TB preventive treatment among pregnant women with HIV.

BACKGROUND: The WHO recommends TB preventive treatment (TPT) for people living with HIV, including pregnant women. Uptake of this policy recommendation in this subpopulation and country alignment with WHO guidance is unclear.METHODS: We conducted a policy review in 38 WHO high TB and TB-HIV burden countries to assess if the uptake of TPT policy among pregnant women living with HIV was in line with the WHO´s 2018 Updated and Consolidated Guidelines for Programmatic Management for LTBI. Data sources included TB national guidelines and HIV/AIDS/ART national guidelines, complemented by results from a previous survey on policy uptake held at the WHO.RESULTS: Uptake of WHO policy to provide TB preventive treatment among women with HIV accessing antenatal care was moderate: 64% (23 of 36 countries) explicitly recommended at least one clinical guideline or policy recommendation on screening, testing or treatment of LTBI among pregnant women living with HIV. There was considerable variation between countries on the stages in pregnancy that TPT should be provided. Two countries (5%) provided clinical monitoring recommendations for pregnant women.CONCLUSIONS: There is moderate uptake of TPT policy for pregnant women with HIV. Failure to provide TPT as part of antenatal or prevention of mother-to-child services is a missed opportunity for TB control.

[99cmTc]Tc-PSMA-I&S-SPECT/CT: experience in prostate cancer imaging in an outpatient center.

BACKGROUND: Prostate-specific membrane antigen (PSMA) SPECT imaging in prostate cancer (PCa) could be a valuable alternative in regions where access to PSMA-PET imaging is restricted. [99mTc]Tc-PSMA-I&S is a new 99mTc-labeled PSMA-targeting SPECT agent, initially developed for radio-guided surgery. We report on the diagnostic use of [99mTc]Tc-PSMA-I&S-SPECT/CT in PCa. RESULTS: [99mTc]Tc-PSMA-I&S-SPECT/CT was performed and evaluated in 210 outpatients with PCa at a single center. Patients were imaged for biochemical recurrence (BCR, n = 152, mean PSA 8.7 ng/ml), for primary staging of high-risk PCa (n = 12, mean PSA 393 ng/ml), and restaging in advanced recurrent PCa (n = 46, mean PSA 101.3 ng/ml). Number and location of positive lesions were determined for the different subgroups. For BCR, detection rates were calculated, defined as the proportion of scans with at least one PSMA-positive lesion. PSMA positive lesions were detected in 65.2% of all 210 patients. Tumor tissue was mainly detected in lymph nodes (59%), in the bone (42%), and in the prostate (fossa) (28%). In the subgroup of patients referred for detection of BCR the detection rate increased from 20% at a PSA level < 1 ng/ml to 82.9% and 100% at PSA levels > 4 ng/ml and > 10 ng/ml, respectively. In the subgroup of high-risk patients referred for primary staging, 42% demonstrated metastatic disease. Restaging of advanced recurrent PCa revealed detectability of PSMA positive tumor lesions in 85% of the scans. CONCLUSIONS: [99mTc]Tc-PSMA-I&S-SPECT/CT was useful in PSMA-targeted imaging of PCa at various clinical stages. At low PSA levels (< 4 ng/ml), detection rates of [99mTc]Tc-PSMA-I&S-SPECT/CT in BCR are clearly inferior to data reported for PET-imaging and should thus only be considered for lesion detection if imaging with PET is unavailable. However, at higher PSA levels (> 4 ng/ml) [99mTc]Tc-PSMA-I&S-SPECT/CT provides high detection rates in BCR. [99mTc]Tc-PSMA-I&S-SPECT/CT can also be used for primary staging and for restaging of advanced recurrent PCa. However, further studies are needed to assess the clinical value in these indications.

Efficacy of Testosterone Suppression with Sustained-Release Triptorelin in Advanced Prostate Cancer.

INTRODUCTION: Androgen deprivation therapy (ADT) is a mainstay of treatment against advanced prostate cancer (PC). As a treatment goal, suppression of plasma testosterone levels to <50 ng/dl has been established over decades. Evidence is growing though that suppression to even lower levels may add further clinical benefit. Therefore, we undertook a pooled retrospective analysis on the efficacy of 1-, 3-, and 6-month sustained-release (SR) formulations of the gonadotropin-releasing hormone (GnRH) agonist triptorelin to suppress serum testosterone concentrations beyond current standards. METHODS: Data of 920 male patients with PC enrolled in 9 prospective studies using testosterone serum concentrations as primary endpoint were pooled. Patients aged 42-96 years had to be eligible for ADT and to be either naïve to hormonal treatment or have undergone appropriate washout prior to enrolment. Patients were treated with triptorelin SR formulations for 2-12 months. Primary endpoints of this analysis were serum testosterone concentrations under treatment and success rates overall and per formulation, based on a testosterone target threshold of 20 ng/dl. RESULTS: After 1, 3, 6, 9, and 12 months of treatment, 79%, 92%, 93%, 90%, and 91% of patients reached testosterone levels <20 ng/dl, respectively. For the 1-, 3-, and 6-month formulations success rates ranged from 80-92%, from 83-93%, and from 65-97% with median (interquartile range) serum testosterone values of 2.9 (2.9-6.5), 5.0 (2.9-8.7), and 8.7 (5.8-14.1) ng/dl at study end, respectively. CONCLUSION: In the large majority of patients, triptorelin SR formulations suppressed serum testosterone concentrations to even <20 ng/dl. Testosterone should be routinely monitored in PC patients on ADT although further studies on the clinical benefit of very low testosterone levels and the target concentrations are still warranted.

Calpain mediates caspase-dependent apoptosis initiated by hydrogen peroxide in pancreatic acinar AR42J cells.

Several studies have shown that oxidative stress induces apoptosis in many cellular systems including pancreatic acinar cells. However, the exact molecular mechanisms leading to apoptosis remain partially understood. This study aimed to investigate the role of the cytosolic cysteine protease calpain in H2O2-induced apoptosis in pancreatic AR42J cells. Apoptosis was evaluated using flow cytometric analysis of sub-G1 DNA populations, electron-microscopic analysis, caspase-3-specific αII-spectrin breakdown, and measuring the proteolytic activities of the initiator caspase-12 and caspase-8, and the executioner caspase-3. H2O2 induced an increase in the calpain proteolytic activity immediately after starting the experiments that tended to return to a nearly normal level after 8 h and could be attributed to m-calpain. Whereas no caspase-12, caspase-8 and caspase-3 activations could be detected within the first 0.5 h, significantly increased proteolytic activities were observed after 8 h compared with the control. At the same time, the cells showed first ultrastructural hallmarks of apoptosis and a decreased viability. In addition, αII-spectrin fragmentation was identified using immunoblotting that could be attributed to both calpain and caspase-3. Calpain inhibition reduced the activities of caspase-12, caspase-8, and caspase-3 leading to a decrease in the number of apoptotic cells. Immunoblotting analyses of caspase-12 and caspase-8 indicate that calpain may be involved in the activation process of both proteases. The results suggest that H2O2-induced apoptosis of AR42J cells requires activation of m-calpain initiating the endoplasmic reticulum stress-induced caspase-12 pathway and a caspase-8-dependent pathway. The findings also suggest that calpain may be involved in the execution phase of apoptosis.

The use of high-dose melatonin in liver resection is safe: first clinical experience.

Experimental data suggest that melatonin decreases inflammatory changes after major liver resection, thus positively influencing the postoperative course. To assess the safety of a preoperative single dose of melatonin in patients undergoing major liver resection, a randomized controlled double-blind pilot clinical trial with two parallel study arms was designed at the Department of General and Transplantation Surgery, Ruprecht-Karls-University, Heidelberg. A total of 307 patients, who were referred for liver surgery, were screened. One hundred and thirteen patients, for whom a major liver resection (≥3 segments) was scheduled, were eligible. Sixty-three eligible patients refused to participate, and therefore, 50 patients were randomized. A preoperative single dose of melatonin (50 mg/kg BW) dissolved in 250 mL of milk was administered through the gastric tube after the intubation for general anesthesia. Controls were given the same amount of microcrystalline cellulose. Primary endpoint was safety. Secondary endpoints were postoperative complications. Melatonin was effectively absorbed with serum concentrations of 1142.8 ± 7.2 ng/mL (mean ± S.E.M.) versus 0.3 ± 7.8 ng/mL in controls (P < 0.0001). Melatonin treatment resulted in lower postoperative transaminases over the study period (P = 0.6). There was no serious adverse event in patients after melatonin treatment. A total of three infectious complications occurred in either group. A total of eight noninfectious complications occurred in five control patients, whereas three noninfectious complications occurred in three patients receiving preoperative melatonin (P = 0.3). There was a trend toward shorter ICU stay and total hospital stay after melatonin treatment. Therefore, a single preoperative enteral dose of melatonin is effectively absorbed and is safe and well tolerated in patients undergoing major liver surgery.

Trends in occupational exposure to styrene in the European glass fibre-reinforced plastics industry.

AIM: This study presents temporal trends of styrene exposure for workers in the European glass fibre-reinforced plastics (GRP) industry during the period 1966-2002. METHODS: Data of personal styrene exposure measurements were retrieved from reports, databases and peer-reviewed papers. Only sources with descriptive statistics of personal measurements were accepted. The styrene exposure data cover personal air samples and biological monitoring data, that is, urinary styrene metabolites (mandelic acid and/or phenylglyoxylic acid) and styrene in blood. Means of series of measurements were categorized by year, country, production process, job and sampling strategy. Linear mixed models were used to identify temporal trends and factors affecting exposure levels. RESULTS: Personal exposure measurements were available from 60 reports providing data on 24145 1-8-h time-weighted average shift personal air samples. Available data of biological exposure indicators included measurements of mandelic acid in post-shift urine (6361 urine samples being analysed). Trend analyses of the available styrene exposure data showed that the average styrene concentration in the breathing zone of open-mould workers in the European GRP industry has decreased on average by 5.3% per year during the period 1966-1990 and by only 0.4% annually in the period after 1990. The highest exposures were measured in Southern Europe and the lowest exposures in Northern Europe with Central Europe in between. Biological indicators of styrene (mandelic acid in post-shift urine) showed a somewhat steeper decline (8.9%), most likely because urine samples were collected in companies that showed a stronger decrease of styrene exposure in air than GRP companies where no biological measurements were carried out.

Alterações morfológicas nos órgãos genitais de cães e gatos provenientes de Vilas Rurais da região de Umuarama-PR / Morphological alterations in the genital organs of cats and dogs from Rural Villages in the Region of Umuarama-PR / Alteraciones morfológicas en los órganos genitales de perros y gatos provenientes de villas rurales de la región de umuarama ­ pr

Enfermidades nos órgãos reprodutivos de cães e gatos têm variados graus de morbidade, mortalidade e sofrem influências do histórico reprodutivo, de tratamentos farmacológicos prévios e de condições ambientais, podendo assim haver variações regionais na incidência de determinadas anormalidades reprodutivas. O objetivo deste estudo foi fazer um levantamento da incidência das alterações morfológicas nos órgãos genitais de cães e gatos provenientes de Vilas Rurais da região de Umuarama, associar a freqüência de cada alteração à espécie, sexo, uso de contraceptivo e número de partos e discutir as principais alterações encontradas. Foram examinados os órgãos reprodutivos de 208 animais, assim distribuídos: 36,06% eram cadelas, 33,65% cães, 14,90% gatas e 15,38% gatos, todos sem raça definida e idade variando de um mês a 10 anos. Dos animais examinados, 9,13% apresentaram alterações, classificadas como hiperplasia cística do endométrio (5,29%), endometrite (0,96%), retenção de placenta (0,48%), fibrose endometrial (0,48%), degeneração testicular (0,96%), hipoplasia testicular (0,48%) e hemangiossarcoma no pênis (0,48%). Ao se agruparem as alterações, não se observou associação entre freqüência de alterações e espécie (P>0,05), sendo 10,30% e 6,30% para alterações nas espécies canina e felina, respectivamente. No entanto observou-se associação (P<0,05) entre freqüência de alterações e sexo, sendo que 14,15% estavam presentes em fêmeas e 3,90% em machos. Animais velhos apresentaram maior freqüência de alterações nos órgãos genitais (P<0,05) do que animais jovens. A freqüência de alterações não se associou ao uso de contraceptivo, à presença de gestação e ao número de partos, embora se tenha observado maior número de alterações patológicas em fêmeas que já haviam parido.

ABSTRACT: The purpose of the present study is to determine the incidence of pathologic alterations in the genital organs of apparently healthy dogs and cats and to correlate the frequency of each alteration to species, sex, the number of parturitions and the previous use of contraceptives. A total of 208 genital organs from 145 (69.7%) dogs and 63 (30.3%) cats castrated as part of a project of birth control for animals were examined macroscopically and histologically, in selected cases. Seventy fi ve (51.7%) of the dogs were female and 70 (48.3%) were male; 31 (49.2%) of the cats were female and 32 (50.8%) were male. Their race was undefi ned and their ages varied from one month to ten years. The following alterations were diagnosed in the dogs: nine (4.3%) had cystic endometrial hyperplasia, two (0.96%) had endometritis, one (0.48%) had retained placentas, one (0.48%) had testicular degeneration and one (0.48%) dog had a hemangiosarcoma in its penis. The following pathological alterations were diagnosed in the cats: two (0.96%) had cystic endometrial hyperplasia, one (0.48%) had endometrial fi brosis, one (0.48%) had testicular degeneration and one (0.48%) cat had testicular hipoplasia. There were no differences between species for the incidence of alterations. However, females were signifi cantly more affected than males (p<0.05), where 14.15% of the sick animals were female and 3.90% were male. Older animals showed greater incidences of pathological alteration in genital organs (p<0.05). There was no association among the incidence of alterations to the previous use of contraceptive, current pregnancy or number of previous gestations.

RESUMEN: Enfermedades de los órganos reproductivos de perros y gatos tienen variados grados de morbidad, mortalidad y sufren infl uencias de la historia reproductiva, de los tratamientos farmacológicos previos y de las condiciones ambientales, pudiendo así haber variaciones regionales en la incidencia de determinadas anormalidades reproductivas. El objetivo de este estudio fue hacer una encuesta de la incidencia de alteraciones morfológicas de los órganos genitales de perros y gatos provenientes de Villas Rurales de la región de Umuarama, asociar la frecuencia de cada alteración a la especie, sexo, uso de anticonceptivos y el número de partos, discutiendo las alteraciones encontradas. Fueron examinados los órganos reproductivos de 208 animales así distribuidos: 36,06% eran perras, 33,65% perros, 14,90% gatas y 15,38% gatos, todos sin raza defi nida y edad variando de un mes hasta diez años. De los animales examinados, 9,13% presentaron alteraciones, clasifi cadas como hiperplasia cística del endometrio (5,29%), endometritis (0,96%), retención de la placenta (0,48%), fi brosis endometrial (0,48%), degeneración testicular (0,96%), hipoplasia testicular (0,48%) y hemangiosarcoma del falo (0,48%). Al agruparse las alteraciones, no se observó asociación entre frecuencia de alteraciones y especie (P>0,05), siendo 10,30% y 6,30% para alteraciones en las especies canina y felina, respectivamente. Sin embargo, se observó asociación (P<0,05) entre frecuencia de alteraciones y sexo, sendo que 14,15% estaban presentes en hembras y 3,90% en machos. Animales viejos presentaron mayor frecuencia de alteraciones en los órganos genitales (P<0,05) que los animales jóvenes. La frecuencia de alteraciones no se asoció al uso de anticonceptivo, a la presencia de preñez y al número de partos, mismo que se tenga observado mayor número de alteraciones patológicas en hembras que ya habían parido.

Calpain activation contributes to oxidative stress-induced pancreatic acinar cell injury.

Oxygen radicals have been implicated as mediators in the pathogenesis of pancreatic acinar cell necrosis. However, the sequence of events between the oxidative insult and cell damage remains unclear. In the current study, we investigated whether the Ca(2+)-regulated cytosolic cysteine protease calpain is activated by oxidative stress and contributes to oxidant-induced acinar cell damage. Isolated rat pancreatic acinar cells were exposed to hydrogen peroxide (H(2)O(2))-generated oxidative stress in the presence or absence of the Ca(2+) chelator 1,2-bis-(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetraacetoxymethyl ester (BAPTA-AM) and different calpain inhibitors including benzyloxycarbonyl-valyl-phenylalanine methyl ester. Calpain activation was studied by fluorescence spectrophotometry and immunoblotting. Cell injury was assessed by lactate dehydrogenase (LDH) release and characterization of the cellular ultrastructure including fluorescence-labeled actin filaments. Exposure of acinar cells to H(2)O(2) provoked a time- and dose-dependent increase in calpain proteolytic activity involving the ubiquitous isoforms mu- and m-calpain. The activation of calpain reflected the time course of developing cytotoxicity as demonstrated by increased LDH release. Inhibition of oxidant-induced calpain activity by BAPTA-AM and various calpain inhibitors provoked a decline in oxidant-induced cell injury. In particular, changes in the actin filament organization characterized by an increase in the basolateral actin and by a detachment of actin from the cell membrane in the region of membrane blebs were clearly reduced. In summary, our findings suggest that acinar cell damage through oxidative stress requires activation of calpain and that the actin cytoskeleton belongs to the cellular targets of the protease. The results support the hypothesis that calpain activation may play a role in the development of acute pancreatitis.

5-Fluorouracil/irinotecan induced lethal toxicity as a result of a combined pharmacogenetic syndrome: report of a case.

Combination cancer chemotherapy induced toxicity can be associated with combined pharmacogenetic syndromes. Dihydropyrimidine dehydrogenase (DPD) is the principal enzyme involved in the catabolic detoxification of 5-fluorouracil (5FU). A heterozygous G > A transition at the 5' splicing donor consensus sequence in intron 14 leading to exon 14 skipping (IVS14+1 G > A, DPYD*2A) with partial loss of enzyme activity may be partly responsible for 5FU induced toxicity, whereas irinotecan associated toxicity may in part be explained by an aberrant UGT1A1 promoter (TA)(n) genotype underlying Gilbert's syndrome with reduced liver glucuronidation activity. This report describes a 44 year old white woman who suffered from severe gastrointestinal and haematological toxicity while undergoing 5FU(24h)/folinic acid/irinotecan treatment for adenocarcinoma of the sigmoid colon. Despite appropriate supportive treatment, her condition rapidly deteriorated and led to death. Molecular analysis revealed a hitherto undescribed combined pharmacogenetic syndrome, consisting of heterozygosity for the DPD IVS14+1 G > A mutation and UGT1A1 (TA)(6/7) heterozygosity, which probably contributed to the fatal outcome in this patient.

Predicting the risk of early atherosclerotic disease development in children after repair of aortic coarctation.

AIMS: Increased cardiovascular morbidity is manifested a long time after the repair of aortic coarctation (CoA). By way of impaired flow-mediated vasodilation (FMD) and increased intima media thickness (IMT), surrogate parameters of atherosclerosis, cardiovascular risk factors (RFs) can be correlated with early vascular wall changes in children. This study investigated whether changes in arterial wall function and morphology are detectable in children after coarctation repair. METHODS AND RESULTS: We examined 28 children after successful repair of CoA vs. 30 control subjects. All children underwent identical screening, with a broad RF profile and FMD/IMT measurements. CoA-children presented significantly (P < 0.001) impaired FMD (4.87 +/- 2.6 vs. 10.2 +/- 3.1%) and higher IMT values (P < 0.001) than the controls (0.48 +/- 0.08 vs. 0.38 +/- 0.05 mm). The blood pressure during rest and exercise and the left ventricular mass were significantly elevated, but no additional RF could be identified in CoA-children. Only a remaining pressure gradient related significantly to FMD. CONCLUSION: This study documents early vascular wall changes in children after successful coarctation repair. Arterial hypertension and a resting pressure gradient are the major contributing factors to early atherosclerotic development and should be primary targets for therapy. Vascular status should be monitored regularly by FMD and IMT.

Treatment of AIDS-associated myelopathy with L-methionine: a placebo-controlled study.

BACKGROUND: The histopathology of AIDS-associated myelopathy (AM) closely resembles that of myelopathies due to cobalamin or folate deficiency, with white matter vacuolization in the spinal cord. The pathogenesis of AM appears unrelated to direct HIV infection of the spinal cord. There is abnormal trans-methylation metabolism in AM, with decreased availability of the methyl group donor S-adenosyl-methionine (SAM). The authors hypothesized that treatment with l-methionine, the direct metabolic precursor of SAM, might improve AM. OBJECTIVE: To determine the safety and efficacy of l-methionine treatment in AM. METHODS: Fifty-six patients with clinical diagnosis of AM were randomized to a Phase II, double-blind, placebo-controlled study comparing the effect of l-methionine 6 g/day in two divided doses with that of placebo. Study duration was 12 weeks. All patients had somatosensory evoked potentials with prolonged central conduction time (CCT) at entry. Change in CCT was the primary endpoint of the study. Frequency of adverse events (AEs) was used to assess safety. Secondary endpoints were strength, spasticity, and urinary function. Biochemical measurements included serum methionine and homocysteine and CSF SAM. RESULTS: There were no significant differences in AEs between the two groups. Serum homocysteine increased in l-methionine-treated patients from 7.2 (+/-5.2 SD) to 12.6 (+/-6.15 SD) micromol/L. The mean CCT at baseline was 25.9 milliseconds (+/-7.3 SD) for the treatment group and 24.1 milliseconds (+/-7.0 SD) for the placebo group. At completion, it was 3.0 milliseconds (+/-6.1 SD) for the treatment group and 23.6 milliseconds (+/-5.5 SD) for the placebo group (p = 0.17). In a subset of 15 patients with CSF studies, SAM levels increased in the l-methionine but not in the placebo group (p = 0.07). There was no significant effect of treatment on strength, spasticity, or urinary function. CONCLUSIONS: l-methionine was safe and well tolerated although in some patients induced an increase of serum homocysteine. There was a nonsignificant improvement in CCT in treated patients but no benefit in any of the clinical measures.

Distal myasthenia gravis frequency and clinical course in a large prospective series.

OBJECTIVES: In Myasthenia gravis (MG) proximal limb, ocular and/or bulbar muscles are most commonly affected, whereas distal extremity muscles are typically spared. The aim of the current study was to assess the frequency of primarily distal MG in the Tyrol and to describe its clinical peculiarities. MATERIAL AND METHODS: Over the past 20 years 84 patients with MG have undergone follow-up at the Department of Neurology of Innsbruck University. Types of presentation, clinical course and treatment response were followed over a period of 20 years (1980-2000). RESULTS: Six of 84 MG patients showed a predominance of muscle weakness and fatigability in distal limb muscles (two at presentation, four over the later course of the illness). There was no difference between distal MG and MG with a more typical distribution of muscle weakness regarding age, gender and response to therapy. CONCLUSIONS: The case series indicates that predominantly distal presentations of otherwise typical MG are more frequent than generally assumed and should be considered in the differential diagnosis of diseases with distal limb weakness.

Abnormal cobalamin-dependent transmethylation in AIDS-associated myelopathy.

BACKGROUND: White matter vacuolization of the spinal cord is common in patients with AIDS and may lead to clinical manifestations of myelopathy. The pathogenesis of AIDS-associated myelopathy (AM) is unknown and may be related to metabolic abnormalities rather than to direct HIV infection. The striking pathologic similarity between AM and the vacuolar myelopathy associated with vitamin B(12) deficiency suggests that abnormal metabolism of the B(12)-dependent transmethylation pathway may be important in the pathogenesis of AM. METHODS: The authors compared S-adenosyl-methionine (SAM), methionine, homocysteine, and glutathione in serum and CSF of 15 patients with AM vs. 13 HIV-infected controls without myelopathy (HWM). They also compared the results with a non-HIV--infected reference population (NC). All patients had normal B(12), folate, and methylmalonic acid levels. RESULTS: There was a decrease in CSF SAM in the AM group compared with the HWM group (p < 0.0001) and the NC group (p < 0.0001). CSF SAM in the HWM group was also lower than that in the NC group (p = 0.015). Serum methionine was also reduced in serum of the myelopathic group compared with the NC group (p = 0.006). CONCLUSIONS: AM is associated with an abnormality of the vitamin B(12)-dependent transmethylation pathway.

[Possible value of positive PSA levels in malignant and nonmalignant breast diseases]. / Mögliche Bedeutung eines positiven PSA-Nachweises bei Patientinnen mit benignen und malignen Erkrankungen der Brust.

Measurement of serum levels of PSA is widely used as a screening tool for prostate cancer. PSA has been shown to be associated with malignancies of many other organs than prostate, including the female breast. Therefore, PSA is not prostate-specific. PSA serum levels in females increase with excess of androgens. Variable PSA expression was observed in membranes of adipocytes of fat tissue and in the endothelium of small vessels in female and male breast. There is increasing evidence that androgens play a significant role in the development and progression of breast cancer. 5alpha-reductase is an enzyme that is expressed in androgen-dependent tissues, including the female breast, catalyzing the reduction of testosterone to its more bioactive form, dihydrotestosterone, which then transactivates a number of genes. One of these genes encodes for PSA, a favorable prognostic factor in breast cancer. Interactions of PSA and sex hormones in physiological processes and in prostatic and mammary cancer have been reported. The possible influence of PSA on breast cancer growth and progression and even its physiological functions are still under controversial debate. There are some findings which might indicate similarities in the influence of steroid hormones on the development of prostate and breast malignancies, perhaps a unique hormone-dependent molecular pathway for both types of cancer.

COMT-dependent protection of dopaminergic neurons by methionine, dimethionine and S-adenosylmethionine (SAM) against L-dopa toxicity in vitro.

L-dopa may be toxic to dopamine neurons, possibly due to catechol-autoxidation. Catechols are O-methylated by catechol-O-methyltransferase (COMT) in a SAM consuming reaction, preventing the initiation of catechol autoxidation. We hypothesized that SAM or SAM-precursors ameliorate L-dopa neurotoxicity, in a COMT-dependent fashion. We tested this hypothesis in primary mesencephalic cultures by adding 200 microM L-dopa with 2 mM methionine or 1 mM dimethionine or 0.5 mM SAM with or without 0.2 microM of the COMT-inhibitor 2', 5'-dinitrocatechol (OR 486). L-dopa was found to be neurotoxic as the surviving neurons had fewer and shorter processes. Methionine, dimethionine and SAM all protected DA neurons against damaged induced by L-dopa. The COMT inhibitor dinitrocatechol (DNC) completely abolished the protective effect against L-dopa toxicity. We conclude that supplementation with methionine, dimethionine or SAM ameliorates L-dopa neurotoxicity to dopamine neurons, while inhibition of COMT may aggravate or unmask L-dopa neurotoxicity.

S-Adenosyl-Methionine improves depression in patients with Parkinson's disease in an open-label clinical trial.

We report a pilot study of S-adenosyl-methionine (SAM) in 13 depressed patients with Parkinson's disease. All patients had been previously treated with other antidepressant agents and had no significant benefit or had intolerable side effects. SAM was administered in doses of 800 to 3600 mg per day for a period of 10 weeks. Eleven patients completed the study, and 10 had at least a 50% improvement on the 17-point Hamilton Depression Scale (HDS). One patient did not improve. Two patients prematurely terminated participation in the study because of increased anxiety. One patient experienced mild nausea, and another two patients developed mild diarrhea, which resolved spontaneously. The mean HDS score before treatment was 27.09 +/- 6.04 (mean +/- standard deviation) and was 9.55 +/- 7.29 after SAM treatment (p < 0.0001). Although uncontrolled and preliminary, this study suggests that SAM is well tolerated and may be a safe and effective alternative to the antidepressant agents currently used in patients with Parkinson's disease.

AIDS myelopathy is not associated with elevated HIV viral load in cerebrospinal fluid.

The pathogenesis of AIDS-associated myelopathy is unknown. Elevated HIV-1 viral load in CSF has been associated with cognitive impairment. The authors investigated if a similar association exists in patients with myelopathy. The authors evaluated levels of HIV-1 RNA in the CSF of 16 individuals with AIDS myelopathy and in 16 nonmyelopathic HIV-infected control subjects. There was no correlation between levels of HIV-1 RNA and the presence or severity of myelopathy.

Phenol sulphotransferase SULT1A1 polymorphism in prostate cancer: lack of association.

Preliminary evidence suggests that genetic polymorphisms in certain enzymes involved in xenobiotic metabolism and chemical defense could modify a susceptibility to prostate cancer. In the present study, two recently described phenol sulphotransferase SULT1A1 alleles (SULT1A1*1, SULT1A1*2) were investigated using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) approach. Genotyping was performed on DNA isolated from white blood cells from 134 patients with prostate cancer and 184 healthy control subjects. Both the prostate cancer patients and the controls demonstrated similar frequencies of the variant allele SULT1A1*2 (35.1% vs 39.1%). Homozygosity for the variant allele was slightly less frequent in cancer patients than controls (12.7% vs 17.4%). Our study does not support the hypothesis that the phenol sulphotransferase variant allele SULT1A1*2 with a G/A transition at nucleotide 638 is a risk modifier for prostate cancer in the Caucasian population.