Congenital macrothrombocytopenia is a heterogeneous disorder in India.

INTRODUCTION: Inherited macrothrombocytopenia represents a heterogeneous group of disorders which are characterized by the presence of a reduced number of abnormally large platelets in the circulation, which may or may not be associated with a bleeding tendency. In spite of several causative genes having been identified, the underlying genetic defects remain to be identified in approximately half of the cases. AIMS: To understand the molecular pathology of isolated giant platelet disorder from India. MATERIALS AND METHODS: We studied 112 cases that were referred for investigation of macrothrombocytopenia. Agonist induced platelet aggregation and platelet GP1b/IX/V receptor expression were investigated to assess GP1b/IX/V receptor expression and the GP1BA, GP1BB, GP9, ABCG5, ABCG8, TUBB1 and MYH9 genes were analysed to identify candidate gene defects. RESULTS: Twenty-three candidate gene defects were identified in 48 of 112 cases, 20 of which were novel. Of the candidate defects identified, 91% were missense and 9% were nonsense variations. The missense variations were in GP9 (9), ABCG5 (4), GP1BB (3), GP1BA (3) and MYH9 (2), while the nonsense defects occurred in MYH9 (1) and GP1BA (1). CONCLUSIONS: This study increases the understanding of the molecular basis of an isolated giant platelet disorder, a common heterogeneous condition prevalent in north and eastern India.

Probes for investigating the effect of magnetic field, field orientation, temperature and strain on the critical current density of anisotropic high-temperature superconducting tapes in a split-pair 15 T horizontal magnet.

We present the designs of probes for making critical current density (Jc) measurements on anisotropic high-temperature superconducting tapes as a function of field, field orientation, temperature and strain in our 40 mm bore, split-pair 15 T horizontal magnet. Emphasis is placed on the design of three components: the vapour-cooled current leads, the variable temperature enclosure, and the springboard-shaped bending beam sample holder. The vapour-cooled brass critical-current leads used superconducting tapes and in operation ran hot with a duty cycle (D) of ~0.2. This work provides formulae for optimising cryogenic consumption and calculating cryogenic boil-off, associated with current leads used to make J(c) measurements, made by uniformly ramping the current up to a maximum current (I(max)) and then reducing the current very quickly to zero. They include consideration of the effects of duty cycle, static helium boil-off from the magnet and Dewar (b'), and the maximum safe temperature for the critical-current leads (T(max)). Our optimized critical-current leads have a boil-off that is about 30% less than leads optimized for magnet operation at the same maximum current. Numerical calculations show that the optimum cross-sectional area (A) for each current lead can be parameterized by LI(max)/A = [1.46D(-0.18)L(0.4)(T(max) - 300)(0.25D(-0.09)) + 750(b'/I(max))D(10(-3)I(max)-2.87b') × 106 A m⁻¹ where L is the current lead's length and the current lead is operated in liquid helium. An optimum A of 132 mm(2) is obtained when I(max) = 1000 A, T(max) = 400 K, D = 0.2, b' = 0.3 l h(-1) and L = 1.0 m. The optimized helium consumption was found to be 0.7 l h(-1). When the static boil-off is small, optimized leads have a boil-off that can be roughly parameterized by: b/I(max) ≈ (1.35 × 10(-3))D(0.41) l h(­1) A(-1). A split-current-lead design is employed to minimize the rotation of the probes during the high current measurements in our high-field horizontal magnet. The variable-temperature system is based on the use of an inverted insulating cup that operates above 4.2 K in liquid helium and above 77.4 K in liquid nitrogen, with a stability of ±80 mK to ±150 mK. Uniaxial strains of -1.4% to 1.0% can be applied to the sample, with a total uncertainty of better than ±0.02%, using a modified bending beam apparatus which includes a copper beryllium springboard-shaped sample holder.

von Willebrand factor variant p.Arg924Gln marks an allele associated with reduced von Willebrand factor and factor VIII levels.

BACKGROUND: von Willebrand factor (VWF) variant c.2771G>A; p.R924Q has been described as a benign polymorphism or a possible marker for a null allele and been associated with mild bleeding phenotypes. It was identified in several patients in recent type 1 von Willebrand disease (VWD) studies. OBJECTIVES: To determine whether the p.R924Q allele contributes to reduced VWF levels and type 1 VWD. METHODS: One thousand one hundred and fifteen healthy controls and 148 index cases from the MCMDM-1VWD study were genotyped for c.2771G>A; VWF and FVIII levels were analyzed in ABO blood group stratified individuals and the p.R924Q variant was expressed in 293 EBNA cells. RESULTS: c.2771G>A was present in six index cases, five of whom had a second VWF variant which probably contributed to the phenotype. A common core haplotype identified in families, which included the rare G allele of c.5843-8C>G, was present in the majority of 35 c.2771G>A heterozygous controls. c.2771G>A contributed about 10% variance in VWF and FVIII levels in controls and 35% variance when co-inherited with blood group O. Recombinant p.R924Q VWF had no effect on in vitro expression and heterozygous family members had normal VWF-FVIII binding and normal clearance of VWF and FVIII. CONCLUSIONS: The allele bearing c.2771A leads to reductions in VWF and FVIII levels particularly in combination with blood group O. Its inheritance alone may be insufficient for VWD diagnosis, but it appears to be associated with a further VWF level reduction in individuals with a second VWF mutation and it contributes to population variance in VWF and FVIII levels.

The molecular landscape of ASPM mutations in primary microcephaly.

BACKGROUND: Autosomal recessive primary microcephaly (MCPH) is a model disease to study human neurogenesis. In affected individuals the brain grows at a reduced rate during fetal life resulting in a small but structurally normal brain and mental retardation. The condition is genetically heterogeneous with mutations in ASPM being most commonly reported. METHODS AND RESULTS: We have examined this further by studying three cohorts of microcephalic children to extend both the phenotype and the mutation spectrum. Firstly, in 99 consecutively ascertained consanguineous families with a strict diagnosis of MCPH, 41 (41%) were homozygous at the MCPH5 locus and all but two families had mutations. Thus, 39% of consanguineous MCPH families had homozygous ASPM mutations. Secondly, in 27 non-consanguineous, predominantly Caucasian families with a strict diagnosis of MCPH, 11 (40%) had ASPM mutations. Thirdly, in 45 families with a less restricted phenotype including microcephaly and mental retardation, but regardless of other neurological features, only 3 (7%) had an ASPM mutation. This report contains 27 novel mutations and almost doubles the number of MCPH associated ASPM mutations known to 57. All but one of the mutations lead to the use of a premature termination codon, 23 were nonsense mutations, 28 deletions or insertions, 5 splicing, and 1 was a translocation. Seventeen of the 57 mutations were recurrent. There were no definitive missense mutations found nor was there any mutation/phenotype correlation. ASPM mutations were found in all ethnic groups studied. CONCLUSION: This study confirms that mutations in ASPM are the most common cause of MCPH, that ASPM mutations are restricted to individuals with an MCPH phenotype, and that ASPM testing in primary microcephaly is clinically useful.

Disordered nanocrystalline superconducting PbMo6S8 with a very large upper critical field.

Large increases in the upper critical field B(C2)(0) are reported in bulk superconductors that demonstrate another novel property for nanocrystalline materials. Disordered nanocrystalline PbMo6S8 superconductors were fabricated by mechanical milling and hot isostatic pressing. Conventional PbMo6S8 has B(C2)(0) approximately 50 T. The nanocrystalline materials have higher resistivity (rho(N)) and B(C2)(0) approximately 100 T. The disorder produced in these nanocrystalline materials is significantly different from that produced by doping because it increases rho(N) and, hence, B(C2)(0) without significantly reducing the electronic density of states or superconducting transition temperature (T(C)). Furthermore, the disorder reduces the electron mean-free path to approximately 1 nm which is more than an order of magnitude smaller than the grain size and necessary to achieve the unprecedented increase in B(C2)(0).

Autosomal recessive primary microcephaly: an analysis of locus heterogeneity and phenotypic variation.

BACKGROUND AND OBJECTIVES: Locus heterogeneity is well established in autosomal recessive primary microcephaly (MCPH) and to date five loci have been mapped. However, the relative contributions of these loci have not been assessed and genotype-phenotype correlations have not been investigated. DESIGN: A study population of 56 consanguineous families resident in or originating from northern Pakistan was ascertained and assessed by the authors. A panel of microsatellite markers spanning each of the MCPH loci was designed, against which the families were genotyped. RESULTS: The head circumference of the 131 affected subjects ranged from 4 to 14 SD below the mean, but there was little intrafamilial variation among affecteds (+/- 1 SD). MCPH5 was the most prevalent, with 24/56 families consistent with linkage; 2/56 families were compatible with linkage to MCPH1, 10/56 to MCPH2, 2/56 to MCPH3, none to MCPH4, and 18/56 did not segregate with any of the loci. CONCLUSIONS: MCPH5 is the most common locus in this population. On clinical grounds alone, the phenotype of families linked to each MCPH locus could not be distinguished. We have also shown that further MCPH loci await discovery with a number of families as yet unlinked.

Kufor-Rakeb syndrome, pallido-pyramidal degeneration with supranuclear upgaze paresis and dementia, maps to 1p36.

Kufor-Rakeb syndrome is an autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration. The onset is in the teenage years with clinical features of Parkinson's disease plus spasticity, supranuclear upgaze paresis, and dementia. Brain scans show atrophy of the globus pallidus and pyramids and, later, widespread cerebral atrophy. We report linkage in Kufor-Rakeb syndrome to a 9 cM region of chromosome 1p36 delineated by the markers D1S436 and D1S2843, with a maximum multipoint lod score of 3.6.

The evolution of decision support in a managed care organization.

As managed care organizations (MCOs) develop in the 1990s, a challenge for managers is the transformation of data into information. This transformation process is responsible for organizations developing decision support systems. Decision support enables an individual to combine financial analysis and operational data to enhance managerial decision making and strategic planning, and institute the closed-loop process. This system evolution will help to determine those MCOs that will become more adept at enhancing profitability and streamlining decision making.