Structural and developmental differences between three types of Na channels in dorsal root ganglion cells of newborn rats

Summary The changes in Na current during development were studied in the dorsal root ganglion (DRG) cells using the whole-cell patch-clamp technique. Cells obtained from rats 1–3 and 5–8 days after birth were cultured and their Na currents were compared. On top of the two types of Na currents reported in these cells (fast-FA current and slow-S current) a new fast current was found (FN). The main characteristics of the three currents are: (i) The voltages of activation are –37, –36, and –23 mV for the FN, FA and S currents, respectively. (ii) The activation and inactivation kinetics of FN and FA currents are about five times faster than those of the S current. (iii) The voltages at which inactivation reaches 50% are –139, –75 and –23 mV for the FN, FA and S currents, respectively.The kinetics and voltage-dependent parameters of the three currents and their density do not change during the first eight days after birth. However, their relative frequency in the cells changes. In the 1–3 day-old rats the precent of cells with S, FA, and mixed S+FN currents is 22, 18, and 60% of the cells, respectively. In the 5–8 day-old, the percent of cells with S, FA, and FN+S is 10, 66 and 22%. The relative increase in the frequency of cells with FA current during development can contribute to the ease of action potential generation compared with cells with FN currents, which are almost completely inactivated under physiological conditions. The predominance of FA cells also results in a significant decrease in the relative frequency of cells with the high-threshold, slow current.Antibodies directed against a part of the S₄ region of internal repeat I of the sodium channel (C ₁ ⁺ , amino acids 210–223, eel channel numbering) were found to shift the voltage dependence of FA current inactivation (but not of FN or S currents) to more negative potentials. The effect was found only when the antibodies were applied externally. The results suggest that FN, FA and S types of Na currents are generated by channels, which are different in the topography of the C ₁ ⁺ region in the membrane.     

Expression of common fragile sites in two Ceboidea species: Saimiri boliviensis and Alouatta caraya (Primates: Platyrrhini)

Fragile sites are points of preferential breakage that may be involved in chromosome rearrangements. Induction of common fragile sites (c-fra) and spontaneous breakage were analyzed in two New World Monkeys species: Saimiri boliviensis (SBO) and Alouatta caraya (ACA). Spontaneous chromosome aberrations were analyzed on untreated lymphocyte cultures with Brögger''s formula (1977). SBO presented a low level of spontaneous breakage, while higher frequencies were detected in ACA in which bands 1q23; 2q13 and 11q19 were significantly affected (p < 0.01). The populational distribution of c-fra was analyzed by the Chi² test in FUdR plus caffeine treated cultures. A total of 21 c-fra was identified in SBO and 24 in ACA. Fragile sites A₁q33, B₁p21, B₄p14, C₃q23 and C₅q22 were identified in all analyzed SBO specimens. The most frequent c-fra identified in ACA specimens were 1q23, 1q31, 1q33, 2q22, 8q14, 12q31, 13q22, 14q15 and Xq22. Fragile sites A₁q31, A₁q33, B₁q14, B₃q13, B₄q21 and Xq22 identified in SBO and 1q31, 1q33, 2q22, 4q21, 6q13, 13q22 and Xq22 from ACA were the most conserved sites. A low coincidence between the location of c-fra and that of heterochromatin and breakpoints involved in euchromatic rearrangements known for these genera, was established.     

Human T Cell Leukemia Virus Reactivation with Progression of Adult T-Cell Leukemia-Lymphoma

Background

Human T-cell leukemia virus-associated adult T-cell leukemia-lymphoma (ATLL) has a very poor prognosis, despite trials of a variety of different treatment regimens. Virus expression has been reported to be limited or absent when ATLL is diagnosed, and this has suggested that secondary genetic or epigenetic changes are important in disease pathogenesis.

Methods and Findings

We prospectively investigated combination chemotherapy followed by antiretroviral therapy for this disorder. Nineteen patients were prospectively enrolled between 2002 and 2006 at five medical centers in a phase II clinical trial of infusional chemotherapy with etoposide, doxorubicin, and vincristine, daily prednisone, and bolus cyclophosphamide (EPOCH) given for two to six cycles until maximal clinical response, and followed by antiviral therapy with daily zidovudine, lamivudine, and alpha interferon-2a for up to one year. Seven patients were on study for less than one month due to progressive disease or chemotherapy toxicity. Eleven patients achieved an objective response with median duration of response of thirteen months, and two complete remissions. During chemotherapy induction, viral RNA expression increased (median 190-fold), and virus replication occurred, coincident with development of disease progression.

Conclusions

EPOCH chemotherapy followed by antiretroviral therapy is an active therapeutic regimen for adult T-cell leukemia-lymphoma, but viral reactivation during induction chemotherapy may contribute to treatment failure. Alternative therapies are sorely needed in this disease that simultaneously prevent virus expression, and are cytocidal for malignant cells.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00041327","term_id":"NCT00041327"}}NCT00041327     

Distinct cardiac and renal effects of ETA receptor antagonist and ACE inhibitor in experimental type 2 diabetes

Diabetic nephropathy is associated with cardiovascular morbidity. Angiotensin-converting enzyme (ACE) inhibitors provide imperfect renoprotection in advanced type 2 diabetes, and cardiovascular risk remains elevated. Endothelin (ET)-1 has a role in renal and cardiac dysfunction in diabetes. Here, we assessed whether combination therapy with an ACE inhibitor and ET(A) receptor antagonist provided reno- and cardioprotection in rats with overt type 2 diabetes. Four groups of Zucker diabetic fatty (ZDF) rats were treated orally from 4 (when proteinuric) to 8 mo with vehicle, ramipril (1 mg/kg), sitaxsentan (60 mg/kg), and ramipril plus sitaxsentan. Lean rats served as controls. Combined therapy ameliorated proteinuria and glomerulosclerosis mostly as a result of the action of ramipril. Simultaneous blockade of ANG II and ET-1 pathways normalized renal monocyte chemoattractant protein-1 and interstitial inflammation. Cardiomyocyte loss, volume enlargement, and capillary rarefaction were prominent abnormalities of ZDF myocardium. Myocyte volume was reduced by ramipril and sitaxsentan, which also ameliorated heart capillary density. Drug combination restored myocardial structure and reestablished an adequate capillary network in the presence of increased cardiac expression of VEGF/VEGFR-1, and significant reduction of oxidative stress. In conclusion, in type 2 diabetes concomitant blockade of ANG II synthesis and ET-1 biological activity through an ET(A) receptor antagonist led to substantial albeit not complete renoprotection, almost due to the ACE inhibitor. The drug combination also showed cardioprotective properties, which however, were mainly dependent on the contribution of the ET(A) receptor antagonist through the action of VEGF.     

Party political preferences of US Hispanics: The varying impact of religion,social class and demographic factors

The focus of this article is the pattern of party political preferences among the fast‐growing and increasingly politically significant Hispanic population. The source of our data is the 1990 City University of New York [CUNY] National Survey of Religious Identification, a nationally representative sample that includes 4,868 Hispanic adult respondents. One unique aspect of our large data set is that for the first time we disaggregate the one‐third who are Protestant and of No Religion from the Roman Catholic majority of Hispanics in order to see how religious identification affects political outlook. We found that Hispanics are most likely to be Democrats: 41 per cent, compared with 27 per cent who identified as Independents and 24 per cent as Republicans. Our research suggests that Hispanics are rapidly adopting mainstream American political characteristics. As a whole, the Hispanic population politically resembles non‐Hispanic white America more closely than it does black America. Among Hispanics, Protestantism and higher income favour the Republicans, and femaleness and older age assist the Democrats. The local political environment and individual social attributes are the determining factors in Hispanic political preferences. In fact, the geographical variable, state of residency, has the strongest effect on Democratic Party preference in the multivariate analysis. Overall, the dynamics of social trends among Hispanics seem to favour the Republican Party.