Kernicterus in an adult who is heterozygous for Crigler-Najjar syndrome and homozygous for Gilbert-type genetic defect

Gilbert syndrome is a common genetic disorder associated with mild unconjugated hyperbilirubinemia and no clinical illness. In contrast, Crigler-Najjar syndrome types I and II are rare genetic disorders associated with severe unconjugated hyperbilirubinemia and a life-long risk of kernicterus. Patients with Gilbert syndrome have low levels of a normal form of uridinediphosphoglucuronate glucuronosyltransferase because of a defect in the promoter region of both alleles, whereas patients with Crigler-Najjar syndrome are homozygous for a defect that yields an abnormal form of the enzyme that has limited or no activity. This case report describes a young adult with Crigler-Najjar syndrome type II in whom kernicterus developed after a laparoscopic cholecystectomy. The development of kernicterus was the result of a largely preventable series of events that lead to an increase in the free fraction of his serum bilirubin. Analysis of his genetic defect showed that he was homozygous for the mutation associated with Gilbert syndrome and heterozygous for a second mutation in the open reading frame of one allele of the bilirubin uridinediphosphoglucuronate glucuronosyltransferase gene. The combined defect leads to severe hyperbilirubinemia and shows how seemingly benign genetic defects, when combined, can cause serious clinical disease. (Gastroenterology 1997 Jun;112(6):2099-103)     

Shear-induced platelet aggregation requires von Willebrand factor and platelet membrane glycoproteins Ib and IIb-IIIa

Different types of platelets in various types of plasma were subjected to levels of shear stress that produce irreversible platelet aggregation in normal platelet-rich plasma (PRP). At shear stresses of 90 or 180 dyne/cm2 applied for 30 seconds or five minutes, aggregation was either absent or only transient and reversible using severe von Willebrand's disease (vWD) PRP (less than 1% von Willebrand factor, vWF); Bernard-Soulier syndrome (BSS) PRP (platelets deficient in the membrane glycoprotein Ib, GPIb); normal PRP plus monoclonal antibody (MoAb) to GPIb; thrombasthenic PRP (platelets deficient in membrane glycoprotein IIb-IIIa complex, GPIIb-IIIa); and normal PRP plus MoAb to GPIIb-IIIa. Shear-induced aggregation was inhibited under the above conditions, even though the platelets were activated to release their granular contents. Sheared normal platelets in vWD plasma aggregated in response to added vWF. These studies demonstrate that the formation of stable platelet aggregates under conditions of high shear requires vWF and the availability of both GPIb and GPIIb-IIIa on platelet membranes. The experiments demonstrate that vWF-platelet interactions can occur in the absence of artificial agonists or chemical modification of vWF. They suggest a possible mechanism for platelet aggregation in stenosed or partially obstructed arterial vessels in which the platelets are subjected to relatively high levels of shear stress.     

Modulation of polymorphonuclear leukocyte function by cetiedil

Cetiedil citrate monohydrate inhibits sickling of red cells and aggregation of platelets. We assessed its ability to attenuate polymorphonuclear leukocyte (PMN) function. PMN aggregation in response to 2 X 10(-7) M formyl-met-leu-phe (FMLP) was inhibited in a dose- dependent fashion by cetiedil concentrations ranging from 60 to 250 microM. Additionally, 125 microM cetiedil inhibited PMN aggregation in response to 2 X 10(-7) M FMLP, 20 ng/ml phorbol myristate acetate (PMA), and 1 X 10(-6) M A23187 by 69% +/- 18%, 72% +/- 20%, and 65% +/- 4%, respectively. Inhibition of FMLP-induced aggregation was provided by only 5 min of incubation of the drug with the cells and was partially reversible. Cell viability was unaffected by exposure of PMN to the drug. Correspondingly, 125 microM cetiedil prevented the translocation of calcium from the PMN membrane as assessed by chlorotetracycline fluorescence. Paralleling the effect of the drug on PMN aggregation, 125 microM cetiedil inhibited release of superoxide by 55% and decreased the number of available 3H-FMLP receptors. However, its effect on release of the primary granule constituent, myeloperoxidase, was minimal (4.5% inhibition), while the effect on release of the specific granule product, lactoferrin (27% inhibition), was modest. These studies indicate that cetiedil affects PMN aggregation and superoxide release to a much greater extent than PMN degranulation. Thus, cetiedil may have potential uses in modulating inflammatory response in vivo.     

Increased soluble interleukin-1 type II receptor concentrations in postoperative patients and in patients with sepsis syndrome

Plasma interleukin-1 (IL-1) activity is modulated in part through the simultaneous appearance of several inhibitors of IL-1 action, including interleukin-1 receptor antagonist (IL-1ra) and the soluble IL-1 type II receptor (IL-1RII). However, little is known concerning the plasma appearance of these inhibitors in patients following operative trauma or those with sepsis syndrome. In the present report, plasma IL-1beta, IL-1ra, and soluble IL-1RI and IL-1RII concentrations were evaluated in 118 patients with sepsis syndrome or after elective operative trauma. Plasma concentrations of IL-1ra increased significantly following elective operative repair of thoraco-abdominal and abdominal aortic aneurysms, and after bowel resection for inflammatory bowel disease, but did not increase after laparoscopic cholecystectomy. Plasma IL-1ra levels were also elevated in patients with sepsis syndrome. In contrast, soluble IL-1RII levels were only increased in patients after operative repair of thoraco-abdominal aortic aneurysms and in sepsis syndrome, whereas concentrations were unaffected by the other more modest surgical procedures. Plasma IL-1RI concentrations decreased in all postoperative patients in the first 24 hours after surgery. We conclude that both plasma IL-1ra and soluble IL-1RII concentrations often increase in sepsis and following some operative trauma. Less severe operative trauma increases the plasma concentration of only IL- 1ra, whereas both IL-1ra and soluble IL-1RII are increased in patients with sepsis syndrome or following thoraco-abdominal aneurysm repair.     

Expected gains in life expectancy from various coronary heart disease risk factor modifications

BACKGROUND. Despite much evidence that modifying risk factors for coronary heart disease can decrease morbidity and mortality, little is known about the impact of risk-factor modification on life expectancy. METHODS AND RESULTS. We used the Coronary Heart Disease Policy Model, a state-transition computer simulation of the US population, to forecast potential gains in life expectancy from risk-factor modification for the cohort of Americans turning age 35 in 1990. Among 35-year-old men, we projected that the population-wide increase in life expectancy would be about 1.1 years from strict blood pressure control, 0.8 years from smoking cessation, 0.7 years from reduction of serum cholesterol to 200 mg/dl, and about 0.6 years from weight loss to ideal body weight. For women, reducing cholesterol to 200 mg/dl would have the greatest estimated impact-a gain of 0.8 years-whereas smoking cessation, blood pressure control, or weight loss would yield population-wide gains of 0.7, 0.4, and 0.4 years, respectively. Gains for 35-year-old individuals having a given risk factor are greater. We estimate that, on average, male smokers would gain 2.3 years from quitting smoking; males with hypertension would gain 1.1-5.3 years from reducing their diastolic blood pressure to 88 mm Hg; men with serum cholesterol levels exceeding 200 mg/dl would gain 0.5-4.2 years from lowering their serum cholesterol level to 200 mg/dl; and overweight men would gain an average of 0.7-1.7 years from achieving ideal body weight. Corresponding projected gains for at-risk women are 2.8 years from quitting smoking, 0.9-5.7 years from lowering blood pressure, 0.4-6.3 years from decreasing serum cholesterol, and 0.5-1.1 years from losing weight. Eliminating coronary heart disease mortality is estimated to extend the average life expectancy of a 35-year-old man by 3.1 years and a 35-year-old woman by 3.3 years. CONCLUSIONS. Population-wide gains in life expectancy from single risk-factor modifications are modest, but gains to individuals at risk can be more substantial.     

Calcium phosphate ceramics as bone graft substitutes in filling bone tumor defects

Background:

Synthetic bio-inert materials are currently used as an alternative to autogenous bone graft. Calcium hydroxyapatite (HA) and Beta tri-calcium phosphate (β-TCP), which belong to the calcium phosphate ceramics group, are biocompatible and osteo-conductive. The purpose of this study is to analyse the use of HA and β-TCP in their ceramic forms as a bone graft substitute in filling bone voids after curettage of benign bone tumors.

Materials and Methods:

Twenty-four patients in the age range of 3.5-55 years (mean 14.3 years) having benign bone tumors with bone defects were filled with bone graft substitute following curettage. In 20 patients bone defects were filled with block/granules of HA ceramic and in four with β-TCP. Fibular strut graft was packed with HA in four patients. The patients were followed up for an average of 18 months (range 12-36 months).

Results:

The functional status of the patients at follow-up was evaluated and compared with preoperative functional status. Early incorporation of graft substitutes became evident radiologically between 6 and 10 weeks (Stage I). Complete incorporation (Stage III) was observed in an average of nine months (6-18 months). Clinical healing was observed before radiological healing. The average time taken to return to preoperative function was 14 weeks. There was no recurrence of lesion or growth retardation.

Conclusion:

Calcium hydroxyapatite and β-TCP are excellent bone graft substitutes for autogenous bone graft in filling voids after curettage of benign bone tumors.