Tacrolimus reduces urinary excretion of leukotriene E(4) and inhibits aspirin-induced asthma to threshold dose of aspirin

BACKGROUND: The exact mechanism of aspirin-induced asthma is not clear. It has been postulated that precipitation of asthma attacks by aspirin is linked to inhibition of COX activity and massive release of cysteinyl leukotriene into the airway. Tacrolimus, a macrolide-derived immunosuppressant, is used for immunosuppression in organ transplantation and also for allergic diseases such as atopic dermatitis. OBJECTIVE: We evaluated the effects of tacrolimus in aspirin-induced asthma by using a double-blind, crossover study design. METHODS: Twelve patients with aspirin-induced asthma (male:female, 3:9; mean age +/- SD, 36.7 +/- 7.2 years) received either tacrolimus (0.1 mg/kg) or placebo 2 hours before the threshold dose of oral aspirin. RESULTS: In the placebo arm, oral aspirin significantly decreased FEV 1 concomitant with significant increases in sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. Tacrolimus significantly inhibited bronchoconstriction and abrogated aspirin-induced increase in both sputum eosinophilic cationic protein and urinary leukotriene E(4) levels. CONCLUSION: The current study suggested that tacrolimus inhibited bronchoconstriction to a threshold dose of aspirin by inhibition of cysteinyl leukotriene excretion.     

Effect of injury to the zone of the medial forebrain bundle and preoptic region on activity of an epileptiform focus induced by penicillin (on the phenomenon of the hyperactive determinant dispatch station)

Experiments on cats showed that injury to the medial forebrain bundle (MFB) and also partly to the preoptic region on the side of application of penicillin to the cerebral cortex (middle suprasylvian gyrus) causes depression of paroxysmal activity (spike potentials) in the penicillin focus, and also in a secondary mirror focus arising in the symmetrical zone of the opposite cortex. Injury to MFB on the side of the mirror focus causes depression of paroxysmal spike potentials only in that focus and does not affect activity in the primary epileptiform focus. The effects described are examined from the standpoint of views regarding the role of the determinant dispatch station (DDS) in the activity of the CNS: A primary epileptiform focus is a hyperactive DDS which induces the appearance of secondary foci, supports them, and determines the character of their activity. The results of the investigation suggests a role for MFB in the modulation of cortical epileptiform activity.Laboratory of General Pathology of the Nervous System, Institute of General Pathology and Pathophysiology, Academy of Medical Sciences of the USSR, Moscow. Laboratory of Electrophysiology, V. F. Filatov Odessa Research Institute for Eye Diseases and Tissue Therapy, Ministry of Health of the Ukrainian SSR. Translated from Byulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 82, No. 12, pp. 1413–1416, December, 1976.     

Study of carrier frequency of Warsaw breakage syndrome in the Ashkenazi Jewish population and presentation of two cases

Warsaw breakage syndrome (WABS), caused by bi‐allelic variants in the DDX11 gene, is a rare cohesinopathy characterized by pre‐ and postnatal growth retardation, microcephaly, intellectual disability, facial dysmorphia, and sensorineural hearing loss due to cochlear hypoplasia. The DDX11 gene codes for an iron–sulfur DNA helicase in the Superfamily 2 helicases and plays an important role in genomic stability and maintenance. Fourteen individuals with WABS have been previously reported in the medical literature. Affected individuals have been of various ethnic backgrounds with different pathogenic variants. We report two unrelated individuals of Ashkenazi Jewish descent affected with WABS, who are homozygous for the c.1763‐1G>C variant in the DDX11 gene. Their phenotype is consistent with previously reported individuals. RNA studies showed that this variant causes an alternative splice acceptor site leading to a frameshift in the open reading frame. Carrier screening of the c.1763‐1G>C variant in the Jewish population revealed a high carrier frequency of 1 in 68 in the Ashkenazi Jewish population. Due to the high carrier frequency and the low number of affected individuals, we hypothesize a high rate of miscarriage of homozygous fetuses and/or subfertility for carrier couples. If the carrier frequency is reproducible in additional Ashkenazi Jewish populations, we suggest including DDX11 to Ashkenazi Jewish carrier screening panels.     

Gender-specific haplotype association of collagen α2 (XI) gene in ossification of the posterior longitudinal ligament of the spine

Among Japanese, ossification of the posterior longitudinal ligament of the spine (OPLL) is a leading cause of myelopathy, showing ectopic bone formation in the paravertebral ligament. We have provided genetic evidence that the collagen α2 (XI) (COL11A2) locus of chromosome 6 constitutes susceptibility for OPLL. Five distinct single nucleotide polymorphisms (SNPs), identified in COL11A2, were combined to construct possible haplotypes by the use of a maximum likelihood program. Estimated haplotype frequency was compared in OPLL patients and non-OPLL controls. We report a gender-specific association of the COL11A2 haplotype with OPLL. The frequency of the most commonly observed haplotype was significantly higher in male patients (P = 0.0003) compared with controls, but not in female patients (P = 0.21). OPLL is predominantly observed in males, with a prevalence ratio of 2 : 1, and our gender-specific associations indicate that genetic factors involving COL11A2 play a specific role in the etiology of OPLL exclusively in males. Received: September 5, 2000 / Accepted: October 2, 2000     

Prevalence of chromosomal abnormalities in 2078 infertile couples referred for assisted reproductive techniques

BACKGROUND: This study analyses the prevalence of karyotype changes and Yq11 microdeletions among couples referred for assisted reproduction techniques. METHODS: Prior to receiving either IVF or ICSI treatment, each partner of 2078 infertile couples was screened for karyotype changes by GTG-banding technique on peripheral lymphocytes. No subject presented with obvious phenotype of chromosomal rearrangement. All the oligo/azoospermic men with normal karyotype were further investigated by PCR for Yq11 microdeletions. RESULTS: Eighty-two out of 2078 couples (3.95%) had one partner carrying a chromosomal change, and 10 out of 202 (4.95%) men showed Yq11 microdeletions. The chromosomal rearrangements were 44 (2.1%) translocations, 23 (1.1%) gonosomal mosaics, six (0.3%) 47,XXY, five (0.24%) marker chromosomes, three (0.14%) inversions and one (0.05%) duplication. Frequency of anomalies in men and women were similar: 42 and 40 cases respectively. CONCLUSIONS: Partners of infertile couples requiring IVF or ICSI treatment appear to be affected by higher frequency of chromosomal rearrangements than the general population. Categories with greater risk were represented by men with sperm cell count <20 x 10(6) sperm/ml, and women with history of pregnancy loss.     

Linkage analysis between manic-depressive illness and markers on the long arm of chromosome 11

The long arm of chromosome 11 is one of the most interesting regions in the search for major genes involved in the etiology of manic-depressive illness. Several candidate genes have been identified, including the gene encoding the dopamine D2 receptor, the M1 muscarinic receptor, and porfobillinogen deaminase. Furthermore, different families with co-segregation of psychiatric illness and structural chromosome abnormalities involving regions 11q21, 11q22.3, and 11q25 have been reported. Using narrow as well as broad phenotypic models, conservative genetic parameters, models with dominant or recessive modes of inheritance, and various methods to reduce misclassification, the present study did not find evidence for a major gene causing manic-depressive illness on the long arm of chromosome 11. In the broader phenotypic models multi-point analyses excluded at least 11q14 to 11q23.3, approximately 60 cM, even in one large family. Assuming homogeneity close linkage to DRD2 was excluded for all dominant models, and also in the affecteds-only analyses in the large family alone. © 1995 Wiley-Liss, Inc.     

New HLA-A*11 allele,A*1112, identified by sequence-based typing

In this report, we describe the identification of HLA-A*1112, a novel HLA-A*11 allele found in two Italian families. The new allele was detected during routine HLA typing by a polymerase chain reaction sequence-specific primer and was confirmed by high-resolution sequencing-based typing. The nucleotide sequences of HLA-A*1112 exons 2 and 3 are identical to HLA-A*11011 except for a single nucleotide substitution in codon 90 (GAC-->GCC).     

Velo-cardio-facial syndrome and DiGeorge sequence with meningomyelocele and deletions of the 22q11 region

Approximately 5% of children with neural tube defects (NTDs) have a congenital heart defect and/or cleft lip and palate. The cause of isolated meningomyelocele, congenital heart defects, or cleft lip and palate has been largely thought to be multifactorial. However, chromosomal, teratogenic, and single gene causes of combinations of NTDs with congenital heart defects and/or cleft lip and palate have been reported. We report on 3 patients with meningomyelocele, congenital heart defects, and 22q11 deletions. Two of the children had the clinical diagnosis of velo-cardio-facial syndrome (VCFS); both also have bifid uvula. The third child had DiGeorge sequence (DGS). The association of NTDs with 22q11 deletions has not been reported previously. An accurate diagnosis of the 22q11 deletions is critical as this micro-deletion and its associated clinical problems is transmitted as an autosomal dominant trait due to the inheritance of the deletion-bearing chromosome. We recommend that all children with NTDs and congenital heart defects, with or without cleft palate, have cytogenetic and molecular studies performed to detect 22q11 deletions. © 1994 Wiley-Liss, Inc.     

Characterization of a cosmid library from flow-sorted chromosomes 11

A cosmid library specific for human chromosome 11 has been constructed from flow-sorted chromosomes. The flow-purified chromosomes were prepared from the hamster/human hybrid line J1 which contains chromosome 11 as the only human chromosome. Individual clones were sampled in 187 microtitre plates, resulting in a total of 17 952 colonies. Hybridization analysis revealed that 83.7% of these clones were of human and 10.4% of hamster origin. The average insert size was estimated at 33.6 kb, and only 2.4% of insert fragments appear to be rearranged. This should result in 494 487 kb of cloned human DNA representing 3.5 chromosome 11 equivalents. We have prepared high-density nylon membranes of the arrayed library containing 1 536 single colonies per filter. We have demonstrated the usefulness of the library in the molecular genetic analysis of human chromosome 11 by testing for the presence of possibly polymorphic simple repeat motifs, by identifying cosmids that contain inserts from the telomeric ends of chromosome 11 and by assessing the potential of the library for rapid chromosome walking.