Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6

Pseudoxanthoma elasticum (PXE) is a systemic heritable disorder that affects the elastic tissue in the skin, eye, and cardiovascular system. Mutations in the ABCC6 gene cause PXE. We performed a mutation screen in ABCC6 using haplotype analysis in conjunction with direct sequencing to achieve a mutation detection rate of 97%. This screen consisted of 170 PXE chromosomes in 81 families, and detected 59 distinct mutations (32 missense, eight nonsense, and six likely splice-site point mutations; one small insertion; and seven small and five large deletions). Forty-three of these mutations are novel variants, which increases the total number of PXE mutations to 121. While most mutations are rare, three nonsense mutations, a splice donor site mutation, and the large deletion comprising exons 23-29 (c.2996_4208del) were identified as relatively frequent PXE mutations at 26%, 5%, 3.5%, 3%, and 11%, respectively. Chromosomal haplotyping with two proximal and two distal polymorphic markers flanking ABCC6 demonstrated that most chromosomes that carry these relatively frequent PXE mutations have related haplotypes specific for these mutations, which suggests that these chromosomes originate from single founder mutations. The types of mutations found support loss-of-function as the molecular mechanism for the PXE phenotype. In 76 of the 81 families, the affected individuals were either homozygous for the same mutation or compound heterozygous for two mutations. In the remaining five families with one uncovered mutation, affected showed allelic compound heterozygosity for the cosegregating PXE haplotype. This demonstrates pseudo-dominance as the relevant inheritance mechanism, since disease transmission to the next generation always requires one mutant allelic variant from each parent. In contrast to other previous clinical and molecular claims, our results show evidence only for recessive PXE. This has profound consequences for the genetic counseling of families with PXE.     

XX true hermaphroditism in Southern African Blacks: Exclusion of SRY sequences and uniparental disomy of the X chromosome

A molecular investigation of 16 Bantu-speaking Black XX true hermaphrodites was undertaken in an attempt to determine the cause of the disorder. Y-specific sequences, including sequences mapping to the sexdetermining region of the Y, were shown to be absent from lymphocyte tissue of all 16 patients tested. Y chromosome sequences were also absent from the ovarian and testicular components of both ovotestes of a single XX true hermaphrodite, thus excluding gonadal mosaicism involving Y chromosome sequences. Since there is evidence for Xp genes involved in testis determination/differentiation, uniparental disomy of the X chromosome was investigated in 14 XXTH families. Uniparental disomy was excluded in 12 of the 14 families, and isodisomy was excluded in the remaining two cases. © 1995 Wiley-Liss, Inc.     

Neutrophil mobilization and clearance in the bone marrow

The bone marrow is the site of neutrophil production, a process that is regulated by the cytokine granulocyte colony‐stimulating factor (G‐CSF). Mature neutrophils are continually released into the circulation, with an estimated 10 11 neutrophils exiting the bone marrow daily under basal conditions. These leucocytes have a short half‐life in the blood of ～6·5 hr, and are subsequently destroyed in the spleen, liver and indeed the bone marrow itself. Additionally, mature neutrophils are retained in the bone marrow by the stromal cell‐derived factor (SDF‐1α)/chemokine (C‐X‐C motif) receptor 4 (CXCR4) chemokine axis and form the bone marrow reserve. Following infection or inflammatory insult, neutrophil release from the bone marrow reserve is substantially elevated and this process is mediated by the co‐ordinated actions of cytokines and chemokines. In this review we discuss the factors and molecular mechanisms regulating the neutrophil mobilization and consider the mechanisms and functional significance of neutrophil clearance via the bone marrow.     

Nanoarchitectures for efficient IgE cross-linking on effector cells to study amoxicillin allergy

Background

Amoxicillin (AX) is nowadays the β-lactam that more frequently induces immediate allergic reactions. Nevertheless, diagnosis of AX allergy is occasionally challenging due to risky in vivo tests and non-optimal sensitivity of in vitro tests. AX requires protein haptenation to form multivalent conjugates with increased size to be immunogenic. Knowing adduct structural features for promoting effector cell activation would help to improve in vitro tests. We aimed to identify the optimal structural requirement in specific cellular degranulation to AX using well-precised nanoarchitectures of different lengths.

Method

We constructed eight Bidendron Antigens (BiAns) based on polyethylene glycol (PEG) linkers of different lengths (600–12,000 Da), end-coupled with polyamidoamine dendrons that were terminally multi-functionalized with amoxicilloyl (AXO). In vitro IgE recognition was studied by competitive radioallergosorbent test (RAST) and antibody–nanoarchitecture complexes by transmission electron microscopy (TEM). Their allergenic activity was evaluated using bone marrow-derived mast cells (MCs) passively sensitized with mouse monoclonal IgE against AX and humanized RBL-2H3 cells sensitized with polyclonal antibodies from sera of AX-allergic patients.

Results

All BiAns were recognized by AX-sIgE. Dose-dependent activation responses were observed in both cellular assays, only with longer structures, containing spacers in the range of PEG 6000–12,000 Da. Consistently, greater proportion of immunocomplexes and number of antibodies per complex for longer BiAns were visualized by TEM.

Conclusions

BiAns are valuable platforms to study the mechanism of effector cell activation. These nanomolecular tools have demonstrated the importance of the adduct size to promote effector cell activation in AX allergy, which will impact for improving in vitro diagnostics.

     

Obesity and upper body fat distribution in Mexican American children from families with a diabetic proband

Upper and centralized body fat distribution is associated with non-insulin dependent diabetes mellitus (NIDDM). Few studies have focused on anthropometric characteristics of preadults from families in which there is a diabetic (NIDDM) proband. This study explores the prevalence of upper and centralized body fatness in Mexican American children from the Diabetes Alert study (1981–1983) in Starr County, Texas. Anthropometric data on 165 males and 224 females 9–19 years include measures of adiposity such as skinfold thicknesses and the body mass index (BMI), a measure of overweight. They show rates of obesity two to three times that of White children of comparable age and sex from National Health Surveys. In comparison with U.S. White subjects, Mexican American adults are shorter, have more adiposity and arm muscle mass and have sitting heights and body breadths at the mean of these dimensions for the U.S. population. Children from Diabetes Alert families show only marginal excess of severe obesity (> 95th percentile of BMI) when compared to the general population of children surveyed in Starr County schools. Girls from these families, but not boys, have excess fatness in the BMI compared to Mexican American children from the Hispanic Health and Nutrition Examination Survey (HHANES); suprailiac skinfold thicknesses are also greater in children of the Diabetes Alert study than in HHANES children. From 1972 through 1982, Mexican American children in South Texas showed an increase in average stature, weight, and the BMI. These data together suggest that excessive obesity exists and may be increasing in children in populations at risk for NIDDM. The prevention of NIDDM in the Mexican American population may be more effective if educational and promotional interventions include the school aged population. © 1993 Wiley-Liss, Inc.     

Spectrum of CLN6 mutations in variant late infantile neuronal ceroid lipofuscinosis

The neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurodegenerative diseases of childhood. CLN6, the gene mutated in variant late infantile NCL (vLINCL), was recently cloned. We report the identification of eight further mutations in CLN6 making a total of 18 reported mutations. These mutations include missense, nonsense, small deletions or insertions, and two splice-site mutations. Ten mutations affect single amino acids, all of which are conserved across vertebrate species. Minor differences in the pattern of disease symptom evolution can be identified. One patient with a more protracted disease progression was a compound heterozygote for a missense mutation and an unidentified mutation. Fifteen CLN6 mutations occur in one or two families only, and families from the same country do not all share the same mutation. Unlike NCLs caused by mutations in CLN1, CLN3, CLN5, and CLN8, there is no major founder mutation in CLN6. However, one mutation (E72X) is significantly more common in patients from Costa Rica than two other mutations present in that same population. In addition, a 1-bp insertion (c.316insC) is associated with families from Pakistan and I154del may be common in Portugal. A group of Roma Gypsy families from the Czech Republic share two disease-associated haplotypes, one of which is also present in a Pakistani family, consistent with the proposed migration of the Roma from the Indian subcontinent 1,000 years ago. All mutations are recorded in the NCL Mutation Database together with their country of origin for use in the development of rapid screening assays to confirm diagnosis and to facilitate carrier testing appropriate to a population.     

Enhancement of excitability and inhibitory processes in hippocampal dentate gyrus by noradrenaline: a pharmacological study in awake, freely moving rats.

Idazoxan (IDA), an alpha 2 receptor antagonist which increases firing rate of noradrenergic neurons in the locus coeruleus (LC) and release of noradrenaline (NA) in target structures, was used to study the neuromodulatory effects of NA in the hippocampus in awake rats. After IDA the population spike in the dentate gyrus (DG), evoked by a single pulse to the perforant path, was greatly enhanced with no effect of the drug on excitatory postsynaptic potentials (EPSPs). Paired pulses with short interpulse intervals (25-30 ms) produced inhibition of the response to the second pulse which was increased by IDA. This drug effect was independent of its effect on the amplitude of the first spike, since the increase in inhibition was seen at stimulation intensities which did not increase the response amplitude to the initial pulse. Thus both excitability and inhibitory processes can be enhanced in the same population of neurons by an alpha 2 adrenoceptor antagonist.     

Quality of mobility measures among individuals with acquired brain injury: an umbrella review

Quality of Life Research - While several mobility measures exist, there is large variability across measures in how mobility is conceptualized, the source of information and the measurement...     

Clinical utility of PTSD,resilience, sleep,and blast as risk factors to predict poor neurobehavioral functioning following traumatic brain injury: A longitudinal study in U.S. military service members

Quality of Life Research - This study examined the clinical utility of post-traumatic stress disorder (PTSD), low resilience, poor sleep, and lifetime blast exposure as risk factors for predicting...