Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP).
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Adult↗
Biomedical subjects
T Ebeling
Publications and source records attributed to T Ebeling.
Effect of multiple endocrine neoplasia type 1 (MEN1) gene mutations on premature mortality in familial MEN1 syndrome with founder mutations.
Estimation of mortality and the natural course of a disease is usually based on information of carefully studied individuals with or at risk for a specific disease. Genealogical information has rarely been accurate enough for such studies. With the help of church records and multiple endocrine neoplasia type 1 (MEN1) family information of the two founder MEN1 mutations in Northern Finland (1466del12 and 1657insC), we could trace back common ancestors born in the beginning of the 1700s (1466del12) and approximately 1850 (1657insC) and find 67 probable gene carriers born between 1728 and 1929, which were identified among their offspring. Information was gathered from 34 obligatory MEN1 gene carriers and 31 spouses. The mean age (+/- sd) of death of affected males (n = 16) was 61.1 +/- 12.0 yr vs. 65.8 +/- 15.3 yr for unaffected males (n = 16) and for affected females (n = 16) was 67.2 +/- 10.7 yr vs. 67.7 +/- 14.7 yr for unaffected females (n = 13). The ages of death of the obligatory heterozygotes did not differ from that of the spouses in sex groups or from the sex-matched life expectancy estimates derived from Finnish national statistics. Causes of death differed significantly between female probands and spouses. In conclusion, obligatory MEN1 gene carrier status did not show a harmful effect on survival in this retrospective analysis tracing back to almost 300 yr.
Adult↗
Founder effect in multiple endocrine neoplasia type 1 (MEN 1) in Finland.
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Chromosomes, Human, Pair 11↗
Genetic, autoimmune, and clinical characteristics of childhood- and adult-onset type 1 diabetes.
OBJECTIVE: To assess whether there are any differences in genetic, autoimmune, or clinical features between type 1 diabetes presenting in childhood and that diagnosed later. RESEARCH DESIGN AND METHODS: We studied 352 individuals (252 children and adolescents <20 years of age and 100 adults > or =20 years of age) manifesting clinical signs of type 1 diabetes over a period of 7.5 years at a university hospital in northern Finland with a primary catchment area population of approximately 300,000. The patients were analyzed for susceptible and protective HLA-DQB1 alleles (*02, *0302, *0301, *0602, *0603, and *0604), islet cell antibodies (ICA), insulin autoantibodies, and antibodies to GAD and IA-2 (IA-2A). Their clinical symptoms and signs were recorded at diagnosis. RESULTS: The adult patients carried the high-risk DQB1*02/0302 genotype less frequently than the children and more often had protective genotypes. They also had a decreased frequency of all 4 single autoantibody specificities and of multiple (> or =3) autoantibodies. The proportion of patients testing negative for all autoantibodies was lower among the children than among the adults. IA-2A were associated with the DQB1*0302/x genotype in both the children and adults, and the same held true for ICA among the adults. The adults were characterized by a higher proportion of males, a longer duration of symptoms, and a lower frequency of infections during the preceding 3 months. In addition, they had a higher relative body weight on admission and milder signs of metabolic decompensation (higher pH, base excess, and bicarbonate concentrations) and a lower glycated hemoglobin level at diagnosis than the children. CONCLUSIONS: Clinical manifestation of type 1 diabetes before the age of 20 years is associated with a strong HLA-defined genetic disease susceptibility, an intensive humoral immune response to various beta-cell antigens, a higher frequency of preceding infections, and a shorter duration of symptoms and more severe metabolic decompensation at diagnosis. Taken together, these observations suggest that the age at clinical onset of type 1 diabetes is determined by the intensity of the beta-cell-destructive process, which is modulated by both genetic and environmental factors.
Adolescent↗
Smoking and drinking habits in adolescence--links with psychiatric disturbance at the age of 8 years.
Smoking and drinking habits were studied among 1098 14-15-year-old adolescents using a mailed questionnaire. The subjects were drawn from a representative population of 5813 randomly selected 8-year-old children previously studied in the National Epidemiological Child Psychiatry Study in Finland in 1989. The questionnaire included items on the adolescents' smoking habits and alcohol consumption. Regular smoking was more common among boys (and girls) who, in childhood, had been rated by their parents (Rutter Parent Questionnaire) (RA2) as disturbed, 14.6% (30.3%), than among the nondisturbed, 6.6% (8.4%). Similarly, more of the previously disturbed (according to the RA2) adolescent boys drank alcohol regularly, 19.7%, as compared to the nondisturbed boys, 9.3%. Among girls, regular alcohol consumption was more common among those who previously had behavioural or mixed type problems (according to the RA2), 70.7%, as compared to those who previously had emotional or no problems, 12.2%. More of the previously depressed girls smoked regularly, 45.1%, than those who had not been depressed, 7.9%. Behavioural and emotional problems in childhood seemed to predispose to smoking and drinking in adolescence. The parents were more sensitive than the teachers in recognising the long-lasting problems of their children.
Adolescent↗
Clozapine reduces severe self-mutilation and aggression in psychotic patients with borderline personality disorder.
BACKGROUND: Clozapine has been reported to be effective in diminishing violence toward others in psychotic patients. This article describes the impact of clozapine on severe self-mutilation among patients with the dual diagnoses of borderline personality disorder and persistent psychoses. METHOD: Seven subjects known to the authors were selected for careful chart audits. These subjects had been admitted to 2 state psychiatric hospitals owing to severe self-mutilation and/or violence and subsequently treated with clozapine. A mirror-image design anchored to the start date of clozapine treatment and extending in either direction to a maximum of 1 year was used to extract data. Data extracted included incidents of self-mutilation (restraint), seclusion, the as and when needed (p.r.n.) use of medications, injuries to staff and peers, hospital privileges, and Global Assessment of Functioning (GAF) scores. RESULTS: The subjects were all white women with a mean age of 37 years. All subjects carried DSM-III-R or DSM-IV borderline personality disorder diagnoses and an Axis I disorder diagnosis. They had received trials of several psychotropic agents, often in combination and mostly without benefit. After clozapine treatment, there were statistically significant reductions in incidents of self-mutilation (restraint), seclusion, the use of p.r.n. antianxiety medications, and injuries to staff and peers. These subjects received higher levels of hospital privileges, and their GAF scores nearly doubled following clozapine treatment. Four subjects were subsequently discharged from hospital. CONCLUSION: These preliminary but nonetheless favorable results suggest that clozapine deserves careful consideration for a controlled study in patients with borderline personality disorder and psychoses, especially if the clinical issues include severe self-mutilation, aggression, and violence. Until such studies are done, the risk-to-benefit ratio of clozapine treatment needs to be carefully evaluated on an individualized basis in such subjects.
Adult↗
Effect of apolipoprotein E polymorphism on serum lipid response to the separate modification of dietary fat and dietary cholesterol.
BACKGROUND: The magnitude of the influence of the apolipoprotein (apo) E genotype on the lipid response to different cholesterol-lowering diet modifications has been controversial. OBJECTIVE: The aim of the study was to investigate the effect of apo E genotype on serum lipid response to the separate modification of dietary fat and cholesterol. DESIGN: A prospective study design with the 3 main apo E genotype groups (3/3, 3/4, and 4/4; n = 15 in each group) was used. Groups were matched for sex, age, body mass index, menopausal status, and baseline serum cholesterol concentration. Subjects followed 3 different diets in fixed order: 1) a standardized baseline diet (38% fat, 300 mg cholesterol/d), 2) a modified National Cholesterol Education Program (NCEP) diet (34% fat, 265 mg cholesterol/d), and 3) the modified NCEP diet + cholesterol (566 mg cholesterol/d). Subjects were middle-aged (50.9 +/- 8.0 y) and mildly hypercholesterolemic (6.55 +/- 1.05 mmol/L). RESULTS: The genotype groups differed in their total cholesterol response to the NCEP diet; the mean (95% CI) decrease being greatest, -14.1% (-19.8%, -8.6% ), in subjects with apo E genotype 4/4 (P = 0.03, analysis of variance). The increase in total cholesterol after addition of 300 mg cholesterol was also greatest in subjects with apo E 4/4 [10.4% (5.8%, 15.1%)] (P = 0.03, analysis of variance). CONCLUSIONS: Apo E genotype modified the lipid response to changes in both dietary fat and cholesterol in mildly hypercholesterolemic subjects; the response was greatest in subjects with apo E genotype 4/4 and even a moderate increase in dietary cholesterol resulted in a 10% elevation in serum total cholesterol in them.
Adult↗
Screening of the 3' two-thirds of the coding area of the apo B gene in Finnish hypercholesterolemic patients report of six new genetic variants.
Hypercholesterolemia clustering in families not explained by either low density lipoprotein (LDL)-receptor mutations producing familial hypercholesterolemia (FH), or the apolipoprotein B (apo B) Arg3500-->Gln mutation with familial defective apo B (FDB), is common in the Finnish population. In search of previously unknown apo B mutations, we screened exons 26 to 29 of the apo B gene in 68 Finnish severely hypercholesterolemic (> or = 8 mmol/l) non-FH, non-FDB patients, using a single-strand conformation polymorphism analysis based screening method. Four rare and two polymorphic previously unreported DNA variations were detected. The rare variants were a three-nucleotide deletion, with the deletion of Asp2186, an A11961-->G change leading to a Thr3918-->Ala change, a T12922-->G change causing a Val4238-->Ala substitution, and a neutral T12935-->C change leading to a new RsaI cutting site. The polymorphic G12937-->C and G13569-->A changes leading to Arg4243-->Thr and Ala4454-->Thr substitutions, respectively, had minor allele frequencies of 0.03 and 0.02. None of these variants seemed to explain the hyperlipidemia in these patients. A major Finnish mutation causing severe hypercholesterolemia is unlikely to exist in the 3' two-thirds of the coding area of the apo B gene.
Apolipoproteins B↗
Screening for mutations in the exon 26 of the apolipoprotein B gene in hypercholesterolemic Finnish families by the single-strand conformation polymorphism method.
To date, the only known apolipoprotein B (apo B) mutation causing hypercholesterolemia is the apo B 3500 Arg-->Gln or the familial defective apo B (FDB) mutation. This mutation has not been detected in the Finnish population. We have set up a systematic single-strand conformation polymorphism (SSCP) analysis-based screening method to search for other mutations in the exon 26 of the apo B gene in 21 Finnish hypercholesterolemic probands. The 7572-bp exon 26 covers half of the coding region of the gene including the DNA sequence coding for the putative low-density lipoprotein (LDL) receptor binding site on the apo B protein. Exon 26 was amplified as six 1190- to 1435-bp fragments, each of which was further split into three smaller 213- to 579-bp segments by restriction enzymes. These digestion products were run on nondenaturing polyacrylamide gels using at least three different electrophoretic conditions and autoradiographed. All previously known genetic variants in the exon 26 were detected by the SSCP method. A C-->T change at nucleotide 7064, in complete association with the XbaI site, was characterized by direct sequencing. This variant did not affect the amino acid sequence of the apo B protein. The SSCP-based procedure appears suitable for systematic screening for DNA sequence changes in large coding regions.
Apolipoproteins B↗
Validation of a short dietary questionnaire and a qualitative fat index for the assessment of fat intake.
In connection with a population-based study on familial and non-familial determinants of serum total cholesterol an interviewer-administered short questionnaire, including 21 food items, and a qualitative fat index based on four questions were developed. Subjects for the validation study, 51 women and 31 men, aged 16-71 years, were selected from the population-based study (n = 892). The short questionnaire and the qualitative fat index were validated with a 3 day food record as the reference method. The short questionnaire captured 90-97% of the mean intakes of total fat, saturated, monounsaturated and polyunsaturated fatty acids and cholesterol. The Pearson correlation coefficients between the fat intakes based on the questionnaire and the diet records were strongest for the intake of total fat (r = 0.80). The qualitative fat index was based on four questions concerning type of fat: the higher the scores the higher the intakes of polyunsaturated fatty acids. The Spearman correlation coefficients between the qualitative fat index and the intakes based on the diet records were -0.55 for saturated, 0.34 for monounsaturated and 0.52 for polyunsaturated fatty acids. The respective correlation for the P/S ratio (total amounts of polyunsaturated fatty acids/saturated fatty acids) and the PM/S ratio (total amounts of polyunsaturated and monounsaturated fatty acids/saturated fatty acids) were 0.50 and 0.53. An inverse association between serum total cholesterol and the qualitative fat index was found in the whole study population, suggesting the impact of dietary fat on serum cholesterol in this study population. In conclusion, the short questionnaire proved to be accurate in measuring the intake of different fatty acids at the group level, whereas the simpler fat index measured the quality of fat quite well.
Adolescent↗
Ultrasonography in the detection of Achilles tendon xanthomata in heterozygous familial hypercholesterolemia.
We have examined the usefulness of ultrasound (US) in the detection of Achilles tendon (AT) xanthomata in heterozygous familial hypercholesterolemia. Our study is based on 30 adult subjects with heterozygous familial hypercholesterolemia (FH) (16 men, 14 women), 27 subjects with other non-familial forms of severe hypercholesterolemia (non-FH) with serum total cholesterol levels > or = 8 mmol/l (13 men and 14 women) and 31 subjects without marked hypercholesterolemia of the same age (control group; serum total cholesterol < 8 mmol/l) (15 men, 16 women). The three groups were comparable with respect to age, sex and body mass index. In the control group the mean sagittal thickness of AT was 4.5 mm (95% CI 3.2, 5.9 mm) and the mean coronal breadth of AT 11.0 (95% CI 9.0, 13.0 mm). Mean thickness of AT was 4.9 (range 4-7) mm in the non-FH group and 11.1 (5-16) mm in the FH group. The mean breadth of AT was in these groups 12.0 (10-17) mm and 19.2 (12-27) mm, respectively. Using the upper 95% confidence interval cut-off point in the control group as a criterion for normal AT thickness and breadth, 6 (22%) of non-FH and 29 (97%) of FH patients had increased AT thickness and 5 (19%) vs. 26 (87%) patients had increased AT breadth, respectively. The sensitivity of AT thickness for identifying FH was 0.97, specificity 0.78 and positive predictive value 0.83. The sensitivity of AT breadth in identifying FH was 0.87, specificity 0.81 and positive predictive value 0.84. None of the control subjects and none of the non-FH patients showed structural abnormalities of AT in the US, whereas 89% of FH-patients showed hypoechogenicity of AT. FH-score obtained by summing up the number of abnormal US findings gave a sensitivity of 0.93, a specificity of 0.96 and a positive predictive value of 0.96 for AT US in discriminating FH from non-FH. In conclusion, US examination of AT is a useful method in the detection of AT xanthomata and thus of help in the diagnosis of heterozygous FH.
Achilles Tendon↗
Prevalence and geographical distribution of major LDL receptor gene rearrangements in Finland.
In order to determine the prevalence of major rearrangements of the low density lipoprotein (LDL) receptor gene in Finland, DNA samples of 199 unrelated Finnish patients with the heterozygous form of familial hypercholesterolaemia (FH) were examined by Southern blot analysis. The FH-Helsinki mutation, characterized by a 9.5-kb deletion in the 3'-end of the LDL receptor gene, was found in 75 (38%) of the patients. The prevalence of this mutation ranged from 26-58% in different areas of Finland. A striking exception was the North Karelia region, where only one out of 26 (4%) FH patients was found to carry the FH-Helsinki allele. Two patients were found to carry other types of large nucleotide rearrangements of the LDL receptor gene. One mutation was a 7.5-kb deletion eliminating exons 7 to 10, and the other was a 13-kb deletion covering exons 11 to 16 of the LDL receptor gene. Serum lipoprotein levels were very similar in each category of mutation, i.e. in patients with the FH-Helsinki gene, those with the two other types of deletion, and the remaining patients with as yet unknown types of LDL receptor gene defects. These results show that, even in genetically uniform populations, FH may be heterogeneous at the DNA level. DNA techniques enable an unequivocal diagnosis for almost 40% of the Finnish patients with the heterozygous form of FH.
Blotting, Southern↗
Lathosterol and other noncholesterol sterols during treatment of hypercholesterolemia with lovastatin alone and with cholestyramine or guar gum.
Sixty-two patients aged 19-64 years with primary hypercholesterolemia (mean level of total cholesterol, 10.8 mmol/l) were treated with 80 mg/day lovastatin (L) alone for 18 weeks and, after randomization to either L + 20 g/day guar gum (L + GG) or L + 16 g/day cholestyramine (L + C) treatments, for an additional 18 weeks. The total cholesterol level declined from baseline by 34% during L and by 44% and 48% during L + GG and L + C, respectively. In terms of micromoles per millimole of cholesterol, serum levels of the cholesterol synthesis precursors cholestenol, desmosterol, and lathosterol were decreased and those of the plant sterols campesterol and sitosterol were increased by treatment with L. The serum contents of cholesterol precursors were increased markedly after the combination of either GG or C with L, but the increase was greater after the addition of C (e.g., the lathosterol to cholesterol ratio was 51% versus 212% for L + GG and L + C, respectively; p less than 0.001). Thus, a higher rate of removal of bile acids by C than by GG reduced more effectively the low density lipoprotein cholesterol level but simultaneously stimulated cholesterol synthesis compensatorily to a higher level even under concurrent treatment with L. The serum sitosterol to cholesterol ratio declined by 13% during L + GG but increased by 49% during L + C compared with the value under L alone, suggesting different effects of GG and C on the metabolism of plant sterols.
Adult↗
Comparison between lovastatin and cholestyramine in the treatment of moderate to severe primary hypercholesterolaemia.
120 patients (64 men, 56 women) aged 19-66 years with primary hypercholesterolaemia (mean serum total cholesterol 10.1 mmol/l, range 6.5-16.3 mmol/l) with normal or moderately raised concentrations of serum triglycerides were randomised after four weeks' diet and four weeks' diet+placebo phase either to cholestyramine (40 patients) or lovastatin (80 patients) treatments for the succeeding 12 weeks. The maximal daily doses were 24 g of cholestyramine and 80 mg of lovastatin. The baseline data of the treatment groups were comparable with the exception of HDL-cholesterol concentrations, which were lower in the lovastatin group. The mean reductions in total serum cholesterol concentrations were 24.3% for cholestyramine (P less than or equal to 0.01) and 33.4% for lovastatin (P less than or equal to 0.01) (P less than or equal to 0.01 between the treatment groups), in LDL-cholesterol 32.1% (P less than or equal to 0.01) and 40.7% (P less than or equal to 0.01) (P less than or equal to 0.05 between the treatment groups) and in apolipoprotein B 23.3% (P less than or equal to 0.01) and 33.3% (P less than or equal to 0.01) (P less than or equal to 0.01 between the treatment groups), respectively. Lovastatin was the only drug to reduce serum triglyceride concentrations, it did so by 26.0%. HDL-cholesterol increased by 7.7% (P = NS) when cholestyramine was taken and by 13.5% (P less than or equal to 0.05) with lovastatin (P = NS between the treatment groups). Apolipoprotein A1 remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Combination therapy with lovastatin and guar gum versus lovastatin and cholestyramine in treatment of hypercholesterolemia.
Sixty-two patients (34 men and 28 women) aged 19-64 years, half of whom had familial hypercholesterolemia, treated initially for 18 weeks with lovastatin alone were randomly allocated either to lovastatin (L) and cholestyramine (16 g/day) or lovastatin and guar gum (L + GG 20 g/day) treatment for 18 additional weeks to compare the hypocholesterolemic effects of these two combination therapies. The patients were selected for this study from a larger study of patients (n = 120) with severe hypercholesterolemia [serum total cholesterol (serum Chol) 6.5-16.3 mM before treatment], and only those patients in whom serum Chol after lovastatin alone (dose 80 mg/day) remained greater than or equal to 5.2 mM were eligible for evaluation of combination therapies. Serum Chol decreased from 10.6 +/- 1.6 to 5.9 +/- 1.3 mM (mean +/- SD) (p less than 0.001) and low-density lipoprotein cholesterol (LDL Chol) from 8.5 +/- 1.8 to 4.1 +/- 1 mM (p less than 0.001) in patients treated with L + GG (values before the beginning of lovastatin and at the end of the combination therapy). The respective changes were from 10.9 +/- 2.2 to 5.5 +/- 1.2 mM (p less than 0.001) and from 8.7 +/- 2.3 to 3.5 +/- 1.2 mM (p less than 0.001) in patients treated with lovastatin and cholestyramine (L + C). At the end of the study, both serum Chol (p less than 0.005) and LDL Chol (p less than 0.01) were significantly lower with L + C than with L + GG.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
[Septic shock following septoplasty].
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Adult↗