Skeletal findings in the first 12 months following initiation of glucocorticoid therapy for pediatric nephrotic syndrome.

UNLABELLED: Incident vertebral fractures and lumbar spine bone mineral density (BMD) were assessed in the 12 months following glucocorticoid initiation in 65 children with nephrotic syndrome. The incidence of vertebral fractures was low at 12 months (6 %) and most patients demonstrated recovery in BMD Z-scores by this time point. INTRODUCTION: Vertebral fracture (VF) incidence following glucocorticoid (GC) initiation has not been previously reported in pediatric nephrotic syndrome. METHODS: VF was assessed on radiographs (Genant method); lumbar spine bone mineral density (LS BMD) was evaluated by dual-energy X-ray absorptiometry. RESULTS: Sixty-five children were followed to 12 months post-GC initiation (median age, 5.4 years; range, 2.3-17.9). Three of 54 children with radiographs (6 %; 95 % confidence interval (CI), 2-15 %) had incident VF at 1 year. The mean LS BMD Z-score was below the healthy average at baseline (mean ± standard deviation (SD), -0.5 ± 1.1; p = 0.001) and at 3 months (-0.6 ± 1.1; p < 0.001), but not at 6 months (-0.3 ± 1.3; p = 0.066) or 12 months (-0.3 ± 1.2; p = 0.066). Mixed effect modeling showed a significant increase in LS BMD Z-scores between 3 and 12 months (0.22 SD; 95 % CI, 0.08 to 0.36; p = 0.003). A subgroup (N = 16; 25 %) had LS BMD Z-scores that were ≤-1.0 at 12 months. In these children, each additional 1,000 mg/m(2) of GC received in the first 3 months was associated with a decrease in LS BMD Z-score by 0.39 at 12 months (95 % CI, -0.71 to -0.07; p = 0.017). CONCLUSIONS: The incidence of VF at 1 year was low and LS BMD Z-scores improved by 12 months in the majority. Twenty-five percent of children had LS BMD Z-scores ≤-1.0 at 12 months. In these children, LS BMD Z-scores were inversely associated with early GC exposure, despite similar GC exposure compared to the rest of the cohort.

The development of bone mineral lateralization in the arms.

UNLABELLED: Bone mineral content (BMC) is known to be greater in the dominant arm after the age of 8 years. We studied a group of children and found that BMC sidedness gradually increased up to the age of 6 years and then remained stable into late adolescence. INTRODUCTION: Bone mineral content (BMC) exhibits sidedness in the arms after the age of 8 years, but it is not known whether BMC is greater in the dominant arm from birth or whether lateralization develops in early childhood. To address this, we examined bone mineral status in relation to handedness and age. METHODS: Subjects (N = 158) were children recently initiating glucocorticoids for underlying disease (leukemia 43 %, rheumatic conditions 39 %, nephrotic syndrome 18 %). Handedness was determined by questionnaire and BMC by dual-energy X-ray absorptiometry. RESULTS: Median age was 7.2 years (range, 1.5 to 17.0 years), 49 % was male, and the spine BMD Z-score was -0.9 (SD, 1.3). By linear regression, BMC sidedness in the arms was significantly related to age (r = 0.294, p = 0.0005). Breakpoint analysis revealed two lines with a knot at 6.0 years (95 % CI, 4.5-7.5 years). The formula for the first line was: dominant:nondominant arm BMC ratio = 0.029 × age [in years] + 0.850 (r = 0.323, p = 0.017). The slope of the second line was not different from 0 (p = 0.332), while the slopes for the two lines were significantly different (p = 0.027). CONCLUSIONS: These results show that arm BMC sidedness in this patient group develops up to age 6 years and then remains stable into late adolescence. This temporal profile is consistent with mechanical stimulation of the skeleton in response to asymmetrical muscle use as handedness becomes manifest.

Phenazepam and cannabinomimetics sold as herbal highs in New Zealand.

A smokeable product called Kronic, is legally available, sold under five product names, and marketed in New Zealand as containing natural extracts. Two such products called Pineapple Express and Purple Haze were purchased from shops in Auckland city. They were investigated for the presence of synthetic drugs specifically synthesized for recreational purposes. The synthetic cannabinomimetics identified were JWH-018, JWH-073, JWH-122, JWH-250, and 1-pentyl-3-(4-methoxybenzoyl)indol. A compound not previously reported in such designer drug preparations 1-butyl-3-(4-methoxybenzoyl)indol was also seen. There was a marked variation in the content of these compounds within a named brand. The pharmaceutical benzodiazepine phenazepam (fenazepam) was identified as a constituent, along with certain cannabinominetics, in nearly all of the Kronic samples examined. Phenazepam has not previously been reported as a constituent of designer drug or herbal high products. The amount of phenazepam was approximately 1 mg per gram of Kronic leaf material. Use of these products could result in severe toxicity.

Measurement of serum lamotrigine by high performance liquid chromatography using a phenyltriazine as internal standard.

Lamotrigine, an anti-epileptic drug with a phenyltriazine molecular structure, is commonly measured for therapeutic drug monitoring purposes by high performance liquid chromatography (HPLC) or gas liquid chromatography (GLC). A convenient internal standard is the structurally related phenyltriazine compound BWA725C previously obtainable from the Wellcome Foundation, UK. Irsogladine is also structurally similar to lamotrigine and was therefore tested as a possible replacement for BWA725C. A GLC procedure with thermionic detection (NPD) has been utilized routinely for lamotrigine in our drug monitoring facility. Irsogladine was unsuitable, however, because the retention times of irsogladine and a co-prescribed drug, carbamazepine, were very similar. An HPLC method utilizing a Prodigy Phenomenex ODS3 column performed well using either of the internal standards. The pH of the mobile phase had a distinct impact on the spectra of lamotrigine and BWA725C. A mobile phase at pH 3, with detection at 225 nm was required to effectively resolve lamotrigine from sulthiame and irsogladine from phenobarbitone. Comparison of the HPLC and the existing GLC method with routine patient specimens (n = 43) gave an equation, y = 0.9382x + 0.8238, R(2) = 0.9862. Irsogladine was found to be a suitable internal standard for an HPLC analysis of lamotrigine.

Novel and functional norepinephrine transporter protein variants identified in attention-deficit hyperactivity disorder.

Attention-deficit hyperactivity disorder (ADHD) is a highly heritable disorder of impaired behavioral inhibition, increased motor activity, and inattention. The norepinephrine transporter (NET, SLC6A2) represents an important candidate gene for contribution to ADHD because it regulates catecholamine extracellular and tissue concentrations and contributes to executive functions disrupted in ADHD, and NET is a target for most effective ADHD therapeutics. We identified four NET coding single nucleotide polymorphisms (SNPs) in two ADHD sample sets; two SNPs produce protein variants (T283M, V245I), one of which, T283M, is a novel variant. Examination of the maternal family members through whom the T283M mutation was transmitted, provided no additional ADHD diagnoses. Given the previous identification of a NET mutation that contributes to a familial tachycardia syndrome, we examined autonomic function to reveal in the proband the highest standing-induced increase in heart rate among the ADHD subjects examined. We measured [3H]NE and [3H]dopamine transport for T283M, V245I, and a previously identified NET variant, T283R. T283M and V245I demonstrated decreased substrate transport, as did T283R, suggesting that the T283 residue is sensitive to mutation. Identification of polymorphic sites within NET, specifically those that produce functional consequences, is one critical step in elucidating the genetic variation contributing to the heritable component of diseases such as ADHD.

Humoral and cell-mediated immune responses of humans to inactivated influenza vaccine with or without QS21 adjuvant.

To evaluate humoral (antibody) and cell mediated immune (CMI) responses, 30 healthy young adults were either given inactivated influenza vaccine with or without QS21 adjuvant. Vaccination site pain and postvaccination myalgias were greater in the QS21 group. Serum antibody increases occurred in 73-93% of subjects for each vaccine and antigen at 2 weeks and 4 weeks but frequencies and mean titers for the two vaccines were not different. No differences in T cell cytotoxicity were detected for either vaccine for influenza A or B infected cells. IFN-gamma for both vaccine groups was increased in supernates after 3 days but not 7 days of stimulation in the cytotoxicity tests; amounts for the two vaccines were similar. To further evaluate CMI, remaining PBMCs were stimulated overnight with cells infected with each vaccine strain; an increase in spot forming cells (sfc) for Granzyme B and IFN-gamma was found for all subjects and in 51 of 54 sfc tests. A slightly higher response in the Gran B test for QS21 subjects was suggested, but no clear immune response advantage was identified among healthy adults for QS21 adjuvanted influenza vaccine.

Sequence variation in the human dopamine transporter gene in children with attention deficit hyperactivity disorder.

The activity of the presynaptic dopamine (DA) transporter (DAT) is critical in mediating the magnitude and duration of dopaminergic signaling in the brain. Multiple genetic studies have found an association between attention deficit hyperactivity disorder (ADHD) and a variable number tandem repeat (VNTR) in the 3'-untranslated region (3'VNTR) of the hDAT gene (SLC6A3), however none of these studies examined the hDAT coding region for polymorphisms. Thus, we sought evidence of polymorphisms in hDAT, focusing on the coding region and splice junctions, utilizing genomic DNA from children diagnosed with ADHD. Two separate ADHD cohorts (N=70 and N=42) were screened and sampled for both status of the 3'VNTR and for common/novel genomic variants. We found evidence of increased DAT variation in African-American subjects as well as in predominantely hyperactive-impulsive probands. Cumulatively, multiple hDAT sequence variants were identified, including five novel variants, as well as one nonsynonymous single nucleotide polymorphism (SNP), converting Ala559 to Val (A559V). A559V was identified in two Caucasian male siblings with ADHD and both subjects were homozygous for the ADHD-associated, 10-repeat 3'VNTR allele. Interestingly, the A559V variant was previously identified in a subject with bipolar disorder [. Molecular Psychiatry 5, 275], a psychiatric disorder that has a significant number of overlapping symptoms with ADHD.

Can methadone concentrations predict the severity of withdrawal in infants at risk of neonatal abstinence syndrome?

AIM: To assess the usefulness of cord and serum methadone concentrations at 2 days of age in predicting the severity of neonatal abstinence syndrome (NAS) in infants whose mothers received methadone during pregnancy. METHODS: After informed consent, infants were enrolled if they were delivered at 35 weeks gestation or greater. Relevant information was collected from maternal notes. A sample of cord blood was taken at delivery, with a follow up sample at 48 hours of age. The samples were analysed in batches, and the results were unavailable to the attending clinical staff. Infants were treated for NAS on clinical grounds according to a standardised scoring system. RESULTS: Twenty five of 36 eligible infants over the 21 month period of the study were enrolled. Of these, 12 required treatment for NAS. Maternal methadone dose did not predict the need for treatment. However, infants who required treatment had significantly lower methadone concentrations in cord blood than the group who did not receive treatment (31 v 88 ng/ml respectively; p = 0.029). Paired blood samples for methadone concentrations were available for 17 infants. All but one of the 12 infants who required treatment had undetectable concentrations of methadone in the postnatal sample, whereas the median postnatal methadone concentration in untreated infants was 23 ng/ml (p = 0.002). CONCLUSIONS: Methadone concentrations taken from cord blood may identify infants at greater risk of neonatal withdrawal and therefore requiring treatment.

An overview of serum antibody responses to influenza virus antigens.

Serum antibody responses after exposure to influenza virus antigens follow expected patterns for protein antigens. Induction of primary responses occurs in organized lymphoid tissues while secondary responses may occur in the periphery; in primary responses, IgM antibody is initially dominant whereas IgG antibody is dominant in secondary responses. Serum antibody responses have been ascribed to the HA, NA, M2, NP, and M1 proteins. Only the HA and NA antibodies have been shown to provide immunity in humans. Anti-HA antibody mediates neutralization and serum IgG anti-HA antibody is the dominant antibody in the lower respiratory tract. Since evidence indicates that most infections are acquired by the airborne route with deposition of virus in the lower respiratory tract, serum IgG anti-HA antibody is the primary mediator of immunity to influenza. Homotypic immunity is high for decades. Both antigenic drift and shift of the surface antigens reduce the effectiveness of antibody to the HA and NA and lead to renewed susceptibility to infection. Nevertheless, heterotypic antibody can convey substantial immunity with the degree dependent upon the extent of cross-reactivity for the infecting virus antigens. While serum anti-HA antibody is the major need for optimal immunity to influenza, a full complement of immune modalities is desirable to ensure maximum immunity.

The influence of food on the bioavailability of a twice-daily controlled release carbamazepine formulation.

Carbatrol, a new dosage form of carbamazepine (CBZ), was developed consisting of three different types of pellets (immediate release, controlled release, and enteric release). The objective of this study was to explore the influence of food on absorption of CBZ. This was a randomized, open-label, single-dose crossover study conducted in 12 healthy volunteers. Treatments were 2 x 200 mg Carbatrol with a high-fat meal, fasted, or sprinkled over applesauce (but otherwise fasted). Each subject received one dose of each treatment separated by a washout period of at least 2 weeks. CBZ bioequivalence was established based on the equivalence of AUC (extent of absorption) in all three conditions. Carbatrol may be taken with or without food or the capsule opened and sprinkled on food.

Immunization against influenza: comparison of various topical and parenteral regimens containing inactivated and/or live attenuated vaccines in healthy adults.

Methods for enhancing immune responses to influenza were explored in 2 double-blind, placebo-controlled trials. Intranasal (inl) immunization with monovalent, live attenuated, cold-adapted recombinant (CR) or inactivated influenza virus (MIV) vaccine and intramuscular (im) immunization with MIV were evaluated in various combinations. Healthy susceptible adults were assigned randomly to receive 10(7.1) TCID(50) of CR (A/H1N1 or A/H3N2), homologous MIV (15 microg), or placebo inl and placebo or homologous MIV im (6 groups in each study). Serum antibody responses were greatest in groups given im vaccine (with or without inl vaccine). A 2-fold increase in nasal wash antibody response frequencies was seen in groups given combined inl (CR or MIV) and im vaccine, compared with subjects given a single im (MIV) or inl (CR or MIV) vaccine. Combined inl and im immunization is a promising approach for enhancing both local and systemic immune responses against influenza.

Influenza: prospects for control.

Influenza is a disease of antiquity that annually imposes a major burden of morbidity and mortality. The available inactivated vaccine is effective for preventing influenza and the serious disease and death that can accompany it. However, annual recommendations for vaccination among persons at risk have never been adequately implemented. This remains the most pressing current need for control of influenza. Amantadine, rimantadine, and the newly available drugs zanamivir and oseltamivir are effective for influenza prevention and treatment (the former two for influenza A only). The availability of four antiviral agents that effectively prevent and treat influenza provides the physician with considerable flexibility for their use in influenza control. Optimal application of the currently available vaccine and antiviral agents should substantially reduce the impact of influenza. Other methods for influenza treatment and control are under development, and a live attenuated vaccine with substantial potential for control is nearing approval. However, better inactivated vaccines, better rapid diagnostic tests, and an increased understanding of options for use of antiviral agents are still needed. When all of these things are available and optimally applied, effective control of influenza should result. The prospect is compelling. Full participation by the practicing physician will be necessary to achieve this goal.

Initial fluid management of diabetic ketoacidosis in children.

The purpose of this study was to review the emergency department management of children presenting in diabetic ketoacidosis (DKA) to determine if current recommendations for fluid therapy are practiced. A 5-year retrospective chart review was conducted of all pediatric patients admitted with DKA to the University of Alberta Hospital. Presenting clinical and laboratory data, the initial fluid therapy, and insulin dose were analyzed. The therapy was also compared between sites of initial presentation (primary, secondary, or tertiary hospital). A total of 49 cases of DKA in 37 patients were reviewed. There were no significant clinical or biochemical differences between patients presenting at the three levels of hospital. Forty-one cases (84%) were given a saline bolus and the mean fluid volume given by 1 hour was 18.3 mL/kg. In the first hour 82% of patients presenting at a primary or secondary centre and 67% of those at the tertiary centre received more than 10 mL/kg. This excessive fluid therapy was also evident after 4 hours. Fluid management of children in DKA is excessive and not in keeping with current recommendations. Education of emergency physicians is needed to reduce fluid therapy and the risk of neurologic complications.

Impact of respiratory virus infections on persons with chronic underlying conditions.

CONTEXT: While hospitalization rates have declined overall, hospitalizations for acute lower respiratory tract infections have increased steadily since 1980. Development of new approaches for prevention of acute respiratory tract conditions requires studies of the etiologies of infections and quantification of the risk of hospitalization for vulnerable patients. OBJECTIVE: To determine the frequency of specific virus infections associated with acute respiratory tract conditions leading to hospitalization of chronically ill patients. DESIGN: Analysis of viral etiology of patients hospitalized with acute respiratory tract conditions between July 1991 and June 1995. SETTING: Four large clinics and related hospitals serving diverse populations representative of Harris County, Texas. PATIENTS: A total of 1029 patients who were hospitalized for pneumonia, tracheobronchitis, bronchiolitis, croup, exacerbations of asthma or chronic obstructive pulmonary disease, and/or congestive heart failure. MAIN OUTCOME MEASURE: Virus infection, defined by culture, antigen detection, and significant rise in serum antibodies, by underlying condition; hospitalization rates by low- vs middle-income status. RESULTS: Ninety-three percent of patients older than 5 years had a chronic underlying condition; a chronic pulmonary condition was most common. Patients with chronic pulmonary disease from low-income populations were hospitalized at a rate of 398.6 per 10000, almost 8 times higher than the rate for patients from middle-income groups (52.2 per 10000; P<.001). Of the 403 patients (44.4% of adults and 32.3% of children) who submitted convalescent serum specimens for antibody testing, respiratory tract virus infections were detected in 181 (44.9%). Influenza, parainfluenza, and respiratory syncytial virus (RSV) infections accounted for 75% of all virus infections. CONCLUSIONS: Our study suggests that respiratory virus infections commonly trigger serious acute respiratory conditions that result in hospitalization of patients with chronic underlying conditions, highlighting the need for development of effective vaccines for these viruses, especially for parainfluenza and RSV.

Rhinovirus infections in myelosuppressed adult blood and marrow transplant recipients.

Scant data are available on the clinical significance of rhinovirus infections in immunocompromised patients. We reviewed the clinical courses of and outcomes for 22 myelosuppressed adult blood and marrow transplant recipients with rhinovirus infections who were hospitalized at the M.D. Anderson Cancer Center (Houston) from January 1992 to January 1997. In 15 patients (68%), illnesses remained confined to the upper respiratory tract. Seven patients (32%) developed fatal pneumonia. These patients had profound respiratory failure a mean of 12 days (range, 3-21 days) after the onset of symptoms. In six of these seven cases, rhinovirus was isolated before death from a bronchoalveolar lavage fluid specimen and/or an endotracheal aspirate. Five patients underwent autopsies, one of which revealed disseminated aspergillosis and four of which revealed interstitial pneumonitis and/or acute respiratory distress syndrome and no other organisms. In conclusion, rhinovirus infections may be associated with considerable pulmonary-related morbidity and mortality in severely myelosuppressed immunocompromised patients.