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Biomedical subjects

B Kremer

Publications and source records attributed to B Kremer.

At least 127 records · Page 7Linked to original sources
PubMed1994

Selective uptake of high-density lipoprotein-associated cholesteryl esters by human hepatocytes in primary culture.

High-density lipoprotein cholesteryl esters are taken up by many cells without simultaneous uptake of high-density lipoprotein apolipoproteins. This selective uptake was investigated in human hepatocytes in primary culture. Human high-density lipoprotein-3 (density, 1.125 to 1.21 gm/ml) was radiolabeled in both its apolipoprotein and in its cholesteryl ester moiety; uptake of these high-density lipoprotein3 tracers by hepatocytes was investigated. Apparent high-density lipoprotein3 particle uptake as measured with the cholesteryl ester tracer was in excess of that from the apolipoprotein tracer, indicating selective uptake of high-density lipoprotein3 cholesteryl esters by hepatocytes. This selective uptake is a regulated pathway in hepatocytes, as demonstrated by an inverse relationship between cell cholesterol and the rate of selective uptake. Studies on the mechanism of selective uptake have used inhibitors such as monensin, chloroquine, heparin, and a monoclonal antibody directed against low-density lipoprotein receptors. These experiments provide no evidence for a role of cell-secreted apolipoprotein E, endocytosis or retroendocytosis in selective uptake. The intracellular fate of high-density lipoprotein3-associated cholesteryl esters was investigated with [3H]cholesteryl oleate-labeled high-density lipoprotein3. Hepatocytes hydrolyzed [3H]cholesteryl oleate internalized from labeled high-density lipoprotein3; this catabolism was not inhibited by the presence of chloroquine. In parallel hepatocytes were incubated with [3H]cholesteryl oleate-labeled low-density lipoprotein. Cells hydrolyzed [3H]cholesteryl oleate taken up with low-density lipoprotein; however, this hydrolysis was inhibited by chloroquine, indicating lysosomal low-density lipoprotein cholesteryl ester catabolism. These experiments show that high-density lipoprotein3 cholesteryl esters selectively taken up by hepatocytes are hydrolyzed independently from the classical lysosomal catabolic pathway. The question was addressed if selective uptake mediates a net mass uptake of cholesterol rather than an isotope exchange phenomenon. Incubation of hepatocytes with high-density lipoprotein-3 suppressed endogenous sterol synthesis from sodium [14C]acetate. Hepatocytes were incubated in the presence of high-density lipoprotein3; medium cholesteryl esters decreased as a result of incubation with hepatocytes. These results show a net mass delivery of high-density lipoprotein cholesteryl esters to hepatocytes. In conclusion, the pathway for selective uptake of high-density lipoprotein cholesteryl esters could be demonstrated in human hepatocytes in primary culture. A role for selective uptake in high-density lipoprotein-mediated cholesterol delivery to the liver in human beings in vivo is proposed.

Animals↗
PubMed1994

Huntington disease without CAG expansion: phenocopies or errors in assignment?

Huntington disease (HD) has been shown to be associated with an expanded CAG repeat within a novel gene on 4p16.3 (IT15). A total of 30 of 1,022 affected persons (2.9% of our cohort) did not have an expanded CAG in the disease range. The reasons for not observing expansion in affected individuals are important for determining the sensitivity of using repeat length both for diagnosis of affected patients and for predictive testing programs and may have biological relevance for the understanding of the molecular mechanism underlying HD. Here we show that the majority (18) of the individuals with normal sized alleles represent misdiagnosis, sample mix-up, or clerical error. The remaining 12 patients represent possible phenocopies for HD. In at least four cases, family studies of these phenocopies excluded 4p16.3 as the region responsible for the phenotype. Mutations in the HD gene that are other than CAG expansion have not been excluded for the remaining eight cases; however, in as many as seven of these persons, retrospective review of these patients' clinical features identified characteristics not typical for HD. This study shows that on rare occasions mutations in other, as-yet-undefined genes can present with a clinical phenotype very similar to that of HD.

Adult↗
PubMed1993

Attitudes toward direct predictive testing for the Huntington disease gene. Relevance for other adult-onset disorders. The Canadian Collaborative Group on Predictive Testing for Huntington Disease.

OBJECTIVE: To assess attitudes toward, and projected utilization of, direct mutation testing by individuals at risk for Huntington disease (HD). DESIGN: Prior to the cloning of the gene for HD, a questionnaire concerning the use of a definitive test was constructed and mailed to 354 participants in the Canadian Collaborative Study for HD. Completed questionnaires were received from 250 participants (response rate, 71%). Persons were asked to indicate whether they would participate in a new predictive test that was either 100% accurate (the definitive test, requiring blood only from the proband) or only 99% accurate. RESULTS: Most (72%) of the persons who had previously received a result in a predictive testing program said they would request testing in either situation. Significantly more persons would request the definitive test than the 99% accurate test (72% vs 58%; P < .02). Respondents for whom testing was uninformative in the linkage test program or who had previously received an increased-risk result were more likely to indicate they would use the test than those who received a decreased-risk result or chose not to have the original test (P = .0003). Less than half (46%) of the participants who initially chose not to have the linkage test said they would return for the new direct test. The major factor that has limited acceptance of predictive testing for this group is the concern about receiving an increased-risk result in the absence of any therapy to alter progression of the disease. CONCLUSIONS: A direct mutation test for HD will most readily be accepted by persons who wanted but could not previously receive a result in the linkage test program and those who previously received an increased-risk result. In the absence of therapy, the majority of persons who previously chose not to have predictive testing are unlikely to participate in a new test despite improved accuracy. This has implications for the expected demands for testing services for other adult-onset genetic disorders.

Attitude to Health↗
PubMed1993

Diagnosis of Huntington disease: a model for the stages of psychological response based on experience of a predictive testing program.

Persons diagnosed as affected with Huntington's disease (HD) may have similar stages of psychological response to the clinical presentation of the illness. Here we describe a model of these stages of response based on our experience during a predictive testing program for HD. During the Warning Stage, asymptomatic persons are aware of their risk status for HD and develop defenses which favor adaptation to their genetic risk. In response to the initial signs and symptoms of HD (the Incipient Stage) unconscious working through of this realization occurs while it is still kept out of conscious awareness. When symptoms become obvious such that recognition of disease onset is inevitable (Breakthrough Stage) the possibility of the diagnosis of HD is assimilated. After the delivery of the diagnosis during the Adjustment Stage, short- and long-term adaptive responses to living with HD occur. Recognition of the stage of psychological response of a patient who presents with HD is important prior to delivering a clinical diagnosis. In a significant minority of cases, the psychological readiness lags behind the clinical symptomatology and premature presentation of a diagnosis may result in significant untoward adverse events. Understanding of the stages of response may provide a framework for evaluating the psychological state of the person with HD and determining their readiness to receiving the diagnosis. This model may have relevance to the psychological responses of patients to the diagnosis of other late onset autosomal dominant disorders.

Adaptation, Psychological↗
PubMed1993

Invasion of HeLa cells by Bordetella bronchiseptica.

Invasion, defined as adhesion to, followed by entrance into HeLa cells by Bordetella bronchiseptica was determined by (i) specific staining of intracellular bacteria and (ii) counting of viable intracellular bacteria after killing extracellular bacteria with colistin. It was demonstrated for the first time that B. bronchiseptica, like Bordetella pertussis and Bordetella parapertussis, is able to invade HeLa cells. Comparison of the invasiveness of Bvg+ and Bvg- B. bronchiseptica showed that B. bronchiseptica, in contrast to B. pertussis, invaded HeLa cells in both phases. The number of viable intracellular bacteria isolated after invasion of bacteria in the Bvg- (flagellated) phase was ten-fold lower than when Bvg+ (fimbriated) bacteria were used. Strains which are deficient in the production of either FimX or Fim2 fimbriae were as invasive as wild-type B. bronchiseptica, which indicates that not these fimbriae but probably filamentous haemagglutinin (FHA) is the major adhesin of B. bronchiseptica.

Bacterial Adhesion↗
PubMed1993

The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease.

Huntington's disease (HD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene. We have assessed 360 HD individuals from 259 unrelated families and found a highly significant correlation (r = 0.70, p = 10(-7)) between the age of onset and the repeat length, which accounts for approximately 50% of the variation in the age of onset. Significant associations were also found between repeat length and age of death and onset of other clinical features. Sib pair and parent-child analysis revealed that the CAG repeat demonstrates only mild instability. Affected HD siblings had significant correlations for trinucleotide expansion (r = 0.66, p < 0.001) which was not apparent for affected parent-child pairs.

Adolescent↗
PubMed1993

Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effects.

Huntington's disease (HD) is associated with expansion of a CAG repeat in a novel gene. We have assessed 21 sporadic cases of HD to investigate sequential events underlying HD. We show the existence of an intermediate allele (IA) in parental alleles of 30-38 CAG repeats in the HD gene which is greater than usually seen in the general population but below the range seen in patients with HD. These IAs are meiotically unstable and in the sporadic cases, expand to the full mutation associated with the phenotype of HD. This expansion has been shown to occur only during transmission through the male germline and is associated with advanced paternal age. These findings suggest that new mutations for HD are more frequent than prior estimates and indicate a previously unrecognized risk of inheriting HD to siblings of sporadic cases of HD and their children.

Adult↗
PubMed1993

"Endoscopy friendly" resection technique of choledochal cysts.

The resection of a choledochal cyst was performed in two patients (22 and 31 years old, both type Todani IVa). Reconstruction of the biliary-intestinal drainage was performed by interposition of a 15 cm jejunal segment between the liver hilum and duodenum. In both patients, hepatico-jejunostomy could be endoscopically evaluated 5-6 months after the operation, showing patent anastomoses without any signs of reflux or cholangitis.

Adult↗
PubMed1993

[Liver regeneration in man. A prospective CT-volumetric study].

To get reliable data on human liver regeneration we performed CT volumetry in 25 patients who underwent partial hepatectomy for benign and malignant liver tumours preoperatively and at least one year postoperatively in regular intervals in a prospective study. All patients received standardised CT-scans preoperatively and two weeks, 3, 6 and 12 months post-operatively. The resected specimen size was determined by water displacement. We were able to demonstrate human liver regeneration. Contrary to the well-known animal model the amount of regeneration in humans is less and regeneration takes a longer time. We did not find any statistical correlation to extent of resection, age of patients and other parameters. On the contrary, the human liver seems to regenerate until a certain relationship of liver volume and body-surface area is reached: 0.8 l/m2.

Adult↗
PubMed1993

Familial predisposition to recurrent mutations causing Huntington's disease: genetic risk to sibs of sporadic cases.

Huntington's disease (HD) is associated with expansion of a CAG repeat in a new gene. We have recently defined a premutation in a paternal allele of 30 to 38 CAG repeats in the HD gene which is greater than that seen in the general population (< 30 repeats) but below the range seen in patients with HD (> 38). These intermediate alleles are unstable during transmission through the germline and in sporadic cases expand to the full mutation associated with the clinical phenotype of HD. Here we have analysed three new mutation families where, in each, the proband and at least one sib have CAG sizes in the HD range. In one of these families, two sibs with expanded CAG repeats are both clinically affected with HD, thus presenting a pseudorecessive pattern of inheritance. In all three families the parental intermediate allele has expanded in more than one offspring, thus showing a previously unrecognised risk of inheriting HD to sibs of sporadic cases of HD.

Adult↗
PubMed1993

Molecular analysis of late onset Huntington's disease.

Late onset Huntington's disease is characterised by onset of symptoms after the age of 50 and is usually associated with a milder course. We have analysed the CAG trinucleotide repeat within the HD gene in 133 late onset patients from 107 extended families. The median upper allele size for the CAG repeat was 42 with a range of 38 to 48 repeats. A significant negative correlation (r = -0.29, p = 0.001) was found between the length of repeat and age of onset for the total cohort. However, for persons with age of onset greater than 60, no significant correlation was found. In addition, no significant correlation was found between age of onset and size of the lower allele and the sex of the affected parent or grandparent. There was no preponderance of maternal descent for late onset cases in this series. This study shows that variation in repeat length only accounts for approximately 7% of the variation in age of onset for persons beyond the age of 50 and clearly shows how with increasing onset age the effect of the repeat length on this onset age seems to diminish.

Age of Onset↗
PubMed1993

Autonomic nervous system dysfunction in Parkinson's disease: relationships with age, medication, duration, and severity.

Heart rate variability at rest, during deep breathing, or standing up and with the Valsalva manoeuvre did not differ significantly between 67 patients with idiopathic Parkinson's disease (PD) and 31 healthy age matched controls. Blood pressure (BP) responses to standing up and sustained handgrip revealed diminished autonomic function in the PD group. In a preliminary analysis of the PD group older age, anti-Parkinson medication and higher Hoehn and Yahr (HY) stages were each associated with poor autonomic responsiveness. Disease duration was only related to the systolic BP fall on standing up. Multiple stepwise regression analysis showed that older age explained most of the variance of heart rate variability (up to 36%), and the only significant PD related factor was the use of medication, which explained less than 7%. The HY stage accounted for 12.7% of the variance in the standing up BP test, and the use of medication explained 10.6% of the variance of the systolic BP change in the sustained hand grip test. The unmedicated PD subgroup (n = 33), who had mild disease of short duration, showed no evidence of autonomic dysfunction. Cardiovascular autonomic dysfunction in PD is mild, mainly affects blood pressure responses, and occurs only in advanced cases.

Adult↗
PubMed1993

Injuries of the portal vein in patients with blunt abdominal trauma.

Between January 1987 and September 1991, 68 severely traumatized patients underwent emergency laparotomy because of blunt abdominal trauma. Intraoperatively, 54.4% of the patients had a major injury to one organ, 23.5% had injuries to two organs, 16.2% had injuries to three organs and 5.9% to four or more organs. Additionally, in 11.8% of these cases (n = 8) a major vascular injury (portal vein n = 5, vena cava n = 2, mesenteric root n = 1) was found. Injuries to the portal vein were always associated with complete rupture of the pancreas, requiring distal pancreatic resection in four cases and a duodenum preserving resection of the head of the pancreas in one. In two of these patients the portal vein had to be reconstructed with a Goretex prosthetic graft. Mortality was 14.7% for the whole group (n = 68) and 0% for patients with additional portal venous injuries.

Abdominal Injuries↗
PubMed1993

AMPA and NMDA binding sites in the hypothalamic lateral tuberal nucleus: implications for Huntington's disease.

The excitatory amino acid (EAA) hypothesis of neuronal loss in Huntington's disease predicts that structures that show neuronal loss and gliosis will contain receptor-bearing neurons. In accordance with this hypothesis, the hypothalamic lateral tuberal nucleus, severely affected in Huntington's disease, showed a high density of NMDA and AMPA binding sites in four normal subjects.

Aged↗
PubMed1993

Partial duodenopancreatectomy with radical lymphadenectomy in patients with pancreatic and periampullary carcinomas: initial results.

Encouraged by the improved results of radical lymphadenectomy in patients with pancreatic carcinoma we designed and carried out a prospective study. Between Jan 88 and Jan 91, 17 patients (group A: cancer of the head of the pancreas, n = 5, periampullary cancer, n = 12) underwent a partial duodenopancreatectomy with radical lymphadenectomy, and 17 patients (group B: cancer of the head of the pancreas, n = 11), periampullary cancer, n = 6) underwent a partial duodenopancreatectomy without lymphadenectomy. Perioperative mortality was 17% (n = 3) in group A and 11.7% (n = 2) in group B. All three deaths in group A were due to erosion and hemorrhage of the completely dissected hepatic artery, and those in group B were due to pancreatitis and pneumonia, respectively. The cumulative 1-, 2- and 3-year survival rates for patients with pancreatic cancer who survived the operation were 50%, 50% and 50% for group A and 25%, 25% and 0% for group B. In patients with periampullary carcinoma 1-, 2-, and 3-year survival rates were all 47% for group A, and 100% for group B.

Ampulla of Vater↗