Antibodies to the serine rich Entamoeba histolytica protein (SREHP) prevent amoebic liver abscess in severe combined immunodeficient (SCID) mice

Amoebic liver abscess caused by Entamoeba histolytica is a major cause of morbidity and mortality worldwide. We used mice with severe combined immunodeficiency (SCID mice) to study the role of antibody in protection from amoebic liver abscess, and to identify protective antigens of E. histolytica. Antisera to recombinant versions of two major surface antigens of E. histolytica, the serine rich E. histolytica protein (SREHP) and the 170 kDa adhesin were used in this study. We found that 100% of SCID mice passively immunized with antiserum to the recombinant SREHP molecule were protected from developing amoebic liver abscess after intrahepatic challenge with virulent E. histolytica trophozoites. In contrast, preimmune serum, antiserum to a portion of the 170 kDa adhesin, and antiserum to the trpE fusion partner of SREHP did not protect SCID mice from amoebic liver abscess. Our study demonstrates that antibodies to a recombinant version of the amoebic SREHP molecule can protect against amoebic liver abscess, and suggest the recombinant SREHP molecule should be considered as a possible vaccine candidate to prevent amoebic liver abscess.     

THYROID DISEASE AND OTHER AUTOIMMUNE PHENOMENA IN A FAMILY STUDY OF PRIMARY SJOGREN'S SYNDROME

Autoimmune diseases and autoantibodies have been documentedin 42 index cases with definite primary Sjögren's syndrome(1° SS), 207 relatives and 39 spouses. The results werecompared with control data from a local population survey. Thyroiddisease, 1° SS and their associated autoantibodies werethe commonest autoimmune abnormalities observed and found predominantlyin older female relatives. The HLA-DR3 phenotype associatedwith 1° SS, antinuclear factor, hypothyroidism, and thyroidmicrosomal antibody. Rheumatoid arthritis and systemic lupuserythematosus were not found in excess in the families. PrimarySjögren's syndrome is frequently associated with thyroiddisease and we suggest that there is a common genetic predispositionbetween these diseases which differs from 2° SS associatedwith rheumatoid arthritis and systemic lupus erythematosus.This includes MHC and non-MHC genes. KEY WORDS: Thyroid disease, Genetics, HLA-DR3, Sjögren's syndrome     

Evaluation of Changes in the Secretion of Immunoactive Inhibin by Adult Rat Seminiferous Tubules in Vitro as an Indicator of Early Toxicant Action on Spermatogenesis

Evaluation of Changes in the Secretion of Immunoactive Inhibinby Adult Rat Seminiferous Tubules in Vitro as an Indicator ofEarly Toxicant Action on Spermatogenesis. Allenby, G., Foster,P. M. D., and Sharpe, R. M. (1991). Fundam. Appl. Toxicol 16,710–724. A method for culturing isolated seminiferoustubules (ST) from adult rats for 1–3 days has been developedand optimized rigorously on the basis of the secretion of immunoactiveinhibin under basal conditions and after maximal stimulationwith rat FSH or dibutyryl cyclic AMP. The effect on these culturesof three known testicular toxicants was assessed. Of these,two are thought to act on the Sertoli cell, meta-dinitrobenzene(mDNB) and nitrobenzene (NB), while the third, methoxy aceticacid (MAA), is thought to act on pachytene spermatocytes. Inaddition, the effect of a possible testicular toxicant, 3-mononitrotoluene(3-MNT), was investigated. These data were compared with thoseobtained using cultures of immature rat Sertoli cells (SC) orSC + germ cells and with data on the effect of equivalent dosesof the compounds on the secretion of immunoactive inhibin invivo. In studies designed to optimize conditions for the secretionof immunoactive inhibin by ST in culture, significant effectswere found of the type of culture medium used, the durationof culture, the total and individual length of tubules used,etc. All subsequent studies with toxicants utilized optimalconditions. Addition of either mDNB or NB to ST cultures at10^–5 or 10^–3 m, or MAA at 10^–4 m, stimulatedbasal secretion of immunoactive inhibin by two- to fourfoldon Days 1, 2, or 3 of culture while FSH or dibutyryl cyclicAMP-stimulated secretion of immunoactive inhibin was eitherunaffected or was enhanced to a small extent. At the same doses,mDNB or NB also enhanced secretion of immunoactive inhibin bySC cultures, although these effects were more variable and ofsmaller magnitude than the effects on ST cultures. In contrast,addition of up to 10^–3 m MAA to cocultures of SC + germcells had no effect on the secretion of immunoactive inhibin.Exposure of rats in vivo to levels of mDNB, NB, or MAA similarto those which stimulated secretion of immunoactive inhibinin vitro resulted in a two-to fourfold increase in the levelsof immunoactive inhibin in testicular interstitial fluid (IF)at 1 and 3 days post-treatment, and this was associated withearly impairment of spermatogenesis (as judged by testis weight).In contrast to these effects, addition of 3-MNT to ST or SCcultures had no effect except at 10^–3 m, when the secretionof immunoactive inhibin was increased marginally. Treatmentof rats with an equivalent dose of 3-MNT in vivo resulted indeath, but exposure to the highest nonlethal dose (1 g/kg) hadno significant effect either on spermatogenesis or on the levelsof immunoactive inhibin in testicular IF. In view of these findings,it is concluded that modulation of the secretion of immunoactiveinhibin by isolated ST from adult rats has considerable potentialas an in vitro screening method for investigating potentialadverse effects of chemicals on spermatogenesis, and thus meritsmore detailed evaluation. Moreover, because of the agreementbetween in vitro and in vivo findings, measurement of the levelsof immunoactive inhibin levels in vivo in testicular IF (orblood) may also be useful in the detection of early adverseeffects of chemicals on spermatogenesis.     

EN BLOC NEPHRECTOMY IN PATIENTS UNDERGOING POST-CHEMOTHERAPY RETROPERITONEAL LYMPH NODE DISSECTION FOR NONSEMINOMATOUS TESTIS CANCER: INDICATIONS, IMPLICATIONS AND OUTCOMES

Purpose

We review the indications for nephrectomy at post-chemotherapy retroperitoneal lymph node dissection, identify patients at risk for nephrectomy and assess the impact of nephrectomy on outcome.

Materials and Methods

Using a computerized data base and chart review we retrospectively reviewed the records of 848 patients who underwent retroperitoneal lymph node dissection after chemotherapy.

Results

En bloc nephrectomy was performed at retroperitoneal lymph node dissection after chemotherapy in 162 of the 848 patients (19%). The indications for nephrectomy included contiguous involvement of perirenal structures in 73% of the cases, renal vein thrombosis in 6%, a poorly functioning or nonfunctioning renal unit in 5% and a combination of these conditions in 16%. Pathological studies of the hilum revealed cancer in 20% of the cases, teratoma in 49% and fibrosis in 31%. Patients requiring nephrectomy had significantly more advanced disease and larger disease volume at presentation and after chemotherapy. There were no significant differences in perioperative morbidity or mortality compared with patients who did not undergo nephrectomy. Only 3 patients required perioperative dialysis and none required long-term renal support.

Conclusions

These findings support en bloc nephrectomy at post-chemotherapy retroperitoneal lymph node dissection in select patients with large volume perihilar retroperitoneal disease.     

Randomized controlled trial of oral captopril, of oral isosorbide mononitrate and of intravenous magnesium sulphate started early in acute myocardial infarction: safety and haemodynamic effects: ISIS-4 (Fourth International Study of Infarct Survival) Pilot Study Investigators

The purpose of this randomized controlled study was to assessthe haemodynamic effects, safety and tolerability in acute myocardialinfarction (AMI) of one month of oral captopril, one month oforal isosorbide mononitrate and 24 h of intravenous magnesium.It was carried out in four United Kingdom and six Polish hospitalsin consecutive phases; oral captopril vs oral mononitrate vsplacebo were compared among 400 patients in a ‘three-way’study; and then oral captopril vs placebo and oral mononitratevs placebo were compared among 474 patients in ‘2x2’and ‘2 x 2 x 2’ factorial studies (with 208 patientsin the latter study also randomized between intravenous magnesiumand open control). The factorial studies differed from the three-waystudy in that one group of patients was allocated both oralcaptopril and oral mononitrate, a higher maintenance dose ofcaptopril was used (following the same initial dose), and oncedaily controiled-release mononitrate was used. In the three-waystudy, the mean of the lowest systolic blood pressures recordedduring the first 4 h after randomization were (mmHg ±standard error): 104 ± 2 captopril vs 105 ± 1mononitrate vs 112 ±2 placebo (P<0.001 for captoprilor for mononitrate vs placebo), and in the factorial studieswere 105 ± 1 captopril vs 110 ± 1 placebo (P<0.01)and 106 ± 1 mononitrate vs 108 ±1 placebo (NS).There was an excess of hypotension recorded among patients allocatedactive treatment (captopril>mononitrate>placebo) and therewas a small, but significant, excess of cardiogenic shock withcaptopril compared with control in the factorial study. However,in these studies, neither captopril nor mononitrate were associatedwith any overall increase in the incidence of hypotension consideredsevere enough to lead to treatment being stopped. No other seriouscomplications were observed, and compliance with study tabletsat hospital discharge was not significantly different betweenthe active and placebo groups. Patients allocated magnesiumin the 2 x 2 x 2 factorial study had a slightly lower mean systolicblood pressure just after the initial 15 min bolus injection(126 ± 2 magnesium vs 134 ± 3 control; P<0.05)but there were no significant differences during the subsequent24 h maintenance infusion period. Apart from some facial flushing,magnesium did not appear to be associated with any complications.These pilot studies indicate that, although the study treatmentregimens produced moderate early reductions in blood pressure,they were all generally well tolerated when started in the acutephase of MI.     

CHARACTERIZATION, LOCALIZATION AND DISTRIBUTION OF alpha1 ADRENOCEPTOR SUBTYPE IN MALE RABBIT URETHRA

Purpose

The subtype specificity, localization and distribution of urethral alpha_{1-adrenoceptors} were studied in the male rabbit urethra.

Materials and Methods

The properties of the urethral alpha_{1-adrenoceptors} were investigated using radioligand receptor binding and light microscopic autoradiography with [(¹²⁵) I]iodo-2-[b-(4-hydroxyphenyl)-ethylaminomethyl]tetralone (HEAT), and immunohistochemistry with monoclonal anti-alpha smooth muscle actin and anti-alpha sarcomeric actin antibodies.

Results

Saturation experiments with [(¹²⁵) I]HEAT demonstrated the presence of significant amounts of a single high affinity binding site for alpha₁ adrenoceptors in the male rabbit urethra. The pharmacological profile of the alpha₁ adrenoceptors in rabbit urethra, determined by inhibition experiments with subtype selective alpha₁ adrenoceptor antagonists, was characterized by the following rank order of potency of inhibition constants (K_i values): prazosin <or= to WB 4101 < spiperone < 5-methylurapidil < BMY 7378. The pKi values for the rabbit urethra were correlated with the pKi values for rat spleen, submaxillary glands, and vas deferens and for those reported for cloned alpha_1d receptors with correlation coefficients of 0.68, 0.929, 0.909, and 0.523, respectively.

Conclusions

The pharmacological characterization demonstrates the predominance of alpha_1A or alpha_1A + alpha_1B adrenoceptor subtype(s) in male rabbit urethral smooth muscle. Furthermore, the autoradiographic and immunohistochemical studies show a heterogeneous distribution of alpha₁ adrenoceptors along the longitudinal axis of the urethra, within the smooth muscle fibers, with the receptors being localized more densely in the proximal than in the distal urethra.