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Biomedical subjects

P Lohse

Publications and source records attributed to P Lohse.

At least 19 recordsLinked to original sources
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↗
PubMed2001

Thrombophilic gene mutations and recurrent spontaneous abortion: prothrombin mutation increases the risk in the first trimester.

PROBLEM: Thrombophilic predisposition may be one of the underlying causes of recurrent spontaneous abortions (RSA). We studied the prevalence of five thrombophilic gene mutations in patients with RSA. METHOD OF STUDY: 102 patients with two or more consecutive abortions and 128 women without miscarriage were analyzed for factor V Leiden mutation (FVL), prothrombin G20210A mutation (PTM), C677T mutation in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, glycoprotein IIIa (GPIIIa) C1565T polymorphism, and beta-fibrinogen G-455A polymorphism by polymerase chain reaction (PCR) techniques. RESULTS: No differences in the prevalence of FVL, MTHFR T/T, GPIIIa and 1-fibrinogen polymorphism were detected. Heterozygous PTM occurred more often in patients with RSA. This effect was significant in a subgroup with abortions exclusively in the first trimester (6.7%, vs. 0.8%, P = 0.027, OR 8.5). CONCLUSIONS: In contrast to the other mutations and polymorphisms, heterozygous PTM is more common in patients with abortions in the first trimester. This might reflect an influence of PTM on pathogenesis of early pregnancy loss.

Abortion, Habitual↗
PubMed2001

R116C mutation of cationic trypsinogen in a Turkish family with recurrent pancreatitis illustrates genetic microheterogeneity of hereditary pancreatitis.

Hereditary pancreatitis is due to heterozygosity for gain-of-function mutations in the cationic trypsinogen gene which result in increased levels of active trypsin within pancreatic acinar cells and autodigestion of the pancreas. The number of disease-causing defects is generally considered to be low. To gain further insight into the molecular basis of this disorder, DNA sequence analysis of all five exons was performed in 109 unrelated patients with idiopathic chronic pancreatitis in order to determine the variability of the underlying mutations. Two German females and one German male were carriers of the most common N29I and R122H mutations (trypsinogen numbering system). In a Turkish proband, an arginine (CGT) to cysteine (TGT) substitution at amino acid position 116 was identified. Family screening demonstrated that the patient had inherited the mutation from his asymptomatic father and that he had transmitted it to both of his children, his daughter being symptomatic since the age of 3 years. In addition, a German male was found to be a heterozygote for a D100H (GAC-->CAC) amino acid replacement. Our data provide evidence for genetic heterogeneity of hereditary pancreatitis. The growing number of cationic trypsinogen mutations is expected to change current mutation screening practices for this disease.

Adult↗
PubMed2001

Long-term administration of the HMG-CoA reductase inhibitor lovastatin in two patients with cholesteryl ester storage disease.

OBJECTIVE: In order to suppress de novo cholesterol and VLDL biosynthesis, a long-term therapy trial with lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, was initiated in two patients with cholesteryl ester storage disease (CESD), and concentrations of plasma lipids were monitored over a period of 9 years. METHODS: We studied two male patients with enzymatically confirmed CESD in whom long-term lovastatin therapy (8 and 9 years) was begun at the age of 7 and 19 years. The diagnosis of CESD was confirmed by the measurement of human lysosomal acid lipase (hLAL) activity in cultured skin fibroblasts and leukocytes. Restriction fragment length polymorphism (RFLP) analysis revealed that both subjects are homozygotes for the common CESD splice site mutation. Levels of serum lipids and lipoproteins were measured yearly. RESULTS: During the first year, total serum cholesterol decreased from 317 to 201 mg/dl in Patient A and from 228 to 120 mg/dl in Patient B, due mainly to the reduction of low-density lipoprotein (LDL) cholesterol from 262 to 151 mg/dt in Patient A and from 166 to 66 mg/dl in Patient B. Accordingly, the LDL cholesterol : high density lipoprotein (HDL) cholesterol ratio was markedly reduced in both patients after one year of therapy. The treatment was continued and, after 9 years of further medication, low total cholesterol and LDL cholesterol levels were still maintained. CONCLUSIONS: The study demonstrates that HMG-CoA reductase inhibitors are well tolerated drugs during long-term treatment of CESD patients and may help to prevent the development of premature atherosclerosis.

Adult↗
PubMed2001

Fluorescence-based detection of the CETP TaqIB polymorphism: false positives with the TaqMan-based exonuclease assay attributable to a previously unknown gene variant.

BACKGROUND: Previous studies have shown an association between the TaqIB polymorphism of the cholesteryl ester transfer protein (CETP) gene with plasma CETP and HDL concentrations and the progression of coronary artery disease (CAD). The aim of the present study was to determine the performance of two new fluorescence-based detection systems in the analysis of the TaqIB genotype. METHODS: CAD patients (n = 150) with known TaqIB genotype, as determined by restriction fragment length polymorphism (RFLP) analysis, were selected, including three groups of 50 patients, carrying the B1/1, B1/2, and B2/2 genotypes, respectively. The genotypes were also analyzed by fluorescence-based allele-specific TaqMan PCR and melting curve analysis (LightCycler). In addition, DNA sequencing was applied. RESULTS: The TaqIB genotypes obtained by fluorescence analysis corresponded to those determined by RFLP analysis with the exception of three heterozygous patients (B1/2), who were misclassified as homozygous B2 carriers with the TaqMan system. Melting curve analysis of these samples demonstrated an additional melting point at 59.1 degrees C, which was also found in four patients homozygous for the B1 allele. DNA sequencing revealed a previously unknown C270T nucleotide exchange in intron 1 of the CETP gene, only nine base pairs from the TaqIB site. CONCLUSIONS: Determination of the TaqIB polymorphism with the TaqMan system led to misclassifications because of a previously unknown C270T polymorphism of the CETP gene. The base substitution was detected with the LightCycler because of the occurrence of an additional melting point. Our data indicate the importance of thorough evaluation of new gene analysis systems before using them on a routine basis.

Carrier Proteins↗
PubMed2000

Subclinical course of cholesteryl ester storage disease in an adult with hypercholesterolemia, accelerated atherosclerosis, and liver cancer.

Few cases of asymptomatic cholesteryl ester storage disease (CESD) due to low enzymatic activity of human lysosomal acid lipase/cholesteryl ester hydrolase (hLAL) have been reported thus far in adults Here, we describe a 51-year-old man with a long clinical history of mixed hyperlipoproteinemia and severe premature atherosclerosis, but with no signs of hepatomegaly, liver dysfunction, or splenomegaly. The disease was discovered by chance in a biopsy performed because of suspected liver cancer (proven to be a cholangiocarcinoma). Residual hLAL activity in peripheral leukocytes was determined to be 6% of control values. DNA sequence and restriction fragment length polymorphism analysis demonstrated that the patient was a compound heterozygote for the prevalent CESD exon 8 splice site mutation (G934A) and the deletion of a C (nucleotide 673, 674, or 675) in exon 6 of the hLAL gene, resulting in premature termination of protein translation at residue 195. The patient died of liver failure as a consequence of extensive tumor infiltration at age 52. Lipid analysis revealed moderate cholesteryl ester storage in the liver and in the suprarenal cortex, and massive accumulation in the testicular histiocytes and Leydig cells, resulting in a pronounced secondary atrophy of the seminiferous tubules. Our case study demonstrates that hepatomegaly is an inconstant feature, even in CESD patients compound heterozygous for a Wolman mutation which results in complete loss of hLAL enzymic activity. It also highlights the need to be aware of this condition as it may be underdiagnosed.

Adult↗
PubMed2000

The number of dichorionic twin pregnancies is reduced by the common MTHFR 677C-->T mutation.

In multiple pregnancies, demands for folic acid are considerably increased. The most common inborn error of folate metabolism is mild methylenetetrahydrofolate reductase (MTHFR) deficiency due to the synthesis of a thermolabile variant of the enzyme with impaired catalytic activity which leads to reduced 5-methyltetrahydrofolate (5-methyl-THF) and mildly elevated homocysteine plasma concentrations when folate status is inadequate. To investigate whether the number of offspring is influenced by this mutation, we determined the frequency of the 677C-->T substitution in 156 singleton and 40 twin mothers with dichorionic placentation. The T allele frequency in singleton (0.30) and twin mothers (0.16) was significantly different (P = 0.011). Mothers with the 677C-->T mutation had a 2.28 times lower risk of having a twin pregnancy than those without (95% confidence interval = 1.18-4.66; P = 0.008). Our observation would explain, at least in part, the hereditary trait of multiple gestations and is in agreement with the ethnic distribution pattern of the T allele which has been found to be inversely correlated with the incidence of dichorionic twins. Our findings suggest that the MTHFR 677C-->T mutation interferes with human brood size, probably by influencing the proliferation of rapidly dividing embryonic and maternal cells.

Abortion, Spontaneous↗
PubMed2000

Compound heterozygosity for a Wolman mutation is frequent among patients with cholesteryl ester storage disease.

Cholesteryl ester storage disease and Wolman disease are rare autosomal recessive lipoprotein-processing disorders caused by mutations in the gene encoding human lysosomal acid lipase. Thus far we have elucidated the genetic defects in 15 unrelated CESD patients. Seven were homozygotes for the prevalent hLAL exon 8 splice junction mutation which results in incomplete exon skipping, while eight probands were compound heterozygotes for E8SJM and a rare mutation on the second chromosome. In this report, we describe the molecular basis of CESD in three compound heterozygous subjects of Czech and Irish origin. RFLP and DNA sequence analysis revealed that they were heteroallelic for the common G(934)-->A substitution in exon 8 of the hLAL gene and a mutation which, if inherited on both alleles, would be expected to result in complete loss of enzyme activity and to cause Wolman disease. In patients A. M. and J. J., two nucleotide deletions in exons 7 and 10 were detected, involving a T at position 722, 723, or 724 and a G in a stretch of five guanosines at positions 1064;-1068 of the hLAL cDNA. Both mutations result in premature termination of protein translation at residues 219 and 336, respectively, and in the production of truncated, inactive enzymes. Subject D. H., in contrast, is a compound heterozygote for the Arg(44)-->Stop mutation previously described in a French CESD proband. Combined with data in the literature, our results demonstrate that compound heterozygosity for a mutation causing Wolman disease is common among cholesteryl ester storage disease patients.

Base Sequence↗