Partial trisomy 3p and partial monosomy 11q associated with atrial septal defect, cleft palate, and developmental delay: a case report.

Unbalanced translocation involving both chromosome 3p duplication and 11q deletion in the same patient is extremely rare; only 1 live-born case was reported previously. This karyotype was also detected during prenatal diagnosis of 2 different pregnancies in a Taiwanese family which were both terminated. In all 3 cases, only standard karyotyping was done to detect the abnormal karyotypes. Here, we report a 4-year-old boy with cleft palate, atrial septal defect, and hypotonia with gross and fine motor delay. Oligonucleotide-based array comparative genomic hybridization showed copy number gain from 3pter to 3p24.2 (approximately 24.5 Mb) and copy number loss from 11q25 to 11qter (approximately 5.8 Mb). This de novo unbalanced translocation event involving a terminal 3p duplication and a terminal 11q deletion provides candidate genes for further investigation of dosage effect leading to the patient's multiple phenotypic abnormalities. Genotype-phenotype correlation is difficult to make in this case due to the large number of genes involved. However, the description of such cases together with precise gene-level mapping of chromosomal breakpoints will add to further refinement of candidate genes to be investigated for terminal imbalances in 3p and 11q when more similar cases are reported.

The protein CD63 is in platelet dense granules, is deficient in a patient with Hermansky-Pudlak syndrome, and appears identical to granulophysin.

The levels and expression of the proteins CD63 and granulophysin in platelets from control and from a Hermansky-Pudlak syndrome subject (a condition characterized by dense granule and lysosomal deficiencies and the accumulation of ceroid-like material in reticuloendothelial cells) were examined. Immunofluorescence studies indicated that anti-CD63 and anti-granulophysin antibodies recognized similar numbers of granules; coapplication of antibodies did not identify more granules than the individual antibodies. Significantly fewer granules were recognized in Hermansky-Pudlak syndrome platelets than in control using either antibody. Immunoblotting studies demonstrated that anti-CD63 and anti-granulophysin antibodies apparently recognize the same protein, which was deficient in Hermansky-Pudlak platelets. Analysis by fluorescence-activated cell sorter (FACS) showed biphasic expression of CD63 and granulophysin after thrombin stimulation of control but not Hermansky-Pudlak platelets. Anti-CD63 effectively blocked detection of the protein by anti-granulophysin using immunofluorescence, ELISA, immunoblotting, and FACS analysis. Amino-terminal sequencing over the first 37 amino acids revealed that granulophysin was homologous to CD63, melanoma antigen ME491, and pltgp40. These results suggest that granulophysin and CD63 are possibly identical proteins. This is the first report of a protein present in platelet dense granules, lysosomes, and melanocytes, but deficient in a patient with Hermansky-Pudlak syndrome.

Delipidation of a hepadnavirus: Viral inactivation and vaccine development.

Many viruses including HIV, hepatitis C and hepatitis B, have an outer lipid envelope which maintains inserted viral peptides in the "correct" functional conformation and orientation. Disruption of the lipid envelope by most solvents destroys infectivity and often results in a loss of antigenicity. This communication outlines a novel approach to viral inactivation by specific solvent delipidation which modifies the whole virion rendering it non-infective, but antigenic. Duck hepatitis B virus (DHBV) was delipidated using a diisopropylether (DIPE) and butanol mixture and residual infectivity tested by inoculation into day-old ducks. Delipidation completely inactivated the DHBV (p < 0.001). Delipidated DHBV was then used to vaccinate ducks. Three doses of delipidated DHBV induced anti-DHBs antibody production and prevented high dose challenge infection in five out of six ducks. In comparison, five of six ducks vaccinated with undelipidated DHBV and four of four ducks vaccinated with glutaraldehyde inactivated DHBV were unprotected (p < 0.05). Although this solvent system completely inactivated DHBV, viral antigens were retained in an appropriate form to induce immunity. Delipidation of enveloped viruses with specific organic solvents has potential as the basis for development of vaccines.

Disposition of and clinical response to salicylates in patients with rheumatoid disease.

The disposition of salicylic acid (SA) and its metabolites and the clinical response to long-term aspirin treatment at varying doses were assessed in patients with rheumatoid disease. Steady-state kinetics of SA (total and unbound), salicyluric acid (SUA), gentisic acid (GA), and clinical status were estimated weekly in 10 patients with rheumatoid arthritis. Eight received a soluble aspirin form and two received an enteric-coated form. The starting dose of aspirin in each patient was 1.8 gm (soluble) or 1.95 gm (enteric-coated) daily. Weekly increments in dose were made until a satisfactory clinical outcome was achieved. The final aspirin dose range was 3.6 to 8.1 gm daily, which resulted in mean steady-state plasma SA concentrations (CpSA) from 56 to 375 mg/l. Since the mean total CpSA increased approximately proportionately over the dose range, there was little change in total SA clearance. By contrast, increasing aspirin dosage resulted in decreased clearance and disproportionate increases in unbound SA (CpuSA). The maximum velocity of conversion of SA to SUA (Vm) increased significantly, from 57.3 +/- 11.7 mg/hr at an aspirin dose of 1.8 gm/day to 71.4 +/- 19.4 mg/hr at the next highest dose (2.7 to 3.6 gm/day), with no further change with increasing dosage. Km ranged from 0.4 to 1.2 mg/l for CpuSA and from 5.5 to 17.2 for total CpSA. Renal clearance of SUA (ClSUA) ranged from 124 to 893 ml/min and correlated with creatinine clearance. ClGA ranged from 23 to 164 ml/min, and ClSA ranged from 0.1 to 17.1 ml/min; neither correlated with creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Salicylate metabolite kinetics after several salicylates.

Single oral doses of aspirin (ASA, 1,500 mg), sodium salicylate (NaSA, 1,500 mg, 1,200 mg), and salicyluric acid (SUA, 500 mg) were given to five subjects. Serial plasma and urine samples were collected for 24 hr (plasma) and up to 48 hr (urine); salicylic acid (SA), SUA, and gentisic acid (GA) were measured by high-pressure liquid chromatography. The plasma concentration/time profiles for SUA after ASA and NaSA were fitted to the empirical equation CpSUA = A-Bt-Ce-alpha t -- (A-C)e-beta t. Michaelis constants (Vm and Km) for the conversion of SA to SUA were calculated from the equation (formula see text), where Cl is the renal clearance of SUA, ke is the rate constant of elimination of SUA, CpSA is the plasma concentration of salicylic acid. The term Cl (formula see text) is the estimated rate of formation of SUA from SA at any time (t). The calculated values (mean +/- SD) of Vm, Km, and Kmf (Km in terms of unbound SA) were 43.4 +/- 10.1 mg SA/hr, 14.3 +/- 3.4 mg SA/l plasma, and 0.75 +/- 0.15 mg unbound SA/l plasma. The Vm values were in accord with those reported, but the value for Km was considerably lower. Renal clearances of SUA and GA were 340 +/- 51 and 65 +/- 10 ml/min.

Glycoalkaloids from Solanum sodomaeum are effective in the treatment of skin cancers in man.

A cream formulation containing glycoalkaloids purified from the plant species Solanum sodomaeum L. is effective in the treatment of the malignant human skin tumours; basal cell carcinomas (BCCs), squamous cell carcinomas (SCCs) and the benign tumours; keratoses and keratoacanthomas. Histological analyses of biopsies taken before, during and after treatment give compelling evidence of the efficacy of the formulation. The treated lesions did not recur for at least 3 years after cessation of therapy. The observed complete regressions were; 20/24 for the BCCs; 5/6 for the SCCs; 23/23 for the keratoses; and, 9/9 for the keratoacanthomas. Biochemical, haematological and urinanalytical studies demonstrated that there were no adverse effects on the liver, kidneys or haematopoietic system during treatment. Normal skin treated with the formulation likewise was free from adverse histological or clinical effects. The data indicate that glycoalkaloids of this type are therefore potentially useful in the treatment of several types of human skin cancers.

Solasodine glycosides. Selective cytotoxicity for cancer cells and inhibition of cytotoxicity by rhamnose in mice with sarcoma 180.

BEC, a standard mixture of solasodine glycosides is effective in vivo against murine sarcoma 180 (S180), whereas the aglycone solasodine at equimolar concentrations is ineffective. The efficacy of BEC against S180 in vivo can be inhibited by rhamnose. Mice which are in their terminal stage with S180 can tolerate and become symptom-free of cancer by single dose administration of BEC at concentrations of BEC three times the LD100 for normal mice. These observations suggest that the binding of solasodine glycosides on tumour cells may be mediated through the monosaccharide rhamnose, which forms part of solasonine, solamargine and di-glycosides of solasodine in BEC. Furthermore, these results provide evidence that BEC selectively destroys tumour cells relative to normal cells in vivo.

Solasodine glycosides. In vitro preferential cytotoxicity for human cancer cells.

Solamargine [(22R,25R)-spiro-5-en-3 beta-yl-alpha-L-rhamnopyranosyl- (1----2glu)-O-alpha-L-rhamnopyranozyl (1----4glu)-beta-D-glucopyranoze], a glycoside of solasodine preferentially inhibits the uptake of tritiated thymidine by cancer cells. In contrast, solamargine at equivalent concentration, and the mono- and diglycosides of solasodine have a limited effect on the uptake of tritiated thymidine for other cell types, including unstimulated lymphocytes and lymphocytes stimulated with Con A. In contrast the solasodine glycosides do not inhibit the uptake of tritiated thymidine by lymphocytes stimulated with PHA or PWM. The inhibition of tritiated thymidine uptake by solamargine and the mono- and di-glycosides of solasodine are dependent upon their cellular uptake by endogenous endocytic lectins (EELs). The mode of action of the solasodine glycosides, in particular solamargine, appears to be the induction of cell lysis, as determined by morphological examination.

Topical treatment of malignant and premalignant skin lesions by very low concentrations of a standard mixture (BEC) of solasodine glycosides.

A cream formulation containing high concentrations (10%) of a standard mixture of solasodine glycosides (BEC) has been shown to be effective in the treatment of malignant and benign human skin tumours. We now report that a preparation (Curaderm) which contains very low concentrations of BEC (0.005%) is effective in the treatment of keratoses, basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) of the skin of humans. In an open study, clinical and histological observations indicated that all lesions (56 keratoses, 39 BCCs and 29 SCCs) treated with Curaderm had regressed. A placebo formulation had no effect on a smaller number of treated lesions. Curaderm had no adverse effect on the liver, kidneys or haematopoietic system.

Posterior mediastinal sarcoidosis.

We report two cases of enlargement of the posterior mediastinal lymph nodes due to sarcoidosis. Bilateral hilar enlargement, pulmonary parenchymal involvement, or extrathoracic manifestations of sarcoidosis were absent. A diagnostic thoracotomy had to be performed in both instances.

Complete replacement of the ascending aorta with reimplantation of the coronary arteries: new surgical approach.

Thirty patients had total replacement of the ascending aorta with reimplantation of the coronary arteries, 20 for a fusiform aneurysm of the ascending aorta and 10 because of a dissection of the ascending aorta, of which there were acute. All had associated aortic insufficiency. The technique consists of implantation, within the aneurysmal sac, of a Dacron prosthesis containing a Björk-Shiley aortic valve. The coronary orifices are anastomosed to the tubular Dacron prosthesis by means of a second smaller Dacron tube. The aneurysmal pouch is then closed over the entire appliance and a fistula between the aneurysmal sac and the right atrial appendage is created to drain oozing from the prosthesis. The operative mortality was 10% (three deaths) and the late mortality has been 14.8% (four deaths). The deaths, early and late, have been confined to the first 10 cases, during which time the technique was being developed. There has been no mortality among the last 20 patients. The 23 survivors followed for an average of 19 1/2 months (range 6 months to 5 1/2 years) are in NYHA Functional Class I (21) or II (two). The technical modifications utilized in this series have simplified the operation and permit the proposal of this technique for aneurysm involving the entire ascending aorta.

The Gambian National Impregnated Bed Net Programme: evaluation of effectiveness by means of case-control studies.

Two case-control studies, one on mortality and the other on malaria morbidity, were carried out in order to evaluate the impact of the Gambian National Insecticide Bed Net Programme during the second year of intervention and to explore the feasibility of such a study for the evaluation of programme effectiveness. For the mortality study, children 1-9 years old who died during the 1993 rainy season were matched by age and sex with 2 healthy controls from the same village. For the morbidity study, children 1-9 years old attending Fatoto or Jahalia Health Centres in The Gambia and who had fever and parasitaemia > or = 5000/microL were matched by age with a child attending the health centres without fever or parasitaemia. An additional healthy control was recruited from the case's village. No impact of insecticide-treated bed nets on mortality was detected and this was in keeping with the results obtained by prospective surveillance. A protective effect of insecticide-treated nets on malaria morbidity was detected when cases were compared with controls recruited at the health centres. However, this disappeared when cases were compared with controls recruited from the cases' villages. The mortality case-control study suggested that reducing the time between onset of disease and treatment may have an important impact on childhood mortality. In order to calculate programme cost-effectiveness, important for informed resource allocations to be made by health managers, it is essential to obtain evidence of effectiveness. This can be done by means of case-control studies, which are easier to carry out and require fewer resources than prospective surveillance. Nevertheless, it is necessary to be conscious of their pitfalls, particularly of the bias involved in the choice of cases and controls. The measurement of insecticide on the nets of the cases or controls is essential for such studies.

PIP: The impact of the Gambian National Impregnated Bed Net Program was evaluated during its second year of implementation through two case-control studies on malaria mortality and morbidity. The first study matched 167 children 1-9 years of age who died during the 1993 rainy season with two healthy controls (n = 334) of the same age and sex from the same village. The second study matched 143 children 1-9 years of age attending Fatoto or Jahalia Health Centers with fever or parasitemia with a child the same age attending the health centers without these symptoms and an additional healthy control from the same village. The mortality study failed to document any protective effect of insecticide-treated bed nets. Child survival was more closely linked to consultation with a village health worker during serious illness, household availability of chloroquine tablets, sponging, and maternal awareness of fever and convulsions as symptoms of malaria. A protective effect of the bed nets on malaria morbidity was revealed when cases were compared with health center controls, but this effect disappeared when cases were compared with controls from the same village. Going to bed early and father having a job other than working on the family farm were the two variables associated with significant protection against malaria in the multivariate analysis. Case-control studies are easier to conduct and require fewer resources than large prospective community-based studies. However, it is recommended that any future such studies of malaria control programs clarify the criteria used to select cases and controls and incorporate insecticide measurements of study nets.

Lipid associated tissue ferritin.

Delipidation of liver homogenates, using an organic solvent system which does not denature proteins, increases measurable ferritin by 25-33%, compared to ferritin concentrations by standard heat supernatant assays. When applied to polyacrylamide gradient gels, lipid-associated ferritin does not enter the gel but after delipidation, this ferritin co-migrates with cytosolic ferritin and with purified liver ferritin. The biological significance of the association of ferritin with lipid has yet to be examined.

Interdependence of serum concentrations of vitamin K1, vitamin E, lipids, apolipoprotein A1, and apolipoprotein B: importance in assessing vitamin status.

Vitamin E (alpha-tocopherol) and vitamin K1 (phylloquinone) are fat-soluble vitamins and are important nutrients in health and disease. In this study serum concentrations of vitamin E and vitamin K1, lipids and apolipoproteins A1 and B were measured in neonates, normal and hyperlipidaemic individuals in an attempt to establish their interrelationships. A high degree of correlation was observed between the concentrations of the vitamins and those of lipids and apolipoproteins (r ranged from 0.42 to 0.92; p<0.001). Stepwise linear regression methods determined that serum concentrations of both vitamin E and vitamin K1 could best be predicted by using equations excluding lipids but containing only apolipoprotein A1 and B concentrations. Correlation coefficients between predicted and measured values were 0.89 for serum vitamin E, and 0.83 for serum vitamin K1 concentrations. To test the validity of the derived formulae, measured and estimated vitamin K1 and vitamin E concentrations in serum were determined in another group of neonates, normal adults and hypercholesterolemic adults and the comparisons were shown to be very good. These results indicate that the serum levels of both vitamins depend critically on the concentration of the lipoprotein carriers, apolipoproteins A1 and B. Hence, in order to identify variations in serum vitamin K1 and vitamin E concentrations, which are independent of variations in carrier concentration, it will be necessary to express these serum vitamins as ratios of vitamins to apolipoprotein A1 and B carriers.

Importance of apolipoproteins in lipid metabolism.

Lipids, which serve as a source of energy and are an important constituent of cell membrane structure, are readily stored in the body. By definition they are insoluble in water. Specific proteins called apolipoproteins interact with lipids to form soluble lipid-protein complexes called lipoproteins. It is in this form that the major lipids--cholesterol, triglyceride and phospholipid--circulate in plasma. Unesterified fatty acids, another major lipid group, are bound to albumin in the circulation. The plasma lipoproteins are complex macromolecules composed of lipids, apolipoproteins and carbohydrates. The relative proportions of these components differ markedly between lipoprotein classes. Hyperlipidemia is a term used for increased concentrations of plasma cholesterol and/or triglycerides. Any one plasma lipid is present in several types of lipoproteins. Thus, hyperlipidemia implies the presence of hyperlipoproteinemia. The latter has important therapeutic implications. Most of the recent attempts at classification have been directed at the lipoprotein level of plasma lipid organization. Decreased concentrations of lipids in plasma can be achieved by altering the rates of metabolism of lipoproteins. Decrease in lipoprotein synthesis, increased catabolism or impaired release from cells into the blood stream may all result in a decrease of plasma lipids. Drugs which affect one or more of these factors are used to treat hyperlipoproteinemia. In order to elucidate the mechanism of action of hypolipidemic drugs it is necessary to understand the lipoprotein defect at the molecular level. This requires a more detailed knowledge of lipoprotein metabolism than is presently available for most of the hyperlipoproteinemias. This paper will review some of the generally accepted properties of the plasma lipoproteins, describe some difficulties which hamper the understanding of lipoprotein metabolism, and identify possible mechanisms by which drugs may affect lipoprotein metabolism.

The prevention of myocardial ischaemia by the method of profound selective myocardial hypothermia during open heart surgery.

A new method of myocardial protection, profound selective myocardial hypothermia has been employed in order to avoid the effects of cardiac ischaemia during aortic cross clamping in the course of operations undertaken under extracorporeal circulation. It consists of the irrigation of the aortic root immediately after cross clamping with 4 liters of Ringer Lactate at 4 degrees C which perfuses the entire coronary bed and induces complete uniform profound coling of the intrapericardial mass to a temperature of approximately 10 degrees C with resultant flat electrocardiogram and cessation of all electrical activity of the myocardium. This inactivity remains complete until the aorta is unclamped permitting reoxygenation and rewarming of the heart with resumption of its function. This method has been used in the course of 250 cardiac procedures involving the use of extracorporal circulation including 177 valve replacements, either aortic or mitral and aortic, 54 saphenous vein bypass procedures, either simple or with valve replacement and 19 other assorted procedures including cardiac transplantation and complex congenital malformations. Thermal, electrocardiographic, hemodynamic, histologic, histochemical and enzymatic observations have proven the minimal significance of the ischemic lesions produced in hearts protected in this manner. The total mortality was 6.4% which proves the value of this method and its superiority over the 2 techniques most often used at the present time, coronary perfusion or topical myocardial hypothermia according to Shumway's method.

Comparison of auscultation, continuous wave Doppler imaging, intravenous digital subtraction angiography and conventional angiography in diagnosis of carotid artery disease.

The reliability of auscultation, continuous wave (CW) Doppler imaging, and intravenous digital subtraction angiography (IV DSA) in the assessment of carotid artery disease has been evaluated in comparison with conventional angiography in 30 patients. With auscultation, specificity and sensitivity for internal carotid artery (ICA) stenosis of 50% or more were 81% and 67% respectively. CW Doppler imaging detected ICA stenosis of 50% or more with a sensitivity of 83% and a specificity of 92% and ICA occlusion with a sensitivity of 60%. The specificity of IV DSA was 95% and the sensitivity for ICA stenosis of 50% or more and ICA occlusion were 75% and 100% respectively. Combining CW Doppler and IV DSA findings raised sensitivity for ICA stenosis of 50% or more and ICA occlusion to 89% and 100% respectively and specificity to 95%. The combination of CW Doppler and IV DSA is a safe and accurate test battery in the detection and categorization of carotid disease.

[Immediate and long-term results of surgery of the tricuspid valve. APropos of 62 operated cases]. / Résultats immédiats et à long terme de la chirurgie de la valve tricuspide. A propos de 62 cas opérés

Operative and late results in a series of patients operated on the tricuspid valve (replacement or annuloplasty) at the moment of surgery upon mitral and aortic valves are reported. Functional tricuspid insufficiency carries a greater risk than organic tricuspid disease. Considering the duration of the underlying mitral disease, four grades are set up for the mitro-tricuspid patient allowing for prognosis and indication of the type of surgery to be done on the tricuspid valve.

Left ventricular right atrial communication. A case report.

Left ventricular-right atrial communication is a relatively rare surgically corrigible congenital heart defect. We report a case with review of the literature.

Group B streptococcal endocarditis mimicking mitral valve myxoma.

A patient with group B streptococcal endocarditis and large vegetations resembling mitral valve myxoma is described. Group B streptococcal endocarditis and the differential diagnosis of vegetations and cardiac tumors are briefly reviewed.