The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

A Chinese adolescent girl with Fechtner-like syndrome

We describe a 15-y-old girl with Fechtner-like syndrome, who is the first Chinese reported to have this rare syndrome. She presented with left homonymous hemianopia and neuroimaging revealed haemorrhage in both parietal and occipital lobes. Peripheral blood smear showed macrothrombocytopenia and intracytoplasmic inclusion bodies inside leucocytes. Thrombocytopenia and proteinuria responded to intravenous immunoglobulin and pulsed methylprednisolone. This case illustrates that life-threatening haemorrhage can occur in patients with Fechtner syndrome. Although there was no effective treatment reported in the literature, high dose steroid and immunoglobulin seemed to be useful in our patient. Our patient also had nephritic-nephrotic syndrome with renal insufficiency, which is unusual in adolescent female patients.     

Solid and papillary epithelial neoplasms of the pancreas: CT findings

Five female patients and one male patient with solid and papillary epithelial neoplasms of the pancreas were examined with computed tomography (CT). The mean age of the patients was 27 years (range, 13-46 years). All cases showed well-encapsulated, round or lobulated masses consisting of both cystic and solid areas. Cystic portions showed CT numbers that suggested hemorrhagic necrosis. There were no internal septations within the masses. In three tumors located in the head of the pancreas, dilatation of the biliary tree was absent or minimal, although the masses were large. Two tumors contained calcifications. One tumor demonstrated metastatic deposits in liver and lymph nodes. Metastatic masses appeared similar to the primary pancreatic mass. Solid and papillary neoplasm of the pancreas should be the primary diagnostic consideration when characteristic CT findings are detected in a young female patient.     

Schistosoma mansoni infection in a recently exposed community in Senegal: lack of correlation between liver morphology in ultrasound and connective tissue metabolites in serum

Summary Four hundred and seventy villagers of Ndombo, a village with recently established intensive transmission of Schistosoma mansoni in the Senegal River Basin, were enrolled in a study with the intention to assess hepatosplenic morbidity. All patients were examined parasitologically and by ultrasound. Hepatic fibrosis serum markers were determined in 153 adult patients (aminoterminal propeptide of procollagen type III, hyaluronan and laminin). By ultrasound, about 60% of the patients showed early stages of hepatic involvement, 3% of the patients unequivocally showed severe hepatosplenic pathology (grade 3 according to the Managil classification), whereas in another study performed in the same village 3 years earlier, no patients with severe hepatosplenic pathology had been found. No correlation between the aminoterminal propeptide of procollagen type III, hyaluronan or laminin and the ultrasound findings could be established. These hepatic fibrosis serum markers do not seem to be a sensitive method to detect early hepatic fibrosis in schistosomiasis.     

High throughput parallel analysis of hundreds of patient samples for more than 100 mutations in multiple disease genes

As more mutations are identified in genes of known sequence, there is a crucial need in the areas of medical genetics and genome analysis for rapid, accurate and cost-effective methods of mutation detection. We have developed a multiplex allele-specific diagnostic assay (MASDA) for analysis of large numbers of samples (> 500) simultaneously for a large number of known mutations (> 100) in a single assay. MASDA utilizes oligonucleotide hybridization to interrogate DNA sequences. Multiplex DNA samples are immobilized on a solid support and a single hybridization is performed with a pool of allele-specific oligonucleotide (ASO) probes. Any probes complementary to specific mutations present in a given sample are in effect affinity purified from the pool by the target DNA. Sequence-specific band patterns (fingerprints), generated by chemical or enzymatic sequencing of the bound ASO(s), easily identify the specific mutation(s). Using this design, in a single diagnostic assay, we tested samples for 66 cystic fibrosis (CF) mutations, 14 beta-thalassemia mutations, two sickle cell anemia (SCA) mutations, three Tay-Sachs mutations, eight Gaucher mutations, four mutations in Canavan disease, four mutations in Fanconi anemia, and five mutations in BRCA1. Each mutation was correctly identified. Finally, in a blinded study of 106 of these mutations in > 500 patients, all mutations were properly identified. There were no false positives or false negatives. The MASDA assay is capable of detecting point mutations as well as small insertion or deletion mutations. This technology is amenable to automation and is suitable for immediate utilization for high-throughput genetic diagnostics in clinical and research laboratories.      

Characterization of DEAE-dextran by means of light scattering and combined size-exclusion chromatography/low-angle laser light scattering/viscometry

Ten DEAE (2-(diethylamino)ethyl) dextran samples were investigated by means of static and dynamic light scattering, viscometry and size-exclusion chromatography (SEC) in combination with on-line small-angle laser light scattering (LALLS) and viscometry (VISC). In dilute solution the behavior of DEAE-dextran was compared with that of unsubstituted dextran and the molecular weight M dependences of the radius of gyration R_g, hydrodynamic radius R_h, intrinsic viscosity [η], second virial coefficient A₂ and z-average diffusion coefficient D _z were determined. The relationships for DEAE-dextran dissolved in a 0,8 molar sodium nitrate solution were nearly the same as for dextran dissolved in water with 0,05 wt.-% sodium azide and gave the same exponents. The molecular weight dependence of the intrinsic viscosity cannot be described by a Kuhn-Mark-Houwink relationship with a constant exponent. The slope in the plot of log [η] versus log M decreases with increasing molecular weight which indicates the occurrence of branching. By means of SEC/LALLS/VISC measurements the molecular weight distributions were determined. The distributions were calculated (1) directly from the light scattering signal, (2) from a calibration line obtained by light scattering data of a DEAE-dextran sample with a broad distribution and (3) from the intrinsic viscosity distribution obtained by the on-line viscosity/refractive index detector in combination with the [η]-M relationship. In order to get the correct molecular-weight dependence of the intrinsic viscosity it is necessary to determine the molecular weight distribution directly by LALLS (technique 1) and to combine this with the appropriate intrinsic viscosity data from the viscometer. Only the third technique, which is an extension of technique 1, gave satisfactory results over the whole molecular weight region observed.     

The role of individualized care in a service delivery system for children and adolescents with severely maladjusted behavior

Individualized care is a total system of care that is tailored to a child with severely maladjusted behavior. The services are unconditional, flexible, child and family focused, and interagency coordinated. The services follow the child until the child is adjusting in a normalized, mainstream environment. Individualized care is illustrated through two different projects. One is the Alaska Youth Initiative where individualized care was used to return children from out-of-state, residential programs. The other is Project Wraparound where it was used to prevent children from being removed from their families. This paper begins with the principles of individualized care and then describes the ecological, multilevel assessment process that coincides with the delivery of services. A case example from Project Wraparound is provided for clarification. Following the case example is a discussion of the need for evaluation data with some suggested strategies for documenting effectiveness. The final section focuses on two barriers to the implementation of individualized care. One is the tendency to think in terms of component programs rather than individualized services. The other barrier is the competition for scarce resources. Strategies are presented for overcoming both barriers.     

Environmental, medical, and family history risk factors for Parkinson's disease: a New England-based case control study

Controversy persists about the etiology of Parkinson's disease (PD). Pesticides, herbicides, well-water consumption, head injury, and a family history of PD have been reported as risk factors for PD. The purpose of this study was to (1) investigate the impact of environmental factors on PD risk (2) estimate the chronology, frequency, and duration of those exposures associated with PD; and (3) investigate the effects of family history on PD risk. One-hundred and forty PD cases were recruited from Boston University Medical Center. The control group was composed of 147 friends and in-laws of PD patients. Environmental, medical, and family history data were obtained by structured interview from each participant for events recalled prior to PD onset for cases, or corresponding censoring age for controls (mean age = 56 years of age for each group). A traditional stratified analysis, adjusting for birth cohort and sex, was employed. Four factors were associated with increased risk for PD: (1) head injury (OR=6.23, confidence interval [CI]: 2.58-15.07); (2) family history of PD (OR=6.08, CI: 2.35-15. 58); (3) family history of tremor (OR=3.97, CI: 1.17-13.50); and (4) history of depression (OR=3.01, CI: 1.32-6.88). A mean latency of 36. 5 (SE=2.81) years passed between the age of first reported head injury and PD onset. A mean latency of 22 (SE=2.66) years passed between the onset of the first reported symptoms of depression and onset of PD. Years of education, smoking, and well-water intake were inversely associated with PD risk. PD was not associated with exposure to pesticides or herbicides. These findings support the role of both environmental and genetic factors in the etiology in PD. The results are consistent with a multifactorial model. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 88:742-749, 1999.     

Comparing sulindac with indomethacin for closure of ductus arteriosus in preterm infants

Objectives: A prospective study comparing the efficiacy and side-effects of oral sulindac with intravenous indomethacin in clinically stable preterm infants (<1750 g) requiring non-invasive closure of haemodynamically significant patent ductus arteriosus.
Methodology: As maturity and birthweight are the two major determinants of ductal closure, infants were matched as closely as possible for these parameters. An eligible patient was first assigned to the sulindac group and a subsequent patient with similar gestational age (± 1 week) and birthweight (±100 g) to the previously recruited infant would automatically receive indomethacin. A total of eight infants were enrolled in each group.
Results: The ductus arteriosus was successfully closed in all eight infants receiving indomethacin, and in seven of eight infants receiving sulindac. No significant differences were found with regards to the ductal size between the two groups at diagnosis or on each of the consecutive days of treatment ( P >0.25). More renal adverse effects were encountered in the indomethacin group. Significant differences in changes from baseline value for urine output, plasma sodium, urea and creatinine concentrations were noted at 24, 48 and 72 h after commencement of treatment between the two groups ( P <0.05). All the parameters returned to normal or pre-treatment levels 48 h after stopping therapy. Unexpectedly, severe gastrointestinal complications were encountered in the sulindac group.
Conclusions: Sulindac is capable of promoting ductal constriction in clinically stable preterm infants without compromising the renal function. The spectrum of gastrointestinal complications observed in sulindac treated infants were similar to those described for indomethacin. The use of sulindac for ductal closure in the preterm infant should remain experimental.