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H Martin

Publications and source records attributed to H Martin.

At least 37 records · Page 2Linked to original sources
PubMed2001

A model on the regulation of 3alpha-hydroxysteroid dehydrogenase/carbonyl reductase expression in Comamonas testosteroni.

3alpha-Hydroxysteroid dehydrogenase/carbonyl reductase (3alpha-HSD/CR) from Comamonas testosteroni is a key enzyme involved in the degradation of steroids and xenobiotic carbonyl compounds. The enzyme has recently been cloned and characterized by our group. A strong induction of enzyme activity is observed in the presence of steroids like testosterone. In the present investigation, two repressor proteins (Rep1 and Rep2) containing 78 and 420 amino acids, respectively, were found to regulate 3alpha-HSD/CR gene (hsdA) expression. Gel shift experiments showed that Rep2 binds to a 10 nucleotide sequence 9 bp upstream of the hsdA promoter. The deletion of this cis-regulating sequence significantly increases hsdA expression. About 1633 bp further upstream, a second ten nucleotide sequence, complementary to the first one, was found, which is also recognized by Rep2 and increases hsdA expression, if deleted. To purify the repressor proteins, the genes encoding each were cloned into His-tag expression vectors and overexpressed in Escherichia coli. Rep1 does not bind to DNA but may bind to 3alpha-HSD/CR mRNA as predicted by its secondary structure. Concluding from our data, induction of 3alpha-HSD/CR in C. testosteroni by steroids in fact appears to be a de-repression, where the steroidal 'inducer' prevents the binding of the two repressor proteins to the hsdA promoter and mRNA, respectively.

3-Hydroxysteroid Dehydrogenases↗
PubMed2001

Human 11beta-hydroxysteroid dehydrogenase 1/carbonyl reductase: additional domains for membrane attachment?

11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) is a membrane integrated glycoprotein, which physiologically performs the interconversion of active and inactive glucocorticoid hormones and which also participates in xenobiotic carbonyl compound detoxification. Since 11beta-HSD 1 is fixed to the endoplasmic reticulum (ER) with a N-terminal membrane spanning domain, the enzyme is very difficult to purify in an active state. Upon expression experiments in Escherichia coli, 11beta-HSD 1 turns out to be hardly soluble without detergents. This study describes attempts to increase the solubility of 11beta-HSD 1 via mutagenesis experiments by generating several truncated forms expressed in E. coli and the yeast Pichia pastoris. Furthermore, we investigated if the codon for methionine 31 in human 11beta-HSD 1 could serve as an alternative start codon, thereby leading to a soluble form of the enzyme, which lacks the membrane spanning segment. Our results show that deletion of the hydrophobic membrane spanning domain did not alter the solubility of the enzyme. In contrast, the enzyme remained bound to the ER membrane even without the N-terminal membrane anchor. However, activity could not be found, neither with the truncated protein expressed in E. coli nor with that expressed in P. pastoris. Hydrophobicity plots proved the hydrophobic nature of 11beta-HSD 1 and indicated the existence of additional membrane attachment sites within its primary structure.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2001

Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation.

Disease recurrence following stem cell transplantation (SCT) remains a major problem. Despite the sensitivity of leukaemias to chemotherapy and irradiation, conventional conditioning before SCT is limited by significant organ toxicity. Targeted irradiation of bone marrow and spleen by radioimmunotherapy may provide considerable dose escalation, with limited toxicity to non-target organs. In this study, 27 patients with high-risk or relapsing leukaemia were treated with rhenium-188-labelled CD66a,b,c,e radioimmunoconjugates (188Re-mAb) specific for normal bone marrow in addition to conventional conditioning with high-dose chemotherapy and 12 Gy total body irradiation prior to SCT. A mean activity of 10.2+/-2.1 (range 6.9-15.8) GBq 188Re-mAb was administered intravenously. Acute side-effects were assessed according to the CTC classification and patient outcome was determined. Mean radiation doses (Gy; range in parentheses) to relevant organs and whole body were as follows: 13.1 (6.5-22) to bone marrow, 11.6 (1.7-31.1) to spleen, 5.0 (2.0-11.7) to liver, 7.0 (2.3-11.6) to kidneys, 0.7 (0.3-1.3) to lungs and 1.4 (0.8-2.1) to the whole body. Stem cells engrafted in all patients within 9-18 days post SCT. Acute organ toxicity of grade II or less was observed. During follow-up for 25.4+/-5.3 (range 18-34) months, 4/27 (15%) patients died from relapse, and 9/27 (33%) from transplantation-related complications. Fourteen patients (52%) are still alive and in ongoing complete clinical remission. Radioimmunotherapy with the bone marrow-seeking 188Re-labelled CD66 mAb can double the dose to bone marrow and spleen without undue extramedullary acute organ toxicity, when given in addition to high-dose chemotherapy and 12 Gy TBI before allogeneic SCT. This intensified conditioning regimen may reduce the relapse rate of high-risk leukaemia.

Adolescent↗
PubMed2001

[Clinical laboratory diagnosis and aging. 3: Evaluation of a study of aging--complete blood and urine status].

The results of the determination of hematologic values from 262 men and 242 women, participants of an aging study and half of each group 44.4 +/- 0.9 and 63.0 +/- 0.9 (men) and 44.4 +/- 0.9 and 62.8 +/- 0.8 years old (women), respectively, are compared. In men, one analyte (hemoglobin decreasing) and four indices show significant differences (MCV increasing, MCH decreasing, MCHC decreasing, RDW increasing). In the older group, the iron level and the transferrin saturation are also significantly lower. In women, erythrocytes and the hematocrit are significantly higher in the older group whereas the indices MCH and MCHC are lower and the RDW increases. At the same time, the iron level, transferrin and the transferrin saturation decrease whereas ferritin doubles. The sex differences of the hematologic parameters are more pronounced in the younger participants and especially remarkable in ferritin in both age groups. The results of the semiquantitative analysis of ten urine parameters by reagent strip show differences with respect to sex (e.g., leucocytes and erythrocytes) and age (e.g., specific gravity, pH, nitrite, protein, erythrocytes). The usefulness of the estimation of glucose in urine is discussed in connection with the corresponding serum glucose levels.

Adult↗
PubMed2001

AC133 expression on acute myeloid leukemia blasts: correlation to FAB and to CD34 expression and possible implications for peripheral blood progenitor cell purging in AML.

AC133 is an antigen expressed on CD34+ hematopoietic progenitor cells. In acute myeloid leukemia (AML) it is expressed on leukemic blasts of most FAB subtypes. However, few data are available regarding coexpression of other surface antigens. We measured AC133 expression on AML blasts from 28 consecutive patients at initial diagnosis (n=26) or at diagnosis of first relapse (n=2) and on 26 leukapheresis products from 14 patients. In AML AC133 correlated with CD34 expression (Spearman r=0.4711, P=0.0114) and even stronger with combined CD34/CD33 expression (Spearman r=0.5083, P=0.0068). In leukapheresis products AC133 expression correlated with CD34 expression (Spearman r=0.7495, P=0.002) and the yield of the obtained amount of CD34+ cells (Spearman r=0.6484, P=0.0121). In conclusion AC133 expression is closely related to CD34 expression in AML. In leukapheresis products AC133 provides an additional marker for selection of PBPC autografts in AC133- AML.

AC133 Antigen↗
PubMed2001

Apoptosis in ultrasound-produced threshold lesions in the rabbit brain.

Focused ultrasound (US) surgery has been used to induce high temperature elevations in tissue to coagulate the proteins and kill the tissue. The introduction of noninvasive online temperature monitoring has made it possible to induce well-controlled thermal exposures. In this study, we used magnetic resonance imaging (MRI) thermometry to monitor thermal exposures near the threshold of tissue damage, and then investigated if apoptosis was induced. Rabbit brains were sonicated with an eight-sector phased array to create a large region of uniform temperature elevation at the end of a 30-s sonication. Histological examination demonstrated that apoptosis was induced in some cells. At 4 h after the sonications, the apoptotic cells constituted 9 +/- 7% of identifiable cells. By 48 h after the sonications, the number of apoptotic cells had increased up to 17 +/- 9%. The impact of this finding for therapy needs to be explored further.

Animals↗
PubMed2001

Hematologic and cytogenetic remission by STI571 (Glivec) in a patient relapsing with accelerated phase CML after second allogeneic stem cell transplantation.

We describe the clinical activity of the ABL kinase inhibitor STI571 in a patient with accelerated phase of chronic myeloid leukemia (CML) relapsing after a second allogeneic BMT and with minimal levels of donor chimerism. STI571 resulted in rapid elimination of leukemic cells with ensuing prolonged severe leukopenia and neutropenia complicated by neutropenic fever and colitis. Subsequent hematopoietic recovery was driven by donor derived cells and was associated with grade 3 graft-versus-host disease (GVHD). STI571 induced sustained hematological and cytogenetic remission combined with controllable GvHD, therapeutic goals not achieved by two preceding allogeneic transplants and repeated donor lymphocyte transfusions (DLT).

Antineoplastic Agents↗
PubMed2001

Older patients with high-risk fungal infections can be successfully allografted using non-myeloablative conditioning in combination with intensified supportive care regimens.

Leukaemic patients with advanced disease and severe fungal infections as well as older patients with substantial co-morbidity are usually excluded from conventional allotransplantation because of increased morbidity and mortality. We approached allogeneic transplantation in four patients with a median age of 62 years (one chronic myeloid leukaemia in blast crisis, one high-risk acute myeloid leukaemia (AML) in first complete remission (CR1), one AML in 2nd relapse, one AML in CR2 with pre-existing fungal lung infections (two aspergillus, two mucor) and additional co-morbidity (diabetes n = 2, aortic aneurysm n = 1, arterial sclerosis n = 2) by combining non-myeloablative conditioning with an intensified supportive care regimen, including amphotericin B and 4-12 (median 9) prophylactic granulocyte transfusions from granulocyte colony-stimulating factor (G-CSF)-stimulated volunteer donors. G-CSF was also given to patients until neutrophil recovery. All four patients recovered to a neutrophil count of 0.5 x 109/l after a median of 11.5 d (range 11-13 d). Prophylactic granulocyte transfusions also reduced the need for platelet transfusions and minimized mucositis. All patients were discharged at a median of 25 d (range 18-59 d) and are alive and well after a median follow-up of > 390 d (range 336-417 d) without evidence of leukaemia. Regression of the fungal lesions was documented in three patients, with a slight progression detected by computerized tomography scan of the chest in one patient. We conclude that pulmonary fungal infections are not a contraindication for allogeneic stem cell transplantation, if non-myeloablative conditioning regimens are used in combination with granulocyte transfusions, intravenous amphotericin B and G-CSF.

Acute Disease↗
PubMed2001

Dose-reduced conditioning for allografting in 44 patients with chronic myeloid leukaemia: a retrospective analysis.

This retrospective study describes the outcome of patients with chronic myeloid leukaemia after allografting using dose-reduced conditioning with fludarabine and busulphan. Forty-four Philadelphia chromosome (Ph)-positive patients were transplanted in nine German centres; 26 patients were in chronic phase, 11 in accelerated phase and seven in blast crisis. Thirty-four patients achieved complete remission, with 18 alive and disease-free at a median follow-up of 562 d (range 244-922 d). Grade II-IV acute graft-versus-host disease (GVHD) incidence was 43%. Twenty patients died, 15 of causes unrelated to relapse. Risk factors predisposing to graft failure by univariate analysis were an unrelated donor (8/23 compared with a related donor 2/21, P = 0.07) and interferon therapy within 90 d of transplant (4/6 versus 3/17, P = 0.025). At the last follow-up, of 31 patients for whom molecular or cytogenetic data were available, 16 (52%) were polymerase chain reaction-negative, and seven (23%) were Ph-negative by fluorescent in situ hybridization. These findings demonstrate that dose-reduced conditioning with fludarabine and busulphan provides durable engraftment and a low rate of relapse. However, in this population, many of whom were not eligible for high-dose conditioning due to age, reduced performance status, previous complications or extensive pre-treatment, these data highlight the need for effective anti-infectious and GVHD prophylaxis. In addition, this study supports the discontinuation of interferon therapy at least 90 d before transplant

Adult↗
PubMed2001

A new approach to evaluating intestinal acute graft-versus-host disease by transabdominal sonography and colour Doppler imaging.

An objective and non-invasive method to assess the extent, severity, course and prognosis of acute graft-versus-host disease (aGvHD) of the gastrointestinal tract would be of great importance. As high-resolution ultrasonography (HRU) and colour Doppler imaging (CDI) are used in inflammatory and ischaemic bowel diseases, we introduced these techniques to evaluate acute intestinal GvHD. In this study, 12 patients with suspected intestinal and/or severe cutaneous aGvHD were investigated by HRU and CDI. The structure and thickness of the bowel wall and the blood flow pattern in the superior mesenteric artery (SMA) as well as in the bowel wall were evaluated. All patients showed thickened bowel wall segments, especially in the ileocaecal region. Even in patients without any clinical signs of intestinal involvement (3/12), sonographic changes were observed. In six patients with severe diarrhoea, sonographic signs of secretory diarrhoea were observed. In 4/12 patients, an increased arterial blood flow in the bowel wall was demonstrated as a typical characteristic of an inflammatory bowel process. In contrast, in 4/12 patients, ischaemic bowel wall lesions with high-resistance flow pattern in the SMA were found. These patients did not respond to immunosuppressive therapy and died. In conclusion, HRU is a useful tool for detecting acute bowel GvHD even before clinical symptoms. Moreover, HRU and CDI can be applied to define the severity of aGvHD and to identify patients with a poor prognosis.

Acute Disease↗
PubMed2001

Incidence of endomycoses in autopsy material.

From 1970 to 1993, 93 endomycoses confirmed by postmortem examination were diagnosed in the autopsy material of the Berlin Charité, a large hospital with an average of 1,500 Hospital beds and maximum medical care. These comprised 51 candidoses (54.8%), 24 aspergilloses (36.5%), five cryptococcoses (5.4%), one zygomycosis, one trichosporosis and one coccidioidomycosis. This corresponded to 0.7% of the 13,275 deceased persons autopsied during this period. The frequency of autopsy was 85.3%. In 3,770 cases (2,418 adults and 1,352 children), brain dissection was performed. An adequate clinical putative diagnosis was made in only six out of 28 patients (18 adults, 10 children) with histologically confirmed cerebral mycosis: 11 candidoses (39.3%), 10 aspergilloses (35.7%) five cryptococcosis (17.8%), one trichosporosis and one coccidioidomycosis. About 80% of the mycoses of the CNS thus remained undetected while the patients were alive. The observations made in the present paper underscore the importance of clinical autopsy in endomycoses.

Adult↗
PubMed2001

Peroxide sensors for the fission yeast stress-activated mitogen-activated protein kinase pathway.

The Schizosaccharomyces pombe stress-activated Sty1p/Spc1p mitogen-activated protein (MAP) kinase regulates gene expression through the Atf1p and Pap1p transcription factors, homologs of human ATF2 and c-Jun, respectively. Mcs4p, a response regulator protein, acts upstream of Sty1p by binding the Wak1p/Wis4p MAP kinase kinase kinase. We show that phosphorylation of Mcs4p on a conserved aspartic acid residue is required for activation of Sty1p only in response to peroxide stress. Mcs4p acts in a conserved phospho-relay system initiated by two PAS/PAC domain-containing histidine kinases, Mak2p and Mak3p. In the absence of Mak2p or Mak3p, Sty1p fails to phosphorylate the Atf1p transcription factor or induce Atf1p-dependent gene expression. As a consequence, cells lacking Mak2p and Mak3p are sensitive to peroxide attack in the absence of Prr1p, a distinct response regulator protein that functions in association with Pap1p. The Mak1p histidine kinase, which also contains PAS/PAC repeats, does not regulate Sty1p or Atf1p but is partially required for Pap1p- and Prr1p-dependent transcription. We conclude that the transcriptional response to free radical attack is initiated by at least two distinct phospho-relay pathways in fission yeast.

Activating Transcription Factor 1↗
PubMed2001

HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway.

HMG-CoA reductase inhibitors (statins) have been developed as lipid-lowering drugs and are well established to reduce morbidity and mortality from coronary artery disease. Here we demonstrate that statins potently augment endothelial progenitor cell differentiation in mononuclear cells and CD34-positive hematopoietic stem cells isolated from peripheral blood. Moreover, treatment of mice with statins increased c-kit(+)/Sca-1(+)--positive hematopoietic stem cells in the bone marrow and further elevated the number of differentiated endothelial progenitor cells (EPCs). Statins induce EPC differentiation via the PI 3-kinase/Akt (PI3K/Akt) pathway as demonstrated by the inhibitory effect of pharmacological PI3K blockers or overexpression of a dominant negative Akt construct. Similarly, the potent angiogenic growth factor VEGF requires Akt to augment EPC numbers, suggesting an essential role for Akt in regulating hematopoietic progenitor cell differentiation. Given that statins are at least as potent as VEGF in increasing EPC differentiation, augmentation of circulating EPC might importantly contribute to the well-established beneficial effects of statins in patients with coronary artery disease.

Animals↗
PubMed2001

Tescalcin, a novel gene encoding a putative EF-hand Ca(2+)-binding protein, Col9a3, and renin are expressed in the mouse testis during the early stages of gonadal differentiation.

To identify genes that are differentially expressed in the developing testis we used representational difference analysis of complementary DNA from gonads of mouse embryos at 13.5 days postcoitum (dpc). Three genes were identified. One of them was a novel gene termed tescalcin that encoded a putative EF-hand Ca(2+)-binding protein. The open reading frame consisted of 642 nucleotides encoding a protein with 214 amino acids. Analysis of the predicted amino acid sequence revealed an N:-myristoylation motif and several phosphorylation sites in addition to an EF-hand Ca(2+)-binding domain. TESCALCIN: messenger RNA (mRNA) was present in fetal testis, but not in ovary or mesonephros, and was restricted to the testicular cords. Its expression was first detected in the male gonad at 11.5 dpc and demonstrated a pattern consistent with a role in the testis at the early stages of testis differentiation. Tescalcin is expressed in the testis of Kit(W/W-v) mice, indicating that it is not dependent on the presence of germ cells. The other two genes identified were collagen IX alpha3 (Col9a3) and RENIN: Col9a3 expression was present at low levels in male and female gonads at 11.5 dpc. Thereafter, it was markedly up-regulated in the male, but remained very low in the female. Expression of Col9a3 was restricted to testicular cords and was also detected in testis of Kit(W/W-v) mice. RENIN: mRNA was first detected in testis at 12.5 dpc, increased thereafter, and reached a peak at 16.5 dpc. RENIN: mRNA was localized in cells of the interstitium and cells at the border between the gonad and mesonephros. Expression of RENIN: in the ovary was not detected using standard conditions.

Amino Acid Sequence↗
PubMed2001

Reactive hyperemia and interleukin 6, interleukin 8, and tumor necrosis factor-alpha in the diagnosis of early-onset neonatal sepsis.

OBJECTIVE: To evaluate the diagnostic value of peripheral circulatory reactive hyperemia and serum levels of interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-alpha) in early-onset neonatal sepsis. METHODS: Reactive hyperemia in the dorsal hand and serum levels of IL-6, IL-8, and TNF-alpha were studied in newborn infants (n = 32; gestational age 39 +/- 3 weeks) who had been admitted to the neonatal unit because of suspected sepsis <48 hours after birth. On admission, reactive hyperemia after a standardized arterial occlusion was measured with laser Doppler technique, and blood samples were taken for cytokine analyses. On the basis of predetermined criteria, the infants subsequently were classified as septic (n = 12) or not (n = 20). RESULTS: The degree of reactive hyperemia was higher in the group with sepsis (median + 170% perfusion increase) than in that without (+37%). On admission, serum levels of IL-6, IL-8, and TNF-alpha all were higher in septic (median values: 1620, 331, and 22 pg/mL, respectively) than in nonseptic neonates (median values: 42, 63, and 13 pg/mL, respectively). In the group with sepsis, the degree of reactive hyperemia correlated to log IL-6 (r = 0.80) and log IL-8 values (r = 0.71). CONCLUSION: Newborn infants with septicemia have increased reactive hyperemia and elevated cytokine levels very early in their disease. Reactive hyperemia in skin can be analyzed at the bedside and noninvasively and therefore may serve as an additional diagnostic tool in neonatal sepsis.

Biomarkers↗
PubMed2001

Colonic lymphoid hyperplasia in melanosis coli.

We describe the case of a patient with Rett syndrome, a syndrome characterized by progressive infant encephalopathy, developmental delay, dementia, autism, ataxia, microcephaly, spastic paraparesis, and autonomic neuropathy with constipation. At colonoscopy, multiple foci of tiny white, sessile, polypoid lesions were seen throughout the colon and rectum, mimicking the appearances of small hyperplastic or adenomatous polyps, associated with generalized melanosis coli. This is the first case to our knowledge describing melanosis coli in a patient with Rett syndrome. As melanosis pigment deposition is characteristically not seen in lymphoid tissue, the lymphoid tissue was identifiable at endoscopy as multiple white nodules mimicking generalized colonic polyposis throughout the colon. We discuss the likely mechanisms of lymphoid hyperplasia and coexistent melanosis coli in Rett syndrome.

Abdominal Pain↗