SEROPOSITIVITY FOR ASCARIOSIS AND TOXOCARIOSIS AND CYTOKINE EXPRESSION AMONG THE INDIGENOUS PEOPLE IN THE VENEZUELAN DELTA REGION

The present study aimed at measuring seropositivities for infection by Ascaris suum and Toxocara canis using the excretory/secretory (E/S) antigens from Ascaris suum (AES) and Toxocara canis (TES) within an indigenous population. In addition, quantification of cytokine expressions in peripheral blood cells was determined. A total of 50 Warao indigenous were included; of which 43 were adults and seven children. In adults, 44.1% were seropositive for both parasites; whereas children had only seropositivity to one or the other helminth. For ascariosis, the percentage of AES seropositivity in adults and children was high; 23.3% and 57.1%, respectively. While that for toxocariosis, the percentage of TES seropositivity in adults and children was low; 9.3% and 14.3%, respectively. The percentage of seronegativity was comparable for AES and TES antigens in adults (27.9%) and children (28.6%). When positive sera were analyzed by Western blotting technique using AES antigens; three bands of 97.2, 193.6 and 200.2 kDas were mostly recognized. When the TES antigens were used, nine major bands were mostly identified; 47.4, 52.2, 84.9, 98.2, 119.1, 131.3, 175.6, 184.4 and 193.6 kDas. Stool examinations showed that Blastocystis hominis, Hymenolepis nana and Entamoeba coli were the most commonly observed intestinal parasites. Quantification of cytokines IFN-γ, IL-2, IL-6, TGF-β, TNF-α, IL-10 and IL-4 expressions showed that there was only a significant increased expression of IL-4 in indigenous with TES seropositivity (p < 0.002). Ascaris and Toxocara seropositivity was prevalent among Warao indigenous.     

Cerebrospinal fluid calcium, parathyroid hormone, and monoamine and purine metabolites and the blood-brain barrier function in primary hyperparathyroidism.

Psychiatric disturbances are common in primary hyperparathyroidism (HPT), but their pathogenesis is essentially unknown. This study deals with cerebrospinal fluid (CSF) calcium homeostasis and its connection with parathyroid hormone (PTH), blood-brain barrier (BBB) function, and central monoamine and purine metabolites in patients with primary HPT. In 22 patients with primary HPT (serum calcium 2.85 +/- 0.21 mmol/l), the CSF concentrations of total and ionized calcium were higher (1.21 +/- 0.08 mmol/l, p less than 0.01, and 1.09 +/- 0.05 mmol/l, p less than 0.001, respectively) than in 11 normocalcemic reference subjects. The values correlated with serum calcium concentration (p less than 0.001) and CSF/serum albumin ratio, a measure of BBB permeability. The latter ratio was elevated in one-third of the patients with HPT, indicating BBB damage. CSF immunoreactive intact PTH was higher in the HPT patients than in the reference group (p less than 0.05), and serum and CSF PTH were positively correlated (p less than 0.05). The CSF levels of the monoamine metabolites 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) were lower, and the level of urate in CSF was higher, in the HPT patients than in the reference subjects, while there were no consistent differences in CSF hypoxanthine or xanthine. CSF 5HIAA correlated inversely with CSF ionized calcium (r = -0.42, p = 0.02). After parathyroid surgery, CSF calcium and urate decreased significantly and CSF monoamine metabolites increased slightly. The decrease in CSF ionized calcium correlated with the alleviation of psychiatric symptoms. The results indicate the importance of increased CSF calcium concentrations in patients with primary HPT and suggest a relation between central calcium regulation and central turnover of monoamines.     

Electromechanical properties of perfusion/metabolism mismatch: comparison of nonfluoroscopic electroanatomic mapping with 18F-FDG PET.

The aim of this study was to compare nonfluoroscopic electroanatomic mapping (NOGA), SPECT perfusion imaging, and PET metabolic imaging for assessment of myocardial viability. In particular, we sought to elucidate differences of electromechanical properties between the perfusion/metabolism mismatch as an indicator of a potentially reversible ischemic injury and the perfusion/metabolism match indicating irreversibly damaged myocardial tissue. METHODS: Twenty-one patients with coronary artery disease underwent NOGA mapping of endocardial unipolar voltage, cardiac 18F-FDG PET of glucose utilization, and resting 201Tl SPECT of myocardial perfusion. RESULTS: Electrical activity was 10.8 +/- 4.6 mV (mean +/- SD) in normal myocardium and was unchanged in hypoperfused segments with maintained glucose metabolism (perfusion/metabolism mismatch), 9.3 +/- 3.4 mV (P = not significant). In contrast, hypoperfused segments with a perfusion/metabolism match and nonviable segments showed significantly lower voltage (6.9 +/- 3.1 mV, P < 0.0001 and 4.1 +/- 1.1 mV, P < 0.0001 vs. normal). In hypoperfused segments, metabolic activity was more closely related to endocardial voltage than was myocardial perfusion (201Tl vs. voltage: r = 0.38, SEE = 3.2, P < 0.001; 18F-FDG PET vs. voltage: r = 0.6, SEE = 2.8, P < 0.0001). CONCLUSION: In hypoperfused myocardium, electrical activity by NOGA mapping is more closely related to PET metabolic activity than to SPECT myocardial perfusion. As NOGA mapping does not differentiate hypoperfused myocardium with enhanced glucose utilization from normal myocardium, results from NOGA mapping need to be correlated with results from perfusion imaging to identify hypoperfused, yet viable, myocardium and to stratify patients for revascularization procedures.     

Improved differential diagnosis of hypercalcemia by hypocalcemic stimulation of parathyroid hormone secretion

In vitro experiments have indicated that in primary hyperparathyroidism (HPT) the hyperfunctioning glands have a set point error, i.e., they are not autonomous but regulate serum calcium around a hypercalcémie value. In contrast, parathyroid function is suppressed in patients with hypercalcemia of causes other than HPT (e.g., malignancy or sarcoidosis). The basal measurements of serum parathyroid hormone (PTH) levels, however, cannot, alone, separate with precision HPT from other causes of hypercalcemia.Lowering of calcium, in order to stimulate secretion of PTH, was, therefore, achieved by either infusion of Na₂ EDTA (24 mg/kg per hr) for 1 hour, or intramuscular injection of 100 IU salmon calcitonin. All 35 patients with primary HPT displayed a significant increase of serum PTH concentrations, evaluated by a midregion/intact hormone assay, during the EDTA infusion, which lowered plasma ionized calcium by an average of 0.16 mmol/l. The injection with calcitonin reduced the calcium concentrations by 0.10 mmol/l after 8 hours and caused a rise in PTH in 80% of HPT patients. With both tests, the secretory response by PTH to the reduction of plasma calcium was generally evident while the patients were still hypercalcemic. In 32 patients with other causes for hypercalcemia, primarily malignancy and sarcoidosis, similar reductions of plasma ionized calcium were obtained. In contrast to the HPT patients, none of them raised their serum PTH values during the test. Thus, stimulation of PTH secretion by a moderate reduction of serum calcium considerably improves the differential diagnosis of hypercalcemia since a significant secretory response appears to be exclusive for HPT.

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Resumen Experimentos in vitro han señalado que en el hiperparatiroidismo primario (HPT) las glándulas hiperfuncionantes tienen un error en su set point, o sea que no son autónomas sino que regulan el calcio sérico alrededor de un valor hipercalcémico. Por el contrario, la función paratiroidea es suprimida en pacientes con hipercalcemia de causa diferente de HPT (e.g., neoplasias malignas o sarcoidosis). Las mediciones basales de los nivelés séricos de hormona paratiroidea (PTH) de por sí no son capaces de diferenciar con precision entre el HPT y la hipercalcemia de otras causas.La disminución del nivel de calcio sérico, con el objeto de estimular secreciones de PTH, fue lograda con la infusión de Na₂ EDTA (24 mg/Kg por hora) por 1 hora o la inyección i.m. de 100 UI de calcitonina de salmón.Todos los 35 pacientes con HPT primario exhibieron un aumento significativo de las concentraciones séricas de PTH, determinadas mediante la medición de la fraction media/intacta de PTH en el curso de la infusion de EDTA, la cual redujo el nivel plasmático de calcio ionizado en un promedio de 0.16 mmol/l. La inyección de calcitonina redujo las concentraciones de sérico en 0.10 mmol/l a las 8 horas y resultó en un aumento de la PTH en 80% de los pacientes con HPT. Con ambas pruebas la respuesta secretoria de PTH a la reducción del calcio plasmático generalmente apareció evidente aún mientras los pacientes se hallaban hipercalcémicos.En 32 pacientes con hipercalcemia de causa diferente, se lograron reducciones similares de la concentration plasmática del calcio ionizado. Por el contrario de lo observado en los patientes con HPT, ninguno demostró elevatión de sus niveles séricos de PTH en el curso de la prueba. Por consiguiente, el estímulo de la secretión de PTH mediante la reductión moderada de calcio sérico incrementa considerablemente la (ie501-01)acidad de establecer el diagnóstico diferencial de la hipercalcemia, puesto que una significativa respuesta secretoria parece ser caracteristíca exclusiva del HPT.

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Résumé L'expérimentation in vitro a démontré que dans l'hyperparathyroïdisme (HPT), les glandes hyperactives ont un point mort erroné, c'est-à-dire qu'elles ne sont pas autonomes mais règlent la calcémie autour d'une valeur de référence déjà hypercalcémique. En revanche, la fonction parathyroîde est déprimée chez le patient dont l'hypercalcémie est due à une cause autre que l'HPT (cancer ou sarcoïdose par exemple). La mesure des niveaux de base de la parathormone (PTH), cependant, ne permet pas de distinguer l'hypercalcémie de l'HPT des autres causes d'hypercalcémie avec précision.Dans le but de stimuler la sécrétion de PTH, la calcémie était abaissée soit en perfusant les patients avec une solution de Na₂ EDTA (24 mg/Kg) pendant une heure, soit par une injection intramusculaire de 100 U de calcitonine de saumon.Trente-cinq patients ayant un HPT primitif présentaient une augmentation significative des concentrations en PTH sérique, évaluée par l'étude immunologique de la portion moyenne intacte, pendant la perfusion d'EDTA. La portion de calcium plasmatique ionisée a été abaissée en moyenne de 0.16 mmol/l. L'injection de calcitonine a réduit la concentration en calcium par 0.10 mmol/l après huit heures et a provoqué une augmentation en PTH chez 80% des patients à HPT. Quel que soit le test, la réponse de PTH à la réduction de calcium plasmatique était généralement évidente alors que le patient était toujours hypercalcémique.Chez 32 autres patients ayant pour cause d'hypercalcémie cancer ou sarcoïdose, des réductions similaires en calcium plasmatique ionisé ont été obtenues. Aucun malade, contrairement aux patients HPT, n'a vu son niveau de PTH monter pendant le test. Ainsi, la stimulation de sécrétion de PTH par une réduction modérée de calcium sérique améliore considérablement le diagnostic différentiel des hypercalcémies puisque la réponse sécrétoire significative paraît être le fait exclusif des HPT.

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Presented at the International Association of Endocrine Surgeons in Sydney, Australia, September, 1987.

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Supported by the Swedish Medical Research Council.     

Distribution and pharmacological characterization of somatostatin receptor binding sites in the sheep brain

Somatostatin binding sites have been localized and quantified in the sheep brain using ¹²⁵I-Tyr₀-DTrp₈-somatostatin, by quantitative high resolution light microscopic autoradiography. Sections were analyzed by densitometry on radioautographic film, and subsequently on slides coated with photoemulsion. Specific somatostatin binding sites were concentrated in the medial habenula, superior colliculus, dorsal motor nucleus of the vagus nerve, inferior olive, spinal trigeminal nucleus, and cerebellum. In competition experiments, octreotide, a sst2/sst3/sst5 selective agonist only partially displaced ¹²⁵I-Tyr₀-DTrp₈-somatostatin in the three cerebellar layers while it was fully active as compared to somatostatin 14 and 28 in the deeper layers of the parietal cortex. Moderate to low somatostatin receptor densities were present in the mesencephalic periaqueductal gray, dorsal raphe, thalamic paraventricular nucleus, interpeduncular nucleus, pineal gland, dorsal tegmental, dorsolateral tegmental and parabrachial nuclei, nucleus of the solitary tract. The distribution of somatostatin binding sites generally correlates with the data obtained on slides dipped in photoemulsion which provided better resolution and more precise localization. In most of the labeled areas, ¹²⁵I-Tyr₀-DTrp₈-somatostatin receptor binding was distributed between both neuropil and perikarya. Perikarya bearing ¹²⁵I-Tyr₀-DTrp₈-somatostatin receptors were observed in areas which did not display detectable binding sites on film such as the preoptic-anterior hypothalamic complex and arcuate nucleus and in the locus coeruleus. In conclusion, the distribution of ¹²⁵I-Tyr₀-DTrp₈-somatostatin binding sites in sheep brain is very reminiscent of other mammals being closer to the human than to rodents.     

Antibody reactivity in penicillin-sensitive patients determinated with different penicillin derivatives.

35 individuals showing reactions to penicillin of anaphylactic shock, angioedema or urticaria were investigated. Their skin sensitivity was analysed using 16 different penicillin derivatives. In addition, the content of circulating reagins against the penicilloyl structure in the patient's sera were analysed using RAST. 17 of the patients had negative skin reactions and RAST results to all substances tested. The other 18 were skin test-positive to at least one derivative but showed markedly heterogeneous patterns of skin reactivity. 14 had positive reactions against penicilloyl structures accompanied by anti-penicilloyl reagins. Four patients showed doubtful reactions only to penicillin or penicilloate and/or penilloate. These patients also had very low levels of reagins against penicilloyl in their sera. Positive skin test results using monovalent penicillin derivatives such as penicillin, penicilloate, penilloate, penicilloyl amide, penicilloyl-formyl-lysine, penicillamine, which cannot form a multivalent antigen with penicillyol specificity, indicated formation of other derivatives of importance in penicillin allergy, e.g., penicillamine protein conjugates. Three patients showed skin reactions to ampicillin polymer and two to benzyl-penicillin polymer. The skin tests performed with the penicillin derivatives used do not seem to give more information on the sensitivity of the patients than does the RAST using penicilloyl structures.     

A novel frame shift mutation in the HMG box of the SRY gene in a patient with complete 46,XY pure gonadal dysgenesis.

Pure gonadal dysgenesis or Swyer syndrome is a sex-reversal disorder resulting from embryonic testicular regression sequences especially during the first few weeks of fetal life and is induced by mutations in the SRY gene. In the present report, we describe a nonmosaic XY sex-reversed female with pure gonadal dysgenesis. Molecular analysis using sequential PCR to detect Y chromosomal microdeletions showed the presence of SRY, ZFY and AZFa, b and c regions. Automated sequencing of the SRY region revealed a new mutation (deletion of A (adenine) in codon 82 at position +244), leading to a frame shift mutation within the helix I of the HMG-box domain. This mutation generates a truncated protein and is very likely to produce an impairment of SRY DNA binding activity. The present findings further support the functional importance of the putative DNA binding activity of the SRY HMG-box domain.     

P53 overexpression as an indicator of overall survival and response to treatment in osteosarcomas

The p53 gene located at chromosome 17pl3 is found to be altered (allelic loss or other mutation) in multiple human cancers, including osteosarcomas. The mutated gene produces a protein with a prolonged half-life thus rendering it detectable by conventional immunohistochemistry. We examined the correlation between p53 expression and clinical prognosis as well as response to therapy. Twentyone patients with previously untreated and histologically verified highly malignant osteosarcoma were used for this study. Biopsy material taken both prior to the start of COSS 91 protocol and at the time of surgery (ten weeks later) was examined for alterations in p53 protein expression and drug resistance. Two patients who had strong (+++) p53 protein expression and three others who became positive during the chemotherapy had significantly worse prognosis (all of them died within one year) than those who showed no p53 expression both at biopsy and after chemotherapy (all 11 patients are alive, average follow-up time: 3.5 years). All patients who showed any kind of positive p53 protein expression on initial biopsy were non-respon-ders to chemotherapy. In contrast, 69% (9 out of 13) of those who exhibited no p53 expression on initial biopsy were responders or intermediate responders to chemotherapy. We concluded that p53 expression may be a useful prognostic factor in osteosarcomas. The direct correlation between p53 positive expression and resistance to therapy can help in identifying patients who are in need of a more vigorous or different chemotherapeutical protocol.