Sudden infant death, Williams-Beuren-Syndrom oder beides?

SummaryThe Williams-Beuren syndrome is a genetic disorder caused by a deletion of the elastin gene mapped on chromosome 7 (7q11.23). This results in multi-organ malformation, mental retardation and generalised elastin arteriopathy, which can lead to cardiac and vascular complications and to sudden death. We present two cases in which a postmortem examination was initially carried out with the presumptive diagnosis of sudden infant death, but cardiac malformations and facial dysmorphisms were recognised that could confirm the diagnosis of Williams-Beuren syndrome. In both cases nearly the same pathological findings were seen in the heart and lungs by histological examination. We will discuss if these findings could have caused death and if they can confirm our presumptive diagnosis of a William-Beuren syndrome which could not be verified by a genetic investigation.     

Human autoantibodies to poly(adenosine diphosphate-ribose) polymerase.

The chromatin-bound enzyme poly(ADP-ribose) polymerase (ADPRP) is strongly stimulated by DNA with single- or double-stranded breaks, and transfers the ADP-ribose moiety of NAD to nuclear proteins. The activation of ADPRP is important for DNA repair and replication, and also has been postulated to play a role in the pathogenesis of lymphocyte dysfunction associated with chronic inflammatory diseases, and inborn errors of nucleoside metabolism. We have detected high titers of IgG autoantibodies to the ADPRP protein in six patients with rheumatic complaints. No other autoantibodies were detected in any of the six sera. The specificity of the anti-enzyme antibodies was established by (a) immunoprecipitation of ADPRP activity, (b) immunoprecipitation and immunoblotting of both the native 116-kD enzyme and its proteolytic digestion products. ADPRP was purified from human thymus and calf thymus. The autoantibodies reacted equivalently with both enzymes. The anti-ADPRP antibodies had a distinctive immunofluorescent pattern with HEp-2 cells, reacting intensely with nucleoli and metaphase chromosomes, and diffusely with the nucleus. Autoantibodies to ADPRP have not been described previously. The presence of a specific immune response against an enzyme that has been associated with various immunodeficiency syndromes raises intriguing possibilities concerning the relationship between DNA damage, immunodeficiency, and autoimmunity.     

Postoperative naproxen after coronary artery bypass surgery: a double-blind randomized controlled trial.

OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) are routinely used after coronary artery bypass surgery (CABG), yet their effects have seldom been evaluated in randomized controlled settings. The aim of this study was to examine the efficacy and safety of a commonly used NSAID, naproxen. We hypothesized that naproxen would reduce postoperative pain following CABG without increasing complications. METHODS: Patients (N=98) undergoing primary CABG were randomized to receive naproxen (500 mg q12hX5 doses via suppository started 1h after operation, followed by oral 250 mg q8hX6 doses) or placebo. Standard analgesic and anti-emetic regimens were available to both patient groups. Interventions were double-blinded. Primary end-points were postoperative pain measured before and after chest physiotherapy by visual analog scale and pulmonary slow vital capacity (SVC). RESULTS: Baseline characteristics were equivalent between the two groups. Over the first 4 postoperative days, naproxen decreased pain by 47+/-17% on average before chest physiotherapy (P=0.034), and 44+/-13% after chest physiotherapy (P=0.0092). Patients who received naproxen also had better preservation of SVC over the first 4 postoperative days (mean loss of SVC from baseline: 2.1+/-0.1 vs. 2.5+/-0.1l, naproxen vs. placebo, P=0.0032). This was concomitant with a lower white blood cell count observed in naproxen patients (9.2+/-0.3 vs. 12.7+/-1.5x10(9)/l, naproxen vs. placebo, P=0.03). Patients who received naproxen had more chest tube drainage after 4h postoperatively, but there was no difference in the incidence or amount of transfusions. There was no difference in medication use, length of stay, or in the incidence of atrial fibrillation, azotemia, and other complications. CONCLUSIONS: Naproxen is an effective and low-cost adjunct for optimization of pain control and lung recovery after CABG. Its use may result in increased chest tube drainage, but no apparent increase in other complications.     

Radioanatomy of upper airways in flexion and retroflexion of the neck

Summary Ten flexion-retroflexion radiographs of the cervical spine (in lateral projection) were utilized to study anatomical configuration and topography of the upper air passages in these two positions. Measurement of AP diameters revealed narrowing in flexion and widening in retroflexion, being maximat at the region of the epiglottis, and minimal at the regions of larynx and trachea. The distance from the pharyngeal attachment of the skull-base, to the upper chest aperture proved to be markedly greater in retroflexion than in flexion. As the pharynx virtually does not change its length during these movements, it is drawn up (with respect to the upper chest aperture) in retroflexion, and pushed down in flexion, over a mean distance of 42 mm. The up and down movement of the upper part of the trachea is slightly less: 38 mm. No correction for radiological magnification of 15–20%.     

Preventing percutaneous absorption of industrial chemicals: the "skin" denotation

Percutaneous absorption has received comparatively little attention in occupational health, although this route of entry has repeatedly caused occupation-related intoxications. In practice, the evaluation of skin penetration rates is far from simple. Much evidence has been obtained from studies of chemicals used for cosmetics and topical therapeutics, but the information available on compounds encountered in occupational health is limited. The data obtained from experimental studies have confirmed that the concentration, type of vehicle, skin area, skin condition, and extent of occlusion are important factors in determining the degree of percutaneous absorption, but no general model has been developed. Also, too little is known about the basic chemical properties governing the rate of penetration. Thus, prediction is difficult and bound to be rather inaccurate. Current preventive practice follows the procedure used by ACGIH and is mainly based on a "skin" denotation in official listings of chemicals to which exposure limits have been allocated. The number of substances and groups of chemicals which have received skin denotation in 17 selected countries varies between 24 and 179 and a total of 275 are listed as a skin hazard in one or more countries; ACGIH lists 143. Thus, the denotation practice varies. As an unfortunate result of these discrepancies and the dichotomy of skin denotation, the absence of skin denotation may erroneously indicate that efforts to protect the skin are unnecessary. Thus, an evaluation of skin penetration potentials should be incorporated in occupational health practice as a supplement to the official denotations.     

Antiinflammatory effects of second-generation leukotriene B4 receptor antagonist,SC-53228: Impact upon Leukotriene B4- and 12(R)-HETE- mediated events

Leukotriene B₄ (LTB₄) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig, LTB₄ and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 {7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl]-3,4-dihydro-8-propyl-2H-1-benzopyran-2-carboxylic acid}, a first-generation LTB₄ receptor antagonist, inhibited the chemotactic actions of LTB₄ when given orally with an ED₅₀ value of 1.7 mg/kg. The second-generation LTB₄ receptor antagonist, SC-53228 [(+)-(S)-7-(3-{2-(cyclopropylmethyl)-3-methoxy-4-[(methylamino)carbonyl]phenoxy} propoxy)-3,4-dihydro-8-propyl-2H-1-benzopyran-2-propanoic acid], inhibited LTB₄-induced chemotaxis when given intragastrically with an ED₅₀ value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12(R)-HETE-induced granulocyte chemotaxis with an oral ED₅₀ value of 5.8 mg/kg. When dosed orally over a range of 0.03–100 mg/kg, SC-53228 gaveC _max plasma concentrations of 0.015–41.1g/ml. SC-53228 inhibited LTB₄-primed membrane depolarization of human neutrophils with an IC₅₀ value of 34 nM. As a potent LTB₄ receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB₄ and/or 12(R)-HETE are implicated as inflammatory mediators.     

Comparison of immunofluorescence, enzyme immunoassay, and Western blot (immunoblot) methods for detection of antibody to human T-cell leukemia virus type I.

A total of 3,349 serum samples were screened by the immunofluorescence (IF) method for antibody to human T-cell leukemia virus type I (HTLV-I). Only 9 of 2,409 specimens from selected individuals, blood bank donors, patients with encephalitis-meningitis, and human immunodeficiency virus antibody-positive homosexual or bisexual men were reactive by IF. In addition, 940 serum samples from intravenous drug abusers were tested by IF and also by an HTLV-I enzyme immunoassay (EIA) method. Of these, 222 (24%) were positive for both HTLV-I and HTLV-II antigens by IF, and 191 of these 222 were also reactive in the HTLV-I EIA. Of the 31 IF-positive, EIA-negative serum samples, 20 exhibited optical density readings greater than or equal to 70% of the positive cutoff in the EIA, and 29 samples reacted with 1 or more bands in the Western blot (immunoblot) test. An additional 10 specimens that were EIA negative reacted only with HTLV-I by IF. Differences in staining morphology and in reactions on HTLV-I and HTLV-II antigens before and after absorption of the serum specimens with HTLV-I and HTLV-II-infected cell pellets revealed six distinct serological patterns by IF. These results indicate that infections by HTLV-I or by another closely related retrovirus(es) occur in California. Further studies utilizing statistically valid sampling methods are needed to estimate true prevalence rates among various groups. IF and Western blot tests should supplement the EIA method to maximize sensitivity and specificity of test procedures.     

Indomethacin and glucocorticoid metabolism in rat liver cytosol

3 alpha-Hydroxysteroid dehydrogenase (EC 1.1.1.50) of rat liver cytosol catalyzes the second step in glucocorticoid metabolism, namely the NADPH-dependent reduction of 5 beta-dihydrocortisol to tetrahydrocortisol. The purified enzyme is potently inhibited by the nonsteroidal anti-inflammatory drugs [Penning and Talalay, Proc. natn. Acad. Sci. U.S.A. 80, 4504 (1983)], and the consequences of this inhibition on hepatic glucocorticoid metabolism are now examined. Analyses of the specific activities for the reduction of 5 beta-dihydro-cortisone catalyzed by homogeneous preparations of 3 alpha- and 3 beta-hydroxysteroid dehydrogenases of rat liver cytosol indicated that this steroid was predominantly reduced to the 3 alpha-hydroxysteroid (tetrahydrocortisone). Whether this reaction was catalyzed by the purified 3 alpha-hydroxysteroid dehydrogenase or unprocessed cytosol, it was potently inhibited by indomethacin (IC50 = 0.6 microM). In the presence of 30 microM indomethacin, the rate of reduction of 5 beta-dihydro-glucocorticoids was 16 times smaller than in the absence of drug. Measurement of 5 beta-reductase activity in rat liver cytosol indicated that it was 25-30 times less active than the 3 alpha-hydroxysteroid dehydrogenase. In the presence of 30 microM indomethacin, enough residual dehydrogenase may exist to reduce 5 beta-dihydro-glucocorticoids as they are formed. This was confirmed by incubating the supernatant fraction obtained from the 10,000 g centrifugation of a rat liver homogenate, with [1,2-3H]cortisol plus NADPH in the presence and absence of drug. At the end of the incubation, cortisol metabolites were analyzed by TLC and the results expressed as CL:CM ratio (cortisol left:cortisol metabolized). It was found that no change in this ratio occurred in the presence of the drug. Moreover, the addition of trapping quantities of 5 beta-dihydrocortisol to incubations containing 30 microM indomethacin were insufficient to promote an increase in cortisol levels as reflected by a rather small increase in the CL:CM ratio. Thus, nonsteroidal anti-inflammatory drugs cannot effect a rise in hepatic glucocorticoid levels in vitro, and do not promote a "glucocorticoid saving effect" in this organ.     

Immunohistochemical localization of fibronectin as a tool for the age determination of human skin wounds

Summary We analyzed the distribution of fibronectin in routinely embedded tissue specimens from 53 skin wounds and 6 postmortem wounds. In postmortem wounds a faint but focal positive staining was exclusively found at the margin of the specimens which dit not extend into the adjacent stroma. Vital wounds were classified into 3 groups. The first comprising lesions with wound ages ranging from a few seconds to 30 min, the second comprising those with wound ages upt to 3 weeks, and the third group with lesions more than 3 weeks old. Ten out of 17 lesions with a wound age up to 30 min showed a clear positive reaction within the wound area. Three specimens in this group were completely negative, while in 4 additional cases the result was not significantly different from postmortem lesions. These 7 cases were characterized by acute death with extremely short survival times (only seconds). In wounds up to 3 weeks old fibronectin formed a distinct network containing an increasing number of inflammatory cells corresponding to the wound age. In 2 cases with a survival time of 17 days and in all wounds older than 3 weeks fibronectin was restricted to the surface of fibroblasts and to parallel arranged fibers in the granulation tissue without any network structures. We present evidence that fibronectin is a useful marker for vital wounds with a survival time of more than a few minutes. Fibronectin appears before neutrophilic granulocytes migrate into the wound area. Since a faint positive fibronectin staining is seen in postmortem lesions and bleedings, we propose that only those wounds which show strong positive fibronectin staining also extending into the adjacent stroma should be regarded as vital.This study was supported by a grant from the Deutsche Forschungsgemeinschaft (grant Ei 209/3-1) and by a grant from the Friedrich-Baur-Stiftung University of Munich     

Subarachnoid meperidine (Pethidine) causes significant nausea and vomiting during labor. The Duke Women's Anesthesia Research Group

BACKGROUND: The combined spinal-epidural (CSE) technique using bupivicaine-fentanyl has become an established method of pain control during parturition. One limitation is the relatively short duration of effective analgesia produced by bupivicaine-fentanyl. In contrast, subarachnoid meperidine has been shown to provide a long duration of anesthesia in nonobstetric patients. Therefore, the authors tested the hypothesis that subarachnoid meperidine produces a significant increase in the duration of analgesia compared with bupivicaine-fentanyl. METHODS: Based on a power analysis of preliminary data, the authors intended to recruit 90 patients for the study, randomized to three groups: 2.5 mg bupivicaine-25 microg fentanyl, 15 mg meperidine, or 25 mg meperidine. However, after enrolling 34 patients, the study was discontinued because of a significant increase in nausea or vomiting in the study patients. RESULTS: Nausea or vomiting was substantially increased in both meperidine groups compared with the bupivicaine-fentanyl group: 16 with nausea or vomiting in the meperidine groups (n = 21), compared with 1 in the bupivicaine-fentanyl group (n = 11), P = 0.0011. The mean duration of analgesia provided by 25 mg meperidine was 126 +/- 51 min, compared with 98 +/- 29 min for bupivicaine-fentanyl and 90 +/- 67 min for 15 mg meperidine. These data were not significant (P = 0.27). CONCLUSIONS: Although intrathecal meperidine could potentially prolong subarachnoid analgesia during labor, its use was associated with a significant incidence of nausea or vomiting. These data do not support the use of subarachnoid meperidine in doses of 15 or 25 mg for labor analgesia.