Mammographic changes in postmenopausal women on hormonal replacement therapy

The purpose of this study was to investigate the extent of the effects of hormonal replacement therapy (HRT) on the mammographic breast pattern in postmenopausal women. In a hospital-based study mammographic examinations of 81 postmenopausal women were evaluated retrospectively, before and after 1-2 years of treatment with oestrogens or a combination of oestrogens and progestagens. Each individual mammographic film was examined separately, and the glandular tissue was classified according to a modified Wolfe classification. In a screening-centre-based study two consecutive mammograms, with a 2-year interval, of 645 women, of whom 70 were using some kind of hormone therapy, were evaluated retrospectively. In the hospital-based study 31 % of patients treated with combination HRT showed an increase in fibroglandular tissue compared with only 8.7 % in the group treated with oestrogens alone. The difference was statistically significant (p = 0.046). In the screening-based study 14.3 % of the women using hormonal therapy showed an increase, whereas in the non-users no increase was found (p = 1.24 x 10(-10)). After beginning HRT many women (between 14 and 25 % in our experience) can be expected to undergo a mammographically detectable increase in fibroglandular tissue. Radiologists should be aware of the aetiology of such changes, and can obtain information on HRT most conveniently by having the technologist routinely question each patient.     

Thrombotic thrombocytopenic purpura in 13 Dutch centres: treatment and longterm follow-up

OBJECTIVE: Analysis of the incidence, treatment modalities and disease course of thrombotic thrombocytopenic purpura (TTP) in the Netherlands. DESIGN: Retrospective follow-up study. SETTING: 13 centres in the Netherlands. METHODS: Regarding all patients admitted between 1-1-1979 and 1-1-1992 to one of 13 Dutch haematological centres, in whom the diagnosis of TTP was made for the first time, information was gathered from the medical records and from the patients own physicians on patient characteristics at presentation and the occurrence of relapse or death. The follow-up period tended on 1-4-1995. RESULTS: A total of 65 patients with newly diagnosed TTP were identified: 0.34 per 1,000,000 persons a year (95% confidence interval (95%-CI): 0.26-0.45), increasing to 0.83 in the last year of the study. Forty-six (95%) patients were treated with fresh frozen plasma: 18 (28%) by plasma infusion and 44 (68%) by plasma exchange; 48 (74%) (additionally) received corticosteroids. All 52 patients (80%) who survived the first four weeks after admission reached complete remission. Twelve patients with relapsing TTP underwent splenectomy in remission. The 5-year survival rate was 77% (95% CI: 66-87) and the 5-year relapse-free survival rate 38% (95% CI: 25-52). Cardiac symptoms, severe thrombocytopenia and a high serum LDH were risk factors for acute mortality, but no risk factors for relapse or late-occurring death could be identified. CONCLUSION: TTP is a rare disease which is increasingly being recognized. Plasma exchange and corticosteroids are the most frequently used therapies. The disease has a high mortality rate in the acute phase of the disease.     

Mechanisms for increasing stroke volume during static exercise with fixed heart rate in humans

Ten patients with preserved inotropic function having a dual-chamber (right atrium and right ventricle) pacemaker placed for complete heart block were studied. They performed static one-legged knee extension at 20% of their maximal voluntary contraction for 5 min during three conditions: 1) atrioventricular sensing and pacing mode [normal increase in heart rate (HR; DDD)], 2) HR fixed at the resting value (DOO-Rest; 73 +/- 3 beats/min), and 3) HR fixed at peak exercise rate (DOO-Ex; 107 +/- 4 beats/min). During control exercise (DDD mode), mean arterial pressure (MAP) increased by 25 mmHg with no change in stroke volume (SV) or systemic vascular resistance. During DOO-Rest and DOO-Ex, MAP increased (+25 and +29 mmHg, respectively) because of a SV-dependent increase in cardiac output (+1.3 and +1.8 l/min, respectively). The increase in SV during DOO-Rest utilized a combination of increased contractility and the Frank-Starling mechanism (end-diastolic volume 118-136 ml). However, during DOO-Ex, a greater left ventricular contractility (end-systolic volume 55-38 ml) mediated the increase in SV.     

Activity of liposomal nystatin against disseminated Aspergillus fumigatus infection in neutropenic mice

The purpose of this study was to examine the activity of liposomal nystatin against a disseminated Aspergillus fumigatus infection in neutropenic mice. Mice were made neutropenic with 5-fluorouracil and were administered the antifungal drug intravenously for 5 consecutive days beginning 24 h following infection. Liposomal nystatin, at doses as low as 2 mg/kg of body weight/day, protected neutropenic mice against Aspergillus-induced death in a statistically significant manner at the 50-day time point compared to either the no-treatment, the saline, or the empty-liposome group. This protection was approximately the same as that for free nystatin, a positive control. Histopathological results showed that liposomal nystatin cleared the lungs, spleen, pancreas, kidney, and liver of Aspergillus and that there was no organ damage at the day 5 time point, which was after only three doses of liposomal nystatin. Based on these results in mice, it is probable that liposomal nystatin will be effective against Aspergillus infection in humans.     

Differential reactivity of cardiac and skeletal muscle from various species in a cardiac troponin I immunoassay

The effects of 2-butoxyethanol (2-BE) on poly(ADP-ribosyl)ation were studied in Syrian hamster embryo (SHE) cells by measuring the cellular concentrations of the polymer poly(ADP-ribose) (pADPr) and of NAD+, the substrate of poly(ADP-ribose) polymerase (PARP). As biotransformation pathways of ethylene glycol ethers involve NAD+-dehydrogenases, it was hypothesized that 2-BE could reduce poly(ADP-ribosyl)ation by consuming NAD+. As a result DNA repair could be altered, which would explain that 2-BE had been shown to potentiate the effects of clastogenic substances such as methyl-methanesulfonate (MMS). In this study, the effects of 2-BE on MMS-induced pADPr metabolism were analyzed. The results indicated that: (i) 2-BE (5 mM) by itself did not influence significantly pADPr or NAD+ levels. (ii) 2-BE inhibited pADPr synthesis in MMS (0.2 mM)-pretreated cells, without any change in NAD+ concentrations. (iii) MMS treatment, which rapidly increased pADPr levels, also affected the poly(ADP-ribosyl)ation system as a secondary effect by damaging cell structures. Membrane permeabilization, which occurred at concentrations >1 mM MMS, led to a dramatic leakage of cellular NAD+ resulting in a strong reduction in pADPr levels. (iv) A bleomycin pulse (100 microM) applied after MMS and/or 2-BE treatment confirmed that 2-BE reduced poly(ADP-ribosyl)ation capacities of MMS-treated cells, though the glycol ether had no effect alone. This study confirmed that the inhibition of pADPr synthesis could be responsible for the synergistic effects of 2-BE with genotoxic substances. The mechanism of this inhibition cannot be explained by a lack of NAD+ at the concentrations of 2-BE tested.     

Boron neutron capture therapy of brain tumors: enhanced survival following intracarotid injection of either sodium borocaptate or boronophenylalanine with or without blood-brain barrier disruption

The purpose of the present study was to determine whether the efficacy of boron neutron capture therapy could be enhanced by means of intracarotid (i.c.) injection of sodium borocaptate (BSH) or boronophenylalanine (BPA) with or without blood-brain barrier disruption (BBB-D). For biodistribution studies, F98 glioma-bearing rats were injected i.v. or i.c. with either BSH (30 mg of boron/kg of body weight) or BPA (24 mg of boron/kg of body weight) with or without mannitol-induced, hyperosmotic BBB-D and killed 2.5 h later. The highest tumor boron concentrations for BSH and BPA were attained following i.c. injection with BBB-D (48.6 and 94.0 microg/g, respectively) compared to i.c. (30.8 and 42.7 microg/g) and i.v. injection (12.9 and 20.8 microg). Using the same doses of BSH and BPA, therapy experiments were initiated 14 days after intracerebral implantation of F98 glioma cells. Animals were irradiated 2.5 h after i.v. or i.c. administration of the capture agent with or without BBB-D using a collimated beam of thermal neutrons at the Brookhaven Medical Research Reactor. The median survival times of rats given BSH or BPA i.c. were 52 and 69 days, respectively, for rats with BBB-D; 39 and 48 days for rats without BBB-D; 33 and 37 days for i.v. injected rats; 29 days for irradiated controls; and 24 days for untreated controls. i.c. injection of either BSH or BPA resulted in highly significant enhancement (P = 0.01 and P = 0.0002, respectively) of survival times compared to i.v. injection, and this was further augmented by BBB-D (P = 0.02 and P = 0.04, respectively) compared to i.c. injection. Normal brain tissue tolerance studies were carried out with non-tumor-bearing rats, which were treated in the same way as tumor-bearing animals. One year after irradiation, the brains of these animals showed only minimal radiation-induced changes in the choroid plexus, but no differences were discernible between irradiated controls and those that had BBB-D followed by i.c. injection of either BSH or BPA. Our data clearly show that the route of administration, as well as BBB-D, can enhance the uptake of BSH and BPA, and, subsequently, the efficacy of boron neutron capture therapy.     

Sexual functioning after multimodality treatment for disseminated nonseminomatous testicular germ cell tumor

PURPOSE: We determined sexual functioning after chemotherapy for disseminated nonseminomatous testicular germ cell tumor, and evaluated the impact of resection of post-chemotherapy residual retroperitoneal tumor. MATERIALS AND METHODS: A total of 155 consecutive patients treated with chemotherapy for disseminated nonseminomatous testicular germ cell tumor (between 1980 and 1994) was questioned about their sexual functioning. The patients were divided in 2 subgroups: patients treated with or without resection of post-chemotherapy residual retroperitoneal tumor. Volume and location (divided into left para-aortal or right paracaval/interaortacaval) of the resected tumor were related to absence of ejaculation as well as decreased semen amount. In addition, libido, arousal, erection and orgasm were related to ejaculatory dysfunction. RESULTS: A total of 43 patients (27.7%) was treated with chemotherapy only and 112 (72.3%) had additional resection of post-chemotherapy residual retroperitoneal tumor mass. Overall, 22.4% reported loss of libido, 14.1% decreased arousal, 16% erectile dysfunction, 23.1% decreased orgasmic intensity, 17.4% decreased semen amount and 18.7% complete absence of antegrade ejaculation. With exception of absence of ejaculation, sexual dysfunctions were reported in similar frequencies in both treatment subgroups. In the resection of post-chemotherapy residual retroperitoneal tumor subgroup, 25.9% of the patients had complete absence of ejaculation. The other sexual dysfunctions were related neither to decreased semen amount nor to complete absence of ejaculation. The mean volume of resected tumor was higher (95 cm.3) in patients with absence of ejaculation than in those without (40 cm.3), and patients with right paracaval/interaortacaval tumor (20 of 58, 34.5%) reported more often absence of ejaculation than those with left para-aortal tumor (9 of 54, 16.7%). CONCLUSIONS: In patients treated for disseminated nonseminomatous testicular germ cell tumor, post-chemotherapy sexual morbidity cannot be neglected. Except for loss of antegrade ejaculation, sexual dysfunctions are not related to resection of post-chemotherapy residual retroperitoneal mass. A high volume of tumor and a right paracaval/interaortacaval location predispose to loss of antegrade ejaculation.     

Shelf life and in vivo duration. Impacts on performance of tibial bearings

Polyethylene has been used for more than 30 years as an orthopaedic bearing material; however, recently concern has been focused on the early failure of some polyethylene bearings. The damage seen in some bearings has been linked to gamma radiation sterilization performed in an air environment. Gamma sterilization in air has been documented to cause an increase in oxidation and degradation of mechanical properties that continue with time. However, not all retrieved bearings that are gamma sterilized in air exhibit the elevated oxidation and mechanical property degradation that lead to early component failure. Bearings that are gamma sterilized in air oxidize while sitting in inventory before implantation. Shelf oxidation rate was estimated based on analysis of a series of never implanted tibial bearings. This shelf oxidation rate allowed estimation of in vivo oxidation for retrieved tibial bearings of known sterilization date. Bearings with less than 1 year of shelf life after gamma sterilization in air had lower in vivo oxidation and better in vivo performance than did those with longer shelf life before implantation. Shelf time before implantation appears to be a significant factor in the success or failure of bearings that are gamma sterilized in air.     

An activating mutation in a Caenorhabditis elegans Gs protein induces neural degeneration

Heterotrimeric guanine nucleotide-binding proteins (G proteins) act as signal-transducing molecules that connect serpentine-transmembrane receptors to a variety of intracellular effectors. We characterized a Caenorhabditis elegans G(s) gene, gsa-1, which encodes a G(s) alpha-subunit (G alpha(s)) that is expressed throughout the nervous system and in muscle cells. gsa-1 is an essential gene; a loss-of-function mutation in gsa-1 results in lethality at the first stage of larval development. Partial (mosaic) loss of G alpha(s) expression or overexpression of the protein results in reciprocal defects in movement and egg-laying, suggesting a role for G alpha(s) in the regulation of these behaviors. Expression of a constitutively active form of G alpha(s) from an inducible promotor results in hypercontraction of body-wall muscle cells and vacuolization and degeneration of neurons within hours of induction. Neurons that are susceptible to the degeneration induced by activated G alpha(s) are predominantly motoneurons located within the ventral nerve cord. Phenotypic analysis shows that the induced neural degeneration is not the result of programmed cell death but is probably caused by the activation of ion channels. A genetic suppressor of activated G alpha(s) was isolated that identifies a putative downstream target of G(s) signaling.     

A randomized comparison of dilatation alone versus dilatation plus laser in patients receiving chemotherapy and external beam radiation for esophageal carcinoma

Most patients with carcinoma of the esophagus have advanced disease at presentation. Since cure is usually not possible, the goal of treatment is the palliation of dysphagia. Palliative modalities include bougies, balloons, stents, tumor probe, laser, surgery, chemotherapy, and radiation. In recent years, combined chemotherapy and radiation has shown promising results. However, the relief of dysphagia is slow and frequently incomplete. We compared the effectiveness of dilatation alone versus dilatation plus Nd-YAG laser therapy for the relief of dysphagia while assessing the role of chemotherapy and radiation as an adjunct to surgery. Fifteen patients with squamous cell carcinoma of esophagus who were deemed fit for intensive chemotherapy and radiation were randomized to receive either dilatation alone (N = 7) or dilatation plus laser (N = 8); the end-point for initial success was the passage of a 45 French Savary dilator, and the relief of dysphagia. At entry, 13 of these 15 patients were judged potentially resectable. However, after chemotherapy and radiation, only 3 of 13 (20%) patients could be offered surgery; the remainder were considered too poor a surgical risk. Follow-up was for 30 months, or until death. Further dilatations were performed as needed for relief of dysphagia. No difference was observed between the laser plus dilatation and the dilatation alone group with respect to the degree of dysphagia, weight record, quality of life index (Karnofsky score), or mortality rate. Our results indicate that in patients undergoing chemotherapy and radiation for esophageal carcinoma, dilatation alone provides adequate palliation of dysphagia, and in these patients, chemotherapy and radiation is a poor adjunct to surgical treatment.