Familial protein S deficiency with a variant protein S molecule in plasma and platelets

A protein S deficient family presenting a variant protein S molecule in plasma and platelets is described. The propositus, age 20, and two brothers suffered from venous thrombotic disease. The propositus, the only family member studied while taking oral anticoagulants, had a protein S antigen (ag) level of 17% and undetectable activity. As demonstrated by immunoblotting both the propositus and one clinically affected brother (42% ag, 7% activity) presented variant protein S molecules of 65,000 molecular weight (mol wt) while the other clinically affected brother (64% ag, 11% activity) had only protein S with normal electrophoretic mobility of 70,000 mol wt. The mother had normal protein S levels (93% ag, 100% activity) but had both normal and variant protein S molecules and based on her functional protein S data a normal anticoagulant activity of the variant molecule is suggested. One asymptomatic but protein S deficient sister (68% ag, 9% activity) as well as the asymptomatic protein S deficient father (59% ag, 10% activity) had only protein S molecules of 70,000 mol wt. The variant protein S bound to C4b-binding protein in plasma, and differed from normal protein S in carbohydrate content. Platelets of each family member contained the same immunoblotting pattern of normal and variant protein S forms as found in plasma, consistent with the hypothesis that protein S gene expression involves codominant expression of two alleles that is similar in cells that control the synthesis of both platelet and plasma forms of protein S.     

Acute lymphoblastic leukemia of childhood: identification of two distinct regions of deletion on the short arm of chromosome 12 in the region of TEL and KIP1

Cytogenetic analysis of acute lymphoblastic leukemia (ALL) of childhood identified nonrandom chromosomal abnormalities of the short arm of chromosome 12. The alterations include deletions that are thought to be indicative of the presence of a tumor suppressor gene that is mutated on the remaining allele. To refine further the chromosomal localization of this gene, we analyzed the loss of heterozygosity (LOH) of chromosome 12 in 100 primary ALL samples using 22 polymorphic markers and identified two distinct smallest common deleted regions on chromosome 12p13. One region is flanked by D12S77 and D12S98 and has a size of 4 cM. Twenty-six percent of informative patients showed LOH in this region. This region may contain the TEL gene. The other region is flanked by D12S269 and D12S308 including the KIP1 gene. Forty-four percent of informative patients showed LOH in this second region. Mutational analysis of KIP1 using polymerase chain reaction-single- strand conformation polymorphism analysis and Southern blot analysis showed no homozygous deletions and point mutations suggesting that the altered gene in this second region is not the KIP1. Clinical data showed that LOH of 12p was demonstrated more frequently in precursor-B ALLs (32 of 80; 40%) than in T-ALLs (1 of 20; 5%) (P = .0027). Furthermore, patients with 12p LOH were younger (P = .013), with a lower DNA index (P = .046), but they had the same survival rates at 3 years. In summary, these data suggest that two different tumor suppressor genes are on chromosome arm 12p, which act separately in the development of childhood precursor-B ALLs. One of the tumor suppressor genes is in the region the KIP1 gene, but our data suggest this gene is not abnormal. The other target is in the region of the TEL gene; and this candidate deserves further study.     

Humoral immune function in pediatric patients treated with autologous bone marrow transplantation for B cell non-Hodgkin's lymphoma. The influence of ex vivo marrow decontamination with anti-Y 29/55 monoclonal antibody and complement

Elimination of neoplastic B cell populations from autologous bone marrow grafts also removes normal B lymphocytes. This is potentially hazardous for the reconstitution of the immune system in patients undergoing high-dose chemotherapy and total body irradiation followed by autologous marrow rescue. Five pediatric patients with B cell non- Hodgkin's lymphoma in first remission undergoing such a regimen were studied. They received bone marrow pretreated with anti-Y 29/55 monoclonal antibody and complement. B and T lymphocyte subpopulations reached normal levels within 6 months after autologous bone marrow transplantation (ABMT), and serum immunoglobulin levels became normal within 4 to 9 months. Vaccination with diphtheria and tetanus toxoid, trivalent poliomyelitis vaccine of the Salk type, and pneumococcal capsular antigens (38 to 54 months after transplantation) gave rise to specific antibody production. ABO isoagglutinins could be demonstrated in all patients. The response pattern was similar to that of patients who received unmanipulated autologous bone marrow. It is concluded that ex vivo anti-Y 29/55 depletion of the marrow graft does not induce relevant disturbances of humoral immune functions.     

Evaluation of the potential clinical and economic effects of bodyweight stabilisation with acarbose in patients with type 2 diabetes mellitus. A decision-analytical approach

Bodyweight is an acknowledged independent risk factor for coronary heart disease (CHD). The present model analysis was undertaken to investigate the clinical and economic impact of bodyweight gain in patients with type 2 (non-insulin-dependent) diabetes mellitus and its effects on the development of CHD. Based on a retrospective re-evaluation of data from the Diabetes Intervention Study (DIS), patients with type 2 diabetes mellitus and stable bodyweight (group A) had a significantly lower rate of combined CHD events (30.3%) than patients showing a bodyweight gain (group B; 38.2%) over 10 years. Prevention of bodyweight gain, therefore, appears to be a meaningful strategy in the management of diabetes mellitus. In addition to this clinical advantage, prevention of CHD will also result in economic savings associated with avoided treatment of coronary events. Based on the clinical outcomes from the DIS, the calculated per-patient net savings for a patient with type 2 diabetes mellitus and stable bodyweight amounted to 1085 deutschmarks (DM) when compared with a patient experiencing a bodyweight increase. In a further step, the above situation was projected to current type 2 diabetes mellitus practice. Oral first-line treatment of type 2 diabetes mellitus is usually initiated with glibenclamide (glyburide), which is known to increase bodyweight (reflecting group B). The novel alpha-glucosidase inhibitor acarbose, in contrast, appears to be as effective as glibenclamide, but has the advantage of being bodyweight-neutral (reflecting group A). From the clinical viewpoint, acarbose can thus be considered an alternative to glibenclamide. From the viewpoint of drug costs, monotherapy with acarbose is 4 times as expensive as glibenclamide in Germany, resulting in per-patient incremental costs of DM3527 for acarbose over 10 years. Balanced against the potential 10-year cost saving of DM1085 resulting from the potential of acarbose to prevent CHD, around one-third of the incremental cost of acarbose may be recouped by this single effect. However, further possible benefits of acarbose, including the avoidance of hypoglycaemia and the deferral of costly insulin therapy, may improve the economic value of this novel antidiabetic agent. Given the indirect approach of this evaluation and its many limitations, the above findings need critical appraisal, and comparative trials are urgently required to substantiate our preliminary results.     

Medullary nephrocalcinosis and pancreatic calcifications demonstrated by ultrasound and CT in infants after treatment with ACTH

Thirteen patients who had undergone prolonged adrenocorticotropic hormone (ACTH) therapy for infantile spasms or myoclonic encephalopathy were examined with sonography. Nine patients were found to have appearances characteristic of medullary nephrocalcinosis. In each of these infants the cortical echogenicity was normal in the presence of focal areas of increased echogenicity within the renal pyramids. Five patients also showed a homogeneously increased echogenicity of the whole pancreas on sonography, and two of these showed increased density on computed tomography. Density measurements were in the range of calcific material within the papillae and pancreatic tissue. On abdominal survey radiographs, even in retrospect no calcifications could be recognized.     

Renal sonography in the differentiation of upper from lower urinary tract infection

Increase in renal volume and asymmetry in kidney size determined by sonography proved to be a valuable diagnostic criterion for differentiation between infections of the upper and lower urinary tract in 175 children: acute bacterial interstitial nephritis (79) and lower urinary tract infection (96). Kidney volume in acute pyelonephritis increased to an average of 175% of normal. In 71% of cases, affected kidneys showed an enlargement of at least 2 SD when compared with a group of 325 children without kidney pathology. Most impressive kidney enlargement was seen during the first year of life. In 50% of cases, acute pyelonephritis caused a bilateral increase in renal size and/or distinct volume asymmetry. Kidneys of patients with lower urinary tract infections had a mean volume of 99.68% and a physiologic volume asymmetry comparable to normal kidneys.     

Brain tumors: MR imaging with gadolinium-DTPA

Magnetic resonance (MR) imaging was performed on 40 patients with intracranial tumors, before and after intravenous administration of gadolinium-DTPA (Gd-DTPA). Precontrast studies included a comprehensive protocol of spin-echo sequences. Tumors were visualized on precontrast images either directly or indirectly by anatomic distortion caused by the mass. However, differentiation of the tumor from adjacent tissues was possible in only 17 of 40 cases. Delineation of the tumor was best on precontrast, T2-weighted images. After administration of Gd-DTPA (0.1 mmol/kg), increased signal intensity from the tumor was observed in all patients. The localized increase in signal intensity in the tumor considerably improved the tumor delineation in 36 of 40 patients. Whereas most of the meningiomas, neuromas, and adenomas could be delineated prior to administration of contrast material if appropriate pulse sequences were applied, glioblastomas and intracranial metastases required Gd-DTPA administration for diagnostically sufficient tumor display.