 3-year period at a tertiary care academic medical center. Using stepwise logistic regression, acute pain was determined to be the best predictor of relief. Fisher's exact test showed that those patients with pain lasting less then 6 months were significantly more likely to have greater than 50% relief (P=0.055). Patients with chronic pain longer than 6 months were not found to have pain relief of >50% to any statistical significance, but every patient with acute pain showed improvement. Patients with acute pain (less then 6 months) are more likely to respond to fluoroscopically guided coccygeal steroid injections.


Nosocomial infections in leukemic and solid-tumor cancer patients: distribution, outcome and microbial spectrum of anaerobes.
Nosocomial infections cause significant morbidity and mortality in cancer patients. As a result of their debilitated immune system, cancer patients are likely candidates for colonization with anaerobes. We sought to compare the distribution of nosocomial infections in neutropenic and non-neutropenic cancer patients and to calculate the associated mortality rates. This is the first study to demonstrate a complete microbial spectrum of anaerobes in various infection sites in hospitalized cancer patients. Frequencies of bloodstream infections (BSI), respiratory tract infections (RTI), and GI tract infections (GITI) were significantly higher in neutropenic cancer patients (p < 0.01). Conversely, urinary tract infection (UTI) and skin infection (SI) rates were significantly higher in non-neutropenic cancer patients (p < 0.01). Mortalities attributed to BSI, UTI, RTI, SI, and GITI occured at the respective percentage frequencies of 12.5%, 11.5%, 10.4%, 7.7% and 4.9%. Anaerobes constituted 4.7% of total isolates, and were recovered from SI (66.3%) and GITI (33.6%), but not respiratory tract, urine, or blood. Most anaerobes (79.2%) were isolated from solid-tumor patients. The most common infection in cancer patients was RTI (55.8%), mainly in leukemic patients, followed by SI (18%), only in solid-tumor patients, GITI (9.7%), BSI (9.4%), and UTI (7.1%). The most frequent isolates of Fusobacterium necrophorum (32.7%) and Eubacterium lentum (23.8%) were mostly recovered from solid-tumor patients. These were followed by Clostridium perfringens (11.9%), Clostridium difficile (10.9%), Eubacterium limosum (5.9%), and Veillonella parvula (5%). Control measures are needed to minimize risks of nosocomial infection outbreaks by anaerobes. Continuous monitoring of the presence of anaerobes in various infection sites in hospitalized cancer patients is needed in order to be able to provide the best supportive care for cancer patients.


Long-term study comparing fenoterol and isoproterenol inhalation in asthmatic patients.
In a parallel-group, double-blind study 28 chronic asthmatic patients were treated for 90 days with metered dose inhalers of fenoterol and isoproterenol, at daily doses of 0.4 mg t.i.d. and 0.15 mg t.i.d., respectively. Fenoterol produced significant improvements in FEV1 and FEF25-75%, greater than those achieved with isoproterenol, in tests on days 1, 45 and 90; its median duration of action was two to four times longer than that of isoproterenol. Ratings for overall responses to treatment were higher for fenoterol and mean attack rates showed a greater decline than with isoproterenol.


Stability and evolution of overlapping genes.
When the same sequence of nucleotides codes for regions of more than one functional polypeptide, this sequence contains overlapping genes. Overlap is most common in rapidly evolving genomes with high mutation rates such as viruses, bacteria, and mitochondria. Overlap is thought to be important as: (1) a means of compressing a maximum amount of information into short sequences of structural genes; and (2) as a mechanism for regulating gene expression through translational coupling of functionally related polypeptides. The stability of overlapping codes is examined in relation to the information cost of overlap and the mutation rate of the genome. The degree of overlap in a given population will tend to become monomorphic. Evolution toward partial overlap of genes is shown to depend on a convex cost function of overlap. Overlap does not evolve when expression of overlapping genes is mutually exclusive and produced by rare mutations to the wild-type genome. Assuming overlap increases coupling between functionally related genes, the conditions favoring overlap are explored in relation to the kinetics of gene activation and decay. Coupling is most effective for genes in which the gene overlapping at its 5' end (leading gene) decays rapidly, while the gene overlapping at the 3' end (induced gene) decays slowly. If gene expression can feedback on itself (autocatalysis), then high rates of activation favor overlap.


Patient Navigation for Timely, Guideline-Adherent Adjuvant Therapy for Head and Neck Cancer: A National Landscape Analysis.
Aligned with the NCCN Clinical Practice Guidelines in Oncology for Head and Neck Cancers, in November 2021 the Commission on Cancer approved initiation of postoperative radiation therapy (PORT) within 6 weeks of surgery for head and neck cancer (HNC) as its first and only HNC quality metric. Unfortunately, >50% of patients do not commence PORT within 6 weeks, and delays disproportionately burden racial and ethnic minority groups. Although patient navigation (PN) is a potential strategy to improve the delivery of timely, equitable, guideline-adherent PORT, the national landscape of PN for this aspect of care is unknown. From September through November 2022, we conducted a survey of health care organizations that participate in the American Cancer Society National Navigation Roundtable to understand the scope of PN for delivering timely, guideline-adherent PORT for patients with HNC. Of the 94 institutions that completed the survey, 89.4% (n=84) reported that at least part of their practice was dedicated to navigating patients with HNC. Sixty-eight percent of the institutions who reported navigating patients with HNC along the continuum (56/83) reported helping them begin PORT. One-third of HNC navigators (32.5%; 27/83) reported tracking the metric for time-to-PORT at their facility. When estimating the timeframe in which the NCCN and Commission on Cancer guidelines recommend commencing PORT, 44.0% (37/84) of HNC navigators correctly stated ≤6 weeks; 71.4% (60/84) reported that they did not know the frequency of delays starting PORT among patients with HNC nationally, and 63.1% (53/84) did not know the frequency of delays at their institution. In this national landscape survey, we identified that PN is already widely used in clinical practice to help patients with HNC start timely, guideline-adherent PORT. To enhance and scale PN within this area and improve the quality and equity of HNC care delivery, organizations could focus on providing better education and support for their navigators as well as specialization in HNC.


Association of Myelin Oligodendrocyte Glycoprotein Antibody-associated Disease with Coronavirus Disease 2019 Vaccination and Infection: A Case Report of Cortical Encephalitis and Transverse Myelitis Relapse.
We herein report a case of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) that occurred following coronavirus disease 2019 (COVID-19) vaccination and its subsequent relapse after COVID-19 infection. A 34-year-old woman developed cortical encephalitis in the right temporoparietal lobe one week after receiving the mRNA-1273 vaccine. The cerebrospinal fluid was positive for anti-MOG antibody. Her symptoms gradually improved after three courses of intravenous methylprednisolone therapy. Six months later, she experienced a relapse of transverse myelitis following COVID-19 infection. Despite treatment with plasma exchange, the patient remained paralyzed in both lower limbs. We herein review the relationship between MOGAD and COVID-19 vaccination/infection.


Diet alters delayed selfing, inbreeding depression, and reproductive senescence in a freshwater snail.
Reproductive success is a critical fitness attribute that is directly influenced by resource availability. Here, we investigate the effects of diet-based resource availability on three interrelated aspects of reproductive success: a change in mating system based on mate availability, consequent inbreeding depression, and the deterioration of reproductive efficiency with age (senescence). We employed a factorial experimental design using 22 full-sib families of the hermaphroditic freshwater snail Physa acuta to explore these interactions. Individual snails were reared in one of two mate-availability treatments (isolated [selfing] or occasionally paired [outcrossing]) and one of two diet treatments (boiled lettuce or Spirulina, an algae that is rich in protein, vitamins, and minerals). Spirulina-fed snails initiated reproduction at a 13% earlier age and 7% larger size than lettuce-fed snails. Spirulina also resulted in a 30% reduction in the time delay before selfing. Compared to lettuce, a diet of Spirulina increased inbreeding depression by 52% for egg hatching rate and 64% for posthatching juvenile survival. Furthermore, Spirulina led to a 15-fold increase in the rate of reproductive senescence compared with a diet of lettuce. These transgenerational, interactive effects of diet on inbreeding depression and reproductive senescence are discussed in the context of diet-induced phenotypic plasticity.


Intravenous immunoglobulin therapy for refractory recurrent pericarditis.
Recurrent pericarditis is a troublesome complication of idiopathic acute pericarditis and occurs more frequently in pediatric patients after cardiac surgery (postpericardiotomy syndrome). Conventional treatment with nonsteroidal antiinflammatory drugs, corticosteroids, and colchicine is not always effective or may cause serious adverse effects. There is no consensus, however, on how to proceed in those patients whose disease is refractory to conventional therapy. In such cases, human intravenous immunoglobulin, immunosuppressive drugs, and biological agents have been used. In this report we describe 2 patients with refractory recurrent pericarditis after cardiac surgery who were successfully treated with 3 and 5 monthly high-dose (2 g/kg) intravenous immunoglobulin until resolution of the effusion. Our experience supports the effectiveness and safety of this therapy.


Application of Calcium-Based Nanomaterials in Art Sculpture Reinforcement Technology.
In order to solve the problem of the reinforcement effect of art sculpture, the author proposes the application of a calcium-based nanomaterial in the reinforcement process of art sculpture. This application mainly passes the unconfined compression test, direct shear test, penetration resistance test, and disintegration test, and an in-depth evaluation of the reinforcement effect of different calcium-based reinforcement agents on the site soil was carried out from the perspective of mechanical strength and water stability. The results showed the following: Compared with the untreated samples, the unconfined compressive strength of the samples treated with nano-calcium oxide and nano-calcium hydroxide increased by 13.5% and 25.9%, respectively, and the cohesion increased by 69.8% and 97.7%. Conclusion. Calcium-based nanomaterials fill in the pores between soil particles to support the soil particles, which greatly improves the mechanical strength and water stability of the specimen.


Family history of alcoholism and hypothalamic opioidergic activity.
This study was designed to assess whether nonalcoholic offspring from families with a high density of alcohol-dependent individuals have altered endogenous central nervous system opioid activity. Naloxone hydrochloride stimulates plasma cortisol by blocking opioidergic input on the corticotropin-releasing factor neuron, thereby providing a noninvasive method for measuring hypothalamic opioid tone. Forty-eight nonalcoholic subjects aged 18 to 25 years were enrolled in a protocol to measure endogenous opioid activity by inducing opioid receptor blockade with the receptor antagonist, naloxone. Twenty-six subjects were offspring from families with a high density of alcohol dependence and were designated as family history-positive subjects. Twenty-two subjects were biological offspring of nonalcohol-dependent parents and designated as family history-negative subjects. Subjects received naloxone hydrochloride (0, 125, and 375 microg/kg) in double-blind, randomized order. Serum cortisol levels were monitored. Family history-negative subjects had a graded cortisol response to each dose of naloxone. In contrast, family history-positive subjects achieved a maximal cortisol response to the 125-microg/kg dose of naloxone hydrochloride with no further increase in cortisol levels observed following the 375-microg/kg dose. Family history-negative subjects had a diminished cortisol response to the 125-microg/kg dose compared with the family history-positive subjects. Plasma naloxone concentrations did not differ between family history groups. Individuals from families with a high density of alcohol dependence are more sensitive to naloxone compared with offspring of nonalcohol-dependent parents. This implies that individuals with a family history of alcohol dependence have diminished endogenous hypothalamic opioid activity.


Alphavirus-Induced Membrane Rearrangements during Replication, Assembly, and Budding.
Alphaviruses are arthropod-borne viruses mainly transmitted by hematophagous insects that cause moderate to fatal disease in humans and other animals. Currently, there are no approved vaccines or antivirals to mitigate alphavirus infections. In this review, we summarize the current knowledge of alphavirus-induced structures and their functions in infected cells. Throughout their lifecycle, alphaviruses induce several structural modifications, including replication spherules, type I and type II cytopathic vacuoles, and filopodial extensions. Type I cytopathic vacuoles are replication-induced structures containing replication spherules that are sites of RNA replication on the endosomal and lysosomal limiting membrane. Type II cytopathic vacuoles are assembly induced structures that originate from the Golgi apparatus. Filopodial extensions are induced at the plasma membrane and are involved in budding and cell-to-cell transport of virions. This review provides an overview of the viral and host factors involved in the biogenesis and function of these virus-induced structures. Understanding virus-host interactions in infected cells will lead to the identification of new targets for antiviral discovery.


Genomic profile of Parkinson's disease in Asians.
Parkinson's Disease (PD) has witnessed an alarming rise in prevalence, highlighting the suboptimal nature of early diagnostic and therapeutic strategies. To address this issue, genetic testing has emerged as a potential avenue. In this comprehensive review, we have meticulously summarized the variants associated with PD in Asian populations. Our review reveals that these variants exert their influence on diverse biological pathways, encompassing the autophagy-lysosome pathway, cholesterol metabolism, circadian rhythm regulation, immune system response, and synaptic function. Conventionally, PD has been linked to other diseases; however, our findings shed light on a shared genetic susceptibility among these conditions, implying an underlying pathophysiological mechanism that unifies them. Moreover, it is noteworthy that these PD-associated variants can significantly impact drug responses during therapeutic interventions. This review not only provides a consolidated overview of the genetic variants associated with PD in Asian populations but also contributes novel insights into the intricate relationships between PD and other diseases by elucidating shared genetic components. These findings underscore the importance of personalized approaches in diagnosing and treating PD based on individual genetic profiles to optimize patient outcomes.


Northeast Under/graduate Organization for Neuroscience, A Regional Neuroscience Meeting for Undergraduates, Graduate Students, and Faculty.
The Northeast Under/graduate Organization for Neuroscience (N.E.U.R.O.N.) was established in 1996 to provide a forum for undergraduate and graduate students and faculty in neuroscience to interact with each other. N.E.U.R.O.N. organizes a yearly one-day conference in the Northeast. While scientific meetings exist that serve the purpose of enhancing undergraduate research or neuroscience research, N.E.U.R.O.N. is unique in that it is a small, local conference, aimed specifically at undergraduates looking to pursue careers in neuroscience. During the conference, participants attend workshops, poster sessions, and a keynote address that provide them with information about current topics in neuroscience. Trainees gain valuable experience presenting scientific research in poster sessions and make connections with colleagues.


Diffuse alveolar hemorrhage.
Diffuse alveolar hemorrhage (DAH) is a life-threatening disorder characterized clinically by the presence of hemoptysis, falling hematocrit, diffuse pulmonary infiltrates and hypoxemic respiratory failure. It refers to bleeding that originates in the pulmonary microvasculature instead of the parenchyma or bronchial circulation. DAH should be considered a medical emergency due to the morbidity and mortality associated with failure to treat the disorder promptly. Pulmonary renal syndromes, connective tissue disorders and drugs make up the majority of the cases of DAH. The treatment of DAH ranges from supportive care and withdrawal of offending drugs to high-dose steroids, immunosuppresents and plasmapharesis. The following review will discuss the clinical, radiographic and pathologic findings in a variety of disorders that cause DAH. Standard treatment options, as well as new treatment options will also be discussed.


Durability of BNT162b2 vaccine against hospital and emergency department admissions due to the omicron and delta variants in a large health system in the USA: a test-negative case-control study.
The duration of protection against the omicron (B.1.1.529) variant for current COVID-19 vaccines is not well characterised. Vaccine-specific estimates are especially needed. We aimed to evaluate the effectiveness and durability of two and three doses of the BNT162b2 (Pfizer-BioNTech) mRNA vaccine against hospital and emergency department admissions due to the delta (B.1.617.2) and omicron variants. In this case-control study with a test-negative design, we analysed electronic health records of members of Kaiser Permanente Southern California (KPSC), a large integrated health system in California, USA, from Dec 1, 2021, to Feb 6, 2022. Vaccine effectiveness was calculated in KPSC patients aged 18 years and older admitted to hospital or an emergency department (without a subsequent hospital admission) with a diagnosis of acute respiratory infection and tested for SARS-CoV-2 via PCR. Adjusted vaccine effectiveness was estimated with odds ratios from adjusted logistic regression models. This study is registered with ClinicalTrials.gov (NCT04848584). Analyses were done for 11 123 hospital or emergency department admissions. In adjusted analyses, effectiveness of two doses of the BNT162b2 vaccine against the omicron variant was 41% (95% CI 21-55) against hospital admission and 31% (16-43) against emergency department admission at 9 months or longer after the second dose. After three doses, effectiveness of BNT162b2 against hospital admission due to the omicron variant was 85% (95% CI 80-89) at less than 3 months but fell to 55% (28-71) at 3 months or longer, although confidence intervals were wide for the latter estimate. Against emergency department admission, the effectiveness of three doses of BNT162b2 against the omicron variant was 77% (72-81) at less than 3 months but fell to 53% (36-66) at 3 months or longer. Trends in waning against SARS-CoV-2 outcomes due to the delta variant were generally similar, but with higher effectiveness estimates at each timepoint than those seen for the omicron variant. Three doses of BNT162b2 conferred high protection against hospital and emergency department admission due to both the delta and omicron variants in the first 3 months after vaccination. However, 3 months after receipt of a third dose, waning was apparent against SARS-CoV-2 outcomes due to the omicron variant, including hospital admission. Additional doses of current, adapted, or novel COVD-19 vaccines might be needed to maintain high levels of protection against subsequent waves of SARS-CoV-2 caused by the omicron variant or future variants with similar escape potential. Pfizer.


[Circadian rhythm of corticosteroids in female hamadryas baboons during long-term hypokinesia].
Radioimmunoassay was used to study the effect of restricted motor activity on the circadian rhythms of the content of hydrocortisone, 11-deoxycortisol, corticosterone and aldosterone in the blood plasma of mature female hamadryas baboons in different phases of the menstrual cycle. Intact animals demonstrated distinct circadian rhythms of corticosteroids reproduced stably in both phases of the cycle. Two-week immobilization did not change the general nature of rhythms of the content of glucocorticoids but caused a decrease in their mean daily concentrations which is significant for 11-deoxycortisol and corticosterone of female baboons immobilized in the luteal phase of the cycle. The circadian rhythm of aldosterone got smooth, its level in the blood dropped significantly disregarding a cycle phase at the moment of immobilization. The revealed changes of the circadian rhythms of aldosterone reflect disorders of adrenocortical mineralocorticoid function in female baboons under hypokinesia. Causes of changes in the hormonal activity of the adrenal cortex under clinicostatic hypokinesia are discussed.


The Embryo Project: an integrated approach to history, practices, and social contexts of embryo research.
This essay describes the approach and early results of the collaborative Embryo Project and its on-line encyclopedia (http://embryo.asu.edu). The project is based on a relational database that allows federated searches and inclusion of multiple types of objects targeted for multiple user groups. The emphasis is on the history and varied contexts of developmental biology, focusing on people, places, institutions, techniques, literature, images, and other aspects of study of embryos. This essay introduces the ways of working as well as the long-term goals of the project. We invite others to join the effort, both in this particular project and in joining together in digital collection, archiving, and knowledge generation at the borders of biology and history.


Tolterodine for overactive bladder: time to onset of action, preferred dosage, and 9-month follow-up.
This is a prospective study of 28 patients who had urinary frequency (>8 times/day) and either urgency or urge incontinence (>1 time/day). After a 2-week run-in period (visit 1), the patients were started on tolterodine 1 mg twice a day (bid) (visit 2). They were followed at 4 and 8 weeks (visits 3 and 4). The patients were contacted by telephone 1 week after visit 2. Tolterodine was increased to 2 mg bid if the patient had incomplete improvement at either the initial phone call or during visit 3. Evaluation criteria were daily micturition charts including urinary frequency, nocturia, leakage episodes, average urine volume per day, and average voided volume. Tolterodine was well tolerated without side effects in 20 (80%) of 28 patients. Eight patients (20%) dropped out after enrollment because of side effects in 3, no improvement in 2, and missing visits (>1) in 3. Drug dosage in the 20 patients who tolerated tolterodine was 1 mg bid in 3 and 2 mg bid in 17 (85%). According to micturition charts, urinary frequency, nocturia, and leakage episodes decreased significantly after tolterodine treatment, whereas average urine volume per day and average voided volume did not change significantly. There were no electrocardiographic or biochemical abnormalities due to tolterodine treatment. Mean follow-up was 9.4 months. All 20 patients who tolerated tolterodine continue to take the medication without significant side effects. We conclude that tolterodine is well tolerated and effective for overactive bladders. Two milligrams bid is the dosage preferred by the majority of patients and the onset of action is seen within 1 week of treatment. Long-term compliance and efficacy are excellent, with no dropout in >9 months of follow-up.