Serum Leptin Levels in Treatment-Naive Patients with Clinically Isolated Syndrome or Relapsing-Remitting Multiple Sclerosis

Several studies have investigated leptin levels in patients with multiple sclerosis (MS) with somewhat conflicting results. They have all focused on patients with established relapsing-remitting (RR) MS but have not specifically looked at patients with clinically isolated syndrome (CIS) suggestive of MS, in the early stages of disease. In this study, serum leptin levels were measured in 89 treatment-naïve patients with CIS (53 patients) or RRMS (36 patients) and 73 controls searching for differences between the groups and for associations with several disease parameters. The expected significant sexual dimorphism in leptin levels (higher levels in females) was observed in both MS patients and controls. Increased leptin levels were found in female patients with RRMS compared to female controls (P=.003) and female CIS patients (P=.001). Female CIS patients had comparable levels to controls. Leptin levels correlated positively to disease duration, but not to EDSS, in female patients with RRMS. The results of the present study do not indicate involvement of leptin in the early stages of MS. Normal leptin levels in patients with CIS suggest that leptin does not have a pathogenic role. The ratio leptin/BMI increases during disease course in female MS patients in a time-dependent and disability-independent manner

Spin-Parity Analysis of the Centrally produced KsKs system at 800 GeV

Results are presented of the spin-parity analysis on a sample of centrally produced mesons in the reaction (p p -> p_{slow} K_s K_s p_{fast}) with 800 GeV protons on liquid hydrogen. The spin-parity analysis in the mass region between threshold and 1.58 GeV/c^2 shows that the (K_s K_s) system is produced mainly in S-wave. The f_0(1500) is clearly observed in this region. Above 1.58 GeV/c^2 two solutions are possible, one with mainly S-wave and another with mainly D-wave. This ambiguity prevents a unique determination of the spin of the f_J(1710) meson.Comment: 6 pages, including 6 figures. LaTex, uses 'espcrc2.sty'. To appear in LEAP'96 proceeding

On the Differential Diagnosis of Anxious from Nonanxious Major Depression by means of the Hamilton Scales

Objective. Anxious major depressive disorder (A-MDD) is differentially diagnosed from nonanxious MDD (NA-MDD) as MDD with a cut-off score ≥7 on the HAM-D anxiety-somatization factor (ASF). We investigated whether additional HAM-D items discriminate A-MDD from NA-MDD. Moreover, we tested the validity of ASF criterion against HAM-A, gold standard of anxiety severity assessment. Methods. 164 consecutive female middle-aged inpatients, diagnosed as A-MDD () or NA-MDD () by the normative HAM-A score for moderate-to-severe anxiety (≥25), were compared regarding 17-item HAM-D scores. The validity of ASF ≥7 criterion was assessed by receiver-operating characteristics (ROC) analysis. Results. We found medium and large effect size differences between A-MDD and NA-MDD patients in only four out of the six ASF items, as well as in three further HAM-D items, namely, those of agitation, middle insomnia, and delayed insomnia. Furthermore, the ASF cut-off score ≥9 provided the optimal trade-off between sensitivity and specificity for the differential diagnosis between A-MDD and NA-MDD. Conclusion. Additional HAM-D items, beyond those of ASF, discriminate A-MDD from NA-MDD. The ASF ≥7 criterion inflates false positives. A cut-off point ≥9 provides the best trade-off between sensitivity and specificity of the ASF criterion, at least in female middle-aged inpatients

Comparative RNA editing in autistic and neurotypical cerebella

Adenosine-to-inosine (A-to-I) RNA editing is a neurodevelopmentally regulated epigenetic modification shown to modulate complex behavior in animals. Little is known about human A-to-I editing, but it is thought to constitute one of many molecular mechanisms connecting environmental stimuli and behavioral outputs. Thus, comprehensive exploration of A-to-I RNA editing in human brains may shed light on gene–environment interactions underlying complex behavior in health and disease. Synaptic function is a main target of A-to-I editing, which can selectively recode key amino acids in synaptic genes, directly altering synaptic strength and duration in response to environmental signals. Here, we performed a high-resolution survey of synaptic A-to-I RNA editing in a human population, and examined how it varies in autism, a neurodevelopmental disorder in which synaptic abnormalities are a common finding. Using ultra-deep (>1000 × ) sequencing, we quantified the levels of A-to-I editing of 10 synaptic genes in postmortem cerebella from 14 neurotypical and 11 autistic individuals. A high dynamic range of editing levels was detected across individuals and editing sites, from 99.6% to below detection limits. In most sites, the extreme ends of the population editing distributions were individuals with autism. Editing was correlated with isoform usage, clusters of correlated sites were identified, and differential editing patterns examined. Finally, a dysfunctional form of the editing enzyme adenosine deaminase acting on RNA B1 was found more commonly in postmortem cerebella from individuals with autism. These results provide a population-level, high-resolution view of A-to-I RNA editing in human cerebella and suggest that A-to-I editing of synaptic genes may be informative for assessing the epigenetic risk for autism.Nancy Lurie Marks Family FoundationF. Hoffmann-La Roche & Co. (Applied Science Sequencing Grant Program)Autism Speaks (Organization)Simons FoundationNational Institutes of Health (U.S.) (Grant 1R01MH085143-01

Ringed sideroblasts in βâ thalassemia

Symptomatic βâ thalassemia is one of the globally most common inherited disorders. The initial clinical presentation is variable. Although common hematological analyses are typically sufficient to diagnose the disease, sometimes the diagnosis can be more challenging. We describe a series of patients with βâ thalassemia whose diagnosis was delayed, required bone marrow examination in one affected member of each family, and revealed ringed sideroblasts, highlighting the association of this morphological finding with these disorders. Thus, in the absence of characteristic congenital sideroblastic mutations or causes of acquired sideroblastic anemia, the presence of ringed sideroblasts should raise the suspicion of βâ thalassemia.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136352/1/pbc26324.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136352/2/pbc26324_am.pd

Speeding up HMM algorithms for genetic linkage analysis via chain reductions of the state space

We develop an hidden Markov model (HMM)-based algorithm for computing exact parametric and non-parametric linkage scores in larger pedigrees than was possible before. The algorithm is applicable whenever there are chains of persons in the pedigree with no genetic measurements and with unknown affection status. The algorithm is based on shrinking the state space of the HMM considerably using such chains. In a two g-degree cousins pedigree the reduction drops the state space from being exponential in g to being linear in g. For a Finnish family in which two affected children suffer from a rare cold-inducing sweating syndrome, we were able to reduce the state space by more than five orders of magnitude from 250 to 232. In another pedigree of state-space size of 227, used for a study of pituitary adenoma, the state space reduced by a factor of 8.5 and consequently exact linkage scores can now be computed, rather than approximated

Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice.

Unlike primary myelofibrosis (PMF) in adults, myelofibrosis in children is rare. Congenital (inherited) forms of myelofibrosis (cMF) have been described, but the underlying genetic mechanisms remain elusive. Here we describe 4 families with autosomal recessive inherited macrothrombocytopenia with focal myelofibrosis due to germ line loss-of-function mutations in the megakaryocyte-specific immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor G6b-B (G6b, C6orf25, or MPIG6B). Patients presented with a mild-to-moderate bleeding diathesis, macrothrombocytopenia, anemia, leukocytosis and atypical megakaryocytes associated with a distinctive, focal, perimegakaryocytic pattern of bone marrow fibrosis. In addition to identifying the responsible gene, the description of G6b-B as the mutated protein potentially implicates aberrant G6b-B megakaryocytic signaling and activation in the pathogenesis of myelofibrosis. Targeted insertion of human G6b in mice rescued the knockout phenotype and a copy number effect of human G6b-B expression was observed. Homozygous knockin mice expressed 25% of human G6b-B and exhibited a marginal reduction in platelet count and mild alterations in platelet function; these phenotypes were more severe in heterozygous mice that expressed only 12% of human G6b-B. This study establishes G6b-B as a critical regulator of platelet homeostasis in humans and mice. In addition, the humanized G6b mouse will provide an invaluable tool for further investigating the physiological functions of human G6b-B as well as testing the efficacy of drugs targeting this receptor

A major genetic locus controlling natural Plasmodium falciparum infection is shared by East and West African Anopheles gambiae

Background: Genetic linkage mapping identified a region of chromosome 2L in the Anopheles gambiae genome that exerts major control over natural infection by Plasmodium falciparum. This 2L Plasmodium-resistance interval was mapped in mosquitoes from a natural population in Mali, West Africa, and controls the numbers of P. falciparum oocysts that develop on the vector midgut. An important question is whether genetic variation with respect to Plasmodium-resistance exists across Africa, and if so whether the same or multiple geographically distinct resistance mechanisms are responsible for the trait. Methods: To identify P falciparum resistance loci in pedigrees generated and infected in Kenya, East Africa, 28 microsatellite loci were typed across the mosquito genome. Genetic linkage mapping was used to detect significant linkage between genotype and numbers of midgut oocysts surviving to 7–8 days post-infection. Results: A major malaria-control locus was identified on chromosome 2L in East African mosquitoes, in the same apparent position originally identified from the West African population. Presence of this resistance locus explains 75% of parasite free mosquitoes. The Kenyan resistance locus is named EA_Pfin1 (East Africa_ Plasmodium falciparum Infection Intensity). Conclusion: Detection of a malaria-control locus at the same chromosomal location in both East and West African mosquitoes indicates that, to the level of genetic resolution of the analysis, the same mechanism of Plasmodium-resistance, or a mechanism controlled by the same genomic region, is found across Africa, and thus probably operates in A. gambiae throughout its entire range

Mutations in PYCR2, Encoding Pyrroline-5-Carboxylate Reductase 2, Cause Microcephaly and Hypomyelination

Despite recent advances in understanding the genetic bases of microcephaly, a large number of cases of microcephaly remain unexplained, suggesting that many microcephaly syndromes and associated genes have yet to be identified. Here, we report mutations in PYCR2, which encodes an enzyme in the proline biosynthesis pathway, as the cause of a unique syndrome characterized by postnatal microcephaly, hypomyelination, and reduced cerebral white-matter volume. Linkage mapping and whole-exome sequencing identified homozygous mutations (c.355C>T [p.Arg119Cys] and c.751C>T [p.Arg251Cys]) in PYCR2 in the affected individuals of two consanguineous families. A lymphoblastoid cell line from one affected individual showed a strong reduction in the amount of PYCR2. When mutant cDNAs were transfected into HEK293FT cells, both variant proteins retained normal mitochondrial localization but had lower amounts than the wild-type protein, suggesting that the variant proteins were less stable. A PYCR2-deficient HEK293FT cell line generated by genome editing with the clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 system showed that PYCR2 loss of function led to decreased mitochondrial membrane potential and increased susceptibility to apoptosis under oxidative stress. Morpholino-based knockdown of a zebrafish PYCR2 ortholog, pycr1b, recapitulated the human microcephaly phenotype, which was rescued by wild-type human PYCR2 mRNA, but not by mutant mRNAs, further supporting the pathogenicity of the identified variants. Hypomyelination and the absence of lax, wrinkly skin distinguishes this condition from that caused by previously reported mutations in the gene encoding PYCR2’s isozyme, PYCR1, suggesting a unique and indispensable role for PYCR2 in the human CNS during development