Stage-specific expression of the proline-alanine transporter in the human pathogen Leishmania.

Leishmania are obligatory intracellular parasites that cycle between the sand fly midgut (extracellular promastigotes) and mammalian macrophage phagolysosomes (intracellular amastigotes). They have developed mechanisms of adaptation to the distinct environments of host and vector that favor utilization of both proline and alanine. LdAAP24 is the L. donovani proline-alanine transporter. It is a member of Leishmania system A that translocates neutral amino acids. Since system A is promastigote-specific, we aimed to assess whether LdAAP24 is also expressed exclusively in promastigotes. Herein, we established that upon exposing L. donovani promastigotes to amastigote differentiation signal (pH 5.5 and 37 °C), parasites rapidly and completely degrade LdAAP24 protein in both axenic and in spleen-derived amastigotes. In contrast, LdAAP24 mRNA remained unchanged throughout differentiation. Addition of either MG132 or Bafilomycin A1 partially inhibited LdAAP24 protein degradation, indicating a role for both lysosome- and proteasome-mediated degradation. This work provides the first evidence for post-translational regulation of stage-specific expression of LdAAP24.

Tumefactive demyelination and a malignant course in an MS patient during and following fingolimod therapy.

Finglimod, a sphingosine 1-phosphate receptor modulator, is the first orally administered therapy approved for prophylaxis in multiple sclerosis (MS). Several reports in the last two years suggested that it might be associated with severe augmentation of disease activity upon initiation or discontinuation of therapy. We present an MS patient who developed a giant cavitating brain lesion under fingolimod and in whom cessation of therapy was associated with a very active course. Brain biopsy revealed the lesion to be due to an active demyelinating inflammatory process. With the current wave of immunosuppressive treatments for MS, there is a need to be vigilant to side effects and risks not identified in large multicenter trials, collect the data and set guidelines and precautions for present and future medications.

Preferential transmission of interleukin-1 receptor antagonist alleles in attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder, where family data support substantial heritability.(1) To date, association studies focussed mainly on genes regulating dopaminergic neurotransmission.(2)Interleukin-1 (IL-1) activity in the brain has been implicated with differentiation of dopaminergic neurons(3,4) and modulation of central monoaminergic reactivity.(5) We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) gene variable number tandem repeat (VNTR) polymorphism,(6) in a sample of 86 children with DSM-IV ADHD and their parents. Transmission disequilibrium analysis showed increased transmission of the IL-1Ra 4-repeat allele (chi(2) = 4.07, P = 0.04) and decreased transmission of the 2-repeat allele (chi(2) = 4.59, P = 0.03) to affected children. The 4-repeat allele was associated with a significantly increased risk for ADHD (chi(2) = 4.46, df 1, P = 0.035, RR = 1.292, 95% CI 1.01-1.66). The IL-1Ra 2-repeat allele was associated with a significantly decreased risk for ADHD (chi(2) = 4.65, df 1, P = 0.03, RR = 0.763, 95% CI 0.59-0.98). If replicated, this finding may point to a role for brain cytokine activity in the etiopathogenesis of ADHD.

Unilateral vocal cord paralysis as a result of a Nocardia farcinica laryngeal abscess.

Nocardia farcinica is an emerging pathogen in immunocompromised hosts, accounting for 20% of Nocardia isolates in the USA and 13-44% of isolates in Europe. The case of a 72-year-old lymphoma patient with a laryngeal abscess caused by Nocardia farcinica is presented. The initial clinical manifestation was unilateral vocal cord paralysis, which improved following surgical drainage of the abscess and therapy with imipenem. The English-language literature on human Nocardia farcinica infection is reviewed.

GroES promotes the T to R transition of the GroEL ring distal to GroES in the GroEL-GroES complex.

Curves of initial rates of ATP hydrolysis by GroEL as a function of ATP concentration, in the presence of fixed concentrations of GroES, were found to deviate from sigmoidal kinetics. Instead of the lag phase typical of sigmoidal curves, a linear phase is observed at low ATP concentrations. Consequently, a good fit of the data to the Hill equation could not be achieved. Such curves could be simulated using a linear combination of Hill equations, thus indicating that more than one allosteric transition is taking place in the ATP concentration range studied. The data were fitted to a fractional saturation equation for ATP binding to GroEL based on a partition function that includes both GroES and ATP-liganded states of GroEL. Using this equation, it was possible to estimate in a reliable manner the value of the allosteric constant, L2', for the transition of the ring distal to GroES in the GroEL-GroES complex from the low (T)- to the high (R)-affinity state for ATP. The value of L2' is found to be 4 x 10(-5) whereas the value of the allosteric constant, L2, for the transition of the second ring of GroEL from the T to R state is 2 x 10(-9) [Yifrach, O., & Horovitz, A. (1995) Biochemistry 34, 5303-5308]. Comparison of these values shows that GroES promotes the T to R transition of the ring distal to GroES in the GroEL-GroES complex. Owing to the relatively low affinity of the R conformation for nonfolded proteins, this transition will lead to release of protein substrates from trans ternary complexes of GroEL, GroES, and protein substrate. The role of this release mechanism may be to assist the folding of relatively large proteins that cannot form cis ternary complexes and/or to facilitate degradation of damaged proteins which cannot fold.

Huge saccular cyst of the larynx: a case report.

Lateral laryngeal saccular cysts of the larynx that herniate through the thyrohyoid membrane are quite rare. We present a case of a huge midcervical cyst which occurred as a result of extreme neglect of a lateral saccular cyst. This case provided us with a unique opportunity to characterize the late stages of this pathology. The differential diagnosis of cervical cysts and treatment approaches are discussed.

Laser spectroscopy of molecular cesium near 1064 nm enhanced by a Fabry-Perot cavity.

We made Doppler-broadened and Doppler-free absorption measurement of a cesium cell that was placed inside an external Fabry-Perot ring cavity, using a Nd:YAG laser. We achieved a cavity finesse of ~85, and the sensitivity of the measurement was improved by as much as 26.5 with respect to single-pass absorption. The sensitivity enhancement by the external cavity may enable one to lock the laser frequency to (133)Cs(2) lines at relatively low temperatures, in which the frequency-dependent temperature shift, as well as the collision broadening, is reduced significantly.