Hormone replacement therapy update: who should we be prescribing this to now?

PURPOSE OF REVIEW: To summarize results from the Women's Health Initiative trial and other recent randomized placebo-controlled trials of hormone replacement therapy, which fundamentally changed our understanding of its risks and benefits. RECENT FINDINGS: The Women's Health Initiative study for the first time provided evidence of harmful effects of hormone replacement therapy on the cardiovascular system and also confirmed significantly increased risk of breast cancer which was previously documented in a metaanalysis. Most recent studies indicate a particularly harmful effect of combined estrogen/progestin regimens in terms of increased breast cancer risk. SUMMARY: The effects of hormone replacement therapy on coronary heart disease, stroke, venous thromboembolism, breast cancer, gallbladder, diabetes, cognitive function, health-related quality of life, colorectal cancer, osteoporosis and menopausal symptoms are discussed briefly. The emphasis is on providing concise clinical guidelines for hormone replacement therapy use in new circumstances. We also discuss some alternative therapeutic modalities for women who have menopausal symptoms, but contraindications for hormone replacement therapy.     

Perturbation of blood flow as a mechanism of anti-tumour action of direct current electrotherapy

Anti-tumour effects of direct current electrotherapy are attributed to different mechanisms depending on the electrode configuration and on the parameters of electric current. The effects mostly arise from the electrochemical products of electrolysis. Direct toxicity of these products to tumour tissue is, however, not a plausible explanation for the observed tumour growth retardation in the case when the electrodes are placed into healthy tissue surrounding the tumour and not into the tumour itself. The hypothesis that the anti-tumour effectiveness of electrotherapy could result from disturbed blood flow in tumours was tested by the measurement of changes in blood perfusion and oxygenation in tumours with three different methods (in vivo tissue staining with Patent Blue Violet dye, polarographic oximetry, near-infrared spectroscopy). The effects induced by electrotherapy were evaluated in two experimental tumour models: Sa-1 fibrosarcoma in A/J mice and LPB fibrosarcoma in C57B1/6 mice. We found that perfusion and oxygenation were significantly decreased after electrotherapy. Good agreement between the results of different methods was observed. The effect of electrotherapy on local perfusion of tumours is probably the prevalent mechanism of anti-tumour action for the particular type of electrotherapy used in the study. The importance of this effect should be considered for the optimization of electrotherapy protocols in experimental and clinical trials. The non-invasive technique of near-infrared spectroscopy proved to be a reliable method for detecting perfusion and oxygenation changes in small solid tumours.     

HCH distribution and microbial parameters after liming of a heavily contaminated soil in Rio de Janeiro

The closing down of a lindane factory near Rio de Janeiro, over 45 years ago, left an area heavily contaminated with hexachlorocyclohexane (HCH). Remediation by soil liming was applied by government authorities in 1995. This study aims to evaluate the HCH distribution and impact on soil microbiota due to contamination and liming. Microcosm experiments with uncontaminated soil mixed with HCH and lime indicated that lime-promoted dechlorination of HCH molecules led to leaching and volatilization of metabolites. The treatment applied transformed but did not solve the problem as most of the HCH remains in the soil. Reduced microbial respiratory activity was measured in contaminated field samples. Higher respiration rates in uncontaminated soil were reduced by HCH and lime addition; the sole addition of HCH caused a temporary increase in soil respiration, and stimulation occurred with oxygen and/or nutrient addition. A heterotrophic bacterial population around 10(9)CFU/g was found in polluted field soil, some well-known degraders having been isolated. Native soil microbiota showed resistance to high amounts of HCH and alkaline pH. The results allow considering bioremediation rather than chemical treatments to clean up the area.     

Behavioral effects of buspirone in the marmoset employing a predator confrontation test of fear and anxiety

In order to further validate the recently developed marmoset (Callithrix penicillata) predator confrontation model of fear and anxiety, we investigated the behavioral effects of buspirone with this method. The apparatus consisted of three parallel arms connected at each end to a perpendicular arm, forming a figure-eight continuous maze. A taxidermized wild oncilla cat (Felis tigrina) was positioned facing a corner of the parallel arms, alternating between the left or right side of the maze among animals tested. All subjects were first submitted to seven 30-min maze habituation trials (HTs) in the absence of the predator, and then to five randomly assigned treatment trials (TTs) in the presence of the predator: three buspirone sessions (0.1, 0.5 and 1.0 mg/kg), saline and sham injection controls. Twenty minutes after treatment administration, the animal was released into the maze and had free access to the apparatus for 30 min. All trials were taped for later behavioral analysis. Buspirone significantly decreased the frequency of scent marking, while increasing the time spent in proximity to the 'predator' stimulus, indicating an anxiolytic effect. Neither locomotor activity, exposure to a novel environment, stimulus location and habituation, nor gender influenced the effects of the drug treatments. These results further validate this method and demonstrate the potential usefulness of this ethologically based paradigm to test anxiety and fear-induced avoidance in nonhuman primates and its susceptibility to anxiolytic pharmacological manipulations.     

Subtelencephalic locale of reinforcement and learning: looking for the minimal necessary structures

This report summarizes 4 experiments which deal with the effects of surgical removal of the rat's telencephalic forebrain structures on performance of an inhibitory avoidance response, which was acquired either before or after the lesion was made. Two experiments provide evidence that inhibitory avoidance learning (using the single-trial up-hill avoidance task) is still possible after removal of all of the forebrain structures except for the hypothalamus. A third study using this preparation dealt with the question of whether this conditioned avoidance response can be eliminated as a consequence of it being punished. In a further experiment the conditioned avoidance response was established prior to ablation of the telencephalon plus thalamus. Recall of the conditioned response survived the lesion, suggesting that the avoidance response is also stored at a subtelencephalic level in the brain-intact animal.     

Sensitivity of culture and polymerase chain reaction for the etiologic diagnosis of erythema migrans

Skin biopsy samples from 150 patients with typical cutaneous manifestation of Lyme borreliosis, erythema migrans, were cultivated for the presence of Borrelia burgdorferi sensu lato in modified Kelly Pettenkofer (MKP) medium and analysed with two different polymerase chain reactions using either flagellin or nested OspA primers. Cultivation was successful in 75 of 150 (50%) skin samples. Out of 70 strains that were typed using PFGE, B. afzelii was identified in 60 (86%), B. garinii in 10 (14%) specimens, while no B. burgdorferi sensu stricto strains were found. B. burgdorferi sensu lato DNA was detected with polymerase chain reaction in 28% and 61% of skin samples, using flagellin and nested OspA primers, respectively. Concordant results in all three procedures employed in the present study were found in 62 (41%) specimens: 25/150 (17%) were positive with all three methods and 37/150 (25%) samples were completely negative.     

Partial hand amputation and work

Purpose. To determine whether or not subjects who had had a partial hand amputation were able to return to the same job and whether or not they used their silicone finger prosthesis for work.

Method. Medical records of all the patients who had undergone a traumatic partial hand amputation and who had been treated in the Upper Limb Prosthetic Clinic at the Institute for Rehabilitation in Ljubljana were reviewed. Questionnaires were sent to 112 patients. Forty-eight questionnaires which were returned and had been correctly answered were analysed.

Results. The study found that less than half the patients who had had a partial hand amputation were able to do the same work as before the amputation. Less than one-third wore their silicone prosthesis at work regularly. The subjects who did not have manual jobs and who had an amputation of only one or two fingers were able to keep the same job more easily after the amputation. Only a few subjects found their silicone prosthesis useful at work.

Conclusion. It can be concluded that partial hand amputation may present a great problem in keeping the same job after amputation. An aesthetic (cosmetic) silicone prosthesis is helpful particularly for subjects with higher education whose work involves personal contacts and for whom aesthetics is important. They use the prosthesis for certain activities, such as typing.     

Cerebrospinal fluid findings in adult patients with multiple erythema migrans

This prospective study was performed at the Department of Infectious Diseases, University Medical Centre Ljubljana, Slovenia, in the period from 1991 to 2000. We included all adult patients with multiple erythema migrans who gave consent to lumbar puncture, had routine blood and CSF tests performed, and borrelial antibody titres in CSF and blood determined. In the majority of these patients skin, blood, and CSF specimens were cultured in MKP medium for the presence of Borrelia. Of 332 patients with multiple erythema migrans, 200 (115 females, 85 males, aged 15-80 years) fulfilled inclusion criteria. The median number of skin lesion was three (2-60). Sixty-three (31.5%) patients had no associated symptoms, whereas 137 (68.5%) patients (including two with arthritis, six with radicular pain, a patient with facial palsy, another patient with foot palsy and a patient with transitory diplopia) reported local and/or constitutional symptoms. Routine CSF examination revealed abnormal results in 62/200 (31%) patients: lymphocytic pleocytosis (6-1119 x 10(6)/L leukocytes) was found in 15 (7.5%) patients (six were clinically without systemic symptoms, six had mild systemic symptoms, three reported radicular pains) and elevated CSF protein concentration was present in 52 (26%) patients (nine also had elevated CSF cell counts). Intrathecal borrelial antibody production was demonstrated in eight (4%) patients (only three of them had elevated CSF cell counts) and B. burgdorferi sensu lato was isolated from skin lesions, blood, and CSF in 77/191 (40.3%), 3/154' (1.95%), and 2/200 (1%) patients, respectively. B. afzelii predominated among the isolates. In patients with multiple erythema migrans abnormal CSF findings are not rare and may be present without any clinical sign of central nervous system involvement.     

Tumour necrosis factor superfamily member 11 gene promoter polymorphisms modulate promoter activity and influence bone mineral density in postmenopausal women with osteoporosis

Tumour necrosis factor superfamily member 11 (TNFSF11) gene, that codes for receptor activator of nuclear factor-kappaB ligand, is one of the candidate genes for the genetic susceptibility to osteoporosis. As variations in the TNFSF11 gene promoter could alter its expression, the aim of the study was to evaluate the functional influence of three polymorphisms in the promoter and to investigate their association with bone mineral density (BMD) and biochemical markers in postmenopausal women. A total of 404 postmenopausal women were genotyped for the presence of TNFSF11 gene promoter polymorphisms -290C>T, -643C>T and -693G>C. Two common haplotypes, CCG and TTC, which occur in 44.3 and 49.3% of subjects respectively, were subjected to functional analysis. Amplified fragments were cloned into pGL3-basic reporter plasmid, which was co-transfected with pRL-TK plasmid into HEK293 cells. Dual luciferase reporter assay was performed. BMD and biochemical markers were measured. Reporter gene analysis showed significantly higher luciferase activity in CCG than in TTC haplotype (P=0.018). Both showed association with lumbar spine BMD (BMD-ls; P=0.005 and 0.007 for TTC and CCG respectively), whereas in femoral neck there was no association with BMD. In postmenopausal osteoporosis, association with BMD-ls was established in -290C>T, -643C>T and -693G>C (P values: 0.001, 0.041 and 0.013 respectively). Association with femoral neck BMD was shown in -693G>C (P=0.049). No association was found with biochemical markers in any of the groups. Our results suggest that in postmenopausal osteoporosis, TNFSF11 gene promoter polymorphisms -290C>T, -643C>T and -693G>C play a functional role in the genetic regulation of BMD.