Cathepsin C gene: First compound heterozygous patient with Papillon-Lefèvre syndrome and a novel symptomless mutation

Papillon-Lefèvre syndrome (PLS) has recently been shown to be caused by mutations in the cathepsin C gene resulting in periodontal disease and palmoplantar keratosis. Thirteen different homozygous mutations have been characterised in PLS patients of different ethnic origin. In the present paper, a PLS patient is described who carries two novel mutations (706G>T and 872G>A) in the paternal and maternal chromosomes, respectively. This is the first compound patient described so far. In addition, a novel symptomless mutation (458C>T) in the cathepsin C gene is described in three homozygous individuals. Thus, not all mutations should be considered as a cause of disease, whether case studies or general population screening is performed. Another already described mutation that provoked the Haim-Munk syndrome (HMS) in Indian Jews has also been found to give rise to PLS in a Spanish family from Madrid. On the other hand, PLS patients are ameliorated by retinoids, which indicates that retinoids may be used as therapeutic agents in this immune system deficiency.     

Evolution of MHC-G in humans and primates based on three new 3'UT polymorphisms

MHC-G is a class Ib (non-classical) major histocompatibility complex (MHC) whose functional and evolutionary characteristics are still under scrutiny. The study of noncoding sequences in the MHC genes may provide important phylogenetic information. In this work we have sequenced the MHC-G exon 8, which encodes for the 3'UT region, in different species of primates. It has been shown that: (1) a previously described 14 base pair (bp) deletion polymorphism is human-specific and the HLA-G alleles may be classified according to its absence or presence; (2) another newly described 3 bp deletion/insertion polymorphism is also human-specific; and (3) another newly described 51 bp deletion polymorphism is common to Pongidae and humans, but is not found in other primates belonging to the Cercopithecinae family. A hypothesis on the evolutionary pathway of this gene is put forward in the light of these findings.     

IgH, TCR-gamma, and TCR-beta gene rearrangement in 80 B- and T-cell non-Hodgkin's lymphomas: study of the association between proliferation and the so-called "aberrant" patterns.

The current study analyzes the rearrangement pattern of immunoglobulin H (IgH), T-cell receptor (TCR)-gamma, and TCR-beta genes in a group of 80 non-Hodgkin's lymphomas (NHL) of different histologic subtypes (43 B-cell and 37 T-cell types). The sensitivity and specificity provided by polymerase chain reaction amplification of these loci are evaluated. The association between the proliferation index and the presence of the so-called "aberrant" or "dual" rearrangements is also considered. Ninety-one percent of B-cell NHL showed IgH gene monoclonality, and 21% also exhibited a monoclonal pattern in one of the TCR genes. Among T-cell NHL, the sensitivity of the study was 65% for the TCR-gamma gene and 46% for the TCR-beta gene. The total sensitivity was 76%, amplifying both loci. IgH gene aberrant rearrangements were observed in 16% of T-cell neoplasms. A substantial percentage of dual rearrangements were detected in precursor and mature B- and T-cell NHL. B-cell NHL showed a tendency toward higher values of proliferation when aberrant rearrangements were present; however, this trend was not significant. Furthermore, in the case of T-cell NHL there was a significant negative association between these two variables.     

Extracellular taurine increase in rat hippocampus evoked by specific glutamate receptor activation is related to the excitatory potency of glutamate agonists

Taurine increases in brain extracellular space due to glutamate agonists were studied in vivo in the rat hippocampus using a dialysis technique, both in the absence and in the presence of glutamate receptor antagonists. Extracellular taurine levels increased during perfusions of agonists, listed in descending order of potency: kainate (KA), N-methyl-D-aspartate (NMDA), and quisqualate (QA). While taurine increases due to KA or QA perfusions were inhibited by 6,7-dinitro-quinoxaline-2,3-dione (DNQX), those induced by NMDA were abolished in the presence of 3-(carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP). These results indicate that increases in extracellular taurine levels evoked by NMDA, KA or QA in the rat hippocampus are caused by activation of their specific receptors. Field potentials, concomitantly recorded, were quickly abolished during NMDA or KA perfusions (0.1 mM), while QA (0.25 mM) induced the appearance of bicuculline-like evoked responses. Since taurine has been proposed as an osmoregulatory substance in the rat brain, and cell swelling is known to be an early component of glutamate agonists neurotoxicity, the increases in extracellular taurine reported here could be due to taurine released through an osmoregulatory process, counteracting the neurotoxic cellular oedema induced by glutamate agonists.     

Heat-shock protein (HSP70-2) allelic frequencies in three distinct Mexican populations

The major histocompatibility complex (MHC) genes are highly polymorphic and therefore have been useful in population genetics and disease association studies. We analyzed restriction fragment length polymorphism of HSP70-2 alleles in healthy unrelated Mestizo, Mazatecan and Nahua populations. Both Indian groups, Mazatecans and Nahuas, were in Hardy-Weinberg equilibrium, while Mestizos were in disequilibrium (chi 2 = 0.399; P < 0.05). The Mazatecan Indians presented a high frequency of BB homozygosity (17.35%) compared to Mestizos (5%) (P = 0.01). Mexican ethnic groups present differences in distribution of BB genotype. The low frequency of BB genotype in Mestizos may be the result of a negative selection process.     

Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed hodgkin lymphoma: results of a spanish prospective cooperative protocol.

We report the results of reduced-intensity conditioning allogeneic stem cell transplantation (allo-RIC) in patients with advanced Hodgkin lymphoma (HL). Forty patients with relapsed or refractory HL were homogeneously treated with an RIC protocol (fludarabine 150 mg/m(2) intravenously plus melphalan 140 mg/m(2) intravenously) and cyclosporin A and methotrexate as graft-versus-host disease (GVHD) prophylaxis. Twenty-one patients (53%) had received >2 lines of chemotherapy, 23 patients (58%) had received radiotherapy, and 29 patients (73%) had experienced treatment failure with a previous autologous stem cell transplantation. Twenty patients (50%) were allografted in resistant relapse, and 38 patients received hematopoietic cells from an HLA-identical sibling. Five patients (12%) died from early transplant-related mortality (before day +100 after allo-RIC). One-year transplant-related mortality was 25%. Acute GVHD developed in 18 patients (45%). Chronic GVHD developed in 17 (45%) of the 31 evaluable patients. The response rate 3 months after the allo-RIC was 67% (21 [52%] complete remissions and 6 [15%] partial remissions). Eleven patients received donor lymphocyte infusions (DLIs) for disease relapse. The response rate after DLI was 54% (3 complete remissions and 3 partial remissions). Overall survival (OS) and progression-free survival (PFS) were 48% +/- 10% and 32% +/- 10% at 2 years, respectively. Refractoriness to chemotherapy was the only adverse prognostic factor for both OS (63% +/- 12% versus 35% +/- 13%; P = .05) and PFS (55% +/- 16% versus 10% +/- 9%; P = .006). For patients with failure of a prior autologous hematopoietic stem cell transplantation, results were especially good for those who experienced late relapses (>/=12 months: 2-year OS and PFS were 75% +/- 16% and 70% +/- 18%, respectively). These data suggest that allo-RIC is feasible in heavily pretreated HL patients and has an acceptable early transplant-related mortality. Results are better in patients allografted in sensitive disease. Both responses observed after the development of GVHD and DLI may suggest a graft-versus-HL effect. Allo-RIC has to be considered an effective therapeutic approach for patients who have had treatment failure with a previous autologous hematopoietic stem cell transplantation.     

From rafts to crafts: membrane asymmetry in moving cells

Many important biological events, including the leukocyte-mediated immune response, wound repair, axon guidance and developmental patterning, involve persistent cell movement towards a directional signal, a process termed chemotaxis. Establishment of functional and spatial cell polarity is an absolute requirement for this response. We propose that redistribution of specific membrane microdomains, termed rafts, during cell migration is a pivotal step in achieving polarity. On the one hand, partitioning of molecules into rafts might help to localize proteins at the front or the rear of moving cells, and on the other hand, rafts might function as platforms for local activation and coordination of the signaling pathways involved in cell migration.     

The amygdala is part of the behavioural reinforcement system modulating long-term potentiation in rat hippocampus

Long-term potentiation (LTP) in the dentate gyrus can be modulated and prolonged by emotional/motivational influences when concurrently activated. A similar effect on LTP can be obtained by stimulating the amygdala, suggesting that this limbic structure might be part of the neural system involved in behavioural reinforcement. To confirm this we have performed a series of experiments in which the basolateral amygdala was either temporary inactivated by injection of lidocaine or permanently lesioned electrolytically. Both manipulations completely blocked the reinforcing effect of a motivational stimulus (drinking after 24-h deprivation) on LTP at the perforant pathway-dentate gyrus synapses, whilst leaving intact the non-reinforced potentiation. These results demonstrate that the basolateral amygdala is a key structure within the system involved in the modulatory interaction between the affective status of the animal and the mechanisms of functional plasticity.     

Präzisierung der Reizwirkung mittelfrequenter Wechselströme

Zusammenfassung Bei der Mittelfrequenz-Impuls-Reizung ist streng darauf zu achten, daß keine polaritären Reizkomponenten auftreten. Die diesbezügliche Kontrolle wird am besten mit Hilfe des Konvertibilitätstestes vorgenommen, d. h., es darf beim Vertauschen der Zuführungen zu den Reizelektroden weder die Reizschwelle bzw. die Größe des kollektiven Reizerfolges noch dessen Latenzzeit eine signifikante Änderung erfahren. Auf diese Weise wird die Phasenunabhängigkeit des echten Mittelfrequenz-Reizeffektes nachgewiesen.Diesen Anforderungen entsprechen Mittelfrequenz-Impulse, deren Trägerfrequenz über einige wenige Perioden sich aufschaukelt und ebenso wieder abklingt. Demgegenüber sind Mittelfrequenz-Stromstöße mit phasenstarrem Einsatz und Ende nicht unbedingt frei von polaritären Ein- bzw. Ausschalt-effekten, indem sowohl die erste als auch die letzte Trägerperiode einen polaritären Wechselimpuls-Reizeffekt ergeben kann, je nach Phasenlage bezogen auf die wirksame Reizelektrode und Art der Ansprechbarkeit des Reizobjektes (Nerv) auf entsprechend kurze gleitspiegelsymmetrische Wechselimpulse. Für eine echte Mittelfrequenz-Stromstoß-Reizung ist demnach ebenfalls ein Aufschaukeln und Abklingen der Trägerfrequenz über einige wenige Perioden erforderlich.Es besteht ein prinzipieller Unterschied zwischen der echten Mittelfrequenz-Reizung, die phasen -bzw. periodenunabhängig ist und schon früher als apolaritär bezeichnet wurde, und der konventionellen polaritären Reizung, die als polaritäre Komplikation der Mittelfrequenz-Reizung auftreten kann.Diese Präzisierung der Reizwirkung mittelfrequenter Wechselströme wurde angeregt durch zwei im Text erwähnte Publikationen, in denen in keineswegs überzeugender Weise versucht wird, die Mittelfrequenz-Reizung letzten Endes auf das polare Gesetz der Erregung zurückzuführen.

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Summary The particular excitatory action exerted by middle-frequency alternating current can only be revealed if care is taken to eliminate the occurrence of so-called polarity effects. Such effects are produced by the short alternating impulses represented by the first and the last period of a middle-frequency current pulse and are based on the polar law of excitation.In order to prevent such polarity intrusions, it is necessary to increase and decrease the amplitude of the middle-frequency current pulses over a few carrierperiods, or, to use amplitude-modulated middle-frequency impulses of variable shape and duration of envelope.A true middle-frequency excitatory effect is easily demonstrated by resorting to the convertibility test. It will then become evident that stimulation threshold, magnitude as well as latency of response do not change during reversal of the stimulating poles. This means, that no significant phase change of the response with regard to the carrier-frequency occurs when the leads to the stimulating electrodes are commuted, and that, as a result, true middle-frequency effects do not depend upon one particular catelectrotonic variation among the carrier-periods of a middle-frequency current pulse.It can thus be concluded that a fundamental difference exists between true middle-frequency stimulation, which is based on a non-polarity or apolarity principle, and the conventional stimulation of the polar or polarity type.This paper has been written in the hope of dispelling some errors of interpretation (discussed in the text) tending to ascribe the excitatory effects of middle-frequency impulse stimulation to the classical polar law of excitation.