Biomedical subjects
Publications and source records attributed to H Graf.
A new class of borneol esters that might be considered as biological analogs of paclitaxel regarding their action on microtubules has been found. By structure-activity optimizations, compounds stabilizing microtubules much better than paclitaxel while showing a remarkably reduced cytotoxic activity were obtained. This dissoziation will open completely new therapeutic areas.
Alterations in peripheral blood T-lymphocyte subsets have been implicated to play a role in the pathophysiology of estrogen deficiency-induced bone loss in postmenopausal women. The aim of this study was to investigate this hypothesis further by flow cytometric analysis of peripheral blood lymphocyte subpopulations together with bone histomorphometry using ovariectomized (OVX) rats as an experimental estrogen deficiency model. 104 female 6-month-old Wistar rats were either OVX or sham-operated (SHAM). Eight rats served as baseline controls. Groups of 8 SHAM and 8 OVX rats were killed 1, 2, 4, 6, 9, and 12 weeks after surgery. Blood was collected prior to sacrifice. In whole blood samples, subpopulations of peripheral lymphocytes were analyzed by flow cytometry using FITC- or PE-labeled monoclonal antibodies against rat CD5, CD4, and CD8. CD4 and CD8 positive T-lymphocytes were determined by a double-labeling technique. Serum samples were analyzed for estradiol and progesterone. The cancellous bone of the distal femoral metaphysis was analyzed by quantitative bone histomorphometry. Ovariectomy caused a statistically significant fall in serum estradiol and progesterone levels from 2 weeks postovariectomy until the end of the trial. Deterioration of cancellous bone structure and osteopenia in the distal femur of OVX rats became evident at 2 and 4 weeks postovariectomy, respectively. Flow cytometric analysis of peripheral blood lymphocytes revealed that, except for a transient increase in CD4 positive T-lymphocytes in OVX rats relative to SHAM animals at 1 week post-surgery, the number of CD5, CD4, or CD8 positive lymphocytes or the mean fluorescence per cell for these antigens in OVX rats remained unchanged throughout the study. Also the CD4+/CD8+ ratio of peripheral blood T-lymphocytes was not influenced by ovariectomy, and none of these parameters were significantly correlated with serum estradiol or progesterone levels. These results suggest that consistent changes in peripheral blood T-lymphocyte subpopulations are not demonstrable in OVX rats by the techniques applied in this study, and do not seem to play a pathogenetic role in the development of estrogen deficiency-induced bone loss in the rat.
The pituitary-specific transcription factor Pit-1/GHF-1 is responsible for pituitary development and expression of somatotrophs and lactotrophs as well as hormonal regulation of the prolactin (PRL) and thyrotropin (TSH) beta genes by thyrotropin-releasing hormone (TRH) and cyclic adenosine monophosphate (cAMP). Pit-1 gene mutations result in complete growth hormone (GH) and PRL deficiencies and variable degrees of TSH deficiency, producing the clinical syndrome of combined pituitary hormone deficiency (CPHD). Several cases of mutations in the Pit-1 gene have been reported; the most common one is a sporadic mutation altering an arginine (R) to a tryptophan (W) in codon 271, in one allele of the Pit-1 gene. We describe a case of a 38-year-old woman, born to consanguineous parents, presenting with growth failure and hypothyroidism. Growth failure was noted from early infancy, whereas hypothyroidism was only apparent from adolescence. She had almost undetectable GH and PRL levels and an inappropriate low TSH for very low triiodothyronine (T3) and thyroxine (T4) levels, while the remaining pituitary evaluation was normal. The pituitary gland was hypoplastic by magnetic resonance imaging. A point mutation in exon 6, monoallelic, causing a C to T substitution that changes amino acid 271 from Arg (R) to Trp (W) was identified. Children with Pit 1 mutations and delayed onset of hypothyroidism may be initially diagnosed as isolated GH deficiency.
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Within the last 20 years there was an important change in the operative treatment of breast cancer. New considerations on the tumor biology resulted to the conviction, that the operative radicality does not affect the overall survival rate. This was in addition the birth hour of the breast conserving surgery and of the efforts of reconstructive procedures of the female breast. Muscle flap procedures got more and more importance in clinical practice. This paper gives an overview on our concept of breast conserving therapy and primary reconstruction in case of carcinoma of the breast, which is based on oncoplastic aspects. With consideration this model we are enabled to improve the cosmetic results even in cases with larger tumors.
Hormone Replacement Therapy (HRT) is an approved strategy of health care. Its characteristic features and benefits for women in the perimenopausal and postmenopausal state are represented. HRT is justifiable and necessary for prophylaxis and therapy of estrogen deficiency. The risk of breast cancer is not or only little increased. HRT can even take place after the therapy of breast cancer, if the consequences of the ovarian hormone deficiency can be diminished only by this method. Then the advantages preponderate over the theoretically possible risks. The mortality of women ist rather reduced by HRT.
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The incidence of appendicitis is about 1:1000-1:1500 pregnancies. Therefore, it seems to be in pregnancy as frequent as in the general population. The common signs and symptoms of appendicitis are in pregnancy less reliable than in nonpregnant women. An important role to diagnose appendicitis in suspicious cases has the ultrasonography, first of all the "graded compression ultrasound". Appendicitis increases the rate of spontaneous abortions, preterm delivery, small for gestation babies, and neonatal mortality in the first 7 days of life. After appendectomy the rate for preterm deliveries is increased for seven days. After the 7th postoperative day the pregnancy usually continuous to term. There is no increase of malformations because of appendectomy. At the end of pregnancy appendicitis is frequently complicated by phlegmoneous and perforated forms of illness with and without peritonitis. Before 20th w.o.p. laparoscopy is a recommendable method to diagnose and treat appendicitis. After 20th week of pregnancy laparotomy should be preferred. Cesarean section is not recognized part of treatment for appendectomy and only to be performed for obstetric reasons. Tocolysis should be prevented because of risk of pulmonary injury.
In order to establish whether long-term itraconazole therapy can affect adrenal or testicular function, the adrenal response to corticotrophin and testosterone was evaluated by radioimmunoassay in 15 patients undergoing treatment for chromoblastomycosis. Mean cortisol and testosterone concentrations were 12.4 microg/dL and 454 ng/dL respectively at baseline and 15.4 microg/dL and 480 ng/dL respectively after 12.4+/-5.2 months of treatment with itraconazole (200-400 mg daily). Results were analysed using Student's t-test. There was no clinical or laboratory evidence of steroidogenic or androgenic impairment.
In this retrospective eight-years-study we examine factors to be considered responsible for higher perinatal mortality in twins, especially in twins with discordant body weight. As a main risk factor for this we find vaginal delivery, i.e. from a non-vertex position. Other additional reasons for the higher perinatal mortality of twins are prematurity (less than 34 weeks of gestation) and birthweight lower than 1500 grams. Early hospitalisation has a positive influence on that risk. The perinatal mortality in the second twin (6.7%) is twice as high as in the first twin. The highest perinatal mortality (17.6%), however, is in twins with discordant growth whereas the second twin had a higher birthweight at delivery (15% more than the first twin). In twins with discordant body weight cesarean section gives advantage to the second twin versus vaginal delivery from breech presentation.
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We characterized the cross-talk between activators of protein kinase A (PKA) and thyroid hormone (T3) in T3 receptor (TR)-mediated transcription. U937 cells were cotransfected with a plasmid expressing the TR and a reporter plasmid containing a T3 response element (TRE) oriented either as a direct repeat or as a palindrome upstream of the thymidine kinase promoter linked to the chloramphenicol acetyltransferase gene. T3 activated transcription by 10-fold. T3 response was potentiated 2.5-3-fold by activators of PKA, but an activator of protein kinase C or of guanylate kinase was ineffective. In the absence of T3, activators of PKA had no effect on transcription. TR heterodimerization with the retinoid X receptor may facilitate T3/PKA cross-talk because coexpression of the retinoid X receptor potentiated cross-talk. Synergy was not observed in JEG-3, F9, CV-1, HeLa, L929, and HTC cells, indicating that it may require cell-specific factors. Synergy required the DNA- and ligand-binding domains, but not the amino-terminal domain, indicating that T3- and TRE-induced conformational changes on the TR are essential for cross-talk. PKA phosphorylated the TR in vitro, suggesting that, like other nuclear receptors, the TR is a target for PKA. These results imply that PKA cross-talks with T3 at the level of the TRE-bound TR, enhancing its transcriptional activity in a cell-specific manner.
In breast cancer, the survival rate strongly depends on the number of lymph nodes involved. A drug with a specific inhibitory activity on lymph node and organ metastases would therefore be a candidate for adjuvant therapy after surgery. Prostacyclin and its stable analogues have been shown to interfere with certain steps of the metastatic cascade and to inhibit the number of lung colonies after i.v.-inoculation of various tumor cell lines. Our data reveal that cicaprost, a metabolically stable and orally active analogue of prostacyclin, has pronounced antimetastatic effects in a series of spontaneously metastasizing rodent tumors. In the SMT 2a and 13762 MTLn3 mammary carcinomas of the rat, cicaprost given daily from the day of tumor implantation strongly inhibits the number of lung metastases as well as lymph node weights without exerting an effect on the primary tumor. Even starting treatment when palpable primary tumors are present gives a pronounced antimetastatic activity. To demonstrate that cicaprost has an effect on metastases already settled in the respective organ, treatment was started after surgical removal of the primary tumor. In the SMT 2a tumor, a strong inhibition of the number of metastases was shown. Interestingly, a perioperative treatment schedule was also effective in both models used. As primary tumor growth in vivo or proliferation in vitro remained unchanged by cicaprost, its mode of action seems to be related to one or more mechanisms of the metastatic process. In tumor cell lines expressing a functional prostacyclin receptor, stimulated tumor cell migration is inhibited and changes of differentiation status are obvious. In conclusion, cicaprost strongly inhibits lymph node and organ metastases of spontaneously metastasizing rodent mammary tumors with a mode of action different from cytostatic or antihormonal drugs.
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Recent studies suggest that secondary hyperparathyroidism and/or vitamin D deficiency are responsible for the insulin resistance in chronic renal failure. We investigated the effect of a 12-week intravenous treatment with 1,25 dihydroxycholecalciferol on glucose metabolism in 10 hemodialysis patients compared with 10 healthy control subjects by the frequently-sampled intravenous glucose tolerance test, analyzed with the minimal model technique. Compared to control subjects, the uremic patients featured elevated levels of parathyroid hormone (432 +/- 60 vs. 41 +/- 4 ng/liter, P < 0.001), insulin resistance (insulin sensitivity index, SI: 4.9 +/- 0.8 vs. 9.5 +/- 0.9 min-1/(microU/ml), P < 0.002), increased posthepatic insulin delivery (6.48 +/- 2.48 vs. 2.73 +/- 3.14 nmol/liter in 4 hr, P < 0.001) and a reduced C-peptide fractional clearance (0.033 +/- 0.004 vs. 0.085 +/- 0.009 min-1, P < 0.0002). Following treatment with 1,25 dihydroxycholecalciferol, the parathyroid hormone levels decreased significantly to 237 +/- 30 ng/liter (P < 0.05), the insulin sensitivity index (SI: 9.6 +/- 2.2, P < 0.05) reached a value similar to that of control subjects, and posthepatic insulin delivery decreased to 4.63 +/- 0.83 nmol/liter in 4 hr (P < 0.01), while all the other parameters remained unchanged. In summary, uremic patients with secondary hyperparathyroidism were found to be severely insulin resistant and hyperinsulinemic. Intravenous vitamin D treatment led to a significant reduction of parathyroid hormone levels and to a complete normalization of insulin sensitivity in the hemodialysis patients. Thus, intravenous 1,25 dihydroxycholecalciferol improves insulin resistance in uremic patients, acting per se or by reducing secondary hyperparathyroidism.
Clarification of the reliability associated with probing attachment level measurements and with diagnostic rules derived from them is necessary to examine the potential of these measurements as reliable markers of the disease process and as an outcome measure in clinical treatment studies. The purpose of the present study was to describe and compare the longitudinal reliability of single and double probing attachment level measurable by estimating false positive and false negative rates. In 20 systemically healthy adults with untreated advanced adult periodontitis, probing attachment levels and probing depth were measured at 6 sites in all teeth at the start of the study, and every 30 days thereafter for 11 months. Attachment levels were double measured, using acrylic onlays providing reference points and an electronic pressure sensitive probe. Attachment loss from baseline of 2.5 mm or more was used to accept dynamic attachment loss. The statistical methods for the cross-sectional analysis included mean absolute differences between double measurements and cross-correlations. Longitudinal analyses, expressing estimates of diagnostic error rates were made using maximum likelihood methods. 5 measurement protocols were compared. The results showed that the mean absolute difference between replicate measurements was 0.095 mm in bicuspids and 0.107 mm in molars. The mean absolute differences decreased over time from 0. 128 mm in visit 3 to 0.08 mm in visit 7. Correlation coefficients for replicate measurements were higher than 0.98. In general, false positive rates were markedly lower (< or = 0.02) than false negative rates (< or = 0.31). The relative sample size required to obtain comparable statistical power, was minimized in premolars when using the first of 2 measurements or the mean of 2 measurements, and in molars when using the first of 2 measurements. The methodology used in the present study provides guidelines for designing clinical studies which maintain statistical power by balancing off examiner reliability and sample size.
Prophylactic drug monitoring of mefloquine and its carboxylic acid metabolite were studied in two patients with end-stage renal disease undergoing long-term hemodialysis treatment. The patients, short-term travellers to areas where malaria is endemic, took 250 mg of mefloquine (Lariam) once weekly for 2 weeks before and during their 3-week stay abroad and for one week after their return. Pre- and postdialysis blood samples were drawn before their departure and after their return. The concentration-time profiles of mefloquine and its metabolite in plasma samples taken before and after the 3- to 4-h dialysis sessions were similar. Mefloquine and its metabolite could not be detected in the dialysate. These findings show that mefloquine and its metabolite are not, or are very poorly, removed by hemodialysis. Concentrations in plasma and accumulation kinetics were similar to those reported for healthy volunteers and were associated with high prophylactic efficacy against malaria. No special dosage adjustments have to be made in patients undergoing hemodialysis treatment to achieve concentrations in plasma similar to those in healthy volunteers. The prophylactic dose of mefloquine could be given before, during, or after the hemodialysis session.