Prevention of Bone Loss by Clodronate in Early Postmenopausal Women with Vertebral Osteopenia: A Dose-Finding Study

This double-masked, placebo-controlled study was undertaken to determine the efficacy and safety of oral clodronate in the prevention of bone loss in early postmenopausal women with vertebral osteopenia. Altogether 610 women with a mean age of 53 years were recruited for the study. They were 1–5 years postmenopausal and their lumbar spine bone mineral density (BMD) was at least 1 standard deviation below the mean of premenopausal women (T-score ≤−1). The subjects were randomized into five study groups to receive either placebo, clodronate 65 mg, 400 mg or 800 mg daily, or intermittent clodronate in 3 month cycles with 400 mg daily for 15 days followed with no treatment for 75 days for 3 years. One hundred and eighty-seven of 509 women who completed the primary study continued in the extension study of 2 years in which previous placebo users were switched to clodronate 800 mg daily, while previous users of 400 mg or 800 mg of clodronate used either placebo or 800 mg of clodronate daily. In the primary study clodronate was administered in the evening, and in the extension 1 h before breakfast on an empty stomach. In the primary study mean changes in lumbar spine BMD were −3.4% in the placebo group and +0.4% in 800 mg clodronate group [difference between groups at 3 years 3.8% (95% CI 2.7% to 4.9%, p<0.0001)], and in the trochanter area BMD −1.1% in the placebo group, and + 0.4% in the 800 mg clodronate group [difference between groups at 3 years 1.5% (95% CI 0.05% to 2.9%)]. During the extension study mean changes in lumbar spine BMD were +1.5% in the clodronate group and −0.2 % in the placebo group [difference between groups 1.7% (CI 0.4% to 3.0%, p = 0.010)] and in trochanter BMD were +2.5% in the clodronate group and no change in the placebo group [difference between groups 2.1% (CI 0.3% to 3.9%, p = 0.007)]. No statistically significant differences between the placebo and 800 mg clodronate groups were found in the femoral neck BMD. In the primary study the urinary excretion of type I collagen aminoterminal telopeptide (NTX) decreased by 44% (p<0.0001 compared with placebo) and that of deoxypyridinoline by 18% (p<0.0001) in the clodronate 800 mg group. In the extension study urinary NTX decreased by 51% (p<0.0001) in those who were switched to 800 mg of clodronate and increased by 67% (p<0.0001) in those who stopped using that dose. There was no difference in the frequency of gastrointestinal complaints between clodronate- and placebo-treated patients in the primary study, but they were more common among women who received clodronate in the extension phase. Clodronate in daily doses of 400–800 mg caused a slight elevation of aminotransferase levels, usually within the reference range. In bone biopsies no defect in mineralization was found. In conclusion, clodronate in a daily dose of 800 mg prevents early postmenopausal bone loss at the sites of the skeleton in which cancellous bone predominates. It effectively reduces bone resorption and bone turnover rate. Antifracture efficacy of clodronate remains to be established by prospective, placebo-controlled trials. Received: 4 March 2002 / Accepted: 9 July 2002     

A possible negative feedback control of excitatory transmission via prostaglandins in canine small intestine.

1 Contractile responses of canine intestinal circular and longitudinal muscles to field stimulation (20 Hz, 1 ms, 30 V/cm, for 5 s) were inhibited by treatment with atropine (0.1 microgram/ml), indicating that the response to field stimulation was mediated by acetylcholine (ACh). 2 Prostaglandins E1 (PGE1), PGE2 and PGF2 alpha inhibited the response of circular but not longitudinal muscle to field stimulation, although PGF2 alpha was less effective than PGE1 and E2. 3 PGE1 was much less active in inhibiting the response of circular muscle to ACh than to field stimulation, suggesting that prostaglandins might act predominantly at prejunctional sites to prevent the release of ACh. 4 Indomethacin (1 microgram/ml) potentiated the response of circular muscle but not longitudinal muscle to field stimulation. 5 Release of PGE-like compounds from circular muscle only, was increased by field stimulation at 20 Hz (total of 1000 pulses) and ACh (10 micrograms/ml), but not by a lower frequency (2 Hz, total of 2400 pulses) which produced only a slight contraction. This finding may indicate that prostaglandins were released predominantly from the muscle. 6 Prostaglandins may exert a negative feedback mechanism of excitatory transmission in circular muscle but not in longitudinal muscle of canine small intestine.     

Current trend in the treatment of Hodgkin's disease

The analysis of three subsequent randomized trials carried out within the frame of the European Organization for Research on Cancer (E.O.R.T.C.) enables to define a strategy for the staging and the treatment of early stages of Hodgkin's disease. Several prognostic factors were identified by multivariate analyses: 1) erythrocyte sedimentation rate, which has a greater impact on relapse-free survival than systemic symptoms but which can be combined with them; the combination of the two is a more powerful prognostic indicator than ESR alone; 2) the number of involved lymphatic areas: patients with one or two lymphatic areas involved (CS I and II2) have a better outcome than stage II patients with 3 or more areas involved (CS II3). Patients with favorable prognostic indicators are submitted to staging laparotomy because for them spleen involvement has a pejorative impact. For patients with unfavorable indicators, the spleen involvement has little prognostic significance and therefore those patients who need, anyway, an aggressive treatment do not undergo staging laparotomy. Patients with favorable prognostic indicators and negative staging laparotomy can be treated by radiotherapy alone, patients with positive laparotomy or patients with unfavorable prognostic indicators are treated by combination of multiple chemotherapy and radiotherapy.     

Catabolic effects and the influence on hormonal variables under treatment with gynodian-depot® or dehydroepiandrosterone (DHEA) oenanthate

53 patients from a mainly climacteric population were treated monthly with 200 mg dehydro-epiandrosterone (DHEA) oenanthate or with 1 ampoule Gynodian-Depot®. Pronounced adiposity was present in 15 of these cases. Hormonal variables were determined before the treatment and during the depot effect of the preparations in order to study the principle which supports the oestrogenic influence and any weight-reducing influence under administration of DHEA. The elimination of lowpolar oestrogens increased considerably in 4 out of 13 post-menopausal cases treated with DHEA. This effect is probably indirect and presupposes intact ovaries. The incorporation of exogenous DHEA into the excretion of 17-ketosteroids and of 17-ketogenic steroids, such as those of androsterone + aethiocholanolone, depends on the size of the initial pool inasmuch as it is higher in small initial pools than in saturated pools - the size of the pool being age-dependent.

An average weight loss of >1 kg/mth was observed under DHEA treatment in 7 out 15 adipose cases. In comparison to the other 8 adipose cases, these 7 were younger and therefore also displayed higher values for 17-ketosteroids and their individual fractions. These circumstances appeared to explain why the administration of DHEA resulted in higher levels of free plasma DHEA which, in contrast to the cases without loss of weight, also resulted in an increase of renal DHEA-sulphate clearance. It was concluded from the findings that this is the explanation for the catabolic effect of exogenous DHEA.

Post-menopausally increased FSH and LH fractions were markedly suppressed in about half of the determinations after Gynodian-Depot administration, the findings indicating that DHEA is probably involved in suppression of the LH fraction.     

Sphincter injury after anal dilatation demonstrated by anal endosonography.

Anal dilatation is still used in the treatment of anal fissure and haemorrhoids. Using anorectal physiology and anal endosonography we have studied 12 men presenting with faecal incontinence following anal dilatation. Resting anal pressures were low, pudendal nerve latencies were normal; 11 men had a disrupted internal anal sphincter and in ten this was extensively fragmented. Three also had defects of the external anal sphincter. These findings demonstrate for the first time the nature of the structural injury which may be caused by anal dilatation.     

The brain/mind complex. An epistemological approach.

It is stressed that the brain/mind complex constitutes a monolithic system that functions with emergent properties at several levels of hierarchical organization. These hierarchical levels are non-reducible to one another; they are at least three (neuronal, functional, and semantic), and they function within an interactional plan. From the epistemological view-point, the brain/mind complex uses logical and non-logical mechanisms to deal with day-to-day problems. Logic is necessary for the thinking process, but it is not sufficient. Emphasis is given to non-logical mechanisms; fuzzy logic and heuristics, which allow the mind to develop strategies to find solutions, are analysed.     

Deep venous thrombosis and pulmonary embolism

All surgical patients are at risk for the development of deep venous thrombosis and subsequent pulmonary embolism or postphlebitic syndrome. The evolution of ultrasonographic imaging has increased the awareness of prevention, diagnosis, and treatment of deep venous thrombosis. Duplex imaging and Doppler color flow imaging have made the diagnosis of deep venous thrombosis relatively simple, painless, inexpensive, and definitive. These procedures have gained acceptance by both patients and physicians. Several risk factors have been identified that increase the chance of the development of deep venous thrombosis. These factors include a history of deep venous thrombosis, presence of a malignant process, increasing age, cigarette smoking, obesity, prolonged bed rest, and general anesthesia. The greater the number of risk factors, the more aggressive prophylaxis should be. Means of prophylaxis have improved, and surgeons now generally agree that some form of prophylaxis is required. Heparin and intermittent compression devices appear to be equally effective in preventing deep venous thrombosis. The addition of venous monitoring in high-risk patients permits immediate identification of the presence of deep venous thrombosis. During the last decade, the treatment of patients with deep venous thrombosis has changed little. Heparin followed by warfarin remains the treatment of choice. A small group of patients receive fibrinolytic therapy for deep venous thrombosis. Although the incidence of postoperative deep venous thrombosis has decreased during the last decade, it remains a significant complication.     

NPY hyperinnervation in Hirschsprung's disease: both adrenergic and nonadrenergic fibers contribute.

In Hirschsprung's disease, the aganglionic bowel is characterized by an absence of ganglion cells and an increased number of adrenergic and presumed cholinergic nerve fibers. In addition, a severe derangement of peptide-containing nerve fibers is encountered including a hyperinnervation of neuropeptide Y (NPY)-containing fibers. Using immunochemical and immunocytochemical methods, we examined the nature of the NPY-containing nerve fibers contributing to the hyperinnervation. The concentration of NPY was markedly increased in the aganglionic segment. Coexistence of NPY, vasoactive intestinal peptide (VIP), and the adrenergic enzyme tyrosine hydroxylase (TH) showed small populations of nerve fibers containing NPY/TH, NPY/VIP, or TH alone in ganglionic intestine. Numerous nerve fibers stored VIP but lacked NPY. These fibers did not contain TH, indicating that all VIP-containing fibers are nonadrenergic. In the aganglionic intestine there was a marked increase in the number of nerve fibers storing NPY/TH and NPY/VIP, whereas the fibers storing VIP alone were reduced in number. A small number of nerve fibers storing NPY alone occurred in the hypertrophic nerve bundles. NPY/VIP-containing nerve fibers were particularly numerous in the mucosa in aganglionic intestine, which may be of interest in the diagnosis of Hirschsprung's disease allowing the use of mucosal biopsy specimens. Thus, the proliferating NPY-containing nerve fibers in the aganglionic intestine seem to comprise three different populations, one adrenergic and two nonadrenergic, one of which contains in addition VIP.