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P Lohse

Publications and source records attributed to P Lohse.

At least 19 recordsLinked to original sources
PubMed2007

Substitution of cyclophosphamide and busulfan by fludarabine, treosulfan and melphalan in a preparative regimen for children and adolescents with Shwachman-Diamond syndrome.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only definitive treatment for severe bone marrow dysfunction and clonal disorders in patients diagnosed with Shwachman-Diamond syndrome (SDS). In an attempt to minimize regimen-related toxicity (RRT), we have initiated a fludarabine/treosulfan/melphalan-based pilot protocol avoiding the combination of busulfan and cyclophosphamide. Median age at transplantation was 9.6 years (range 1.5-17 years). All three patients received conditioning with fludarabine (30 mg/m2/day x 6), treosulfan (12 g/m2/day x 3) and melphalan (140 mg/m2/day x 1). CAMPATH-1H (0.1 mg/kg x 2) was added in two cases, while rabbit ATG (Genzyme; 3 x 2.5 mg/kg) was given to the cord blood recipient. One patient was transplanted with a non-manipulated marrow graft from an HLA-identical sibling, one with a marrow graft from a 10/10 matched unrelated donor, and one with a 9/10 matched unrelated umbilical cord blood (UCB) unit. Mean cell doses given were 3.6 x 10(8) nucleated cells/kg BW for the bone marrow recipients and 4.2 x 10(7) nucleated cells/kg BW for UCB recipient. Overall, two of three patients are alive and display 100% donor chimerism. Acute graft-versus-host disease grade II was seen in one patient, while no GVHD exceeding grade I occurred in the remaining two.

Abnormalities, Multiple↗
PubMed2006

The +1059G/C polymorphism in the C-reactive protein (CRP) gene is associated with involvement of the terminal ileum and decreased serum CRP levels in patients with Crohn's disease.

BACKGROUND: Serum C-reactive protein (CRP) levels influence the response to anti-tumour necrosis factor (TNF) therapies. AIM: To analyse the influence of the +1059G/C CRP polymorphism on CRP serum levels and disease susceptibility in patients with Crohn's disease (CD). METHODS: Using restriction fragment length polymorphism (RFLP) analysis, genomic DNA from 241 CD patients and 199 unrelated controls was analysed for the +1059G/C substitution in the CRP gene and the common caspase-activation recruitment domain 15 (CARD15) variants. RESULTS: Homozygous C/C carriers were detected only among CD patients (P = 0.066). Patients with ileal involvement (L1 and L3 phenotype) were found in only 58.4% of patients with the wildtype G/G genotype but in 88.2% of the heterozygous G/C carriers (OR 5.26; 95% CI 1.19-23.92) and four of the five C/C homozygous carriers (80%; OR 4.55; 95% CI 1.64-16.67; P = 0.008 for hetero- and homozygous carriers vs. wildtype) which was independent of the presence of CARD15 variants. Increased CD activity was associated with increased CRP serum levels (P < 0.005). For Crohn's disease activity index (CDAI) < 150, C/C homozygosity for the +1059 G/C polymorphism was associated with significantly lower CRP serum levels (P < 0.01). CONCLUSIONS: The C allele of the CRP +1059G/C polymorphism is associated with decreased serum CRP levels and increased likelihood of disease involvement of the terminal ileum in CD patients.

Adult↗
PubMed2006

Neonatal-onset multisystem inflammatory disease (NOMID) due to a novel S331R mutation of the CIAS1 gene and response to interleukin-1 receptor antagonist treatment.

Neonatal-onset multisystem inflammatory disease (NOMID) is due to mutations in the CIAS1 gene. We describe the case of a 5-year-old boy with neonatal onset of urticaria-like rash, chronic fever, laboratory findings of systemic inflammation, hepatosplenomegaly, and chronic CNS inflammation associated with sensorineural deafness. Sequence analysis of exon 3 of the CIAS1 gene revealed a novel C1754A/S331R mutation. Since experimental evidence suggests that patients with cryopyrin-associated periodic syndromes (CAPS) could respond to inhibition of binding of interleukin IL-1alpha and IL-1beta to the IL-1 receptor type 1, we treated the child with the IL-1 receptor antagonist anakinra. A remarkable clinical and serological response to therapy was observed, suggesting that pharmacological inhibition of the IL-1 signaling pathway offers an important new treatment option for patients with NOMID.

Amino Acid Substitution↗
PubMed2005

Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer.

BACKGROUND: Hereditary non-polyposis colorectal cancer (HNPCC) is clinically defined by familial clustering of colorectal cancer and other associated tumours. METHODS: By thorough molecular and clinical evaluation of 41 families, two different groups were characterised: group 1, 25 families with truncating mutations in MLH1 or MSH2 (12 novel mutations); and group 2, 16 Amsterdam positive families without mutations in these genes and without microsatellite instability in their corresponding tumours. RESULTS: Significant clinical differences between these two groups were found. Firstly, earlier age of onset for all colorectal cancers (median 41 v 55 years; p < 0.001) and all tumours (median 43 v 56 years; p = 0.022) was observed, comparing groups 1 and 2. Secondly, 68% of the index colorectal cancers were localised proximally of the splenic flexure in group 1 compared with 14% in group 2 (p < 0.010). Thirdly, more synchronous and metachronous colorectal (p = 0.017) and extracolorectal tumours (p < 0.001) were found in group 1. Fourthly, a higher colorectal adenoma/carcinoma ratio (p = 0.030) and a tendency towards more synchronous or metachronous adenomas in group 2 (p = 0.084) was observed, indicating a slower progression of adenomas to carcinomas. As three mutation negative tumours revealed chromosomal instability after comparative genomic hybridisation, these tumours may be caused by one or more highly penetrant disease alleles from the chromosomal instability pathway. CONCLUSION: These data show that HNPCC includes at least two entities with clinical and molecular differences. This will have implications for surveillance programmes and for cancer research.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Polymorphisms in the DLG5 and OCTN cation transporter genes in Crohn's disease.

BACKGROUND AND AIMS: Recent data suggest identification of causal genetic variants for inflammatory bowel disease in the DLG5 gene and in the organic cation transporter (OCTN) cluster, both situated in previously described linkage regions. PATIENTS AND METHODS: The polymorphisms in DLG5 (113 G-->A, 4136 C-->A, and DLG5_e26), SLC22A4 (1672 C-->T), and SLC22A5 (-207 G-->C) were assessed in 625 patients with Crohn's disease (CD), 363 patients with ulcerative colitis (UC), and 1012 healthy controls. Association with disease susceptibility, clinical phenotypes, and possible genetic interactions of these polymorphisms with disease associated CARD15/NOD2 mutations was analysed. RESULTS: No significant association of DLG5 polymorphisms with CD or UC was observed. Homozygosity for the OCTN-TC haplotype was associated with an increased CD risk (OR = 1.65), which was even greater in the presence of CARD15 mutations. Genotype-phenotype analysis revealed that this association was particularly strong in patients with colonic disease. The TC haplotype was associated with non-fistulising non-fibrostenotic disease, an earlier age of disease onset, and reduced need for surgery. CONCLUSION: Our observations argue against a role of DLG5 polymorphisms in the susceptibility for inflammatory bowel disease, whereas the OCTN polymorphisms are associated with CD. However, due to the comparable weak association observed herein, extended linkage disequilibrium analyses of these variants with the IBD5 haplotype tagged single nucleotide polymorphims might be advisable before definitive conclusions about their causative role in CD can be drawn.

Adolescent↗
PubMed2004

Extended microsatellite analysis in microsatellite stable, MSH2 and MLH1 mutation-negative HNPCC patients: genetic reclassification and correlation with clinical features.

BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant disorder predisposing to predominantly colorectal cancer (CRC) and endometrial cancer frequently due to germline mutations in DNA mismatch repair (MMR) genes, mainly MLH1, MSH2 and also MSH6 in families seen to demonstrate an excess of endometrial cancer. As a consequence, tumors in HNPCC reveal alterations in the length of simple repetitive genomic sequences like poly-A, poly-T, CA or GT repeats (microsatellites) in at least 90% of the cases. AIM OF THE STUDY: The study cohort consisted of 25 HNPCC index patients (19 Amsterdam positive, 6 Bethesda positive) who revealed a microsatellite stable (MSS)--or low instable (MSI-L)--tumor phenotype with negative mutation analysis for the MMR genes MLH1 and MSH2. An extended marker panel (BAT40, D10S197, D13S153, D18S58, MYCL1) was analyzed for the tumors of these patients with regard to three aspects. First, to reconfirm the MSI-L phenotype found by the standard panel; second, to find minor MSIs which might point towards an MSH6 mutation, and third, to reconfirm the MSS status of hereditary tumors. The reconfirmation of the MSS status of tumors not caused by mutations in the MMR genes should allow one to define another entity of hereditary CRC. Their clinical features were compared with those of 150 patients with sporadic CRCs. RESULTS: In this way, 17 MSS and 8 MSI-L tumors were reclassified as 5 MSS, 18 MSI-L and even 2 MSI-H (high instability) tumors, the last being seen to demonstrate at least 4 instable markers out of 10. Among all family members, 87 malignancies were documented. The mean age of onset for CRCs was the lowest in the MSI-H-phenotyped patients with 40.5 +/- 4.9 years (vs. 47.0 +/- 14.6 and 49.8 +/- 11.9 years in MSI-L- and MSS-phenotyped patients, respectively). The percentage of CRC was the highest in families with MSS-phenotyped tumors (88%), followed by MSI-L-phenotyped (78%) and then by MSI-H-phenotyped (67%) tumors. MSS tumors were preferentially localized in the distal colon supposing a similar biologic behavior like sporadic CRC. MSH6 mutation analysis for the MSI-L and MSI-H patients revealed one truncating mutation for a patient initially with an MSS tumor, which was reclassified as MSI-L by analyzing the extended marker panel. CONCLUSION: Extended microsatellite analysis serves to evaluate the sensitivity of the reference panel for HNPCC detection and permits phenotype confirmation or upgrading. Additionally, it confirms the MSS status of hereditary CRCs not caused by the common mutations in the MMR genes and provides hints to another entity of hereditary CRC.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Genetic analyses permit the differentiation between reactive malfunctions ('promyelocyte arrest') and arising promyelocyte leukemia in a pregnant patient with a history of a medulloblastoma.

We report the case of a 24-year-old woman with a history of radiotherapy for a cerebellar medulloblastoma 2 years prior to detection of a lymph node metastasis of the former disease and a pancytopenia in the peripheral blood. On bone marrow (BM) examination promyelocyte leukemia vs. a reactive 'promyelocyte arrest' were discussed. The translocation t(15;17) was found in some nuclei and there was a PML-RARalpha gene rearrangement detectable by RT-PCR. Furthermore, there was BM infiltration by the primary cancer. All these results led to the diagnosis of a relapse of the medulloblastoma and of a beginning promyelocyte leukemia. As the patient was pregnant, she had to be parted with the baby to facilitate intensive chemotherapy. She did not respond to a therapeutic regimen specific for promyelocytic leukemia but achieved complete remission of the medulloblastoma as well as the leukemia after the administration of polychemotherapy specific for medulloblastoma. One year later, she suffered from a relapse of her leukemia. Now nearly all cells showed a t(15;17) aberration. Immunophenotype analyses showed a shift to a more undifferentiated blast phenotype that was, however, still HLA-DR negative. The patient again received chemotherapy for leukemia but developed a sepsis 3 months later and died of pancytopenia ensuing her leukemia. There was no clinical evidence for recurrence of the medulloblastoma.

Adult↗
PubMed2003

[Persistent polyclonal B-cell lymphocytosis].

HISTORY AND CLINICAL FINDINGS: A 54-year-old woman was referred for ambulant checkup after an episode of acute renal failure due to severe gastroenteritis and recurrent arthralgias. Physical examination was unremarkable except for the presence of palpable small cervical lymph nodes. INVESTIGATIONS: Serum IgM levels showed a polyclonal increase. All the other routinely examined parameters were within normal limits. Microscopical blood smear examination revealed binucleated lymphocytes. Immunophenotyping of peripheral blood showed a polyclonal B-cell lymphocytosis despite normal numbers of leukocytes and lymphocytes. PCR analysis identified cells with a t(14;18) translocation (bcl-2/IgH rearrangement). DIAGNOSIS: A routine medical checkup disclosed the diagnosis of persistent polyclonal B-cell lymphocytosis. This rare benign lymphoproliferative disorder is characterized by binucleated lymphocytes, polyclonal expansion of B-cells, and a polyclonal increase in serum IgM. The diagnosis was established despite the lack of leukocytosis or lymphocytosis in the peripheral blood. CONCLUSIONS: Because of its benign and indolent course without the need for chemotherapy, it is important to discriminate the disorder of persistent polyclonal B-cell lymphocytosis from other malignant lymphoproliferative diseases.

Acute Kidney Injury↗
PubMed2003

Polymorphisms in the ACE and PAI-1 genes are associated with recurrent spontaneous miscarriages.

BACKGROUND: Successful pregnancies require fine tuning of fibrinolytic activities in order to secure fibrin polymerization and stabilization of the placental basal plate as well as to prevent excess fibrin deposition in placental vessels and intervillous spaces. Fibrinolysis is tightly regulated by plasminogen activator inhibitor-1 (PAI-1). Endothelial PAI-1 synthesis is induced by angiotensin II, which is generated by angiotensin I-converting enzyme (ACE). METHODS: We studied the ACE deletion (D)/insertion (I) polymorphism and the PAI-1 4G/5G polymorphism in women with recurrent spontaneous miscarriages (RM). Both polymorphisms have been shown to be associated with ACE and PAI-1 expression levels respectively. A study group of 184 patients with a history of two or more consecutive unexplained spontaneous miscarriages was compared with a control group of 127 patients with uneventful term deliveries and no history of miscarriages. RESULTS: Our findings show: (i) homozygosity for the D allele of the ACE gene, which results in elevated PAI-1 concentrations and hypofibrinolysis, is associated with an elevated risk of RM; (ii) the combination of the D/D genotype with two 4G alleles of the PAI-1 promoter, which further increases PAI-1 plasma levels, is significantly more frequent in RM patients compared with controls. CONCLUSIONS: Based on these results, we recommend the incorporation of these two polymorphisms into the spectrum of thrombophilic mutations which should be analysed in individuals with recurrent spontaneous miscarriages. Patients homozygous for both the ACE D and PAI-1 4G alleles may benefit from the application of low molecular weight heparin as early as possible in the pregnancy in order to prevent uteroplacental microthromboses.

Abortion, Habitual↗
PubMed2002

[Intrahepatic cholestasis in pregnancy. What to consider in jaundice and pruritus].

Intrahepatic cholestasis of pregnancy is a hepatopathy that occurs in the second or third trimester and accounts for 20% of cases of jaundice occurring in pregnancy. Both genetic and hormonal factors appear to play important roles in its development. The leading symptom is pruritus, and jaundice is common. Transaminases, serum bile acids and bilirubin are typically elevated, while gamma-GT is usually normal. For the differential diagnosis, in particular viral hepatitis, cholelithiasis, gestosis and acute fatty liver of pregnancy must be excluded. While the prognosis of intrahepatic cholestasis of pregnancy for the mother is good, the associated increased tendency for a premature birth represents a potential risk for the child. Early treatment with ursodeoxycholic acid appears to have a positive influence on both the mother's symptoms and the course of the pregnancy. Should the symptoms persist after delivery, consideration must be given to a chronic hepatopathy.

Cholestasis, Intrahepatic↗
PubMed2001

Sixteen rare sequence variants of the hMLH1 and hMSH2 genes found in a cohort of 254 suspected HNPCC (hereditary non-polyposis colorectal cancer) patients: mutations or polymorphisms?

5-8% of all colorectal cancer cases are assumed to be due to germline mutations in DNA mismatch repair genes. Mutation analysis of these genes in affected families enables one to identify subjects with an inborn susceptibility to colorectal tumorogenesis and to offer presymptomatic testing to family members at risk, provided that the mutation detected is a truncating one or a missense mutation that has either been judged as disease causing in other families or segregates with the disease and results in a microsatellite instability of the corresponding tumor. Segregation analysis within the family or microsatellite analysis of the tumor is, however, not always possible. In these cases, assessment of the relevance of the sequence variation identified is very difficult. On the other hand, discrimination between inactivating mutations and innocuous sequence polymorphisms is of extreme importance for clinical and genetic counseling of affected families. Here we report 16 rare sequence variants of the hMLH1 and hMSH2 genes including 11 different missense variations found in a cohort of 254 suspected HNPCC patients. We provide evidence, that missense variations in hMLH1 do not necessarily result in microsatellite instability of the corresponding tumor DNA. These patients would have been missed had one followed the recommendations of using only microsatellite analysis for the selection of patients at high risk of hereditary non-polyposis colorectal cancer for mutation analysis.

Adaptor Proteins, Signal Transducing↗
PubMed2001

S680N substitution of the follicle-stimulating hormone receptor is a common polymorphism not associated with spontaneous human twinning.

OBJECTIVE: To determine the influence of the A307/S680 and T307/N680 isoforms of the follicle-stimulating hormone receptor (FSHR) gene on the incidence of spontaneous human twinning. DESIGN: Case-control study. SETTING: Departments of Obstetrics and Gynecology and of Clinical Chemistry-Grosshadern, University Hospital Munich, Germany. PATIENT(S): Fifty-four mothers with dichorionic twin pregnancies and 92 singleton mothers as controls, who had conceived without assisted reproduction. INTERVENTION(S): Exon 10 of the FSHR gene was screened for the G2105A/S680N mutation. MAIN OUTCOME MEASURE(S): Amplification of genomic DNA by the polymerase chain reaction followed by restriction fragment length polymorphism analysis. RESULT(S): Allele frequencies for the G2105A/ S680N substitution of the FSHR in twin mothers were not different from those of controls (genotype (isoform) [twins vs. controls]: G/G (S/S) [24.1% vs. 22.3%]; A/G (N/S) [57.4% vs. 55.4%]; A/A (N/N) [18.5% vs. 22.3%]). Subgroup analysis of women with three or more successful pregnancies gave a similar result (G/G (S/S) [17.7% vs. 13.7%]; A/G (N/S) [64.7% vs. 63.6%]; A/A (N/N) [17.6% vs. 22.7%]). There was no correlation between FSHR isoform and twinning. CONCLUSION(S): The S680N substitution of the follicle-stimulating hormone receptor is a common polymorphism not associated with spontaneous human twinning.

Alleles↗
PubMed2001

Phenotypic correction of lipid storage and growth arrest in wolman disease fibroblasts by gene transfer of lysosomal acid lipase.

Wolman disease is a lethal lysosomal storage disease due to deficiency of lysosomal acid lipase (LAL). Wolman disease is characterized by pronounced hepatic involvement while neurological symptoms are uncommon, making Wolman disease an attractive candidate for liver-directed gene therapy. This study was performed to test the effects of gene replacement in fibroblasts lacking LAL, using a recombinant adenovirus encoding the human LAL cDNA (AdhLAL). Human fibroblasts from a Wolman disease patient were infected with AdhLAL and showed a dose-dependent increase in LAL protein and activity up to 5-fold above levels in control fibroblasts. Furthermore, 72 hr after infection with AdhLAL there was a dose-dependent correction of the severe lipid storage phenotype of Wolman disease fibroblasts. Electron microscopy confirmed significant correction of the lysosomal lipid storage in AdhLAL-infected Wolman disease fibroblasts at the ultrastructural level. Intravenous injection of AdhLAL into wild-type mice resulted in a 13.5-fold increase in hepatic LAL activity, and overexpression of LAL was not associated with toxic side effects. These data demonstrate high-level lysosomal expression of recombinant LAL in vitro and in vivo and show the feasibility of gene therapeutic strategies for the treatment of Wolman disease.

Adenoviridae↗
PubMed2001

Consistent lowering of clotting factors for the treatment of acute cardiovascular syndromes and hypercoagulability: a different pathophysiological approach.

Hypercoagulability is a key contributor to acute cardiovascular syndromes and to various microcirculatory disorders. The use of heparin-mediated extracorporeal low-density lipoprotein/fibrinogen precipitation (HELP) apheresis makes a controlled, immediately effective reduction of clotting factors possible, and induces subsequent positive effects on plasma viscosity, erythrocyte aggregation, and microcirculation. Oxygen supply to an ischemic artery can thus be increased without hemodilution, qualifying the HELP system as a possible therapeutic tool in the treatment of acute cardiovascular syndromes and microcirculatory disorders.

Aged↗
PubMed2001

Increased rate of renal transplant failure in patients with the G20210A mutation of the prothrombin gene.

In patients with thrombophilia caused by reduced physiological anticoagulation, renal transplant failure occurs more frequently. Previous studies showed the importance of the protein C system, a physiological anticoagulatory pathway that inhibits thrombus formation. However, excess activation of the hemostatic system also may result in thrombosis. The G20210A mutation in the prothrombin gene is such a prothrombotic risk factor that results in increased thrombus formation because of elevated factor II levels in plasma. We analyzed graft function in 270 consecutive patients who received 311 renal transplants. The presence of a normal or mutated prothrombin allele was determined by polymerase chain reaction amplification and restriction fragment length polymorphism analysis of genomic DNA. Demographic data were extracted from hospital records. Graft survival was calculated for patients with and without the G20210A mutation. We identified 9 patients heterozygous for the G20210A mutation in the prothrombin gene who had received a total of 12 renal transplants. Of these 12 transplants, 2 grafts were lost within the first year. Median graft survival for patients heterozygous for the 20210A allele was 65.9 months (range, 0 to 101 months) compared with 149 months (range, 0 to 237 months) for patients homozygous for the normal 20210 G allele (P = 0.02). The G20210A mutation represented a 2.95-fold (95% confidence interval, 1.03 to 8.46) increase in risk for graft loss. Only 1 patient with this mutation achieved graft function exceeding 101 months. The G20210A mutation of the prothrombin gene is an independent risk factor for graft failure.

Adult↗