Search PubMed⌕ Search

Biomedical subjects

T Weber

Publications and source records attributed to T Weber.

At least 127 records · Page 7Linked to original sources
PubMed2000

Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men.

Transdermal delivery of testosterone (T) represents an effective alternative to injectable androgens. Transdermal T patches normalize serum T levels and reverse the symptoms of androgen deficiency in hypogonadal men. However, the acceptance of the closed system T patches has been limited by skin irritation and/or lack of adherence. T gels have been proposed as delivery modes that minimize these problems. In this study we examined the pharmacokinetic profiles after 1, 30, 90, and 180 days of daily application of 2 doses of T gel (50 and 100 mg T in 5 and 10 g gel, delivering 5 and 10 mg T/day, respectively) and a permeation-enhanced T patch (2 patches delivering 5 mg T/day) in 227 hypogonadal men. This new 1% hydroalcoholic T gel formulation when applied to the upper arms, shoulders, and abdomen dried within a few minutes, and about 9-14% of the T applied was bioavailable. After 90 days of T gel treatment, the dose was titrated up (50 mg to 75 mg) or down (100 mg to 75 mg) if the preapplication serum T levels were outside the normal adult male range. Serum T rose rapidly into the normal adult male range on day 1 with the first T gel or patch application. Our previous study showed that steady state T levels were achieved 48-72 h after first application of the gel. The pharmacokinetic parameters for serum total and free T were very similar on days 30, 90, and 180 in all treatment groups. After repeated daily application of the T formulations for 180 days, the average serum T level over the 24-h sampling period (C(avg)) was highest in the 100 mg T gel group (1.4- and 1.9-fold higher than the C(avg) in the 50 mg T gel and T patch groups, respectively). Mean serum steady state T levels remained stable over the 180 days of T gel application. Upward dose adjustment from T gel 50 to 75 mg/day did not significantly increase the C(avg), whereas downward dose adjustment from 100 to 75 mg/day reduced serum T levels to the normal range for most patients. Serum free T levels paralleled those of serum total T, and the percent free T was not changed with transdermal T preparations. The serum dihydrotestosterone C(avg) rose 1.3-fold above baseline after T patch application, but was more significantly increased by 3.6- and 4.6-fold with T gel 50 and 100 mg/day, respectively, resulting in a small, but significant, increase in the serum dihydrotestosterone/T ratios in the two T gel groups. Serum estradiol rose, and serum LH and FSH levels were suppressed proportionately with serum T in all study groups; serum sex hormone-binding globulin showed small decreases that were significant only in the 100 mg T gel group. We conclude that transdermal T gel application can efficiently and rapidly increase serum T and free T levels in hypogonadal men to within the normal range. Transdermal T gel provided flexibility in dosing with little skin irritation and a low discontinuation rate.

Administration, Cutaneous↗
PubMed2000

Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men.

Testosterone (T) therapy for hypogonadal men should correct the clinical abnormalities of T deficiency, including improvement of sexual function, increase in muscle mass and strength, and decrease in fat mass, with minimal adverse effects. We have shown that administration of a new transdermal T gel formulation to hypogonadal men provided dose proportional increases in serum T levels to the normal adult male range. We now report the effects of 180 days of treatment with this 1% T gel preparation (50 or 100 mg/day, contained in 5 or 10 g gel, respectively) compared to those of a permeation-enhanced T patch (5 mg/day) on defined efficacy parameters in 227 hypogonadal men. In the T gel groups, the T dose was adjusted up or down to 75 mg/day (contained in 7.5 g gel) on day 90 if serum T concentrations were below or above the normal male range. No dose adjustment was made with the T patch group. Sexual function and mood changes were monitored by questionnaire, body composition was determined by dual energy x-ray absorptiometry, and muscle strength was measured by the one repetitive maximum technique on bench and leg press exercises. Sexual function and mood improved maximally on day 30 of treatment, without differences across groups, and showed no further improvement with continuation of treatment. Mean muscle strength in the leg press exercise increased by 11 to 13 kg in all treatment groups by 90 days and did not improve further at 180 days of treatment. Moderate increases were also observed in arm/chest muscle strength. At 90 days of treatment, lean body mass increased more in the 100 mg/day T gel group (2.74 +/- 0.28 kg; P = 0.0002) than in the 50 mg/day T gel (1.28 +/- 0.32 kg) and T patch groups (1.20 +/- 0.26 kg). Fat mass and percent fat were not significantly decreased in the T patch group, but showed decreases in the T gel groups (50 mg/day, -0.90 +/- 0.32 kg; 100 mg/day, - 1.05 +/- 0.22 kg). The increase in lean mass and the decrease in fat mass were correlated with the changes in average serum T levels attained after transdermal T replacement. These beneficial effects of T replacement were accompanied by the anticipated increases in hematocrit and hemoglobin but without significant changes in the lipid profile. The increase in mean serum prostate-specific antigen levels (within the normal range) was correlated with serum levels of T. The greatest increases were noted in the 100 mg/day T gel group. Skin irritation was reported in 5.5% of subjects treated with T gel and in 66% of subjects in the permeation-enhanced T patch group. We conclude that T gel replacement improved sexual function and mood, increased lean mass and muscle strength (principally in the legs), and decreased fat mass in hypogonadal men with less skin irritation and discontinuation compared with the recommended dose of the permeation-enhanced T patch.

Administration, Cutaneous↗
PubMed2000

Analysis of the transcriptional control region in progressive multifocal leukoencephalopathy.

Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease caused by the human polyomavirus JCV. The hypervariable noncoding transcriptional control region (TCR) largely regulates replication of JCV in glial cells. Two distinct types of the TCR can be distinguished. Type II is derived from the archetype sequence. All type I TCRs, including the prototypical Mad-1 isolate contain a 23 bp deletion at nucleotide position 36. In a prospective study, TCR-DNA could be amplified and sequenced in 16/29 (55%) suspect cases of PML from the cerebrospinal fluid (CSF) and in 14/28 (50%) urine samples. Sequencing of the CSF-TCR identified Mad-1 like sequences in 5/17 (29.5%) instances and a type II TCR in 12/17 (70.5%) of cases. Of 14 urine TCRs, 12 (86%) displayed the archetype sequence, while two showed complex rearrangements. In all type II TCR sequences, the tst-1/oct-6 binding sites present in regions C and E of Mad-1 were missing. In 11/12 type II TCR sequences the pentanucleotide repeat in region A showed a G to T substitution of one nucleotide at position 36 relative to the Mad-1 TCR. All type II TCRs contained an Sp1 binding site at the beginning of region B. Of the 12 TCR type II sequences, 10 (83%) were of the 'D-retaining' pattern. In eight of these (80%) additional juxtapositioned nuclear factor 1, glial factor 1 and/or AP-1 binding motifs were created by duplications and/or insertions in region D. These findings indicate that type II TCRs are frequently present in PML and suggest to use TCR type II constructs for in vitro and in vivo studies of the evaluation of the functional role of DNA binding motifs.

Base Sequence↗
PubMed1999

Rapid and efficient fusion of phospholipid vesicles by the alpha-helical core of a SNARE complex in the absence of an N-terminal regulatory domain.

A protease-resistant core domain of the neuronal SNARE complex consists of an alpha-helical bundle similar to the proposed fusogenic core of viral fusion proteins [Skehel, J. J. & Wiley, D. C. (1998) Cell 95, 871-874]. We find that the isolated core of a SNARE complex efficiently fuses artificial bilayers and does so faster than full length SNAREs. Unexpectedly, a dramatic increase in speed results from removal of the N-terminal domain of the t-SNARE syntaxin, which does not affect the rate of assembly of v-t SNARES. In the absence of this negative regulatory domain, the half-time for fusion of an entire population of lipid vesicles by isolated SNARE cores ( approximately 10 min) is compatible with the kinetics of fusion in many cell types.

Lipid Bilayers↗
PubMed1999

Content mixing and membrane integrity during membrane fusion driven by pairing of isolated v-SNAREs and t-SNAREs.

Membrane bilayer fusion has been shown to be mediated by v- and t-SNAREs initially present in separate populations of liposomes and to occur with high efficiency at a physiologically meaningful rate. Lipid mixing was demonstrated to involve both the inner and the outer leaflets of the membrane bilayer. Here, we use a fusion assay that relies on duplex formation of oligonucleotides introduced in separate liposome populations and report that SNARE proteins suffice to mediate complete membrane fusion accompanied by mixing of luminal content. We also find that SNARE-mediated membrane fusion does not compromise the integrity of liposomes.

Base Sequence↗
PubMed1999

Cathepsin D targeted by acid sphingomyelinase-derived ceramide.

Ceramide has been recognized as a common intracellular second messenger for various cytokines, growth factors and other stimuli, such as CD95, chemotherapeutic drugs and stress factors. To understand the role of ceramide during apoptosis and other cellular responses, it is critically important to characterize direct targets of ceramide action. In this paper, we show that ceramide specifically binds to and activates the endosomal acidic aspartate protease cathepsin D. Direct interaction of ceramide with cathepsin D results in autocatalytic proteolysis of the 52 kDa pre-pro cathepsin D to form the enzymatically active 48/32 kDa isoforms of cathepsin D. Acid sphingomyelinase (A-SMase)-deficient cells show decreased cathepsin D activity, which could be reconstituted by transfection with A-SMase cDNA. The results of our study identify cathepsin D as the first endosomal ceramide target that colocalizes with and may mediate downstream signaling effects of A-SMase.

Animals↗
PubMed1999

Adverse endometrial effects during long cycle hormone replacement therapy. Scandinavian Long Cycle Study Group.

OBJECTIVES: Treatment with unopposed estrogen is known to increase the risk of endometrial hyperplasia, atypia, and carcinoma, and therefore the administration of a progestin during hormone replacement therapy (HRT) is recommended. The addition of a progestin may cause unwanted side effects. Progestin administration of various durations are therefore used in HRT. STUDY DESIGN: Data were obtained about endometrial histopathology, bleeding interval and compliance in 240 early postmenopausal women receiving HRT with a progestin administered for 10 days during 12 week or 4 week cycles of estrogen administration. These regimens were studied for as long as 4 years. The daily estrogen given was 17beta-estradiol 2 mg per day which was reduced to 1 mg day during the last 6 days of each cycle. The progestin used was norethindrone acetate, given at a dose of 1 mg per day. RESULTS: The incidence of endometrial hyperplastic changes, i.e. simple or complex hyperplasia, atypia or cancer, was significantly higher in the 12 weeks cycle than in the monthly cycle group (P = 0.003), with an overall annual incidence of 5.6% in the 12 weeks cycle group and 1% in the monthly cycle group. One case of atypical hyperplasia and one case of endometrial adenocarcinoma was observed in the long cycle group. Long cycle treatment produced more irregular bleeding pattern. Accordingly, the rate of drop-out due to bleeding was significantly higher in the long cycle group (P<0.01). CONCLUSION: We conclude that the long cycle HRT modality investigated did not improve compliance and may increase the risk of endometrial hyperplasia and eventually cancer compared to conventional HRT with a monthly cycle. Caution using long cycle HRT regimens is advisable, and careful monitoring of the endometrium during treatment is recommended.

Biopsy↗
PubMed1999

[Analysis of referral diagnoses of patients with normal coronary angiogram].

BACKGROUND AND AIMS: Angiography permits an evaluation of the morphology of the coronary artery, stratification of risk and optimal therapeutic management in patients with suspected coronary artery disease (CAD). The sophisticated apparatus, cost and invasiveness of the procedure necessitate well-considered application of this method. In spite of an exact documentation of the patient's medical history and careful establishment of the indication, the results of angiography are often normal. Therefore, it appears important to analyse the referral diagnoses in patients with normal coronary angiograms. PATIENTS AND METHODS: We studied 1000 consecutive patients (625 men, 375 women, mean age 63.1 years) who underwent coronary angiography at our institution from January to May 1998. All patients were included in the retrospective analysis of the referral diagnoses. RESULTS: 875 patients (554 men, 321 women) were referred due to suspected CAD; 173 of these had normal angiographic findings (20%; 73 men, 100 women; mean age 58.4 years). The referral diagnoses were as follows: unstable angina in 62 patients (36%), stable angina in 40 patients (23%), chest pain and pathological findings of non-invasive testing in 32 patients (19%), atypical chest pain in 25 patients (14%), previous myocardial infarction and multiple risk factors in 7 patients each (4% each). Gender-related differences were remarkable. Only 73 of the 554 referred men (13%) had normal angiographic findings, whereas in women the rate of normal results was more than twofold higher, i.e. 100 of the 321 referred women (31%) had normal angiographic findings (p < 0.01). CONCLUSIONS: Among 875 patients referred to our catheter laboratory for coronary angiography due to suspected CAD, normal angiographic results were documented in 20%. The high frequency of the referral diagnosis 'unstable angina' and 'pathological result of noninvasive testing' was as remarkable as the high proportion of women among patients with normal findings.

Adult↗
PubMed1999

alpha-tocopheryl succinate-induced apoptosis in Jurkat T cells involves caspase-3 activation, and both lysosomal and mitochondrial destabilisation.

Alpha-Tocopheryl succinate (alpha-TOS), but not a-tocopherol, triggered apoptosis in Jurkat T cells. Apoptosis was induced by alpha-TOS in a time- and concentration-dependent mode, and signs of apoptosis were visible at concentrations of alpha-TOS as low as 30 microM, and within 3-5 h after addition of the ester. Employing a specific fluorogenic substrate, caspase-3 was found to be activated rapidly in response to alpha-TOS at 50 microM. We also found that Jurkat T cells challenged with alpha-TOS, when exposed to the lysosomotropic weak base acridine orange, showed decreased lysosomal uptake of the dye. This is suggestive of the involvement of lysosomal destabilisation in apoptosis of the cells. Apoptosis of Jurkat T cells induced with alpha-TOS also involved a drop in the mitochondrial membrane potential, although this phenomenon occurred after the initiation of lysosomal rupture. All apoptotic features observed with alpha-TOS were very similar to those found when cross-linking of the Fas receptor triggered apoptosis. These findings are consistent with the recent idea that vitamin E can contribute to elimination of malignant cells by the induction of apoptosis, and can be of (patho)physiological significance.

Apoptosis↗
PubMed1999

The Enterococcus hirae copper chaperone CopZ delivers copper(I) to the CopY repressor.

Expression of the cop operon which effects copper homeostasis in Enterococcus hirae is controlled by the copper responsive repressor CopY. Purified Zn(II)CopY binds to a synthetic cop promoter fragment in vitro. Here we show that the 8 kDa protein CopZ acts as a copper chaperone by specifically delivering copper(I) to Zn(II)CopY and releasing CopY from the DNA. As shown by gel filtration and luminescence spectroscopy, two copper(I) are thereby quantitatively transferred from Cu(I)CopZ to Zn(II)CopY, with displacement of the zinc(II) and transfer of copper from a non-luminescent, exposed, binding site in CopZ to a luminescent, solvent shielded, binding site in CopY.

Amino Acid Sequence↗
PubMed1999

Accuracy of biopsy and cytology for the preoperative diagnosis of colorectal adenocarcinoma.

BACKGROUND AND OBJECTIVES: Endoscopic biopsy for the diagnosis of colorectal adenocarcinoma is not accurate in every case. Brush cytology can increase the sensitivity for the diagnosis of gastroesophageal lesions when combined with biopsy, but very little information is available for these techniques in the diagnosis of colorectal adenocarcinoma. METHODS: A retrospective medical records review of 110 patients was performed. All patients underwent a colorectal resection for primary adenocarcinoma after a diagnostic endoscopy. Biopsy and brush cytology was evaluated for their respective sensitivity. Seventy-three patients had both biopsy and cytology. RESULTS: The sensitivity of biopsy was 83.6% (92/110); for cytology, 78.1% (57/73; P = 0.44). From the 73 patients who had both diagnostic techniques, 68.5% (50/73) had both positive biopsy and cytology, 12.3% (9/73) only a positive biopsy, and 9.6% (7/73) only a positive cytology. The two techniques combined were not significantly superior to biopsy alone (90.4%, 66/73, vs. 80.8%, 59/73, respectively; P = 0.16), but tended to be superior to cytology alone (P = 0.07). CONCLUSIONS: Cytology and biopsy have a comparable sensitivity. The combination of the two techniques compares favorably, but does not significantly increase the sensitivity of biopsy alone. Both techniques should be used whenever there are any uncertainties concerning the diagnosis of colorectal adenocarcinoma.

Adenocarcinoma↗
PubMed1999

Disseminated peritoneal adenomucinosis: a critical review.

BACKGROUND: The term pseudomyxoma peritonei has been used in reference to any condition, benign or malignant, in which the peritoneal cavity becomes filled with a gelatinous substance. The term is nonspecific and does not denote therapeutic or prognostic significance. Controversy centers around which patients benefit from and should be treated by aggressive surgical debulking. METHODS: A review of the current literature pertaining to the classification, treatment, and prognosis of patients with pseudomyxoma peritonei was undertaken. RESULTS: Disseminated peritoneal adenomucinosis refers to a subset of patients with pseudomyxoma peritonei who derive the greatest long-term benefit from multimodality therapy including aggressive surgical debulking. These patients have a benign form of the disease in which the peritoneal implants are derived from the extrusion of epithelial cells from an adenoma of the appendix. The pathophysiology of mucin deposition is defined by the redistribution phenomenon. The adenomatous cells are distributed according to the fluid flow and gravitational forces within the peritoneal cavity. The small bowel is relatively spared until late in the disease (visceral sparing), and therefore aggressive surgical debulking should be attempted at the first laparotomy by an experienced surgeon. Preoperative computed tomographic imaging can establish the diagnosis and aid in defining which groups of patients are resectable for cure. CONCLUSIONS: Attempts at curative treatment should include aggressive debulking and intraperitoneal chemotherapy. Those patients with a high-grade malignant process should be treated symptomatically, because aggressive therapy is associated with high morbidity rates and no long-term improvement in survival.

Humans↗
PubMed1999

The length of the flexible SNAREpin juxtamembrane region is a critical determinant of SNARE-dependent fusion.

The topology of a SNARE complex bridging two docked vesicles could act as a mechanical couple to do work on the lipid bilayer resulting in fusion. To test this, we prepared a series of modified SNARE proteins and determined their effects on SNARE-dependent membrane fusion. When two helix-breaking proline residues are introduced into the juxtamembrane region of VAMP, there is little or no effect on fusion, and the same change in syntaxin 1A only reduced the extent and rate of fusion by half. The insertion of a flexible linker between the transmembrane domain and the conserved coiled-coil domain only moderately affected fusion; however, fusion efficiency systematically decreased with increasing length of the linker. Together, these results rule out a requirement for helical continuity and suggest that distance is a critical factor for membrane fusion.

Amino Acid Sequence↗
PubMed1999

Cerebrospinal fluid analysis for the diagnosis of human immunodeficiency virus-related neurologic diseases.

Although early attempts demonstrated increased amounts of p24 antigen in the cerebrospinal fluid (CSF) of AIDS patients with dementia (HADC), gene amplification based assays have recently shown a correlation between the HI virus load in CSF and dementia. Although these correlations are valid for a large population, current evidence does not favor the use of CSF HI virus load measurement for the diagnosis of HADC. By polymerase chain reaction, opportunistic infections of the central (CNS) and peripheral nervous system due to cytomegalovirus, JC virus, and herpes simplex virus types 1 and 2 and primary lymphoma caused by Epstein-Barr virus can be diagnosed with an overall sensitivity ranging from 76% to 98% and a specificity between 98% and 99.5%. In contrast, bacterial, protozal, and fungal infections of the CNS are still better diagnosed by conventional assays such as culture, antigen detection, and empirical therapy. Brain biopsy still remains the ultimate means of obtaining a specific diagnosis in selected cases.

Acquired Immunodeficiency Syndrome↗