Genetic basis of variation in thermal developmental plasticity for Drosophila melanogaster body pigmentation.

Seasonal differences in insect pigmentation are attributed to the influence of ambient temperature on pigmentation development. This thermal plasticity is adaptive and heritable, and thereby capable of evolving. However, the specific genes contributing to the variation in plasticity that can drive its evolution remain largely unknown. To address this, we analysed pigmentation and pigmentation plasticity in Drosophila melanogaster. We measured two components of pigmentation in the thorax and abdomen: overall darkness and the proportion of length covered by darker pattern elements (a trident in the thorax and bands in the abdomen) in females from two developmental temperatures (17 or 28°C) and 191 genotypes. Using a GWAS approach to identify the genetic basis of variation in pigmentation and its response to temperature, we identified numerous dispersed QTLs, including some mapping to melanogenesis genes (yellow, ebony, and tan). Remarkably, we observed limited overlap between QTLs for variation within specific temperatures and those influencing thermal plasticity, as well as minimal overlap between plasticity QTLs across pigmentation components and across body parts. For most traits, consistent with selection favouring the retention of plasticity, we found that lower plasticity alleles were often at lower frequencies. The functional analysis of selected candidate QTLs and pigmentation genes largely confirmed their contributions to variation in pigmentation and/or pigmentation plasticity. Overall, our study reveals the existence and underlying basis of extensive and trait-specific genetic variation for pigmentation and pigmentation plasticity, offering a rich reservoir of raw material for natural selection to shape the evolution of these traits independently.

Ulna length to predict height in English and Portuguese patient populations.

BACKGROUND/OBJECTIVE: This study assessed the extent to which ulna length could be used to predict height and body mass index (BMI) in various groups of English and Portuguese hospitalised patients, and tidal volumes in critically ill patients at risk of requiring ventilatory support. SUBJECTS/METHODS: Bedside measurements of weight, height and ulna length were made in 507 patients (432 English, 75 Portuguese; 264 men, 243 women) with a mean age of 61.8±18.9 years, height 165.1±9.5 cm and BMI 26.7±5.43 kg/m(2). RESULTS: Ulna length could be measured with ease in all subjects. The intra-observer technical error of measurement in the same subjects was 1%. Within each category of men and women aged <65 years and 65 years and over, there was no significant difference between the English and Portuguese in the intercept or regression coefficients for the ulna-height relationships. A strong relationship was found between predicted and measured height (r=0.963, standard error of the estimate 4.6 cm). The overall mean and s.d. of the difference was 0.3±2.7% of height, with no significant difference between English and Portuguese populations. The discrepancy between measured and predicted BMI corresponded to 0.7±5.5% (s.d.) (all subjects) and for ventilatory volumes predicted from height (critically ill subjects only) 0.7±7.1%. CONCLUSION: Height can be predicted from ulna length with precision and ease in a wide range of patient groups, and without the need to use different equations in English and Portuguese populations. The predicted measurements are acceptable in most clinical circumstances.

Apolipoproteína A-V: una nueva apolipoproteína que influye en el metabolismo de los triglicéridos

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[Atrial fibrillation. New views on an old disease]. / Fibrilación auricular. Nuevos aspectos sobre una vieja enfermedad.

Atrial fibrillation (Afib) is clinically the most common arrhythmia. Its main complications are recurrent embolic events and a variable deterioration of functional class. Atrial fibrillation induces changes in cellular ionic channels that self-perpetuate the arrhythmia. The pharmacologic treatment of Afib is directed toward correction of those changes and return to sinus rhythm. It is also intended to maintain adequate heart rates and prevent embolic events through anticoagulation or platelet antiagregation. There are presently several class IC or class III antiarrhythmics available for attempting a return to sinus rhythm. The success rates are irregular, the best achieved with flecainide or propafenone among patients without structural heart disease. Amiodarone is the best choice when there is such a problem. The combination possibilities are huge, so that each case must be individualized. The new class III antiarrhythmics are very effective, but have a relatively high rate of side effects including torsade de pointes. Anticoagulation should be the preferred treatment among the majority of patients, but each case should be individually evaluated. New therapies such as focal or linear catheter ablation techniques, atrial or biatrial programmed stimulation, and atrial cardioverter-defibrillator need longer follow-up and experience to be objectively evaluated, although there are reasons to be optimistic in the future, even if patients need antiarrhythmic support at present. Surgery has high morbi-mortality rates, so it is not the preferred approach.

Cardiac conduction disturbances in mixed connective tissue disease.

BACKGROUND: Myocardial involvement occurs in about 20% of patients with mixed connective tissue disease. The purpose of this study was to determine the prevalence of conduction disturbances, their association with other manifestations of the disease. OBJECTIVE: Determine the prevalence of cardiac conduction disturbances in patients with mixed connective tissue disease attended in an institute in Mexico City and their relation with other manifestations of the disease. METHODS: One hundred thirteen patients admitted to the Institute with a diagnosis of mixed connective tissue disease were divided into those with conduction disturbances (n = 23) and those without (n = 90). Over a mean follow-up of 10.2 +/- 7.8 years, clinical course, treatment, duration of the disease, types of conduction disturbances and systemic alterations were examined. RESULTS: There was an overwhelming predominance of women in both groups. Conduction disturbances occurred in about 20% of the patients with mixed connective tissue disease and that was not possible to find significant differences in the outcome of them. As could be expected a significant difference between the two groups was QRS axis, related to anterior hemiblock, the most common conduction alteration observed. During the follow-up one patient death in-group A, but none in group B. CONCLUSION: Conduction disturbances were present in 20%; in agree with other authors in the literature. However, did not participate in the outcome of the disease.

IRES interaction with translation initiation factors: functional characterization of novel RNA contacts with eIF3, eIF4B, and eIF4GII.

Translation initiation promoted by picornavirus internal ribosome entry site (IRES) elements is dependent on the association of specific IRES sequences to the initiation factor eIF4G. However the RNA determinants interacting with other components of the translational machinery are still unknown. In this study, we have identified novel RNA-protein interactions between the foot-and-mouth disease virus (FMDV) IRES and three translation initiation factors. A doublet of 116/110 kDa that crosslinked to the FMDV IRES is a component of eIF3. We show here that domain 5 holds the preferential binding site for eIF3, although this complex initiation factor can establish multiple contacts with the IRES structure. We have also identified the phylogenetically conserved hairpin of domain 5 as the RNA motif responsible for eIF4B interaction. Mutation of this stem-loop structure abrogated eIF4B, but not eIF3, binding to the IRES. Remarkably, IRES mutants severely affected in their interaction with eIF4B showed a mild reduction in IRES activity when tested in the context of a bicistronic expression vector in transfected cells. Finally, we provide evidence of the interaction of eIF4GII with FMDV IRES, the RNA determinants for this interaction being shared with its functional homolog eIF4GI. The FMDV Lb protease generated a C-terminal fragment of eIF4GII that binds to the IRES as efficiently as the intact protein. Competition experiments showed that titration of eIF4B or p110/116 interaction with the FMDV IRES required a large excess of competitor relative to eIF4G, strongly suggesting that eIF4G-IRES interaction is a limiting factor to titrate the IRES. Comparative analysis of the activity of IRES mutants affected in domains 4 and 5 regarding their pattern of RNA-protein complex formation demonstrates that while binding of eIF4B with the FMDV IRES is dispensable, interaction of eIF4G is a central feature of the activity of this element.

Manifestaciones cutáneas de la diabetes

El conocimiento de las manifestaciones cutáneas de las enfermedades sistémicas puede favorecer un diagnóstico más temprano y un mejor control de la enfermedad. La diabetes, una enfermedad cuya prevalencia en el mundo occidental es del 5 al 7 por ciento y cuyas complicaciones a largo plazo son tan graves, puede provocar en los pacientes que la padecen una gran variedad de manifestaciones cutáneas. En el presente artículo desglosaremos las características de las alteraciones cutáneas del paciente diabético (AU)

La sedación no protocolizada en una Unidad de Medicina Intensiva / Non-Protocolized Sedation In The Intensive Care Unit

Objetivo. Estudio descriptivo de la sedación y de su efectividad, en un Servicio de Medicina Intensiva (SMI) que no dispone de protocolización en su uso. Método. En todos los pacientes ingresados en el SMI entre enero y mayo de 1998 sometidos a ventilación mecánica y a los que su médico había decidido sedar, se recogieron datos acerca de los requerimientos de ventilación mecánica, nivel de sedación del paciente (escala de Ramsay), dosis diarias del fármaco (mg/kg/día) utilizado, y tiempo requerido entre la retirada de sedación e inicio de weaning. Para evitar la variabilidad entre turnos, los datos se recogieron una vez por turno y siempre a la misma hora. El personal del SMI no fue avisado de la realización del estudio. Resultados. En total se recogieron 50 pacientes. El nivel medio de sedación aplicado en 648 determinaciones según la escala de Ramsay fue de 5,2 (1,1), variable no relacionada significativamente con las necesidades de ventilación mecánica. Las dosis medias de midazolam fueron 3,41 mg/kg/día. La tasa de autoextubación fue del 0 por ciento. Por otro lado, el tiempo requerido desde la retirada de la sedación hasta el despertar del paciente fue de 21 horas (mediana). No hubo diferencias estadísticamente significativas entre las dosis de midazolam recibidas, nivel de sedación e intervalo retirada sedación-inicio weaning, entre los pacientes que presentaron o no insuficiencia renal. Conclusiones. Si no se protocoliza la sedación en el SMI, existe una tendencia a dejar al paciente en niveles cercanos al coma profundo (AU)

Modulation of the swelling-activated amino acid channel of Leishmania major promastigotes by protein kinases.

Leishmania promastigotes respond to hypotonic challenges by a mechanism of regulatory volume decrease (RVD), whereby anionic amino acid channels (HAAC) are hypotonically-activated and intracellular amino acids are released from the cells. Irrespective of the experimental conditions, restoration of isotonicity triggered an immediate blockage of the amino acid release. Both the speed and amplitude of the response depended on the hypotonic stimulus and on the operation of intracellular signaling mechanisms. The initial (5 s) hypotonic-induced release of amino acids (ri) and the steady state levels of amino acids attained (5 min) or amplitude (A), were markedly affected by modulators of protein kinase C: phorbol 12-myristate 13-acetate, 1-oleoyl-2-acetylglycerol and phorbol 12,13-diacetate whereas staurosporine and the related analog, bis-indolylmaleimide I (GF-109203.X) inhibited the RVD response. Agonists of cAMP-dependent protein kinase A such as forskolin or (8-(4-chlorophenylthio))-adenosine-3',5'cyclic-monophosphate enhanced the speed of the response but had little effect on its amplitude. Neither 4alpha-phorbol 12,13-didecanoate,1,9-dideoxyforskolin nor genistein, tamoxifen or thapsigargin had any apparent effect on either parameter tested. The most striking stimulation of hypotonic-induced amino acid release was exerted by arachidonic acid or by its non-metabolizable analog, 5,8,11,14-eicosatetraynoic acid (ETYA). These agents caused a major increase in the initial rate of amino acid release as well as a higher amplitude of the response, both of which were markedly inhibited by an anion channel blocker. The present studies indicate not only that hypotonicity is an obligatory and dominant component in HAAC activation, but implicate specific second messengers in the modulation of the RVD response. The modes of activation or attenuation of HAAC activity apparently differ for PKC and PKA modulators as well as for arachidonic acid. The involvement of Ca2+ in HAAC was studied in hypotonic challenged cells which were treated with intracellular Ca2+-chelators or Ca2+-free medium. These cells showed a lag in AA release and a modest inhibition of the amplitude. The inhibition of HAAC was markedly increased when cells were treated with the ionophore A23187 in Ca2+-free media. The HAAC activity was accompanied by a significant increase in internal Ca2+ when performed in Ca2+-containing medium (from 88+/-9 to 179+/-22 nM) but by no significant change when measured in Ca2+-free medium. These studies indicate that although Ca2+ might be involved in the early activation phase of HAAC, it is either not absolutely required or its action might be associated with localized events.

An amino acid channel activated by hypotonically induced swelling of Leishmania major promastigotes.

Leishmania promastigotes accumulate amino acids (AAs) by an uphill transport mechanism that is dependent on membrane potential. The accumulated AAs provide the cell with an osmotic reservoir that can be utilized for osmoregulation. Exposure of Leishmania promastigotes to hypotonic media induced a rapid release of AAs that was proportional to the imposed osmotic gradients and independent of the ionic strength or the presence of Cl-, K+, Na+ or Ca2+ in the medium. The hypotonically activated AA release pathway was of relatively low chemical specificity. The solutes released included most of the zwitterionic and anionic AAs, predominantly alanine, hydroxyproline, glycine and glutamic acid, whereas cationic AAs were virtually excluded. AA release was markedly blocked by classical anion transport inhibitors such as the disulphonic stilbene 4,4'-diisothiocyanostilbene-2,2'-disulphonate (DIDS) and its dihydro derivative H2DIDS and others, by restoration of isotonicity or by lowering the temperature (4 degrees C). The temperature profile of AA release showed a low energy of activation (Ea 46 +/- 1.3 (S.E.M.) kJ/mol) in the range 15-30 degrees C and a very high Ea (147 +/- 8 kJ/mol) in the range 4-15 degrees C. Parasites exposed to hypotonic media containing AAs also showed a hypotonically stimulated AA uptake under favourable solute concentration gradients. This uptake was analogous for L- and D-isomers of threonine. After hypotonic exposure, cells underwent a depolarization that was largely prevented by anion transport blockers. On the basis of all these results we propose that after hypotonic stress Leishmania promastigotes restore their internal volume by a regulated release of AAs, which involves activation of channels that allow the passage of both neutral and anionic AAs and possibly other anionic substances.

Exposure of firefighters to diesel emissions in fire stations.

Personal sampling techniques were used to evaluate firefighter exposure to particulates from diesel engine emissions. Selected fire stations in New York, Boston and Los Angeles were studied. Firefighter exposure to total particulates increased with the number of runs conducted during an 8-hr period. In New York and Boston where the response level ranged from 7 to 15 runs during an 8-hr shift, the resulting exposure levels of total airborne particulates from diesel exhaust were 170 to 480 micrograms/m3 (TWA). Methylene chloride extracts of the diesel particulates averaged 24% of the total. The authors' findings suggest that additional research is necessary to assess fire station concentrations of vehicle diesel exhaust that may have adverse health consequences to firefighters.

In vivo and in vitro release of cyanide from neurotoxic aminonitriles.

Cyanide release from neurotoxic aminonitriles was measured following in vitro incubation with both microsomes and liver slices. Investigation of cyanide released as urinary thiocyanate following ip aminonitrile administration to rats was also measured. The yield of cyanide in the in vivo study, as measured by the mole percent of administered dose, was greatest from dimethylaminonitrile (DMAA), followed by trimethylaminopropionitrile (TMAPN), dimethylaminopropionitrile (DMAPN), 3,3'-iminodipropionitrile (IDPN), dimethylaminobutyronitrile (DMABN), and monomethylaminopropionitrile (MMAPN). Urinary excretion of thiocyanate accounted for 48.9% of the administered DMAA, 11.6% of TMAPN, 8.0% of DMAPN, 6.8% of IDPN, 3.1% of DMABN, and 1.8% of MMAPN. Incubation of aminonitriles and related compounds with microsomes or liver slices from rats yielded measurable quantities of cyanide from all the compounds tested except for DMABN, TMABN, and succiononitrile. Quantitative evaluation of the yield of formaldehyde by demethylation following microsomal incubation was also determined. The signs of acute toxicity in rats after ip administration of KCN were similar only to those in rats administered DMAA.