Differential uptake of estramustine phosphate metabolites and its correlation with the levels of estramustine binding protein in prostate tumor tissue

Estracyt (EMP) has been used for the treatment of hormone refractory prostate cancer for many years. Recently, new data from combination studies have given rise to new interest in this old drug. Explanations for the synergy found in the clinic are many, but one major factor may be the previous indication that the drug accumulates in the prostate tumor. We have, therefore, examined the level of the four metabolites, estromustine (EoM), estramustine (EaM), estrone, and estradiol in the tumor and serum of 14 patients with T2 and T3 prostate cancer receiving a single i.v. dose of 600 mg of EMP, about 12 h before radical prostatectomy. Because it has been suggested that the uptake into the prostate tumor is due to binding to the estramustine binding protein (EMBP), we have in addition measured the level of EMBP in the prostate tumor tissue. The main serum and tissue metabolite in all patients was EoM followed by EaM, estrone, and estradiol. The levels for EoM ranged from 63.8-162.8 ng/ml in the serum and from 64.8-1209 ng/ml in the prostate tumor, resulting in a mean ratio for serum to tumor of 1:5. The levels for EaM ranged from 8.3-51.4 ng/ml in the serum and 73.9-563.4 ng/ml in the tumor, giving a mean ratio for serum to tumor of 1:13. The levels of EMBP were higher in T3 tumors than in T2 tumors, 54.1 and 40.7 ng/g tissue, respectively. A significant correlation was found between the levels of EaM (r = 0.60) and the levels of EMBP in the tumor. These data demonstrate that 12 h after a single i.v. dose of 600 mg of EMP the levels of the cytotoxic metabolites EoM and EaM are substantially higher in the tumor than in the serum of the same patient and that a correlation exists between the levels of EaM in the tumor and the levels of EMBP. Thus, this supports the hypothesis that the EMBP is responsible for the retention of EoM and EaM in the prostate tumor.     

Psychiatric manifestations of multiple sclerosis: a review

OBJECTIVE: To report the occurrence, type, causes, and management of psychiatric manifestations in multiple sclerosis (MS). METHOD: Review of recent, relevant literature. RESULTS: Psychiatric illness, especially depression, occurs much more frequently than expected in patients with MS, is frequently unrecognized or ignored, and is treatable using standard methods, although patients with MS may be unusually sensitive to side effects of tricyclic antidepressants. CONCLUSIONS: Research is needed to better define the causes of psychiatric syndromes in patients with MS. Those treating MS should increase their awareness of and sensitivity to the likelihood of psychiatric disorder in these patients.     

Association between bleomycin hydrolase and Alzheimer's disease in caucasians

A recent study showed modest evidence for an increased frequency of the bleomycin hydrolase (BH) V/V genotype in Alzheimer's disease (AD) patients compared with non-demented controls. To test this hypothesis, we examined this polymorphism in 621 rigorously evaluated patients and 502 control subjects (all caucasian) but were unable to detect an association between BH and AD even after controlling for age, gender, and apolipoprotein E (ApoE) genotype. We conclude that this polymorphism does not account for inherited susceptibility to AD in the populations represented in this sample.     

Dicationic furans inhibit development of Cryptosporidium parvum in HSD/ICR suckling Swiss mice

The efficacy of dicationic diarylfurans was evaluated against Cryptosporidium parvum by a suckling murine model. Candidate drugs were solubilized or suspended in deionized water and administered orally at a constant dose rate on days 0-5 (treatment day 0) to suckling ICR Swiss mice experimentally inoculated with oocysts of C. parvum. Efficacy was based on numbers of oocysts recovered from the intestinal tracts of mice subjected to necropsy examination on day 6. Numerous candidate furans significantly reduced the numbers of oocysts recovered from treated mice compared with control mice. Compounds 1, 2, 4, and 9 demonstrated superior efficacies (10% of controls or better) against C. parvum. Compounds 3, 5, 6, 7, 8, 11, 17, 18, and 19 also significantly reduced the numbers of oocysts recovered from treated mice but demonstrated efficacies ranging from 17 to 65% of controls. Compound 4 was particularly efficacious against C. parvum at a dosage as low as 8.5 mg/kg of body weight. Compound 4 is identified as a lead compound for additional studies in other animal models.     

Endothelial cell injury caused by Candida albicans is dependent on iron

MRL-lpr/lpr mice spontaneously develop manifestations of autoimmunity including arthritis, vasculitis, and glomerulonephritis. The paramagnetic molecule nitric oxide has been implicated as an effector molecule in initiation and propagation of these inflammatory conditions. In this study, we utilized electron paramagnetic resonance spectroscopy to directly detect nitrosylated protein complexes as products of nitric oxide in whole blood and in kidneys of MRL-lpr/lpr mice. Electron paramagnetic resonance spectra of blood samples from MRL-lpr/lpr mice showed nitrosyl hemoglobin species. Amounts of blood nitrosyl hemoglobin in MRL-lpr/lpr mice were significantly increased as compared to age-matched control mice. Electron paramagnetic resonance spectra of MRL-lpr/lpr kidney tissue exhibited a signal characteristic of a dinitrosyl-iron-dithiolate complex at g approximately 2.04. Formation of nitrosylated nonheme protein in diseased kidneys is associated with development of glomerulonephritis in the autoimmune mice. The presence of nitrosylated nonheme protein indicates the formation of nitric oxide within the kidneys of the diseased mice signifying in situ renal nitric oxide formation.     

Rhegmatogenous retinal detachment and hypertension: Schwartz-Matsuo syndrome

BACKGROUND: The pathophysiology of hypertensive crises is poorly understood. To date, no information is available about genetic determinants underlying the individual risk for development of hypertensive urgencies or emergencies. Recently, mutations in the beta subunit (h beta ENaC) and the gamma subunit (h gamma ENaC) of the human epithelial sodium channel (hENaC) have been shown to result in excessive elevation of blood pressure in patients with Liddle's syndrome. METHODS: Using polymerase chain reaction and direct sequencing of amplification products we have screened 90 consecutive out-patients with hypertensive urgency or hypertensive emergency for the presence of mutations in the carboxy terminus of these genes. Furthermore, serum potassium concentrations were determined in all 90 patients, and serum aldosterone levels and plasma renin activity were measured in a subset of 34 patients. RESULTS: Among 71 patients with hypertensive urgency (78.9%) and 19 patients with hypertensive emergency (21.1%) not one individual showed a mutation in genomic DNA extending from codon 532 to codon 637 of h beta ENaC and from codon 525 to codon 651 of h gamma ENaC. Twelve of 90 patients showed mild hypokalaemia (13.3%), 16 of 34 patients had a plasma renin activity below the lower normal range (47.1%) and one of 34 patients had a low serum aldosterone concentration (2.9%). CONCLUSIONS: The present study clearly demonstrates the absence of mutations in the carboxy terminus of the h beta ENaC and h gamma ENaC gene of hENaC in an Austrian cohort of 90 patients suffering from hypertensive crisis.     

Relative strength of scleral tunnel incisions with internal corneal lips constructed in cadaver eyes

We constructed scleral tunnel wounds with internal corneal lips and sutureless closures in ten cadaver eyes without previous intraocular surgery. Each wound differed in width, total incision length, and internal corneal lip size. At a low and high range of initial intraocular pressure (IOP, 10 to 15 mm Hg or 20 to 25 mm Hg), we compared the wounds' resistance to leakage during application of external pressure. A square wound with a 4.0 mm width and 4.0 mm overall length, including a 1.5 mm corneal lip, had the optimum wound dimensions. These produced a stable incision that resisted leakage at external pressures up to 525 pounds per square inch equally well at both IOP ranges. Leakage occurred at lower external pressures for wounds with greater width, smaller corneal lips, or wound widths that were greater than wound lengths; such wounds were also more prone to leakage at the low IOP range. When constructed properly and adequately, the 4.0 mm wide scleral tunnel incision with 1.5 mm internal corneal lip is a strong and safe wound for sutureless cataract surgery.     

Crystal structure of the DpnM DNA adenine methyltransferase from the DpnII restriction system of streptococcus pneumoniae bound to S-adenosylmethionine

BACKGROUND:. Methyltransferases (Mtases) catalyze the transfer of methyl groups from S-adenosylmethionine (AdoMet) to a variety of small molecular and macromolecular substrates. These enzymes contain a characteristic alpha/beta structural fold. Four groups of DNA Mtases have been defined and representative structures have been determined for three groups. DpnM is a DNA Mtase that acts on adenine N6 in the sequence GATC; the enzyme represents group alpha DNA Mtases, for which no structures are known. RESULTS:. The structure of DpnM in complex with AdoMet was determined at 1.80 A resolution. The protein comprises a consensus Mtase fold with a helical cluster insert. DpnM binds AdoMet in a similar manner to most other Mtases and the enzyme contains a hollow that can accommodate DNA. The helical cluster supports a shelf within the hollow that may recognize the target sequence. Modeling studies indicate a potential site for binding the target adenine, everted from the DNA helix. Comparison of the DpnM structure and sequences of group alpha DNA Mtases indicates that the group is a genetically related family. Structural comparisons show DpnM to be most similar to a small-molecule Mtase and then to macromolecular Mtases, although several dehydrogenases show greater similarity than one DNA Mtase. CONCLUSIONS:. DpnM, and by extension the DpnM family or group alpha Mtases, contains the consensus fold and AdoMet-binding motifs found in most Mtases. Structural considerations suggest that macromolecular Mtases evolved from small-molecule Mtases, with different groups of DNA Mtases evolving independently. Mtases may have evolved from dehydrogenases. Comparison of these enzymes indicates that in protein evolution, the structural fold is most highly conserved, then function and lastly sequence.