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Objectives: This is the first study to report the presence of tryptase, a reflection of mast cell activity, in chronic middle ear effusion of patients whose atopic status was characterized., Design and Methods: Mediator activity of mast cells and eosinophils was measured prospectively from effusion of 33 randomly selected patients and 5 control subjects with chronic otitis media with effusion (OME). Atopy was determined by enzyme-linked immunosorbent assay. Middle ear biopsies from a second group of 8 OME patients and 4 controls were fixed in plastic and stained immunohistochemically for mast cells., Results: Sixty-one percent of patients had extensive activation of mast cells in their middle ears. Among those with elevated tryptase in their effusion, 95.6% were atopic and 94.7% also had elevated levels of effusion eosinophilic cationic protein (ECP). Tryptase levels were elevated only in the effusion of atopic patients, as compared with 5 controls (P < .01). Mast cells were present in 6 of 8 OME ears and absent in all 4 normal ears., Conclusion: Mast cells and its mediator tryptase, both indicators of a Th2-driven immune response, are present in a majority of ears that have chronic effusion. These findings support the hypothesis that middle ear mucosa is capable of an allergic response and that the inflammation within the middle ear of most OME patients is allergic in nature.

Fifty-eight previously treated haemophilic subjects were treated exclusively with the recombinant FVIII (rFVIII-KOGENATE) produced by Bayer Corporation (Berkeley, CA) in an international multicentre prospective study of more than 5 years duration. Fifty-four of the 58 had severe haemophilia (< 2% FVIII) and four had moderate haemophilia (2-5% FVIII); 23/58 (40%) were seropositive for HIV, while 35/58 (60%) were HIV seronegative. Patients were monitored for safety and efficacy over a median period of 4.7 years (range 0.9-5.9 years) and received 17 922 infusions totalling 25.7 million units of rFVIII. Of 7107 bleeding episodes reported in home diaries, 5831 (82%) required only one treatment with rVIII. Twenty-five invasive surgical procedures in 17 patients, including eight joint replacements, were successfully accomplished and 13 serious bleeding episodes in eight patients were successfully treated. FVIII recovery performed on 885 occasions using 39 different lots of rFVIII showed mean incremental recovery of 2.48% IU-1 kg-1 (+/- 0.64). Adverse events were associated with 42 infusions (0.2%); none caused discontinuation of therapy. Immunological parameters remained stable in HIV-seronegative subjects treated with rFVIII; a small decrease in CD4 counts was noted in HIV-seropositive individuals (mean - 37.2 cells mm-3 yr-1). No de novo formation of inhibitors to FVIII was noted; and no clinical allergic reactions occurred to murine or hamster proteins. These conclusions from the longest monitored safety study ever performed for a haemophilia treatment product (with more than 5 years of observation) confirm previous interim study reports that rFVIII is well tolerated over the long-term, has biological activity comparable to that of plasma-derived FVIII, and is safe and efficacious for the treatment of haemophilia A.

The aminoalkylindoles (AAIs) are agonists at both the cannabinoid CB1 and CB2 receptors. To determine whether the s-trans or s-cis form of AAIs is their receptor-appropriate conformation, two pairs of rigid AAI analogues were studied. These rigid analogues are naphthylidene-substituted aminoalkylindenes that lack the carbonyl oxygen of the AAIs. Two pairs of (E)- and (Z)-naphthylidene indenes (C-2 H and C-2 Me) were considered. In each pair, the E geometric isomer is intended to mimic the s-trans form of the AAIs, while the Z geometric isomer is intended to mimic the s-cis form. Complete conformational analyses of two AAIs, pravadoline (2) and WIN-55, 212-2 (1), and of each indene were performed using the semiempirical method AM1. S-trans and s-cis conformations of 1 and 2 were identified. AM1 single-point energy calculations revealed that when 1 and each indene were overlayed at their corresponding indole/indene rings, the (E)- and (Z)-indenes were able to overlay naphthyl rings with the corresponding s-trans or s-cis conformer of 1 with an energy expense of 1.13/0.69 kcal/mol for the C-2 H (E/Z)-indenes and 0.82/0.74 kcal/mol for the C-2 Me (E/Z)-indenes. On the basis of the hypothesis that aromatic stacking is the predominant interaction of AAIs such as 1 at the CB receptors and on the demonstration that the C-2 H (E/Z)- and C-2 Me (E/Z)-indene isomers can mimic the positions of the aromatic systems in the s-trans and s-cis conformers of 1, the modeling results support the previously established use of indenes as rigid analogues of the AAIs. A synthesis of the naphthylidene indenes was developed using Horner-Wittig chemistry that afforded the Z isomer in the C-2 H series, which was not produced in significant amounts from an earlier reported indene/aldehyde condensation reaction. This approach was extended to the C-2 Me series as well. Photochemical interconversions in both the C-2 H and C-2 Me series were also successful in obtaining the less favored isomer. Thus, the photochemical process can be used to provide quantities of the minor isomers C-2 H/Z and C-2 Me/E. The CB1 and CB2 affinities as well as the activity of each compound in the twitch response of the guinea pig ileum (GPI) assay were assessed. The E isomer in each series was found to have the higher affinity for both the CB1 and CB2 receptors. In the rat brain membrane assay versus [3H]CP-55,940, the Ki's for the C-2 H/C-2 Me series were 2.72/2.89 nM (E isomer) and 148/1945 nM (Z isomer). In membrane assays versus [3H]SR141716A, a two-site model was indicated for the C-2 H/C-2 Me (E isomers) with Ki's of 10. 8/9.44 nM for the higher-affinity site and 611/602 nM for the lower-affinity site. For the Z isomers, a one-site model was indicated with Ki's of 928/2178 nM obtained for the C2 H/C-2 Me analogues, respectively. For the C-2 H/C-2 Me series, the CB2 Ki's obtained using a cloned cell line were 2.72/2.05 nM (E isomer) and 132/658 nM (Z isomer). In the GPI assay, the relative order of potency was C-2 H E > C-2 Me E > C-2 H Z > C-2 Me Z. The C-2 H E isomer was found to be equipotent with 1, while the C-2 Me Z isomer was inactive at concentrations up to 3.16 microM. Thus, results indicate that the E geometric isomer in each pair of analogues is the isomer with the higher CB1 and CB2 affinities and the higher pharmacological potency. Taken together, results reported here support the hypothesis that the s-trans conformation of AAIs such as 1 is the preferred conformation for interaction at both the CB1 and CB2 receptors and that aromatic stacking may be an important interaction for AAIs at these receptors.

The endogenous cannabinoid anandamide (N-arachidonoylethanolamide) has been shown to possess higher affinity for the cannabinoid CB1 receptor than for the CB2 receptor. Carrier-mediated transport has been proposed to be essential for the termination of the biological effects of anandamide, while hydrolysis of anandamide is performed by a membrane-bound amidohydrolase, fatty acid amidohydrolase (FAAH). As interaction of anandamide with each of these targets occurs in different environments, the conformations of anandamide for interaction with each target may differ. To ascertain what conformations of anandamide, a highly flexible molecule, are favored in polar and nonpolar environments, the new method of Conformational Memories (CM) was used. CM has been shown to achieve complete conformational sampling of highly flexible ligands, to converge in a very practical number of steps, and to be capable of overcoming energy barriers very efficiently (Guarnieri et al. J. Am. Chem. Soc. 1996, 118, 5580). The generalized Born/surface area (GB/SA) continuum solvation models for chloroform and for water were used in the CM calculations. As a means of validation, CM was first applied to arachidonic acid because both experimental and theoretical conformational studies of arachidonic acid have been reported. CM was also applied to sn-2-arachidonylglycerol (2-AG), another endogenous CB ligand; to a 1,1-dimethylheptyl derivative of anandamide, an analogue with higher CB1 affinity than anandamide; and to N-(2-hydroxyethyl)prostaglandin-B2-ethanolamide (PGB2-EA), a prostanoid ligand which does not bind to CB1. Consistent with the literature, arachidonic acid was found to exist in an extended, angle-iron shape and in back-folded conformations which were U, J, or helical in shape. The angle-iron and U-shapes were both highly populated conformations with the angle-iron preferred in CHCl3 and the U-shape preferred in H2O. Results for anandamide and 2-AG paralleled those for arachidonic acid with the exception that anandamide in water does not adopt a pure extended conformation but, rather, favors a hybrid-extended/U-shape. For the dimethyl-heptyl derivative of anandamide, the U-shape was found to be predominant in both environments (42% in CHCl3, 38% in H2O), but the population of the angle-iron shape was still significant (25% in CHCl3, 29% in H2O). For all of these ligands, J-shaped conformers constituted from 7% to 17% of the conformer population, while the helical shape was less than 5%. In both CHCl3 and H2O, the presence of the five-membered ring attenuates the ability of PGB2-EA to adopt an extended conformation. PGB2-EA was found instead to exist predominantly in an L-shape (i.e., distorted U-shape). The low probability of PGB2-EA adopting an extended conformation may be why PGB2-EA shows such low affinity for the CB1 receptor. The conformational information obtained here for anandamide and 2-AG may be useful in the design of rigid analogues which mimic the preferred molecular conformations (shapes) of these ligands. Such rigid analogues may be useful in deducing the bioactive conformation of these endogenous cannabinoids, not only at the CB receptors but also at the FAAH enzyme active site and possibly at the binding site(s) on the newly proposed anandamide transporter.

Continuous infusion of recombinant factor VIII (rFVIII) is desirable in clinical settings in order to maintain haemostatic levels in a cost-effective manner. This study was designed to determine rFVIII stability over time using a minipump set-up, which has been employed by clinicians for continuous infusion of rFVIII. Vials from three lots of Kogenate (Bayer Corporation) were reconstituted in sterile water for injection, pooled and transferred to minipump infusion sets composed of either polyvinylchloride (Medex # IPR86/tube volume 0.5 mL) or polyethylene (McGraw S5904-52, tube and adapter volume 2.1 mL), and held in temperature-controlled rooms at 5 degrees C, 25 degrees C and 30 degrees C. Additional bags of rFVII were prepared with heparin (4 U mL-1), and maintained at 30 degrees C. rFVIII was infused at a rate of 1.0 mL h-1. Samples were analysed for rFVIII activity over a 7-day period at 0, 1, 15, 24, 78 and 168 h. Prior to the start of the timed study, rFVIII activity was measured in the lot pools and in the polyvinylchloride or polyethylene bags, and in the first flush volumes through the tubing. There was no difference in rFVIII activity measured in the pools compared to the bags. rFVIII levels in the initial 3-mL infusion through the tubing showed a slight decrease in activity compared to the initial level which amounted to an insignificant loss of activity for the polyvinylchloride tubing but a significant loss in the polyethylene tubing (approximately 10 IU absolute loss in polyvinylchloride vs. 100 IU loss in polyethylene). After an initial flush of 1.0 mL for polyvinylchloride and 5.0 mL for polyethylene, activity returned to baseline and subsequently remained stable for all time points and temperatures from 5-30 degrees C over the 7-day period. We conclude that the standard polyvinylchloride in polyethylene minipump bags and tubing provide excellent delivery and stability of rFVIII for continuous infusion with or without heparin, and can be used in hospital and ambulatory settings.

Rationale and Objectives: Our purpose was to investigate a "blood pool" contrast agent for abdominal and thoracic MR angiography by comparison with standard ionic and nonionic gadolinium-based contrast agents, which redistribute into the extracellular fluid compartment., Methods: Abdominal and thoracic MR angiography was performed in three adult dogs using a three-dimensional spoiled gradient echo pulse sequence before and after intravenous administration of one of three gadolinium-based contrast agents (gadopentetate dimeglumine, gadobutrol, and gadomer-17). Each compound was tested at five different doses in all three dogs. Quantitative analysis of signal-to-noise ratio (SNR) was performed in the aorta, inferior vena cava (IVC), liver, spleen, kidney (medulla and cortex), fat, and muscle., Results: Gadomer-17 improved visualization of vascular anatomy at doses of 0.025, 0.05, 0.1, and 0.2 mmol/kg with three-fold greater aorta SNR during the arterial phase and more than four-fold greater aorta and IVC SNR during the equilibrium phase, in comparison with gadopentetate dimeglumine and gadobutrol at equal doses., Conclusions: Gadomer-17 is a promising contrast agent for both arterial phase and equilibrium phase MR angiography.

The purpose of this study was to characterize neuronal activity in the deep cerebellar nuclei of the unanesthetized genetically dystonic rat during the neonatal period when the clinical signs of the dystonic syndrome first appear. Previous lesion studies have established cerebellar output as critical to the expression of the dystonic rat's motor syndrome, a disorder that closely resembles generalized dystonia in humans. In the dystonic rat, both cerebellectomy and selective lesions of the deep cerebellar nuclei decrease the frequency of abnormal motor signs and improve performance on tests of motor function. Single-unit activity was recorded from the medial, interpositus and lateral cerebellar nuclei in awake normal (N=49) and dystonic (N=54) rats at postnatal days 12-26. One hundred and eighty-three cells were isolated, 91 from normal and 92 from dystonic rats. Interspike interval histograms, autocorrelations and ratemeter histograms were generated for each cell's spike train. Interspike interval histograms were modeled with single and double gamma distributions. Cells from dystonic rats as young as 12 days of age showed bursting firing patterns, positively skewed or bimodal interspike interval histograms, and sinusoidal autocorrelations. Bursting activity increased linearly with postnatal age in dystonic rats. Cells from normal rats demonstrated non-sinusoidal autocorrelations and unimodal interspike interval histograms. Spike frequency increased linearly with postnatal age in both normal and dystonic rats. There were no statistically significant group differences in spike frequency between normal and dystonic rats. These findings show that functional neuropathology can be detected at the level of single neurons in the deep cerebellar nuclei at the earliest behavioral stages of the dystonic rat's movement disorder. The degree of abnormality in spike train parameters correlates with the severity of the movement disorder. Independent of neuronal firing rates, abnormal neuronal firing patterns can serve as a guide to the localization of pathological cell populations within the central nervous system. These results provide additional evidence that abnormal cerebellar output plays a critical role in the pathophysiology of the dystonic rat's motor syndrome.

In view of reports of FVIII assay discrepancies in post-infusion plasma samples depending on methods used, we compared FVIII results run by each of four different methods following infusion of rFVIII (Kogenate). Nine persons with haemophilia A were infused with each of two lots of product. Plasma samples were obtained at baseline, and at 10 min, 30 min, 1, 2, 4, 8, 12, 14, 30 and 48 h post-infusion for measurement of FVIII. FVIII assay methods were chromogenic, and one-stage APTT using three different types of activators: micronized, silica, ellagic acid, and kaolin. The same reference plasma standard was used throughout. Results demonstrated a consistent difference in FVIII values, with chromogenic assays being considerably higher than those run by one-stage assays. The discrepancy was greatest when kaolin was the activator. These results point out the problems in attempting to determine the "correct" FVIII level in patient plasma samples following infusion of high purity FVIII preparations. Potential "pitfalls" include the standard used for defining product potency, the methods, reagents, instrumentation and standards used in assaying plasma samples and, in some instances, the characteristics of the product itself. This situation has considerable cost implications, potential impact on patient care, and makes it difficult to compare results between laboratories.

A recommended confirmatory procedure for detecting 5 alpha-dihydrotestosterone (DHT) doping in male athletes proposed the use of the urinary concentration ratio of DHT to epitestosterone (EpiT) as the primary marker and those of 5 alpha-androstane-3 alpha,17 beta-diol (5 alpha-Adiol) to EpiT, luteinizing hormone (LH), and 5 beta-androstane-3 alpha,17 beta-diol (5 beta-Adiol) as secondary markers. Here we investigate the effects on these markers of intramuscular administration of DHT heptanoate (250 mg) to six healthy men. Within 24 h of administration all four markers greatly exceeded the published discrimination limits, remaining above these limits for 10-14 days. All ratios returned to basal values by day 28. In contrast to results after percutaneous administration, 5 beta-Adiol excretion decreased, probably as a consequence of greater suppression of testicular steroidogenesis. Results were largely in agreement with those obtained after percutaneous administration, although probably augmented by the larger dose and the different route of delivery.

Nine patients with persistent middle ear effusion and allergy confirmed by skin testing were evaluated for eosinophils by histochemical staining of middle ear mucosal biopsy specimens for eosinophil cationic protein. The study was designed to determine whether eosinophils were present in the middle ear mucosa of these patients and whether the elevated levels of eosinophil cationic protein reported in effusion from patients with chronic otitis media with effusion and allergy might originate within the mucosa itself. Seven of nine patients with otitis media with effusion had eosinophil cationic protein containing eosinophils (12 to 15 per high-power field) and degranulated eosinophil cationic protein material in the stroma of their mucosal biopsy specimens. Positive and negative biopsy findings correlated directly with respective high and low effusion levels of eosinophil cationic protein (p = 0.03), reflecting an intrinsic immune-mediated process occurring within the middle ear mucosa.

Approximately 25% of hemophilia A patients infused with factor VIII (fVIII) mount an immune response, which leads to its inactivation. Anti-fVIII autoantibodies are also seen rarely in individuals with normal fVIII. We have previously demonstrated that some anti-A2 and anti-C2 domain antibodies are fVIII inhibitors and that many patients have additional inhibitors with a fVIII light chain (LCh) epitope outside C2. Because the contribution of the different antibodies to the plasma inhibitor titer had been examined in a limited number of patients (14), we report in this study a more extensive analysis of 55 plasmas. The dominant inhibitors in 62% (13 of 21) of autoantibody plasmas were directed only against C2 or A2, but not both, whereas this pattern was found in only 15% (5 of 34) of hemophilic plasmas. In addition, anti-A2 inhibitors were present in 71% (24 of 34) of hemophilic plasmas, but only 33% (7 of 21) of autoantibody plasmas. These results demonstrated that the inhibitor response in hemophiliacs was more complex and the epitope specificity was somewhat different. A comparison of hemophiliacs treated only with plasma fVIII or recombinant fVIII showed no significant differences in the complexity of the inhibitor response, as > or = 2 different inhibitor antibodies were present in 78% (18 of 23) of the former and 82% (9 of 11) of the latter. In contrast, the major inhibitors in 35% (8 of 23) of hemophiliacs treated with plasma fVIII were directed against C2 and another LCh epitope within residues 1649-2137, but not A2, while none (0 of 11) treated with recombinant fVIII had this pattern.

Purpose: Noonan syndrome (NS) is a congenital disorder characterized by various phenotypic features and congenital anomalies. Bleeding disorders are among the more serious, common, yet poorly defined complications associated with NS. As a means of focusing on these complications, we report three patients with stigmata of NS, each of whom had a combination of different hemostatic disorders, and review the literature on bleeding disorders in NS., Patients and Methods: The clinical course and hemostatic abnormalities in three patients with NS were studied, and a literature review on NS was undertaken., Results: The three patients we report had decreased coagulation factor levels (factors XI and II), von Willebrand disease, various levels of thrombocytopenia, and abnormal platelet function. The literature review on NS discloses multiple types of hemostatic abnormalities and a wide range of clinical presentations. A low level of coagulation factor XI is the most frequently described; thrombocytopenia and abnormal platelet function are also common., Conclusions: The existence of various types of bleeding disorders within one syndrome is unusual and requires further investigation. Recognition of this common complication in children with NS would aid both clinical management and understanding of the spectrum, the frequency, and perhaps even the basis of the hemostatic defects in this syndrome. We recommend performing coagulation screening tests in every patient with NS.

To clarify the relationship of self-esteem and health-related behaviors of primary care clinic patients, 500 family practice residency patients were invited to complete self-esteem and health-risk appraisal instruments. Of the final subject pool (N = 469), 154 responded to the single-mailing solicitation, thereby yielding a 32.8% response rate. Correlational analysis found self-esteem to be associated with predicted longevity, life satisfaction, social ties, overall health, personal loss, seatbelt use, age, physical activity, smoking, exposure to violence, and substance use. Multiple regression analysis of male subjects' data found self-esteem most closely related to the frequency of exposure to danger, self-perceptions of health, and tobacco use. Similar analysis of the women's data most closely associated self-esteem to perceived social support, self-perception of health, diastolic blood pressure, and seatbelt use. The data clearly link individuals' self-esteem to predicted longevity. Those with greater self-regard were predicted to live longer, while those with poorer self-esteem achieved shorter predicted longevity. Contributing factors may have included greater emphasis on self-care.

This study was performed to ascertain the role of allergy, as defined by skin testing and histochemical markers, in the pathogenesis of otitis media with effusion (OME). A historical perspective of allergy as it relates to OME is presented. The study included 89 patients: 48 with persistent effusion but no recent acute infection, 25 with purulent OME complicated by a superimposed infection, and 16 control subjects. All 89 patients had persistent effusion for more than 2 months and subsequently required the placement of tympanostomy tubes. Allergy was defined using the radioallergosorbent test (RAST), serum immunoglobulin E (IgE) levels, and skin tests. Allergies were present in 97% of the patients with nonacute OME. The relationship between allergy and OME was corroborated clinically in 89% of patients and was also substantiated by elevated levels of effusion eosinophil cationic protein (ECP) in 87.5% of OME patients. Histologically, polyclonal antibody staining for ECP demonstrated the presence of eosinophils in middle ear mucosal biopsy specimens. This study confirms that OME is a sign of allergic inflammation in the middle ear that is associated with an increase in eosinophils and a concomitant release of ECP into the effusion in individuals with allergy demonstrated by skin testing.

The findings of hyperechoic and enlarged fetal kidneys on routine antenatal ultrasonography is a non-specific finding that alerts the physician to a differential diagnosis of various genetic and non-genetic disorders, including fetal polycystic disease and Beckwith-Wiedeman syndrome. Detection of fetal or neonatal polycystic kidneys should alert the physician to the possibility of an associated lethal autosomal recessive inborn error of fatty acid metabolism known as multiple acyl-CoA-dehydrogenase defect (MADD). We report a case of fetal nephromegaly associated with rare inborn error of MADD. This case highlights the need for appropriate laboratory investigation of hyperechoic, enlarged fetal kidneys, and neonatal polycystic disease. The association of MADD with postnatally diagnosed polycystic disease of the kidney has been reported. The antenatal detection of nephromegaly followed by the subsequent postnatal diagnosis of MADD has not been previously reported. MADD should be considered in the differential diagnosis of this antenatal finding. Appropriate diagnostic procedures should be conducted, either pre- or postnatally, in order that appropriate genetic counseling may be provided for this autosomal recessively inherited disorder.

Background and Objective: Allergy may play a role in the middle ear inflammation that leads to otitis media with effusion. The purpose of this study was to determine whether an elevated mediator correlated with the patient's disease and thus could be used to differentiate allergy vs. infection as the cause of the middle ear inflammation., Methods: WE evaluated 57 individuals with otitis media with effusion, 32 with persistent effusion but no recent acute infection, 14 with recent infection and purulent otitis media with effusion, and II healthy subjects. The mediator activity of eosinophils and neutrophils in effusion was studied in patients characterized as having allergy by positive intradermal skin test results and positive radioallergosorbent test results. Eosinophils were characterized by measurement of eosinophil cationic protein in the effusion. Neutrophils were characterized by measurement of myeloperoxidase in the effusion. The levels of eosinophil cationic protein and myeloperoxidase in patients with and without allergy were correlated to patient history., Results: Significantly elevated levels of both eosinophil cationic protein and myeloperoxidase indicated that inflammation in the ear of patients with otitis media with effusion was characterized by a pronounced involvement of both eosinophils and neutrophils. Eighty-nine percent of all patients with disease had allergy. A higher ratio of myeloperoxidase to eosinophil cationic protein in patients with purulent otitis media with effusion indicated that in patients with a superimposed acute infection, neutrophil activity was increased even further. The level of eosinophil cationic protein was elevated only during the effusion of patients with allergies as compared with controls (p < 0.01). Among 29 cases of nonpurulent otitis media with effusion, 96.5% had allergic immune-mediated disease proved by skin testing, which was related clinically to their ear disease. Eighty-nine percent (89.6%) of these patients had eosinophil cationic protein levels greater than 10 microgram/L., Conclusion: Middle ear eosinophil cationic protein may be used as a marker of related allergy.

Currently valproic acid is considered to be the drug of first choice for juvenile myoclonic epilepsy (JME) resulting in a 70-90% control rate for all seizure types associated with JME. In those situations where valproic acid fails to control seizure activity, results in unacceptable side-effects, or is declined due to potential side-effects, an alternative effective monotherapy would be desirable. Five adolescent female patients were placed on methsuximide for JME. All five patients have been seizure free with the use of methsuximide and four out of five are now on methsuximide monotherapy with good success. C.L. has now had complete seizure control on methsuximide monotherapy, a total of 1200 mg a day, for 7 years with the exception of one seizure event occurring on an attempted discontinuation of methsuximide after being 5 years seizure free. Methsuximide monotherapy as demonstrated in these five patients is an effective treatment for JME.

Based on the initial successful use of felbamate for infantile spasms in an infant with tuberous sclerosis, three additional infants with infantile spasms of different etiologies who had failed conventional therapies were treated with felbamate. Three of the four patients have shown complete resolution of infantile spasms. All responding patients did so within 1 week of starting felbamate. The one treatment failure had an initial reduction of seizure frequency and severity but has not maintained that response long term. Controlled studies are needed to firmly establish that felbamate is both safe and effective for the treatment of infantile spasms. As these cases document, felbamate is currently available for use in infantile spasms, and the frequent conversion of infantile spasms to Lennox-Gastaut syndrome, for which felbamate is approved, makes its use in infantile spasms logical.

The presenting chest radiographs of 27 new-born patients with D-transposition of the great vessels (D-TGV) were evaluated for the degree of pulmonary flow as well as other findings classically described in D-TGV (narrow superior mediastinum, radiographically absent thymus, inapparent main pulmonary artery, non-visualization of the malpositioned aortic arch, asymmetric pulmonary blood flow, and cardiomegaly). Of the 27 patients, 22 (82%) demonstrated normal or decreased flow. The majority of the D-TGV patients also failed to demonstrate any of the other classically described radiographic findings. A normal chest radiograph is the most common presenting scenario in the neonate with D-TGV.

Recent studies suggest that treatment of hemophiliacs with highly purified factor VIII concentrates may preserve immune function. To test this hypothesis, we prospectively studied 51 hemophilic patients (21 human immunodeficiency virus [HIV] seropositive and 30 seronegative) who were on home therapy exclusively with recombinant factor VIII (Kogenate, Miles Laboratory, Berkeley, CA) for 3.5 years. Patients, all of whom had been previously treated with plasma-derived factor VIII concentrates, were monitored every 6 months with T-lymphocyte subsets and beta 2-microglobulin levels. Mean rate of change in absolute CD4 cell counts, calculated from regression slopes for individual patients, showed a small but statistically significant decrease over the 3.5-year study period for HIV seropositive hemophiliacs. No decrease in CD4 cell counts was seen in HIV seronegative hemophiliacs when the data for children under age 6 years were excluded from the analysis. beta 2-microglobulin levels and CD8 cell counts remained unchanged. These data show stability of immunologic parameters in HIV seronegative hemophiliacs, and a small decrease in CD4 cell counts in HIV seropositive hemophiliacs treated with recombinant factor VIII.

Birth defects in live-born infants were documented for 2 years in Jefferson County, Alabama (USA)--1986 and 1987--and in Uppsala County, Sweden--1985 and 1986. A total of 27,561 live births (9,179 white male, 8,728 white female, 4,883 black male, and 4,771 black female infants) occurred in Jefferson County; 6,896 live births (3,535 male and 3,361 female) were recorded in Uppsala County. These newborns were studied to establish a database of birth defects for the two small geographic areas and to study similarities and differences. Rates of hip dislocation, heart malformations, and clubfoot were high in Swedish infants. Similar frequencies of spina bifida and polydactyly were noted in Alabama whites and Swedish infants. Regional registries offer a systematic approach to detection of clustering of specific birth defects, identification of families for further study, location of patients with unique needs, and enhanced coordination of health services, including genetic counseling.

A review of hospitalized epilepsy patients at Texas Tech University identified 20 children during a 4-year period who had undergone a rapid change from other anticonvulsants to valproate monotherapy. All patients had difficult-to-treat or intractable epilepsy syndromes. In each case, sodium valproate was introduced over a 2- to 4-day period as all other anticonvulsants were withdrawn quickly and sequentially. No acute side effects were seen during hospitalizations, and only one patient reported gastrointestinal complaints. At time of discharge, 12 of the 20 patients were seizure free. Fifteen of the 20 patients were maintained on monotherapy following discharge. By the end of the study period, 12 of the 20 patients showed improvement with valproate, with nine patients experiencing complete seizure control. A rapid switch to valproate monotherapy can be done safely in an inpatient setting.

Eosinophil cationic protein (ECP) is probably responsible for the underlying inflammatory mechanisms seen in asthma. It can be modulated in vivo by immunotherapy or steroids, with an appropriate reduction in symptoms of respiratory tract diseases. ECP is an identifiable mediator in additional target organs involved in allergic reactions, making it of potential interest in the study of otitis media with effusion. A qualitative prospective study was designed to discover the relationship of ECP and serum IgE in patients with middle ear effusion and allergy, as demonstrated by RAST and skin testing. The concentrations of ECP in the middle ear fluid from 23 consecutive patients with otitis media with effusion undergoing the placement of tympanostomy tubes ranged from 2 to 1248 micrograms (normal serum ECP, 5 to 15 micrograms), with 87% being abnormally elevated. There was no correlation between an individual's ear and serum levels of ECP (r = 0.1672; p = 0.6232), suggesting a more localized process. There was no relation between effusion ECP and serum IgE (p = 0.0040). ECP from middle ear effusion did correlate with a patient's having allergy, as confirmed by RAST and skin testing (p = 0.0095). Mechanisms involving immune mediated disease in the middle ear, of which the eosinophil may be one participant, are presented.

Two neonates with a history of diarrhea, abrupt apnea, and suspected sepsis were proved to have infantile botulism. Initial symptoms in both infants suggested other diagnoses. Electrophysiologic studies were important in confirming the diagnosis. Early severe infantile botulism may be rare but should be considered in neonates who have hypotonia and respiratory arrest or a sepsis-like clinical picture.

Purpose: Recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) was administered to two patients with glycogen storage disease, type 1b (GSD-1b), with chronic neutropenia, neutrophil dysfunction, and recurrent infections in an effort to increase neutrophil counts and increase resistance to infections., Patients and Methods: The patients' baseline absolute neutrophil counts (ANC) ranged from 56 to 480 cells/mm3 despite increased granulocyte precursors in the bone marrow. GM-CSF was given s.c. at starting doses of 500 micrograms/m2/day divided into two doses., Results: After 48 h, ANC rose to 2,025 cells/mm3 and 3,132 cells/mm3, respectively. Absolute eosinophil counts also rose to 1,048 cells/mm3 (24%) and 4,820 cells/mm3 (33%) on days 10 and 9 in the two patients. Although an initial 10-day course of GM-CSF was tolerated in one patient without significant reactions, subsequent s.c. injections of GM-CSF were complicated by increasingly painful local reactions that necessitated discontinuation after 7 to 8 days. Intravenous infusion was associated with a febrile systemic reaction. Despite lack of improvement in neutrophil superoxide anion generation measured in one, both patients demonstrated unusually rapid healing of cutaneous infections on GM-CSF., Conclusion: Our experience suggests that GM-CSF may be useful for short-term treatment of serious infections in GSD-1b. However, alternate dosage schedules or different preparations of GM-CSF to diminish local reactions would be required for long-term maintenance therapy. Granulocyte colony stimulating factor (G-CSF) has also been shown to increase neutrophils in this disease and has not been associated with allergic reactions.

Ictal wave form characteristics--frequency, spatial distribution, and duration--were analyzed for 140 complex partial seizures recorded from epidural strip electrodes implanted in 28 patients. None had abnormalities on imaging studies. All had bilateral electrode placements, unilateral seizure onsets, temporal lobectomies, and were followed for a mean of 33 months postoperatively. Sixteen patients (57%) became free of complex partial seizures: 12 had reductions in seizure frequency of at least 50% but were not seizure-free. The only predictor of the seizure-free state was the presence of low voltage fast activity (LVF), in the alpha or beta ranges, localized to one gyrus. This phenomenon occurred in 14/16 seizure-free patients, 2/12 of others (P < 0.001). As seizures progressed, LVF typically increased in amplitude, propagated, and slowed into the theta range. Wave forms were classified into 8 categories based upon their frequency and morphology. Stepwise discriminant analysis of these wave forms, with consideration of whether they were localized or regional, revealed that both frequency and localization were critical for the post-surgical prognosis. The mere presence of a localized seizure onset was unreliable unless the wave form was taken into account. Well-localized rhythmic activity over 8 Hz at seizure onset from epidural subtemporal electrodes predicts surgical success. Slower rhythms imply greater separation in space and time from seizure onset.

The hypothesis that dihydrolipoamide dehydrogenases (E3s) have tertiary structures very similar to that of human glutathione reductase (GR) was tested in detail by three separate criteria: (1) by analyzing each putative secondary structural element for conservation of appropriate polar/nonpolar regions, (2) by detailed comparison of putative active site residues in E3s with their authentic counterparts in human GR, and (3) by comparison of residues at the putative dimeric interface of the E3s with the authentic residues in GR. All three criteria are satisfied in a convincing way for the 7 E3s that were considered, supporting the conclusion that the structural scaffolding and the overall tertiary structure (which determines the location of functional sites and residues) are remarkably similar for the E3s and for GR. These analyses together with the crystal structures of human erythrocyte GR formed the basis for construction of a molecular model for human E3. The cofactor FAD and the substrates NAD and lipoic acid were also included in the model. Unexpectedly, the surface residues in the cleft that holds the lipoamide were found to be highly charged and predominantly acidic, allowing us to predict that the region around the lipoamide in the subunit should be basic in nature. The molecular model can be tested by site-directed mutagenesis of residues predicted to be in the dihydrolipoamide acetyltransferase subunit binding cleft.

Objectives: To facilitate the differential diagnosis of hemoglobin FE in newborn infants (homozygous hemoglobin E vs hemoglobin E-beta O-thalassemia)., Methods: The beta-globin gene in DNA from infants found to have hemoglobin FE in the California newborn screening program was amplified by the polymerase chain reaction, and the product was digested with Mnl I, which fails to cut the product when the hemoglobin E mutation is present. When both amplified alleles fail to be cut, homozygous EE is diagnosed. If only one allele is cut, a beta-globin allele without the E mutation is present (non-E), which is most likely a gene with a beta O-thalassemia mutation., Results: Samples from 18 infants revealed an EE genotype, and from two samples a non-E/E genotype was determined. Clinical examination of these two patients confirmed a diagnosis of hemoglobin E-beta O-thalassemia. An independent clinical diagnosis agreed with DNA analysis for all 17 of the 20 infants for whom follow-up and family studies were available. The DNA results were obtained within a week, but the clinical diagnoses often could not be resolved unequivocally for months., Conclusions: The direct analysis of patient DNA samples for the hemoglobin E mutation allowed rapid and accurate diagnosis in this sample of infants with hemoglobin FE on the newborn screen. This rapid discriminatory test should reduce cost and simplify the diagnostic approach for these patients, which currently consists of expensive and lengthy follow-up until clinical data and family studies result in a diagnosis.

Fecal impaction is a common problem in patients with neurologic impairment. The pulsed irrigation enhanced evacuation (PIEE) procedure is a new method of clearing fecal impactions using pulses of small amounts of warm water to rehydrate stool and improve peristalsis. Thirty-seven PIEE procedures were performed on 28 patients with a variety of neurologic problems. The PIEE procedure was observed to be effective and safe. It should be a useful adjunct to a proper bowel management program.

Study Objective: To evaluate the efficacy and side effects of niacin therapy in dyslipidemic individuals., Design: A retrospective analysis of patients' charts., Setting: An outpatient referral-based clinic specializing in the treatment of lipid disorders., Patients: All patients with dyslipidemia treated by niacin (n = 82) at the Atherosclerosis Detection and Prevention Clinic during 1987 to 1990, including a subgroup of 17 dyslipidemic heart transplant recipients., Results: Niacin was well tolerated in 83% of the nontransplant group (n = 65) at an average dose of 2.5 +/- 0.9 g/day. Similar beneficial lipoprotein effects were found in the transplant and nontransplant patients. The high-density lipoprotein cholesterol (HDL-C) response to niacin therapy was independent of the baseline (HDL-C level. In the transplant group, 11 patients (65%) discontinued treatment, primarily because of hyperglycemia; this was especially prominent in those patients with pretreatment diabetes mellitus. Of the 15 patients using sustained-release niacin, eight cases of hepatitis were recorded, some during therapy with relatively low niacin doses. Several different sustained-release preparations were responsible for this phenomenon, suggesting that the cause was not a contaminant in the preparation. No cases of hepatitis were documented in the 67 patients using regular niacin. One case of hepatitis was recently observed in a patient who switched from one type to regular niacin to another; however, we have data to suggest that the substituted preparation was not an immediate-release niacin. A familial predisposition to hepatitis is suggested by the occurrence of this side effect in identical twin brothers and two sisters. A pharmacy survey disclosed that most pharmacists are unaware of the relationship of sustained-release niacin to hepatitis, have a negative impression of regular niacin, and do not stock this formulation. Finally, we found that in this small sample of patients, niacin used with lovastatin is a particularly effective drug combination and appears to have few side effects beyond those seen with niacin alone., Conclusions: Our experience supports the fact that regular niacin is a useful lipid-modifying drug. When used appropriately, patients can usually tolerate adequate doses for prolonged periods and achieve meaningful results. However, this requires a certain amount of physician skill and patient motivation. The use of sustained-release preparations to overcome this problem can lead to harmful consequences and should only be done under strict medical supervision. In our opinion, the availability of sustained-release niacin as a nonprescription drug is unjustified and should be reexamined. Finally, we have observed that reduction of very-low-density lipoprotein cholesterol (VLDL-C) with niacin alone leads to an elevation in low-density lipoprotein cholesterol in many patients; this indicates to us that the mechanism whereby niacin lowers VLDL-C and total cholesterol is not solely the result of a decreased synthesis of VLDL-C.

Adrenoleukodystrophy, an X-linked recessive disorder characterized by progressive demyelination of the central nervous system and adrenal insufficiency, usually manifests at 4-8 years of age. We report a 20-month-old male who presented with the sudden onset of status epilepticus and cortical blindness; initially, he had complete resolution of these findings, but experienced a relapse 3 months later. The initial computed tomographic scans depicted cerebral edema and possible "watershed infarcts:" however, over the next 2 weeks before discharge from the hospital, the cortical blindness and ataxia both resolved. During the next 2 months, he exhibited no symptoms: he had no seizures and his neurologic examinations were normal. Three months after the initial hospitalization, he developed what the mother believed was "a weakness on his right side." Magnetic resonance imaging confirmed severe white matter disease. Adrenoleukodystrophy was clinically suspected and an assay of plasma levels confirmed an elevation of C26 long-chain saturated fatty acid levels. After the patient's diagnosis of adrenoleukodystrophy was confirmed, long-chain fatty acid levels were obtained on his 5-year-old brother and his mother. This child had the earliest known onset of X-linked adrenoleukodystrophy.

Severe myoclonic epilepsy of infancy (SMEI) is a newly recognized epileptic syndrome. It is characterized by multiple febrile seizures, often prolonged, subsequent development of uncontrollable mixed-myoclonic seizures, and, eventually, psychomotor retardation. Drugs for myoclonic epilepsy--valproate (VPA), the suximides, and the benzodiazepines--have been shown to be useful in SMEI. Among children with seizures in the National Institute of Neurological and Communicative Disorders and Stroke Collaborative Perinatal Project (NCPP), one individual with SMEI was identified. This finding from the NCPP suggests that the incidence of SMEI is approximately 1 in 40,000 children. Such an incidence is supported by observations at the Texas Tech University Health Sciences Center.

Twenty patients classified as having otitis media with effusion (OME) refractory to all previous medical and surgical therapy were entered into a prospective study to see if classic allergy techniques could diagnose and treat otherwise unresolved effusion and persistent hearing loss in lieu of the re-insertion of tympanostomy tubes. RAST testing, skin end point titration and food elimination diets identified a possible allergic etiology in all patients. Among those choosing allergy immunotherapy, 65% maintained normal hearing, normal tympanograms, and the elimination of recurrent infections for three years. The remaining 35% resolved on appropriate food elimination diets. None of the control's symptoms resolved. The history of chronic disease is defined. The pathophysiology of allergic mechanisms and studies attempting to prove or disprove an allergic effect on the middle ear and eustachian tube are reviewed.

The effect of 0.25 mg of terbutaline sulfate, a beta 2-adrenergic agent, on the right and left ventricular ejection fractions (RVEF and LVEF, respectively) was studied in 30 patients with severe stable chronic obstructive pulmonary disease (COPD) with a mean forced expiratory volume in 1 s of 0.79 +/- 0.06 L. All bronchodilator therapy was withdrawn 48 hours before the study. The ECG-synchronized gated equilibrium radionuclide ventriculography showed decreased RVEF in 27 patients and LVEF in 16 patients. Both the RVEF and LVEF significantly increased after the terbutaline injection; this increase was noted both in patients with normal and decreased ejection fractions. We conclude that the increase in ejection fractions after terbutaline injection may contribute to the good clinical response to this drug seen in patients with severe stable COPD even though the bronchodilator effect may be minimal.

Hematologic evaluations of 254 Southeast Asian refugee children from 163 families are reported. Hemoglobin E trait was common in Cambodians (19%) and Laotians (18%), but rare in Vietnamese (1%). beta-Thalassemia trait was most prevalent in Vietnamese (8%), and less common in Cambodians and Laotians (3%). alpha-Thalassemia was prevalent in all three groups. Hemoglobin concentrations and mean corpuscular volumes seen with hemoglobinopathies were compared with those of Southeast Asian children with normal hemoglobin. Both Hb AE and Hb EE were shown to be benign conditions resulting in microcytosis and mild, if any, anemia. In children with Hb AE, mean corpuscular volume ranged from 64 to 78 ft and Hb E from 27% to 34%. In those with Hb EE, microcytosis was more marked (50 to 63 ft). In 15 children with Hb EE, there was a delayed fall in fetal hemoglobin, which can cause diagnostic difficulties in infants.

Cell soma area or diameter distributions are generally very skewed and present some unusual problems in characterization and description. In this study of ganglion cell soma size in rabbit retina, our conclusions are based on a statistical method which not only characterizes this particular neuronal population but which also may be of considerable value in other species and other parts of the nervous system. To facilitate comparisons between retinas, we used ganglion cell density as the measure of retinal location. The rabbit retina has a horizontally extended area centralis, the visual streak, which we show to have a uniformly high peak cell density along most of its length. Cell density maps were used to estimate the total number of ganglion cells in the retina; the mean for three retinas was about 406,000 cells, which corresponds well to an earlier count of optic nerve axons (394,000 +/- 20,000; Vaney, D.I., and A. Hughes (1976) J. Comp. Neurol. 170: 241-252). Contrary to other reports, we could not find any large differences in ganglion cell size distributions between the inferior peripheral retina and the visual streak nor could we confirm the report of a large cell area temporalis (Provis, J. M. (1979) J. Comp. Neurol. 185: 121-138). Cell size distributions in the superior and inferior retina were very different, however, and, within the inferior retina, there was a small but systematic change in cell size between the periphery and the visual streak. In general, small and medium size cells were present in nearly constant proportions throughout the inferior retina, while the large ganglion cells showed a small decrease in proportion from the periphery to the visual streak; the decline in large cells was a linear function of cell density. In terms of ganglion cell soma size, there was no sharp distinction between the visual streak and the peripheral retina.

Cefaclor and tetracycline were compared in a single-blind study designed to treat patients with acute bacterial bronchitis and acute exacerbations of chronic bronchitis. Twenty-five pathogens (including 19 of Haemophilus influenzae and four of Streptococcus pneumoniae) were obtained from sputum samples of 48 patients. No pathogen could be cultured from the sputum of 23 patients. All of these pathogens were susceptible to cefaclor, while 12 (63%) of the 19 H influenzae isolates and three of the four S pneumoniae isolates were resistant to tetracycline. When the susceptibility of the 25 isolates to other commonly used antibacterials was tested, 18 isolates of H influenzae were resistant to erythromycin and one was resistant to ampicillin. (One H influenzae isolate was not tested for erythromycin susceptibility.) The four isolates of S pneumoniae were susceptible to erythromycin and ampicillin. Satisfactory results were achieved in 21 of the 23 patients receiving cefaclor. After four to six days of cefaclor therapy, the other two patients were diagnosed as having bronchopneumonia, and parenteral antibiotic therapy was instituted. Of the 25 patients assigned to the tetracycline regimen, three with resistant H influenzae had unsatisfactory clinical responses and required parenteral antibiotic therapy for recovery. Although patients were randomly assigned to therapy, only three of the 16 patients infected with tetracycline-resistant organisms were assigned to the tetracycline group, and all three failed to respond to treatment. Had the patients been more evenly distributed according to susceptibilities, it is possible that more treatment failures would have occurred in the group receiving tetracycline.

Pulmonary involvement in mixed connective tissue disease (MCTD) is common, frequently severe, and is often clinically inapparent and variably responsive to corticosteroid/cyclophosphamide treatment. Serial pulmonary evaluation of patients with MCTD is important, since deterioration, as in the diffusing capacity over time, may alert the physician to the need for more invasive evaluation. Patients with a greater degree of overlap in rheumatological symptoms with an element of systemic sclerosis (PSS) may later develop severe disease. Nailfold capillary microscopy also may help in determining which patients will develop severe pulmonary involvement. Significant pulmonary hypertension occurs and cannot be accurately predicted on the basis of history, physical examination, pulmonary function tests, gallium scanning, or exercise testing. The characteristic pathological finding was intimal proliferation with medial muscular hypertrophy in the pulmonary arterioles. In contrast, pulmonary interstitial abnormalities were minimal, suggesting the proliferative vascular lesions are more closely associated with pulmonary hypertension in MCTD. Some patients develop rapidly progressive disease with varying response to corticosteroid and cytotoxic agents. More commonly, however, MCTD patients with long-term disabling disease, including pulmonary dysfunction, have had significant improvement with steroid and/or cyclophosphamide treatment, and clinical remission has occurred in 38% of the patients in this series.