LOW-DOSE CYCLOSPORINE A IMPROVES SEVERE DISABLING PSORIASIS IN LATIN AMERICA

Background. Severe forms of psoriasis have been treated successfully with cyclosporine A (cyA) in Europe and North America. The aim of the present investigation was to record and evaluate this drug treatment in Latin American patients with severe psoriasis in a multicenter controlled dose-efficacy study. Patients and Methods. One hundred and fifty-two patients from 10 Latin American countries had on entry to the study a Psoriasis Area Severity Index (PASI) of 18 or more. Initial treatment was with cyA, 2.5 mg per kg per day for 6 weeks. At week 6, 27 patients with a baseline PASI score reduction of < 33% had the dose increased to 4 mg/kg/day. At week 12, 48 patients, who had not improved their baseline PASI scores by 66% or more, had their dose increased to 4 or 5 mg/kg/day, respectively. At the end of the study, 74 patients (56%) received cyA 2.5 mg/kg/day, 41 patients (31%) received 4 mg/kg/day, and 16 patients (12%) received 5 mg/kg/day. Results. Cyclosporine A treatment was considered successful in 84.7% of the patients, who reduced their initial PASI score by 66% or more at the end of treatment at week 18. Adverse effects were seen in 29 patients (19%). Hypertension occurred in 27% and an increase of serum creatinine level above 30% of the initial value in 40% of patients. Among other side effects were gastrointestinal complaints (5.1%), hirsutism (4.3%), muscle pain (2.2%), joint pain (2.2%), respiratory infections (2.2%), headache (1.4%), and hemorrhagic gingivitis (0.7%). Twenty-one patients (13.8%) were withdrawn from the study for various reasons: adverse events in five cases (3.3%), noncompliance in five cases (3.3%), lack of efficacy in three cases (2%) and nonrelated diseases in two cases (1.3%). There were also six patients of a group that finished earlier than planned. A follow-up at 8 weeks after treatment was performed in 106 patients; in this phase 60 patients (56.5%) continued with their previous successful PASI reduction. Relapses (i.e., PASI increasing by more than 50% over baseline) were seen in 22.6% of cases. Conclusions. Cyclosporine A is an effective and well-tolerated treatment for severe psoriasis. An initial dose of 2.5 mg/kg/day is recommended. Most of the patients have a good response to this dose.     

Control of neck nodes in squamous cell carcinoma of the head and neck by radiotherapy: prognostic factors

313 patients with cervical metastases from a squamous carcinoma of the head and neck treated with radiotherapy, were studied by means of a multivariant analysis in order to determine the prognostic factors for cure. These were: lymph node response to irradiation (P= 0.0000), size of node (P= 0.0000), radiotherapy dose (P= 0.0037), condition of the primary (controlled vs non-controlled) (P= 0.0015), recurrent cervical metastases post-surgery (P= 0.0286).     

Characterization of the thiol/disulfide chemistry of peptides corresponding to the 603-609 disulfide loop of the human immunodeficiency virus (HIV) envelope glycoprotein gp41

The redox chemistry of two synthetic model peptides for the 603-609 disulfide loop found in envelope glycoprotein gp41 of the human immunodeficiency virus type 1 (HIV-1) are reported. The two peptides: ((I)) and ((II)) were synthesized by the solid phase method. Peptide I corresponds to amino acids 601–611 of gp41 of the North American/European strain of HIV-1. Peptide II incorporates amino acid replacements frequent in African HIV-1 isolates. The redox chemistry of the disulfide bonds in the two peptides was characterized in aqueous and aqueous/urea solution by studying their thiol-disulfide exchange reactions with the tripeptide glutathione (GSH). GSH reacts with the disulfide bonds to form mixed disulfides, which in turn react with another molecule of GSH to give the dithiol form of the peptide and GSSG. Equilibrium constants were determined for each step and for the overall reduction reactions. Redox potentials of ?0.246V and ?0.241V were calculated from the equilibrium constants for the disulfide bonds in peptides I and II in aqueous solution at 25°C and pH 7.0. The overall equilibrium constants are less in 8 M urea solution, which indicates a stabilization of the reduced, dithiol form of both peptides by secondary structure which can be denatured by urea. This conclusion is supported by nuclear Overhauser enhancement data obtained from 2D-ROESY NMR spectra which provide evidence of elements of secondary structure for the reduced forms of both peptides. The results are discussed in terms of a protein disulfide isomerase catalyzed reduction of the disulfide bond in gp41.     

Acute Inhalation Exposure to Epichlorohydrin Transiently Decreases Rat Sperm Velocity

Acute Inhalation Exposure to Epichlorohydrin Transiently DecreasesRat Sperm Velocity. Slott, V. L., Suarez, J. D., Simmons, J.E., and Perreault, S. D. (1990). Fundam. Appl. To.xicol. 15,597–606. The effect of inhaled epichlorohydrin on ratsperm motility characteristics was evaluated. Male F-344 ratswere exposed to 100 ppm epichlorohydrin via inhalation for 4hr in the morning of Day 0 and killed immediately and on Days1, 2, 6, and 14 postexposure. Videotapes of cauda epididymalsperm were analyzed (300–350 sperm/sample) with a HamiltonThorn motility analyzer (HTM-2000, Hamilton Thorn Research,Danvers, MA). Epichlorohydrin did not affect the percentageof motile sperm at any time. However, transient changes in spermvelocity were found. On Day 1 postexposure mean progressive(straight line) and mean path (smoothed curvilinear) velocitywere significantly decreased to 80 and 85% of control, respectively.The progressive velocities of sperm from both control and treatedrats were normally distributed, indicating a general effectof epichlorohydrin on all sperm as opposed to a more severeeffect on a specific sperm subpopulation. Sperm velocity wasnot significantly affected at later times. Other endpoints (testisand epididymis weights, testicular spermatid counts, and caudaepididymal sperm reserves) were unaltered by epichlorohydrin.Thus, inhaled epichlorohydrin at 100 ppm produced specific,transient decreases in rat sperm velocity. Furthermore, computer-assistedsperm analysis was able to detect these relatively subtle, toxicant-inducedchanges in rat sperm velocity, demonstrating the utility ofthis technology in reproductive toxicology studies.     

Pregnancy is associated with a reduction in the pattern of the cytotoxic activity displayed by lymphokine-activated killer cells.

Several modifications in the homeostasis of the maternal immune system have been implicated in the survival of the fetoplacental graft. We have investigated the adaptive response of the cytotoxic nonmajor histocompatibility complex (MHC)-restricted effector lymphocytes in pregnancy, and have found that the spontaneous lytic activity against both natural killer (NK)-sensitive and NK-resistant target cells is either decreased or lacking in peripheral blood mononuclear cells (PBMNC) from pregnant women. Recombinant interleukin-2 (rIL-2) normalizes the cytotoxic activity of PBMNC from pregnant women against NK-sensitive target cells in a dose- and time-dependent manner, without modification in the normal amounts of HNK-1+, CD16+ (Leu 11, or CD11b+ (OKM-1) present in these effector populations. However, the pattern of lytic activity against NK-resistant target cells found in PBMNC from pregnant women after short- and long-term incubation with rIL-2 was reduced in comparison with that observed in PBMNC from nongravid women in similar conditions. Moreover, rIL-2 incubation of PBMNC from pregnant subjects was not associated with an enhancement of the lytic binding against NK-resistant target cells. These findings demonstrate that pregnancy is not only associated with a reduction in the NK lytic activity of PBMNC, but also with a reduction in the generation of lymphokine-activated killer activity, in terms of the pattern of lytic activity developed.     

Carbohydrate moieties of the interstitial and glandular tissues of the amphibian Pleurodeles waltl testis shown by lectin histochemistry

The amphibian testis is a useful model because of its zonal organisation in lobules, distributed along the cephalocaudal axis, each containing a unique germ cell type. Sperm empty lobules form the so-called glandular tissue at the posterior region of the gonad. Androgen production is limited to the cells of the interstitial tissue surrounding lobules with spermatozoa bundles and to the cells of the glandular tissue. In this work, we have studied the distribution of terminal carbohydrate moieties of N- and O-linked oligosaccharides in the interstitial and glandular tissue of the Pleurodeles waltl testis, by means of 14 lectins combined with chemical and enzymatic deglycosylation pretreatment. Some differences in glycan composition between the interstitial and the glandular tissue have been detected. Thus in both tissues, N-linked oligosaccharides contained mannose, Gal(β1,4)GlcNAc, and Neu5Ac(α2,3)Gal(β1,4)GlcNAc, while O-linked oligosaccharides contained Con A-positive mannose, Gal(β1,3)GalNAc, Gal(β1,4)GlcNAc, Neu5Ac(α2,3)Gal(β1,4)GlcNAc, and WGA-positive GlcNAc. Fucose was also detected in both tissues. However, GlcNAc on N-linked oligosaccharides and GalNAc and Neu5Ac(α2,6)Gal/GalNAc on both N- and O-linked oligosaccharides were found only in the interstitial tissue. As glandular tissue cells arise from the innermost cells of interstitial tissue that surround lobules, the differences in the glycan composition of interstitial and glandular tissue shown in this work may be related to the start of androgen synthesis when steroid hormone (SH)-secreting cells develop.     

Effect of captopril infusion on systemic and renal haemodynamics in conscious hypertensive rats with chronic, progressive aortic ligation

The effect of the converting enzyme inhibitor captopril (5 mg (kg bwt)-1) on systemic and renal haemodynamics has been studied in conscious rats in which a progressive hypertension has been induced by progressive aortic ligation (AL) between the renal arteries, and in a sham-operated (SO) group. Cardiac output (CO), organ blood flow and vascular resistances have been measured using radioactive microsphaeres. Captopril infusion caused increases in CO in both groups of rats, but the increase was higher in SO (9.2 +/- 0.7%) than in AL rats (5.2 +/- 0.6%; P less than 0.005). Plasma renin concentrations were similar in both groups but increased more in AL (10.3 microIU +/- 1.0) than in SO (5.81 microIU +/- 0.62; P less than 0.05) after captopril. Captopril induced also a larger decrease in arterial pressure (36 +/- 4 mmHg), and of the pressure gradient across the stenosis (19 +/- 3) mmHg in AL than in SO rats (5.6 +/- 1.4 and 1.1 +/- 1.3 mmHg, P less than 0.005 for both cases). Vascular resistance of the kidney above the ligature decreased more in AL than in SO rats, but this difference was not observed in the other kidney. From these data it can be concluded that captopril has an acute hypotensive effect despite the normal renin levels of this model of chronic hypertension. In addition, blood flow to the high-pressure perfused kidney seems to be dependent on the increased renin production by the contralateral kidney.     

Octapolar Electrocatheter for His Bundle Recording and Sequential Bedside Electrophysiologic Testing

To reduce the number of electrocatheters required for an electrophysiologic study and to facilitate prolonged monitoring of the electrical properties of the heart, an octapolar electrocatheter was designed and tested in 45 consecutive patients undergoing routine electrophysiologic studies. The electrocatheter introduced into the right ventricle served for: (a) right ventricular pacing; (b) recording of low lateral and low septal right atrial electrograms; (c) recording of the His bundle potential in 39 out of the 45 patients (86%); (d) 24-hour monitoring of the AV conduction intervals and refractory periods at the patients' bedsides. The octapolar electrocatheter reduced the number of probes required for studying the mechanisms of reciprocating tachycardia and allowed 24-hour bedside electrophysiologic monitoring.     

The Effects of Selective Stellate Ganglion Manipulation on Ventricular Refractoriness and Excitability

The effects of selective stellate ganglion stimulation or stellectomy on ventricular excitability were studied in 30 open chest mongrel dogs anesthetized with alpha-chloralose. The elective refractory period (ERP) and strength interval curves (stimulus intensity (S2) = twice the diastolic threshold (ERP), and 2, 3, 5, 7, and 14 mA) were determined using bipolar epicardial electrodes placed in the mid-anterior wall of the right ventricle (RV) and the mid-posterolateral wall of the left ventricle (LV) during left stellate ganglion stimulation (LSGSt, n = 8) or right stellate ganglion stimulation (RSGSt, n = 8), or after left stellectomy (LSGEx, n = 7) or right stellectomy (RSGEx, n = 7). LSGEx prolonged ERP-LV (172 ± 9 vs 167 ± 8 msec, P < 0.05) and ERP-RV (163 ± 10 vs 158 ± 14 msec, P < 0.05). RSGEx prolonged ERP-LV (168 ± 17 vs 162 ± 15 msec, P < 0.01) and ERP-RV (166 ± 14 vs 160 ± 13 msec, P < 0.01), and the times of the strength interval curves obtained for each S2 intensity in both ventricles. LSGSt decreased ERP-LV (157 ± 11 vs 163 ± 12 msec, P < 0.01) and ERP-RV (147 ± 18 vs 157 ± 17 msec, P < 0.05), and the times of the strength interval curves obtained for each S2 intensity in both ventricles. RSGSt did not significantly decreased ERP-LV (152 ± 11 vs 156 ± 9 msec); however, it significantly shortened the times of the strength interval curves obtained for S2 intensities of 2 and 7 mA in the LV, and shortened ERP-RV (139 ± 10 vs 145 ± 7 msec, P < 0.01) and the times of the strength interval curve for S2 intensities of 2, 3, and 5 mA in the RV. A significant interaction (MANOVA test) was observed between the ventricle studied and the ganglion stimulated for S2 intensities of 2 and 3 mA, and between the effect of stimulation and the ganglion stimulated for S2 intensities of 3 and 14 mA. To conclude, selective stellectomy prolonged epicardial ventricular refractoriness in both the mid-anterior wall of the RV and the mid-posterolateral wall of the LV; the magnitude of the epicardial excitability variations in both areas was different during selective stellate ganglion stimulation,