Risk assessment of the mechanical spread of bacterial pathogens due to Lasius neglectus ants infesting a tertiary hospital.

INTRODUCTION: Mechanical spread of microbial pathogens has been investigated in cockroaches, but less well in ants. Considerably less information is available for ants. An investigation into ant-borne mechanical pathogen transmission was triggered by an infestation of a tertiary care hospital with Lasius neglectus ants. METHODS: The L. neglectus infestation of the orthopaedic surgery department, the ear-nose-throat clinic and the eye clinic as well as of outdoor areas was monitored and correlated with seasonal and weather influences. Microbial colonization on the ants' exoskeleton as well as in homogenates of complete insects and decolonization dynamics of artificial Staphylococcus aureus colonization on the exoskeleton was assessed. RESULTS: In a low-level infestation setting, L. neglectus activity showed seasonal variations and was positively correlated with temperature (r = 0.7515; P=0.0368) but not with precipitation (r = 0.4699, P=0.2431). Colonization with environmental commensals dominated, while exoskeleton colonization with bacteria with potential aetiological relevance for nosocomial infections was higher for ants from the inpatient setting (6%) than from outdoor areas (0%). Artificial colonization of the exoskeleton with S. aureus vanished to values statistically indistinguishable from baseline within 72 h. CONCLUSIONS: Low colonization rates with aetiologically relevant bacteria and rapid spontaneous decolonization in the case of contamination make ant-borne transmissions to patients unlikely.

Abnormal thyroid function is common in takotsubo syndrome and depends on two distinct mechanisms: results of a multicentre observational study.

BACKGROUND: Several reports have described Takotsubo syndrome (TTS) secondary to thyrotoxicosis. A complex interaction of central and peripheral catecholamines with thyroid homeostasis has been suggested. In this study, we analysed sequential thyroid hormone profiles during the acute phase of TTS. METHODS: Thyrotropin (TSH), free T4 (FT4) and free T3 (FT3) concentrations were analysed at predefined time points in 32 patients presenting with TTS or acute coronary syndrome (ACS, n = 16 in each group) in a 2-year period in two German university hospitals. Data were compared to age- and sex-matched controls (10 samples, each of 16 subjects), and an unsupervised machine learning (ML) algorithm identified patterns in the hormone signature. Subjects with thyroid disease and patients receiving amiodarone were excluded from follow-up. RESULTS: Among patients with TTS, FT4 concentrations were significantly higher when compared to controls or ACS. Four subjects (25%) suffered from subclinical or overt thyrotoxicosis. Two additional patients developed subclinical or overt thyrotoxicosis during stay in hospital. In four subjects (25%), FT4 concentrations were increased, despite nonsuppressed TSH concentration, representing an elevated set point of thyroid homeostasis. The thyroid hormone profile was normal in only six patients (38%) presenting with TTS. CONCLUSION: Abnormal thyroid function is frequent in patients with TTS. Primary hyperthyroidism and an elevated set point of thyroid homeostasis are common in TTS, suggesting a stress-dependent endocrine response or type 2 thyroid allostasis. Thyroid function may be a worthwhile target in treating or preventing TTS.

Calcium channel gating.

Tuned calcium entry through voltage-gated calcium channels is a key requirement for many cellular functions. This is ensured by channel gates which open during membrane depolarizations and seal the pore at rest. The gating process is determined by distinct sub-processes: movement of voltage-sensing domains (charged S4 segments) as well as opening and closure of S6 gates. Neutralization of S4 charges revealed that pore opening of CaV1.2 is triggered by a "gate releasing" movement of all four S4 segments with activation of IS4 (and IIIS4) being a rate-limiting stage. Segment IS4 additionally plays a crucial role in channel inactivation. Remarkably, S4 segments carrying only a single charged residue efficiently participate in gating. However, the complete set of S4 charges is required for stabilization of the open state. Voltage clamp fluorometry, the cryo-EM structure of a mammalian calcium channel, biophysical and pharmacological studies, and mathematical simulations have all contributed to a novel interpretation of the role of voltage sensors in channel opening, closure, and inactivation. We illustrate the role of the different methodologies in gating studies and discuss the key molecular events leading CaV channels to open and to close.

Correlation between human ether-a-go-go-related gene channel inhibition and action potential prolongation.

BACKGROUND AND PURPOSE: Human ether-a-go-go-related gene (hERG; Kv 11.1) channel inhibition is a widely accepted predictor of cardiac arrhythmia. hERG channel inhibition alone is often insufficient to predict pro-arrhythmic drug effects. This study used a library of dofetilide derivatives to investigate the relationship between standard measures of hERG current block in an expression system and changes in action potential duration (APD) in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The interference from accompanying block of Cav 1.2 and Nav 1.5 channels was investigated along with an in silico AP model. EXPERIMENTAL APPROACH: Drug-induced changes in APD were assessed in hiPSC-CMs using voltage-sensitive dyes. The IC50 values for dofetilide and 13 derivatives on hERG current were estimated in an HEK293 expression system. The relative potency of each drug on APD was estimated by calculating the dose (D150 ) required to prolong the APD at 90% (APD90 ) repolarization by 50%. KEY RESULTS: The D150 in hiPSC-CMs was linearly correlated with IC50 of hERG current. In silico simulations supported this finding. Three derivatives inhibited hERG without prolonging APD, and these compounds also inhibited Cav 1.2 and/or Nav 1.5 in a channel state-dependent manner. Adding Cav 1.2 and Nav 1.2 block to the in silico model recapitulated the direction but not the extent of the APD change. CONCLUSIONS AND IMPLICATIONS: Potency of hERG current inhibition correlates linearly with an index of APD in hiPSC-CMs. The compounds that do not correlate have additional effects including concomitant block of Cav 1.2 and/or Nav 1.5 channels. In silico simulations of hiPSC-CMs APs confirm the principle of the multiple ion channel effects.

Investigación para el diagnóstico situacional local de la epidemia de ETM: Intervenciones preventivas para su contención: Área Programática del Hospital General de Agudos Juan A. Fernández 2015-2016 / Research for the local situational diagnosis of ETM epidemic: Preventive interventions for its containment: Acute General Hospital Juan A. Fernández Programmatic Area 2015-2016

El plan de Prevención y Control de Enfermedades Transmitidas por Mosquito (ETM): Dengue, Fiebre Chikungunya, Amarilla, y Zika de la CABA establece cuatro escenarios teóricos de riesgo que orientan la implementación de las acciones de prevención y control. En el presente informe se presentan los estudios de foco investigados en nuestra Área Programática (AP) y su georreferencia, a fin de obtener un diagnóstico situacional local que permita la ejecución de intervenciones oportunas y eficaces a fin de limitar la aparición de nuevos casos en el contexto epidémico 2015-2016. El objetivo general fue estudiar la epidemia de ETM para su comprensión y abordaje en el Área Programática del Hospital General de Agudos Juan A. Fernández, y el objetivo específico, prevenir y limitar la aparición de nuevos casos de ETM. (AU)

Analysis of ß-Subunit-dependent GABAA Receptor Modulation and Behavioral Effects of Valerenic Acid Derivatives.

Valerenic acid (VA)-a ß2/3-selective GABA type A (GABAA) receptor modulator-displays anxiolytic and anticonvulsive effects in mice devoid of sedation, making VA an interesting drug candidate. Here we analyzed ß-subunit-dependent enhancement of GABA-induced chloride currents (IGABA) by a library of VA derivatives and studied their effects on pentylenetetrazole (PTZ)-induced seizure threshold and locomotion. Compound-induced IGABA enhancement was determined in oocytes expressing α1ß1γ2S, α1ß2γ2S, or α1ß3γ2S receptors. Effects on seizure threshold and locomotion were studied using C57BL/6N mice and compared with saline-treated controls. ß2/3-selective VA derivatives such as VA-amide (VA-A) modulating α1ß3γ2S (VA-A: Emax = 972 ± 69%, n = 6, P < 0.05) and α1ß2γ2S receptors (Emax = 1119 ± 72%, n = 6, P < 0.05) more efficaciously than VA (α1ß3γ2S: VA: Emax = 632 ± 88%, n = 9 versus α1ß2γ2S: VA: Emax = 721 ± 68%, n = 6) displayed significantly more pronounced seizure threshold elevation than VA (saline control: 40.4 ± 1.4 mg/kg PTZ versus VA 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ versus VA-A 3 mg/kg: 57.9 ± 1.9 mg/kg PTZ, P < 0.05). Similarly, VA's methylamide (VA-MA) enhancing IGABA through ß3-containing receptors more efficaciously than VA (Emax = 1043 ± 57%, P < 0.01, n = 6) displayed stronger anticonvulsive effects. Increased potency of IGABA enhancement and anticonvulsive effects at lower doses compared with VA were observed for VA-tetrazole (α1ß3γ2S: VA-TET: EC50 = 6.0 ± 1.0 µM, P < 0.05; VA-TET: 0.3 mg/kg: 47.3 ± 0.5 mg/kg PTZ versus VA: 10 mg/kg: 49.0 ± 1.8 mg/kg PTZ, P < 0.05). At higher doses (≥10 mg/kg), VA-A, VA-MA, and VA-TET reduced locomotion. In contrast, unselective VA derivatives induced anticonvulsive effects only at high doses (30 mg/kg) or did not display any behavioral effects. Our data indicate that the ß2/3-selective compounds VA-A, VA-MA, and VA-TET induce anticonvulsive effects at low doses (≤10 mg/kg), whereas impairment of locomotion was observed at doses ≥10 mg/kg.

New potential binding determinant for hERG channel inhibitors.

Human ether-à-go-go related gene (hERG) 1 channels conduct the rapid delayed rectifier K(+) current (IKr) and are essential for the repolarization of the cardiac action potential. hERG1 inhibition by structurally diverse drugs may lead to life threatening arrhythmia. Putative binding determinants of hERG1 channel blockers include T623, S624 and V625 on the pore helix, and residues G648, Y652 and F656, located on segment S6. We and others have previously hypothesized that additional binding determinants may be located on helix S5, which is in close contact with the S6 segments. In order to test this hypothesis, we performed a detailed investigation combining ionic current measurements with two-microelectrode voltage clamp and molecular modeling techniques. We identified a novel aromatic high affinity binding determinant for blockers located in helix S5, F557, which is equally potent as Y652. Modeling supports a direct interaction with the outer pore helix.

Efficient collection of viable virus aerosol through laminar-flow, water-based condensational particle growth.

AIMS: State-of-the-art bioaerosol samplers have poor collection efficiencies for ultrafine virus aerosols. This work evaluated the performance of a novel growth tube collector (GTC), which utilizes laminar-flow water-based condensation to facilitate particle growth, for the collection of airborne MS2 viruses. METHODS AND RESULTS: Fine aerosols (<500 nm) containing MS2 coliphage were generated from a Collison nebulizer, conditioned by a dilution dryer and collected by a GTC and a BioSampler. The GTC effectively condensed water vapour onto the virus particles, creating droplets 2-5 µm in diameter, which facilitated collection. Comparison of particle counts upstream and downstream revealed that the GTC collected >93% of the inlet virus particles, whereas the BioSampler's efficiency was about 10%. Viable counts of the GTC-collected viruses were also one order of magnitude higher than those of the BioSampler (P = 0·003). CONCLUSION: The efficiency of the GTC for the viable collection of MS2 viruses exceeds that of industry standard instrument, the BioSampler, by a factor of 10-100. SIGNIFICANCE AND IMPACT OF THE STUDY: This study reveals that the GTC is an effective collector of viable MS2 aerosols, and concludes the instrument will be an effective tool for studying viable virus aerosols and the inhalation risks posed by airborne viruses.

Identification of the putative binding pocket of valerenic acid on GABAA receptors using docking studies and site-directed mutagenesis.

BACKGROUND AND PURPOSE: ß2/3-subunit-selective modulation of GABAA receptors by valerenic acid (VA) is determined by the presence of transmembrane residue ß2/3N265. Currently, it is not known whether ß2/3N265 is part of VA's binding pocket or is involved in the transduction pathway of VA's action. The aim of this study was to clarify the localization of VA's binding pocket on GABAA receptors. EXPERIMENTAL APPROACH: Docking and a structure-based three-dimensional pharmacophore were employed to identify candidate amino acid residues that are likely to interact with VA. Selected amino acid residues were mutated, and VA-induced modulation of the resulting GABAA receptors expressed in Xenopus oocytes was analysed. KEY RESULTS: A binding pocket for VA at the ß(+) /α(-) interface encompassing amino acid ß3N265 was predicted. Mutational analysis of suggested amino acid residues revealed a complete loss of VA's activity on ß3M286W channels as well as significantly decreased efficacy and potency of VA on ß3N265S and ß3F289S receptors. In addition, reduced efficacy of VA-induced IGABA enhancement was also observed for α1M235W, ß3R269A and ß3M286A constructs. CONCLUSIONS AND IMPLICATIONS: Our data suggest that amino acid residues ß3N265, ß3F289, ß3M286, ß3R269 in the ß3 subunit, at or near the etomidate/propofol binding site(s), form part of a VA binding pocket. The identification of the binding pocket for VA is essential for elucidating its pharmacological effects and might also help to develop new selective GABAA receptor ligands.

Genetic polymorphisms of twelve X-STRs of the investigator Argus X-12 kit and additional six X-STR centromere region loci in an Egyptian population sample.

Recently, many researchers have focused on analysis of different X-chromosomal STRs as they bear the potential to efficiently complement the analysis of autosomal and Y-chromosomal STRs in solving special complex kinship deficiency cases. In the current study we examined a sample of 250 unrelated Egyptian males with the Investigator Argus X-12 kit (Qiagen GmbH, Hilden, Germany) which detects 12 X-STR markers distributed over the entire X-chromosome as four closely linked clusters. Microvariant off ladder alleles as well as null alleles have been detected in some loci. Furthermore, discordant results were observed between the Investigator Argus X-12 and the Mentype(®) Argus X-8 kits (Biotype AG, Dresden, Germany). New primers were designed for loci DXS10101, DXS10146 and DXS10148 to correct the allele drop outs observed in these loci with the Investigator Argus X-12 kit. Additionally, DNA sequence analysis revealed the polymorphisms responsible for the allele drop outs. Furthermore, six additional X-STRs (DXS10161, DXS10159, DXS10162, DXS10163, DXS10164 and DXS10165) located in the centromere region at Xp11.21-Xq11.1 were examined in a single multiplex reaction. Allele and haplotype frequencies as well as different forensic statistical parameters of the 18 X-STR loci tested indicated that they are highly informative in different forensic applications in the Egyptian population. However, some modifications still need to be performed on the Investigator Argus X-12 kit before its use in forensic casework is validated.

Methods for quantification of pore-voltage sensor interaction in Ca(V)1.2.

Voltage sensors (VSs) initiate the pore opening and closure in voltage-gated ion channels. Here, we propose a technique for estimation of the equilibrium constant of the up- and downward VS movements and rate constants of pore transitions from macroscopic current kinetics. Bell-shaped voltage dependence of the activation/deactivation time constants and Bolzmann distributions of CaV1.2 activation were analyzed in terms of a circular four-state (rest, activated, open, deactivated) channel model: both dependencies uniquely constrain the model parameters. Neutralization of gating charges in IS4 or IIS4 only slightly affects the equilibrium constant of VS transition while affecting simultaneously the rate constants of pore opening and closure. The application of our technique revealed that pore mutations on IS6-IVS6 segments induce pronounced shifts of the VS equilibrium between the resting (down) and activated (up) position. Analyzing a channelopathy mutation highlighted that the leftward shift of the activation curve induced by I781T on IIS6 is only partially (35 %) caused by a destabilization of the channel pore but predominantly (65 %) by a shifted VS equilibrium towards activation. The algorithm proposed for CaV1.2 may be applicable for calculating rate constants from macroscopic current kinetics in other voltage-gated ion channels.

The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study.

OBJECTIVE: To obtain quantitative data on the progression of the most common spinocerebellar ataxias (SCAs) and identify factors that influence their progression, we initiated the EUROSCA natural history study, a multicentric longitudinal cohort study of 526 patients with SCA1, SCA2, SCA3, or SCA6. We report the results of the 1- and 2-year follow-up visits. METHODS: As the primary outcome measure we used the Scale for the Assessment and Rating of Ataxia (SARA, 0-40), and as a secondary measure the Inventory of Non-Ataxia Symptoms (INAS, 0-16) count. RESULTS: The annual increase of the SARA score was greatest in SCA1 (2.18 ± 0.17, mean ± SE) followed by SCA3 (1.61 ± 0.12) and SCA2 (1.40 ± 0.11). SARA progression in SCA6 was slowest and nonlinear (first year: 0.35 ± 0.34, second year: 1.44 ± 0.34). Analysis of the INAS count yielded similar results. Larger expanded repeats and earlier age at onset were associated with faster SARA progression in SCA1 and SCA2. In SCA1, repeat length of the expanded allele had a similar effect on INAS progression. In SCA3, SARA progression was influenced by the disease duration at inclusion, and INAS progression was faster in females. CONCLUSIONS: Our study gives a comprehensive quantitative account of disease progression in SCA1, SCA2, SCA3, and SCA6 and identifies factors that specifically affect disease progression.

Interaction of diltiazem with an intracellularly accessible binding site on Ca(V)1.2.

BACKGROUND AND PURPOSE: Diltiazem inhibits Ca(V)1.2 channels and is widely used in clinical practice to treat cardiovascular diseases. Binding determinants for diltiazem are located on segments IIIS6, IVS6 and the selectivity filter of the pore forming α1 subunit of Ca(V)1.2. The aim of the present study was to clarify the location of the diltiazem binding site making use of its membrane-impermeable quaternary derivative d-cis-diltiazem (qDil) and mutant α1 subunits. EXPERIMENTAL APPROACH: Ca(V)1.2 composed of α1, α2-δ and ß2a subunits were expressed in tsA-201 cells and barium currents through Ca(V)1.2 channels were recorded using the patch clamp method in the whole cell configuration. qDil was synthesized and applied to the intracellular side (via the patch pipette) or to the extracellular side of the membrane (by bath perfusion). KEY RESULTS: Quaternary derivative d-cis-diltiazem inhibited Ca(V)1.2 when applied to the intracellular side of the membrane in a use-dependent manner (59 ± 4% at 300 µM) and induced only a low level of tonic (non-use-dependent) block (16 ± 2% at 300 µM) when applied to the extracellular side of the membrane. Mutations in IIIS6 and IVS6 that have previously been shown to reduce the sensitivity of Ca(V)1.2 to tertiary diltiazem also had reduced sensitivity to intracellularly applied qDil. CONCLUSION AND IMPLICATIONS: The data show that use-dependent block of in Ca(V)1.2 by diltiazem occurs by interaction with a binding site accessible via a hydrophilic route from the intracellular side of the membrane.

Ultrafine particle concentrations and exposures in seven residences in northern California.

UNLABELLED: Human exposures to ultrafine particles (UFP) are poorly characterized given the potential associated health risks. Residences are important sites of exposure. To characterize residential exposures to UFP in some circumstances and to investigate governing factors, seven single-family houses in California were studied during 2007-2009. During multiday periods, time-resolved particle number concentrations were monitored indoors and outdoors and information was acquired concerning occupancy, source-related activities, and building operation. On average, occupants were home for 70% of their time. The geometric mean time-average residential exposure concentration for 21 study subjects was 14,500 particles per cm(3) (GSD = 1.8; arithmetic mean ± standard deviation = 17,000 ± 10,300 particles per cm(3)). The average contribution to residential exposures from indoor episodic sources was 150% of the contribution from particles of outdoor origin. Unvented natural-gas pilot lights contributed up to 19% to exposure for the two households where present. Episodic indoor source activities, most notably cooking, caused the highest peak exposures and most of the variation in exposure among houses. Owing to the importance of indoor sources and variations in the infiltration factor, residential exposure to UFP cannot be characterized by ambient measurements alone. PRACTICAL IMPLICATIONS: Indoor and outdoor sources each contribute to residential ultrafine particle (UFP) concentrations and exposures. Under the conditions investigated, peak exposure concentrations indoors were associated with cooking, using candles, or the use of a furnace. Active particle removal systems can mitigate exposure by reducing the persistence of particles indoors. Eliminating the use of unvented gas pilot lights on cooking appliances could also be beneficial. The study results indicate that characterization of human exposure to UFP, an air pollutant of emerging public health concern, cannot be accomplished without a good understanding of conditions inside residences.

Ultrafine particle concentrations and exposures in six elementary school classrooms in northern California.

UNLABELLED: Potential health risks may result from environmental exposure to ultrafine particles (UFP), i.e., those smaller than 0.1 µm in diameter. One important exposure setting that has received relatively little attention is school classrooms. We made time-resolved, continuous measurements of particle number (PN) concentrations for 2-4 school days per site (18 days total) inside and outside of six classrooms in northern California during normal occupancy and use. Additional time-resolved information was gathered on ventilation conditions, occupancy, and classroom activity. Across the six classrooms, average indoor PN concentrations when students were present were 5200-16,500/cm(3) (overall average 10,800/cm(3)); corresponding outdoor concentrations were 9000-26,000/cm(3) (overall average 18,100/cm(3)). Average indoor levels were higher when classrooms were occupied than when they were unoccupied because of higher outdoor concentrations and higher ventilation rates during occupancy. In these classrooms, PN exposures appear to be primarily attributable to outdoor sources. Indoor emission sources (candle use, cooking on an electric griddle, use of a heater, use of terpene-containing cleaning products) were seen to affect indoor PN concentrations only in a few instances. The daily-integrated exposure of students in these six classrooms averaged 52,000/cm(3) h/day for the 18 days monitored. PRACTICAL IMPLICATIONS: This study provides data and insight concerning the UFP exposure levels children may encounter within classrooms and the factors that most significantly affect these levels in an urban area in northern California. This information can serve as a basis to guide further study of children's UFP exposure and the potential associated health risks.

Trapping and dissociation of propafenone derivatives in HERG channels.

BACKGROUND AND PURPOSE: Human ether-a-go-go related gene (HERG) channel inhibitors may be subdivided into compounds that are trapped in the closed channel conformation and others that dissociate at rest. The structural peculiarities promoting resting state dissociation from HERG channels are currently unknown. A small molecule-like propafenone is efficiently trapped in the closed HERG channel conformation. The aim of this study was to identify structural moieties that would promote dissociation of propafenone derivatives. EXPERIMENTAL APPROACH: Human ether-a-go-go related gene channels were heterologously expressed in Xenopus oocytes and potassium currents were recorded using the two-microelectrode voltage clamp technique. Recovery from block by 10 propafenone derivatives with variable side chains, but a conserved putative pharmacophore, was analysed. KEY RESULTS: We have identified structural determinants of propafenone derivatives that enable drug dissociation from the closed channel state. Propafenone and four derivatives with 'short' side chains were trapped in the closed channel. Five out of six bulky derivatives efficiently dissociated from the channel at rest. One propafenone derivative with a similar bulk but lacking an H-bond acceptor in this region was trapped. Correlations were observed between molecular weight and onset of channel block as well as between pK(a) and recovery at rest. CONCLUSION AND IMPLICATIONS: The data show that extending the size of a trapped HERG blocker-like propafenone by adding a bulky side chain may impede channel closure and thereby facilitate drug dissociation at rest. The presence of an H-bond acceptor in the bulky side chain is, however, essential.

Valerenic acid derivatives as novel subunit-selective GABAA receptor ligands - in vitro and in vivo characterization.

BACKGROUND AND PURPOSE: Subunit-specific modulators of gamma-aminobutyric acid (GABA) type A (GABA(A)) receptors can help to assess the physiological function of receptors with different subunit composition and also provide the basis for the development of new drugs. Valerenic acid (VA) was recently identified as a beta(2/3) subunit-specific modulator of GABA(A) receptors with anxiolytic potential. The aim of the present study was to generate VA derivatives as novel GABA(A) receptor modulators and to gain insight into the structure-activity relation of this molecule. EXPERIMENTAL APPROACH: The carboxyl group of VA was substituted by an uncharged amide or amides with different chain length. Modulation of GABA(A) receptors composed of different subunit compositions by the VA derivatives was studied in Xenopus oocytes by means of the two-microelectrode voltage-clamp technique. Half-maximal stimulation of GABA-induced chloride currents (I(GABA)) through GABA(A) receptors (EC(50)) and efficacies (maximal stimulation of I(GABA)) were estimated. Anxiolytic activity of the VA derivatives was studied in mice, applying the elevated plus maze test. KEY RESULTS: Valerenic acid amide (VA-A) displayed the highest efficacy (more than twofold greater I(GABA) enhancement than VA) and highest potency (EC(50)= 13.7 +/- 2.3 microM) on alpha(1)beta(3) receptors. Higher efficacy and potency of VA-A were also observed on alpha(1)beta(2)gamma(2s) and alpha(3)beta(3)gamma(2s) receptors. Anxiolytic effects were most pronounced for VA-A. CONCLUSIONS AND IMPLICATIONS: Valerenic acid derivatives with higher efficacy and affinity can be generated. Greater in vitro action of the amide derivative correlated with a more pronounced anxiolytic effect in vivo. The data give further confidence in targeting beta(3) subunit containing GABA(A) receptors for development of anxiolytics.

[Hepatomegaly und elevated transaminases in a 24-year-old with type I diabetes mellitus]. / Ausgeprägte Hepatomegalie und Transaminasenerhöhung bei 24-Jährigem mit Typ-1-Diabetes.

Poorly controlled type I diabetes mellitus can lead to excessive hepatic glycogen storage, which is accompanied by elevated transaminases and hepatomegaly. Few cases have been reported and described as glycogenic hepatopathy. There is characteristically no progression to fibrosis and cirrhosis and the symptoms are reversible with improved glycemic control.

Vitamin A deficiency among Brazilian school-aged children in a healthy child service.

BACKGROUND/OBJECTIVES: Vitamin A deficiency (VAD) is a world public health problem contributing to the increase in childhood morbidity and mortality in developing countries and severe deficiency of vitamin A may lead to xerophthalmia and blindness. The objective of this study was to determine the prevalence of VAD among Brazilian school-aged children attended at a primary health unit and to verify if some considered risk factor was associated with VAD in this group. SUBJECTS/METHODS: A descriptive prospective transverse study was conducted on 103 randomly selected children. A total of 54 boys and 49 girls aged 5.5-11 years had the relative dose-response (RDR) test performed on. Possible ocular alterations related to vitamin A and the status of anemia, serum zinc, some acute-phase proteins, and anthropometric situation were determinate by an analytic design. RESULTS: No child presented xerophthalmia. Serum retinol values lower than 1.05 and 0.7 micromol l(-1), respectively were found in 26.2 and 5.8% of the children. The prevalence of hypovitaminosis detected by RDR test was 20.4%. The following variables and their relationship with VAD were evaluated: sex (P=0.33; 95% confidence interval 0.61-4.34), weight and height (P> or =0.5), hemoglobin (P=0.15), C-reactive protein (P=0.56; 95% confidence interval 0.75-18.26), alpha-1-acid-glycoprotein (P=0.56; 95% confidence interval 0.15-15.42) and serum zinc (P=0.31). None of these variables was related to VAD. CONCLUSIONS: In this population, the prevalence of VAD detected could be considered a public health problem. School-aged children can be considered at risk for VAD mainly of a subclinical level, even without some associated risk factors.