Mutation analysis of patients with Hermansky-Pudlak syndrome: a frameshift hot spot in the HPS gene and apparent locus heterogeneity.

Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder in which oculocutaneous albinism, bleeding, and lysosomal ceroid storage result from defects of multiple cytoplasmic organelles-melanosomes, platelet-dense granules, and lysosomes. As reported elsewhere, we mapped the human HPS gene to chromosome segment 10q23, positionally cloned the gene, and identified three pathologic mutations of the gene, in patients from Puerto Rico, Japan, and Europe. Here, we describe mutation analysis of 44 unrelated Puerto Rican and 24 unrelated non-Puerto Rican HPS patients. A 16-bp frameshift duplication, the result of an apparent founder effect, is nearly ubiquitous among Puerto Rican patients. A frameshift at codon 322 may be the most frequent HPS mutation in Europeans. We also describe six novel HPS mutations: a 5' splice-junction mutation of IVS5, three frameshifts, a nonsense mutation, and a one-codon in-frame deletion. These mutations define an apparent frameshift hot spot at codons 321-322. Overall, however, we detected mutations in the HPS gene in only about half of non-Puerto Rican patients, and we present evidence that suggests locus heterogeneity for HPS.

Meningovertebral ligaments and their putative significance in low back pain.

OBJECTIVE: To determine the presence and morphology of the meningovertebral ligaments (ligaments of Hofmann) as well as postulate their possible contribution to low back pain. DESIGN: Sagittal dissections were performed on 12 embalmed cadaver specimens including the L5/S1 intervertebral level cephalad to T1. Meningovertebral ligaments were labeled and documented in both the lumbar and thoracic regions. RESULTS: Meningovertebral ligaments were found in both the lumbar and thoracic regions of all cadaveric specimens. These ligaments were much more prevalent in the lumbar vertebral column but were also present throughout the thoracic vertebral column. The meningovertebral ligaments in the lumbar region were more robust as well as more frequently encountered than those found in the thoracic region. CONCLUSION: Dural sac attachments to the posterior aspect of the vertebral bodies and the posterior longitudinal ligament could act to traction the dural sac in the event of nuclear bulge or herniation. The prevalence of these ligaments in the lumbar spine, coupled with the high incidence of herniated nucleus pulposus and disc bulges in this region, may compound the effects of disc pathology and result in increased low back pain.

A recurrent mutation, ala391glu, in the transmembrane region of FGFR3 causes Crouzon syndrome and acanthosis nigricans.

Mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have previously been identified in Crouzon syndrome, an autosomal dominant condition involving premature fusion of the cranial sutures. Several different missense and other mutations have been identified in Crouzon syndrome patients, clustering around the third immunoglobulin-like domain. We report here the identification of a mutation in the transmembrane region of FGFR3, common to three unrelated patients with classical Crouzon syndrome and acanthosis nigricans, a dermatological condition associated with thickening and abnormal pigmentation of the skin. The mutation within the FGFR3 transcript was determined by direct sequencing as a specific gcg to gag transversion, resulting in an amino acid substitution ala391glu within the transmembrane region.

Oculocutaneous albinism and bruising in two sisters--probable Hermansky-Pudlak syndrome.

Cases of Hermansky-Pudlak syndrome may present to the dermatologist, ophthalmologist or haematologist. Classically the diagnosis rests on the triad of oculocutaneous albinism, a bruising tendency and the presence of characteristic pigmented-containing cells in the bone marrow. Specific tests of platelet function can, however, suggest the diagnosis without recourse to invasive techniques. We describe the disease in two young sisters.

Acrokeratosis paraneoplastica of Bazex.

Bazex disease is one of the rarer cutaneous paraneoplastic syndromes. It is characterized by psoriasiform changes on the digits, and in some patients spread to the ears, nose and in later stages to the limbs and trunk. The associated malignancy is typically a squamous cell carcinoma of the upper aerodigestive tract. We review the literature regarding acrokeratosis paraneoplastica of Bazex and report three cases which illustrate both the typical and some of the less common changes that are seen in the condition.

Detection of IgM autoantibodies in eluates from red blood cells.

Forty-two patients with autoimmune haemolysis, whose red cells were sensitized with IgM, were studied in order to determine suitable techniques for investigating the form of erythrocyte-bound IgM, particular emphasis being placed on identifying forms of low molecular weight. Four elution techniques were assessed for their efficiency in removing cell-bound IgM; these were the heat elution, acid stromal, organic solvent and freeze-thaw methods. Eluted IgM was detected by polyacrylamide gel electrophoresis followed by immunoblotting; the heat elution method proved to be the best. Although oligomeric forms of IgM were found in 64% of patients' sera tested concurrently, only pentameric IgM was eluted; from this it was concluded that low molecular weight IgM was not causing haemolysis in any of the cases studied but that the methods would readily detect its presence.

Lumbar zygapophyseal joint meniscoids: evidence of their role in chronic intersegmental hypomobility.

Meniscoid bodies of the zygapophyseal joints are considered by some to be a cause of the Acute-Locked Back Syndrome. These meniscoid bodies have been identified anatomically and histologically, but not yet in a formal clinical investigation. The authors provide a brief review of the zygapophyseal meniscoid-related literature, present new documentation of histological variations and offer some possible consequences of the presence of mechanically pathological meniscoids. It is herein proposed that an important sequela to the pathophysiology of these structures is that of chronic intersegmental hypomobility. We invite the scientific community to pursue further investigations of these meniscoids. Magnetic resonance imaging is one method suggested to investigate the meniscoid in vivo.

Pathophysiologic effects of acceleration stress in the miniature swine.

Four groups of six animals each were exposed to simulated +Gz aerial combat maneuvers (SACM). The first group was exposed to 5 SACM/d for 1 d. The other three groups were exposed to 5 SACM/d three times per week for 1 week, 1 month, and 6 months, respectively. The SACM was 100 s long and contained two 5-s +9Gz peaks. A control group of four animals was exposed to 1 d of five 100-s +1Gz exposures. All animals were unanesthetized. The animals were necropsied and the hearts were examined macro- and microscopically within 48 h of their respective acceleration regimen. Eight transmural samples were taken from each heart for hydroxyproline analysis. Subendocardial hemorrhage (scale = 0-4) and myocyte damage (damaged cells per tissue section), respectively, were greatest in the control (2.08 and 0.87) and the 1-d (2.39 and 0.84) exposure groups, declining thereafter to the lowest values in the 6-month (0.33 and 0.06) group. Hydroxyproline concentration, as an indicator of possible scar-tissue development, showed a significant positive trend with increasing time at several sample sites on the left ventricular free wall. Heart rate (HR) and ventricular ectopy were highest during the early + Gz exposures and decreased with time thereafter. Seven additional swine were chronically instrumented with an arterial catheter for blood collection during the SACM to determine hematocrit and plasma levels of catecholamines, cortisol, and protein. The animals were exposed to the same 5 SACMs/d, 3 times/week for 4 months. Plasma norepinephrine (norepi), epinephrine (epi), and cortisol increased, respectively, from mean pre-G values of 0.9 ng/ml, 0.8 ng/ml, and 10.8 micrograms/dl to mean high values of 53.8 ng/ml, 58.1 ng/ml, and 34.0 micrograms/dl during 1-d and 1-week +Gz exposure; then declined to high values of 8.6 ng/ml, 4.3 ng/ml, and 18.8 micrograms/dl after 4 months of +Gz. The decline in macro- and microscopic myocardial damage during the approximate time frame of the decline in HR, arrhythmias, norepi, epi, and cortisol suggests a causative relationship. This decline also suggests that the injury observed during +Gz exposures is the result of the emotional stress of handling, restraint, and the unfamiliar environment of the centrifuge and +Gz, to which the animal becomes accustomed with time. However, the hydroxyproline and histologic data also suggest that myocardial scar-tissue may develop as a result of multiple +Gz exposures.

Somatostatin-like immunoreactivity in the retinae of adult and embryonic chickens.

Somatostatin, a tetradecapeptide that inhibits growth hormone release, has a widespread distribution in the central and peripheral nervous systems and other cell types. In the present investigation, the chicken neural retina was studied for the presence of structures exhibiting somatostatin-like immunoreactivity by utilizing an indirect immunofluorescence technique. Controls for specificity of staining were performed on alternate sections. Several types of distinctly labeled neurons and their processes were evident in sections of adult and late embryonic retinae. Cresyl violet staining showed that these neurons, which were scattered peripherally and more numerous centrally, occupied several strata within the inner nuclear, inner plexiform, and ganglion cell layers. Labeled neurites of immunoreactive perikarya coursed within these layers as well, often approaching other immunoreactive cells and fibers. The morphology and position of the somatostatin-containing neurons indicated that these neurons were amacrine, horizontal, or ganglion associational cells. These findings indicate that somatostatin is first detectable in the retina during the late embryonic stages of the chicken.

Modified handling of internal catecholamine standards in radioenzymic assays.

A departure from a radioenzymic procedure widely used for plasma catecholamine assay is reported, in which we use "mean net standards" instead of individual internal standards. Interlaboratory/intermethod analyses validated use of the modified principle and demonstrated its preferential use over the conventional principle. Also demonstrated is use of the modified procedure for calculating catecholamine concentrations of several plasma samples collected from an exercising man and an acceleration-stressed swine. Benefits already derived from use of the procedure include: (a) quantification of certain plasma samples that could not be satisfactorily quantified by conventional options, (b) an apparent gain in analytical precision in virtually all other analyses, and (c) costs of analysis reduced by about 25%.

Axillary hyperhidrosis treated with alcoholic solution of aluminium chloride hexahydrate.

Sixty-five patients with axillary hyperhidrosis took part in a trial of treatment with a solution of 20% aluminium chloride hexahydrate in absolute alcohol, applied topically each night for a week and then whenever the patient thought it necessary. Excellent control of sweating was achieved in 64 patients, and occlusion of the area was found to be unnecessary. No troublesome side effects were reported. The results of this study indicate that 20% aluminium chloride hexahydrate in absolute alcohol is the treatment of first choice for patients with axillary hyperhidrosis.

Human amino acid excretion during and following an extended airborne alert.

The urinary excretion of free amino acids was measured in 15 men who participated in a continuous airborne alert for an extended period of time. These men made up one of three teams which took turns so as to assure that at least one team remained airborne in an EC-135J aircraft at all times during the 96-h alert. The team making up the test group herein reported was airborne for 8.5 h on each of four successive days; flights were flown during the daytime. The data strongly suggest that the participants experienced anticipatory stress during the early part of the first two flight days of the alert, after which the excretion of amino acids was virtually unaltered. Additionally, amino acid excretion during the 24-h period following the alert was essentially in accord with baseline values established for another groups of subjects.

Glucose-6-phosphate dehydrogenase in lichen planus skin.

The apparent Michaelis constant (Km) for glucose-6-phosphate of the enzyme glucose-6-phosphate dehydrogenase has been measured in extracts prepared from biopsies of normal human skin and from both affected and apparently normal skin of patients with lichen planus. No differences of Km were found and starch gel electrophoresis of extracts from lichen planus lesions and normal controls showed similar patterns when stained for glucose-6-phosphate dehydrogenase activity. These results do not support the view that lichen planus is an inborn error of metabolism in which the structure of glucose-6-phosphate dehydrogenase of skin is affected.