A cholesterol-lowering gene maps to chromosome 13q.

A cholesterol-lowering gene has been postulated from familial hypercholesterolemia (FH) families having heterozygous persons with normal LDL levels and homozygous individuals with LDL levels similar to those in persons with heterozygous FH. We studied such a family with FH that also had members without FH and with lower-than-normal LDL levels. We performed linkage analyses and identified a locus at 13q, defined by markers D13S156 and D13S158. FASTLINK and GENEHUNTER yielded LOD scores >5 and >4, respectively, whereas an affected-sib-pair analysis gave a peak multipoint LOD score of 4.8, corresponding to a P value of 1.26x10-6. A multipoint quantitative-trait-locus (QTL) linkage analysis with maximum-likelihood binomial QTL verified this locus as a QTL for LDL levels. To test the relevance of this QTL in an independent normal population, we studied MZ and DZ twin subjects. An MZ-DZ comparison confirmed genetic variance with regard to lipid concentrations. We then performed an identity-by-descent linkage analysis on the DZ twins, with markers at the 13q locus. We found strong evidence for linkage at this locus with LDL (P<.0002), HDL (P<.004), total cholesterol (P<.0002), and body-mass index (P<.0001). These data provide support for the existence of a new gene influencing lipid concentrations in humans.

Molecular genetics of familial hypercholesterolemia in Israel.

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by a multitude of low density lipoprotein receptor (LDL-R) mutations. The purpose of the current investigation was to define the spectrum of mutations causing FH in Israel and determine their relative distribution among diverse origin groups. A total of 193 FH families were recruited in Israel, 54 of them through the MED PED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDL-R using single-strand conformation polymorphism (SSCP) or denaturing gradient gel electrophoresis (DGGE) or both has been completed in 95 index cases. This analysis resulted in the identification of 15 LDL receptor mutations, including 7 novel mutations (del 197, C308G, R385W, splice junction mutation of intron 14, del 328, del 502-505, stop 10, del 165), that were present in 49 index cases (52%). The 15 mutations are mapped to three known functional domains of the receptor (7 in the LDL-binding region, 7 in the epidermal growth factor precursor homology region and 1 in the membrane-spanning region). Screening for the identified mutations in the remaining 98 index cases enabled the molecular diagnosis of 31 additional cases. It is therefore concluded that 80 out of 193 index cases (41%) harbor 1 of the 15 mutations described here. Three mutations-del197 (FH-Lithuania), D147H (FH-Sephardic), and stop660 (Lebanese allele)-were found in a total of 66 index cases (34%); these may be regarded as founder mutations in the three respective origin groups. In conclusion, in Israel molecular heterogeneity at the LDL receptor gene locus reflects the ethnic distribution of its origin groups. The results of the present investigation provide valuable diagnostic tools for a subset of the Israeli patients with FH who are at high risk for atherosclerosis and its complications.

High-dose fluvastatin and bezafibrate combination treatment for heterozygous familial hypercholesterolemia.

This study assessed the long-term use of fluvastatin, alone or in combination with bezafibrate, in patients with severe familial hypercholesterolemia who, in a previous study, did not achieve target levels (European Atherosclerosis Society) of low density lipoprotein cholesterol (LDL-C) with fluvastatin at 60 mg/day plus bezafibrate 200 mg/day, with or without cholestyramine (CME) at 8 g/day. This open-label study comprised 3 periods: period I, 6 weeks of fluvastatin at 40 mg twice daily (at breakfast and at bedtime); period II, fluvastatin at 80 mg/day (40 mg at breakfast, 40 mg at bedtime), and bezafibrate at 200 mg/day (at lunchtime) for 6 weeks in patients not achieving LDL-C target levels; and period III, force-titration of fluvastatin to 800 mg/day (as in period II) and bezafibrate at 400 mg/day (slow release) in patients receiving combination treatment. Patients were excluded if, during the previous study, they had experienced a serious drug-related adverse event or deterioration in liver or kidney function (liver enzymes > 3 times upper limit of normal). The standard physical and laboratory evaluations were performed at regular intervals. Lipid profiles were determined from 12-hour fasting blood samples. All adverse events occurring or worsening during the study, whether spontaneously reported or elicited by questioning, and regardless of relationship to study medication, were recorded.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical and microbiological effects of chlorhexidine and arginine sustained-release varnishes in the mentally retarded.

Local applications of sustained-released varnishes of chlorhexidine and arginine were used in a controlled pilot study of 34 mentally retarded patients, ages 18-45, assigned to one of these groups: chlorhexidine (C), arginine (A), or placebo (P). A professional scaling followed by four weeks of professional brushing to reach a Plaque Index (PII) and Gingival Index (GI) of 1.0 at baseline preceded eight weeks of daily varnish application to the buccal and labial surfaces of all teeth. Clinical parameters (PII and GI) and bacterial samples from selected teeth were collected at predetermined intervals. Four and eight weeks following the baseline, the PII was significantly different among the groups, with the lowest score in the chlorhexidine group. No significant differences among the three groups were noted for the GI. The chlorhexidine and arginine groups showed significant reductions (p < 0.05 and p < 0.01, respectively) in the number of S. mutans. The arginine group showed a nonsignificant increase in the number of S. sanguis. These results suggest that the topical antimicrobial agents may have some relevance to plaque control among patients with mental retardation.

Caries levels, Streptococcus mutans counts, salivary pH, and periodontal treatment needs of adult Down syndrome patients.

The prevalence of dental caries and periodontal treatment needs in an institutionalized Down syndrome (DS) population was examined as well as the relationship between caries prevalence, salivary pH and salivary levels of Streptococcus mutans. Twelve patients with DS, aged 20 to 48, were compared with two similar age and gender control groups: healthy, and non-Down institutionalized mentally retarded patients. The pH levels did not differ significantly among the three groups. As to periodontal needs expressed by the CPITN, the institutionalized groups had the highest needs compared with the healthy group. Down adults, who were cariesfree, had significantly lower S. mutans counts compared with the patients with caries. In addition, the cariesfree patients with DS had much lower CPITN scores compared with the patients with caries.

Caries experience, periodontal treatment needs, salivary pH, and Streptococcus mutans counts in a preadolescent Down syndrome population.

The prevalence of dental caries and periodontal treatment needs in an institutionalized population with Down syndrome was examined and the relationship between caries prevalence, salivary pH, and salivary levels of Streptococcus mutans was studied. Thirty-two children with Down syndrome, aged 8 to 13, were compared with two control groups of similar age ranges: healthy children and non-Down mentally retarded (MR) children living in the same institution as the Down syndrome population. The gender ratio mixtures in each group also matched the study sample. Caries experience as indicated by decayed, missing, and filled surfaces (DMF-S) showed significantly lower mean scores for the Down syndrome group compared with both control groups. A similar pattern was found when evaluating the mean numbers of decayed surfaces. Streptococcus mutans counts, expressed as number of colony-forming units on mitis salivarius agar plates among the Down syndrome group, were the lowest, although not statistically significant compared with the counts of the healthy children. Both groups had bacterial counts which were significantly lower than those of the MR group. Significant differences between the two institutionalized groups and the healthy group were recorded for the salivary pH levels. The periodontal treatment needs as evaluated by the Community Periodontal Index of Treatment Needs showed significant difference between the MR group versus both the healthy population and the Down syndrome group. On the whole, 84% of the Down syndrome children were cariesfree.

Retinal detachment with high myopia in the Rubinstein-Taybi syndrome.

A case of rhegmatogenous retinal detachment with high myopia is presented in a 17 year old boy with the typical characteristics of the Rubinstein-Taybi syndrome. Although multiple eye anomalies are known to occur in this syndrome, the occurrence of retinal detachment has not been reported up to now. The importance of including a thorough fundus examination in the routine eye examination of these patients is emphasized.

Dietary-induced hyperlipidemia and renal function in the uremic rat.

Rats made uremic by 2-stage 5/6 nephrectomy and sham-operated control animals were fed either a normal laboratory chow, a high-sucrose (60%) or a high-fat (10% cholesterol; 20% olive oil) diet, all containing 21% protein and identical amounts of electrolytes, vitamins and trace elements. Serum creatinine levels remained unchanged in the control animals but rose in the 5/6 nephrectomised uremic animals by a factor of 2.7 from a mean of 0.44 +/- 0.05 mg/dl to 1.20 +/- 0.11 mg/dl at 8 weeks, without differences between the dietary groups. During 8 weeks of dietary regimen the high-sucrose and high-fat diets induced significant hypertriglyceridemia, generally similar in control and uremic rats. The uremic animals on a high-sucrose and high-fat diet had the most pronounced rise in serum triglycerides, 331.5 +/- 89.0 and 298.0 +/- 45.0 mg/dl, respectively (control: 159.9 +/- 14.0 mg/dl). After 4 and 8 weeks, only the animals on the high-fat diet had significant hypercholesterolemia, most pronounced in the uremic animals (356 +/- 56.3 mg/dl; control: 71.6 +/- 12.9 mg/dl). The animals in the latter group also had significant proteinuria and renal histologic abnormalities consisting of xanthoma-like glomerular lesions, infiltrates and fibrosis not seen in the other groups of animals. These data indicate that dietary-induced hyperlipidemia of short duration causes or aggravates renal damage in the rat with mild-moderate uremia, induced by ablation.

Intestinal fat malabsorption in the uremic rat.

In the past we have shown that patients with chronic renal failure (CRF) on hemodialysis show evidence of intestinal malabsorption of fat. The present study was designed to verify this finding in an animal model. Male rats weighing +/- 200 g were studied. Uremia (U) was induced by 2-stage subtotal (5/6) nephrectomy. Control (C) animals were sham-operated. Fat absorption was studied after 6 weeks of uremia with the oral fat loading test. Twenty percent intralipid (0.25 g/100 gBW) was given by gastric tube feeding to fasting animals and the appearance of chylomicrons (CHYL) and the rise of triglycerides (TG) in the serum was followed for 5 hrs. In order to isolate the effect of fat absorption, an additional group of U and C animals was pretreated with orotic acid and triton, thus blocking hepatic TG synthesis and neutralizing peripheral lipoprotein lipase activity. The absorption of CHYL was significantly (p less than 0.01) impaired in all U animals and averaged 43 and 70 percent of that of the C animals, 1 and 2 hrs after the load respectively. The rise in serum TG did not differ from C in mildly U animals (Scr 1.0 +/- 0.04). In the more severely uremic animals (Scr 2.6 +/- 0.2), however, pretreated with orotic acid and triton, the rise in serum TG was far less (p less than 0.01) than in C animals (111 +/- 26-903 +/- 111 delta % V.780 +/- 170-5032 +/- 746 delta %) 1 and 5 hrs after the load.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute renal failure in a burn patient: the advantages of continuous peritoneal dialysis.

An 8-year-old girl sustained 65-70 per cent body surface area burns when her clothes caught fire. Two weeks later, she developed acute renal failure (ARF) and needed dialysis therapy. The extensive, infected burn area prevented the establishment of a safe vascular access for haemodialysis. Continuous peritoneal dialysis proved to be a valid alternative form of treatment and even had advantages over haemodialysis. Large amounts of fluids, calories and electrolytes could be administered via the peritoneal route. This facilitated the treatment of the catabolic state of the uraemic burn patient and served to correct the electrolyte losses via the skin. Peritoneal dialysis is a valuable adjunct to the treatment of acute renal failure in burn patients who need renal replacement therapy.

Renal candidiasis in infancy--a case with fungus ball obstruction.

A sixteen day old infant developed candiduria after surgery on a single functioning, hydronephrotic kidney with ureteropelvic junction stenosis. Masses of candida albicans caused obstruction of the ureter with acute anuria. Endoscopic relief of the obstruction together with aggressive antifungal therapy led to irradication of the fungal infection. This case history emphasizes the fact that candida infection in early childhood should be evaluated carefully. Unfortunately no guidelines are yet available for the indications and the preferred mode of treatment, and length of therapy of infantile renal candidiasis.

Dialysis-induced hypoxemia. Continuous monitoring of blood oxygen and carbon dioxide tension in children.

We report our experience with continuous, transcutaneous monitoring of capillary oxygen and carbon dioxide tension (PtcO2, PTlcCO2 ) during the entire length of hemodialysis treatment in 8 pediatric patients. The relative changes in PtcO2 and PtcCO2 observed with this method were in accordance with those reported in the literature, obtained with frequent arterial blood sampling. There was a temporary fall of PtcO2, averaging 26.2% after 2h of dialysis, with a concomitant rise of PtcCO2 of 9.9%. The noninvasive, transcutaneous measurement of PtcO2 and PtcCO2 is a reliable and valuable adjunct for the monitoring of the dialysis patient who is prone to develop hypoxemia. It is particularly useful in the very young.

Unusual presentation of vitamin A intoxication.

A 10.5-year-old boy was admitted to hospital because of a focal motor seizure. He had suffered from impaired attention span and emotional instability from the age of 6 years. From the age of 5 years he received daily a multivitamin preparation containing 5,000 IU vitamin A. The cause of his symptoms was found to be vitamin A intoxication, with an unusual acute presentation of microscopic hematuria, electroencephalographic abnormalities, and convulsions.

Detecting unsuspected thyroid dysfunction by the free thyroxine index.

The free thyroxine index (FTI) was used in 2,704 adults to detect unsuspected thyroid dysfunction. Among 2,581 adults found to be clinically euthyroid without thyroid medication, 2,571 had a truly normal FTI (121 to 360) and ten had a falsely abnormal FTI (seven less than 121, three greater than 360). Among 25 subjects with newly diagnosed thyroid dysfunction, there were eight hyperthyroid (prevalence, 0.31%) and 14 hypothyroid (prevalence, 0.50%) subjects. The sensitivity of the FTI was 1.0, and the specificity was 0.996. The predictive value of an abnormal FTI with a prevalence of 0.81% was 67%. The cost to find a new case averaged $127. The annual incidence of symptomatic hyperthyroidism was 0.05%; of hypothyroidism, about 0.08%. We conclude that the FTI is cost-effective for case finding in thyroid dysfunction.

Comparison of the phospholipase activity of bovine milk lipoprotein lipase against rat plasma very low density and high density lipoprotein.

The hydrolytic activity of a lipoprotein lipase from bovine milk against triacylglycerol and phosphatidylcholine of rat plasma very low density lipoprotein was determined and compared to that against phosphatidylcholine of high density lipoprotein. 85--90% of the triacylglycerol in very low density lipoprotein were hydrolyzed to fatty acids and 25--35% of the phosphatidylcholine to lysophosphatidylcholine. High density lipoprotein phosphatidylcholine was only minimally susceptible to the enzyme. Even with high amounts of enzyme and prolonged incubation periods, lysophosphatidylcholine generation did not exceed 2--4% of the original amounts of labeled phosphatidylcholine in the high density lipoprotein. We conclude that phospholipids in high density lipoprotein are not substrates for the phospholipase activity of this lipoprotein lipase. These observations suggest that factors other than the presence of apolipoprotein C-II and of glycerophosphatides are of importance for the activity of lipoprotein lipases.

Phospholipid removal during degradation of rat plasma very low density lipoprotein in vitro.

The hydrolysis of glycerophospholipids in very low density lipoprotein by enzyme(s) released into circulation after the injection of heparin to rats was studied. [32P]Lysolecithin was formed rapidly from [32P]lecithin when very low density lipoprotein, labeled biosynthetically with 32P, was incubated with postheparin plasma. The [32P]lysolecithin was associated with the plasma protein fraction of density greater than 1.21 g/ml, whereas [32P]lecithin exchanged between very low and high density lipoproteins. Inhibition of the plasma lecithin: cholesterol acyl transferase activity did not change the excess [32P]lysolecithin formation in postheparin plasma, and only a negligible amount of radioactivity was associated with blood cells when the incubation was repeated in whole blood. Analysis of the results has demonstrated that phospholipids are removed from VLDL by two pathways: hydrolysis of glycerophospholipids by the heparin-releasable phospholipase activity (greater than50%) and transfer to high density lipoproteins (less than50%). The tissue origin of the postheparin phospholipase was studied in plasma obtained from intact rats and supradiaphragmatic rats using specific inhibitors of the extrahepatic lipase system (protamine sulfate and 0.5 M NaCl). The phospholipase activity could be ascribed to both the hepatic and extrahepatic lipase systems. It is concluded that hydrolysis of glycerophospholipids is the major mechanism responsible for the removal of phospholipids from very low density lipoprotein during the degradation of the lipoprotein. It is suggested that phospholipid hydrolysis occurs concomitantly with triglyceride hydrolysis, predominantly in extrahepatic tissues.