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Biomedical subjects

A Gerard

Publications and source records attributed to A Gerard.

At least 55 records · Page 3Linked to original sources
PubMed1990

Maturation of the hypothalamic control of pulsatile gonadotropin-releasing hormone secretion at onset of puberty. I. Increased activation of N-methyl-D-aspartate receptors.

In the male rat the timing of puberty can be estimated by the rapid increase in testicular weight occurring between 25-50 days of age. We found that elongated spermatids, the most mature germ cells identified using flow cytometry, were first seen at 25 days (4% of the testicular cells), while an adult proportion (63%) was attained by 45 days of age. We have shown previously that hypothalamic explants could release GnRH in a pulsatile fashion at a frequency increasing around the age of 25 days, thus consistent with the time of onset of puberty. Since pulsatile GnRH secretion could be suppressed by MK-801, a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor activation, we postulated that an increased activation of those receptors could be involved in the neuroendocrine mechanism that activates pulsatile GnRH secretion at the onset of puberty. Such a concept was supported by the NMDA-induced release of GnRH, which was observed using 1 mM NMDA at 25 days, while a dose of 20-50 mM was required at 15 or 50 days of age. MK-801 could provide an index of NMDA receptor activation, since the antagonistic effect of MK-801 is use dependent. This particular property was confirmed by the inability of MK-801 (5 pM) to block the depolarization (veratridine)-induced release of GnRH in the presence of 0.001 mM NMDA, while partial or complete suppression was obtained in the presence of 0.1 and 10 mM NMDA, respectively. Using explants obtained at 5, 10, 15, 20, 25, 30, 35, and 50 days of age, the lowest concentrations of MK-801 that blocked the veratridine-induced release of GnRH were, respectively, 10(7), 10(7), 10(7), 10(3), 10, 10(2), 10(4), and 10(8) pM. In contrast, there was no age-related difference in sensitivity to the inhibitory effect of Mg2+, a noncompetitive NMDA receptor antagonist which is not use dependent. The pulsatile secretion of GnRH occurred at a similar frequency at 25 and 50 days of age (4.7 and 5.4 pulses/3.5 h, respectively) but it was suppressed by a lower MK-801 concentration at 25 days (10(4) pM) than at 50 days (10(8) pM). These data indicate that the NMDA receptors involved in the control of pulsatile GnRH secretion are markedly and transiently activated around the time of onset of puberty in the male rat.

Aging↗
PubMed1990

Internalization of human sex steroid-binding protein in the monkey epididymis.

Human sex steroid-binding protein (hSBP) has been purified from late-pregnancy serum and labelled either by iodination (125I) or by photoaffinity with [3H]delta 6-testosterone. Using a micromanipulator, each labelled protein was separately injected into the lumen of epididymal tubules isolated from the head epididymis of the cynomologus monkey (Macaca fascicularis). Tubules were sampled from 3 to 90 min after the injection and processed for electron microscope autoradiography. Localization of the label occurred over the epididymal epithelium whichever tracer was used. The labelling was not randomly distributed over the different cell types constituting the epithelium, since only the 'principal cells' exhibited a silver grain count significantly greater than the background count. In these cells, labelled protein was found over endocytic organelles (coated structures, endosomes, multivesicular bodies and the trans Golgi network) and nuclei (including the nuclear envelope). Quantitative analysis demonstrated the same pattern of cellular and subcellular distribution for each tracer. Pretreatment with excess unlabelled protein significantly reduced the uptake of radioactivity by the principal cells, demonstrating the specificity of this phenomenon. This is the first study to show direct histological evidence for the internalization of hSBP in the primate epididymis, consistent with earlier immunohistochemical or biochemical localization of this protein. It is concluded that head epididymal cells are able to take up labelled hSBP across their apical membrane. The mechanism of internalization seems to involve endocytosis by the principal cells and leads to labelling of the nuclear compartment. This is strikingly similar to the pattern of uptake of rat androgen-binding protein (rABP) by rat epididymal cells previously demonstrated by our group. To what extent the chemical and structural homology between hSBP and rABP can be held responsible for the common cytophysiological behaviour of these sex steroid-binding proteins remains to be determined.

Affinity Labels↗
PubMed1990

[The combination of penicillin G and ofloxacin: a response to the empirical treatment of community acquired pneumonia].

The aim of this study was to assess the clinical efficacy of a combination of penicillin G and ofloxacin in the treatment of community acquired pneumonia. Thirty eight patients (23 males, 15 females, mean age 62.8 years +/- 19.6) were included. They presented a CAP with the following criteria: fever, abnormal chest X-ray pattern. They received the combination of IV penicillin 12 x 10(6) U daily and IV ofloxacin 200 mg bid. After 48 hours of apyrexia, this treatment was followed by oral ofloxacin alone 200 mg bid. In six cases, the etiologic agent was identified: 2 S. pneumoniae, 1 Chlamydiae psittaci, 2 Staphylococcus aureus, 1 Mycoplasma. In 32 cases, the bacteriological investigation was negative. Five patients were excluded: 2 deaths due to heart failure, 3 alterations of treatment. Twenty eight patients recovered: apyrexia was obtained in 3.5 days. Penicillin G was prescribed for 7.5 days +/- 2.65, followed by ofloxacin alone for 11.43 +/- 3 days. Five patients were considered as clinical failures: 2 deaths due to extensive pneumonia, 3 recoveries after alteration of treatment. Side effects were rare: 1 confusion, 2 skin rashes. As a conclusion: penicillin G and ofloxacin in combination for the initial therapy of CAP, rapidly relayed by ofloxacin alone, permitted 84.3% of recovery in our patients.

Acute Disease↗
PubMed1989

Pulsatile release of gonadotropin-releasing hormone from hypothalamic explants is restrained by blockade of N-methyl-D,L-aspartate receptors.

We have shown previously that N-methyl-D,L-aspartate (NMDA) and kainate, two neuroexcitatory amino acids acting through distinct receptors, may induce the release of GnRH from hypothalamic explants. However, that effect could have no physiological significance, since very high concentrations (50 mM) of NMDA and kainate were required. Here, using agents blocking the activation of receptors to neuroexcitatory amino acids, we evaluated their possible physiological involvement in the pulsatile release of GnRH from the hypothalamus of 50-day-old male rats in vitro. In control conditions (10 nM glycine and 1 mM mg2+), the release of GnRH in 7.5-min fractions collected for 2-4 h showed an obvious pulsatile pattern. The mean (+/- 1 SD) interval between pulses, identified by PULSAR program, was 34.3 +/- 11.4 min. The stimulation of GnRH release by NMDA (50 mM) added to the medium for 7.5 min could be blocked reversibly in the presence of MK-801 (100 microM) using medium without glycine or enriched with Mg2+ (2 mM). The endogenous pulses of GnRH secretion were abolished in the presence of MK-801 or using increased Mg2+ concentrations as well as in the absence of glycine. In contrast, pulsatile release of GnRH was not affected in the presence of 6,7-dinitroquinoxaline-2,3-dione (0.1 mM), a selective inhibitor of kainate and quisqualate receptors which suppressed the increase in GnRH release induced by kainate (50 mM) without affecting the response to NMDA. These data indicate that the physiological mechanism of pulsatile GnRH secretion in the hypothalamus may involve endogenous neuroexcitatory factors acting through NMDA-sensitive receptors.

Animals↗
PubMed1989

Adjuvant radiotherapy and chemotherapy in resectable gastric cancer. A randomized trial of the gastro-intestinal tract cancer cooperative group of the EORTC.

One hundred and fifteen patients with curative and palliative surgery for gastric cancer were randomized to receive radiotherapy alone (1) or in combination with short-term (ST) 5-FU (2), long-term (LT) 5-FU (3), ST and LT 5-FU (4). The ST 5-FU was given at a daily dose of 575 mg/m2, every 4-6 h during the first 4 days of treatment before starting irradiation. The LT 5-FU was given at a dosage of 750 mg/m2 every 2 weeks for 18 months or until progression. The median survival times for treatment 1 to 4 was respectively 12, 10, 15 and 18 months. There was a statistically significant overall difference between the four treatments (P = 0.041). However, when the comparisons were adjusted for the most significant prognostic factors, the difference in survival disappeared. Moreover, no difference was found between treatments in terms of time progression. Nevertheless, among 22 patients with residual tumour, the three who were still alive without disease progression (with survivals of 19+, 49+ and 90+ months at the time of this analysis) had been treated with radiotherapy combined with ST and LT 5-FU.

Adenocarcinoma↗
PubMed1988

Electron microscope radioautographic evidence of in vivo androgen-binding protein internalization in the rat epididymis principal cells.

The androgen-binding protein (ABP) has been purified from rat testes with a yield of 14% using four steps of HPLC and was subsequently iodinated to a specific activity of 0.1 mCi/mg protein. Using a micromanipulator, [125I] iodo-ABP-dihydrotestosterone was injected intraluminally into the proximal caput of the rat epididymis. Epididymides were sampled from 3 to 120 min after the injection of the tracer and processed for transmission electron microscopy autoradiography. Our results showed the accumulation of detectable radioactive sources in the apical cytoplasm of only one of the epithelial cell type lining the ductus, the principal cells. In the interval from 3 to 120 min, the iodinated ABP was mainly present in the supranuclear region and was especially concentrated over coated structures, endosomes, multivesicular bodies, and over the Golgi apparatus. The same pattern was obtained using [3H]dihydrotestosterone-ABP complex instead of iodinated ABP. In addition, there was a negative correlation between the log time and the distribution of the silver grains in the luminal border and in the compartment of the apical vesicles. On the contrary, there was a positive correlation between the log time and the distribution of the silver grains in the Golgi apparatus. These results provide, for the first time, direct histological evidence of the in vivo ABP internalization by the principal cells. Since horseradish peroxidase, a fluid-phase endocytosis marker, when injected under the same conditions was internalized in both apical and principal cells, since labeled radioactive ABP appeared to be bound to the membrane of the endocytic apparatus rather than to its content, and since this binding and uptake could be prevented in the presence of an excess of unlabeled ABP, it is concluded that the internalization of ABP could not be a nonspecific fluid-phase endocytosis but should be dependent on its interaction with the apical plasma membrane of the principal cell. It still remains to be determined if these mechanisms involve the binding of ABP to a specific membrane receptor.

Androgen-Binding Protein↗
PubMed1988

Hepatic artery ligation or embolization and locoregional chemotherapy of liver metastases from colorectal cancer.

If liver metastases are diffuse and spread out in the two lobes of the liver, the question remains as to which treatment should be given. Experimental studies showed that when a tumor grows, its vascular pattern becomes mainly arterial. However, if the tumor is still increasing, its center becomes progressively necrotic. After hepatic artery ligation the blood flow of the liver metastases decreases by 90% in the tumor but depriving the arterial circulation of the tumor is not sufficient to achieve a complete cure since the portal blood supply always saves a rim of neoplastic cells around the necrotic area. On the other hand, local infusion of chemotherapy for liver metastases by the arterial route showed a response rate varying between 34 and 70% and the median survival varying between 8 and 17 months. When FUdR chemotherapy was administered using a totally implantable drug infusion pump no improvement in the survival was observed and moreover a high level of toxicity was described including hepatitis and biliary sclerosis. A combined therapy seems a rational approach to treat tumor cells in surviving to the arterial ligation by perfusing the liver with cytotoxic drugs via the portal vein. Taylor's study was very promising but a randomized phase III clinical trial led by the gastrointestinal cancer group of the EORTC with the aim to evaluate the effectiveness of hepatic artery ligation and portal infusion of 5-FU did not show any difference in the survival of the treated patients when compared with patients treated by hepatic artery ligation alone. 77 patients were registered. Data are now available for 55 patients, respectively 30 and 25 patients in the treated group and in the control group. In both groups the median time to progression was 6 months and the median survival time was 12 months. 20% of the patients treated by hepatic artery ligation and portal chemotherapy had a response, one of them with a complete response, 5 with partial response and 14 patients without significant change in the size of their metastases. On the contrary, in the group treated by hepatic artery ligation alone, only one patient had a partial response with 13 patients having no change in the size of their metastases.(ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1988

Pilot study on the regional treatment of colorectal liver metastases by intermittent arterial ischaemia with degradable starch microspheres and arterial and portal infusion with mitomycin C plus 5-fluorouracil--a clinical trial led by the Gastrointestinal Tumour Cooperative Group E.O.R.T.C.

After interruption of the hepatic artery, the decrease of the arterial flow in the liver is temporary and the tumor periphery remains vascularized by the portal system. A rational approach of therapy for liver metastases seems to be a combined therapy including intermittent ischaemia by distal embolization through the hepatic artery with degradable starch microspheres and locoregional chemotherapy. A pilot study on the regional treatment of colorectal liver metastases by intermittent arterial ischaemia and intra-arterial and portal infusion of mitomycin C and 5-FU has recently been activated by the gastrointestinal tumor group of the European Organization on Research on Treatment of Cancer (EORTC) with the aim to evaluate the feasibility and the therapeutic value of such a clinical trial. Although it is too early to evaluate the results of this therapy, the first data will be commented.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Adjuvant therapy for colorectal cancer. The EORTC experience and a review of the literature.

In spite of the improvements in surgical techniques and intensive care therapy, no appreciable improvement in the prognosis for patients with colorectal cancer has been made in recent years. Several types of adjuvant treatment, including radiotherapy, chemotherapy, and immunotherapy, have therefore been proposed and used in clinical trials, mainly in the United States and western Europe. The results obtained by the Gastrointestinal Group of the European Organization for Research and Treatment of Cancer (EORTC), using preoperative radiation therapy with 3450 rads, are reported here; this therapy results in a reduction in the number of local recurrences and also appears to prolong the five-year survival period, although a longer follow-up is required to confirm this. According to the Gastrointestinal Tumor Study Group (GITSG), postoperative radiation therapy with chemotherapy seems to prolong the tumor-free interval in stages B2 and C when compared to surgery alone. Nonspecific immunotherapy does not appear to improve surgical results either in terms of local recurrences or survival. Some clinical trials suggest that systemic polychemotherapy benefit subgroups of patients with colorectal cancer. Toxicity is still very high, however; 5-FU is the more active and safe single agent but, due to the low response rate, it appears essential to identify new, more active drugs. Particular attention has been focused recently on prophylactic infusion chemotherapy of the liver, and clinical trials are now being made by several groups, including the EORTC. Preliminary results seem to show a reduced incidence of liver metastases in patients infused with 5-FU after radical surgery. Adjuvant therapy in colorectal cancer patients undergoing radical surgery has so far given encouraging results. Future results are awaited with optimism, but they must be achieved through prospective clinical trials conducted by well-organized cooperative groups.

Antineoplastic Agents↗