The burdened life of adults with ADHD: impairment beyond comorbidity.

Since approximately 70% of adult patients with attention-deficit/hyperactivity disorder (ADHD) have at least one comorbid disorder, rating of impairment specifically attributable to ADHD is a hard task. Despite the evidence linking environmental adversities with negative outcomes in ADHD, life events measures have not been used to rate the disorder impairment. The present study tested for the first time the hypothesis that increased ADHD severity is associated with an increase in negative recent life events, independently of comorbidity status. The psychiatric diagnoses of 211 adult ADHD outpatients were based on DSM-IV criteria assessed through structured interviews (K-SADS-E for ADHD and ODD, MINI for ASPD and SCID-IV-R for other comorbidities). ADHD severity was evaluated with the Swanson, Nolan and Pelham rating scale (SNAP-IV) and recent life events with the Life Experience Survey. Higher SNAP-IV inattention and hyperactivity scores, female gender, lower socioeconomic status and the presence of comorbid mood disorders were associated with negative life events. Poisson regression models with adjustment for possible confounders confirmed the effect of inattention and hyperactivity severity on negative life events. Our results suggest that the negative life events experienced by these patients are associated to the severity of ADHD independently from comorbid psychiatric disorders.

Study of bioaccumulation of dalteparin at a therapeutic dose in patients with renal insufficiency.

BACKGROUND: Low-molecular-weight heparins (LMWH) are effective, safe and convenient for anticoagulation. Their use is limited in patients with renal insufficiency (RI) because of bioaccumulation. OBJECTIVES: Evaluate pharmacokinetic data of dalteparin at a therapeutic dose in patients with RI. PATIENTS AND METHODS: Prospective observational cohort study. Inpatients were included into three groups according to glomerular filtration rate (GFR): A > or = 60, B 30-59, C < 30 mL min(-1) 1.73 m(-2). Dalteparin was injected subcutaneously (s.c.) twice daily. Peak plasma anti-factor Xa activity (anti-Xa) was measured and adjusted to applied dose and body weight after the first dose, on day 2, and every 2nd day afterwards. Bioaccumulation factor R was calculated as quotient of the last and the first adjusted anti-Xa. Data are shown as median (interquartile range, IQR). RESULTS: Thirty-two patients (23 men) receiving dalteparin for > or = 2 days were analyzed. Follow-up was 6 days (IQR 4-10, range 2-22). Median dose was 90 (73-106) units kg(-1) per 12 h (P = 0.68). After the first dose, adjusted anti-Xa levels were 3.5 (2.6-5.0), 4.8 (3.3-5.5), 4.5 (3.7-7.5) x 10(-3) for the groups A, B, C; P = 0.26. On the last day, they were 6.1 (3.7-7.3), 7.1 (5.6-8.3), 10.2 (7.8-13.2) x 10(-3); A compared with C, P = 0.002. R was 1.46 (1.15-1.82), 1.36 (1.20-2.16) and 2.28 (1.53-2.93); A compared with C, P = 0.18. CONCLUSION: Therapeutically dosed dalteparin accumulates in patients with severe RI (group C). Dose adjustments according to anti-Xa are recommended for dalteparin if used in this patient population. However, no simple dosing scheme can be suggested yet because of wide inter-individual variation.

Study of bioaccumulation of dalteparin at a prophylactic dose in patients with various degrees of impaired renal function.

BACKGROUND: Low-molecular-weight heparins (LMWH) have been shown to be effective and safe for prophylaxis of thromboembolic diseases. However, issues regarding safety and optimal use of LMWH arise in patients with renal insufficiency (RI). OBJECTIVES: To compare pharmacokinetic data of dalteparin for up to 3 weeks in patients with various degrees of RI. PATIENTS AND METHODS: Patients from general medical and surgical wards were included in this prospective cohort study and divided into three groups according to renal function: A=normal (GFR>or=60 mL min(-1)1.73 m(-2)), B=mild RI (GFR 30-59 mL min(-1)1.73 m(-2)), C=severe RI (GFR<30 mL min(-1)1.73 m(-2)). Dalteparin was injected s.c. once daily at a prophylactic dose. Peak anti-Xa activity levels (anti-Xa) were measured 4+/-1 h after injection on day 1 and every third day up to 3 weeks. Primary objectives were peak anti-Xa levels and adjusted anti-Xa levels, adjustment being carried out for dose and body weight. RESULTS: A total of 42 patients could be analyzed during a median of 10 days (interquartile range IQR 4-13, range 1-20). In all groups, adjusted peak anti-Xa levels were not different on day 10 compared with day 1. No bioaccumulation>30% could be found up to day 10 even in patients with severe RI. CONCLUSION: The use of dalteparin at a prophylactic dose was not associated with a bioaccumulation>30% even in patients with severe renal insufficiency during a median follow-up of 10 days (IQR 4-13, range 1-20).

Serotonin transporter gene polymorphism and the phenotypic heterogeneity of adult ADHD.

The present study investigates possible associations between the 5-HTT control region polymorphism (5-HTTLPR) with adult ADHD, including subtypes, severity, temperament profile and comorbidities. The polymorphic site was genotyped in 312 adult patients with ADHD and 236 controls, all of them Brazilians of European descent. The interviews followed the DSM-IV criteria, using the K-SADS-E for ADHD and oppositional defiant disorder, SCID-I and MINI for comorbidities and the TCI for temperament dimensions. The 5-HTTLPR polymorphism was not associated with ADHD. Carriers of the S allele presented slightly higher inattention and novelty seeking scores, and a higher frequency of drug dependence. These differences do not persist after correction for multiple comparisons. These results suggest that the 5-HTTLPR polymorphism does not have a direct role in the predisposition to adult ADHD. There is suggestive evidence for a small effect in some behavioral phenotypes related to ADHD.

A quantitative system to evaluate diabetic retinopathy from fundus photographs.

PURPOSE: To evaluate a quantitative system to measure the early lesions of diabetic retinopathy seen in stereoscopic fundus photographs. METHODS: Using a quantitative classification system, photographs of 4657 eyes (7 stereo pairs of 35-mm slides per eye) were scored for 16 diabetic lesions. A single severity level (identical to the ETDRS Interim Scale) was calculated for each eye. The reliability of this technique, and its reproducibility by independent examiners, was evaluated for individual lesions and severity levels using percent agreement, kappa, and weighted kappa statistics. RESULTS: This quantitative technique demonstrated an "almost perfect" agreement (weighted kappa > or = 0.810) on all but one lesion by independent observers. For the severity levels, there was a 95.7% perfect agreement (kappa = 0.9428). The reproducibility of agreement over time was "almost perfect" on all but four lesions; with 88% perfect agreement (kappa = 0.8394) for severity levels. CONCLUSIONS: When used to evaluate the early lesions of diabetic retinopathy, the Vanderbilt Classification System is highly reliable between graders and over time. This system can gather quantitative data and evaluate incremental changes in an accurate, reproducible manner.

Hypoxanthine and adenine metabolism in bovine thyroid tissue.

Hypoxanthine was converted primarily to uric acid by thyroid tissue slices and homogenates with little inosine 5'-monophosphate formation while adenine was essentially all salvaged to adenosine 5'-monophosphate by similar tissue preparations. The ratio of hypoxanthine/guanine phosphoribosyltransferase activity to adenine phosphoribosyltransferase activity was 0.15 in the thyroid homogenates.

Purine nucleoside and purine base concentrations in bovine thyroid and plasma.

Concentrations of eight purine nucleosides and bases in bovine thyroid and plasma were determined by high pressure liquid chromatography. Plasma purines were metabolized to uric acid in the absence of inhibitors. The concentrations of these purines were 10-100 times greater in thyroid tissue than in plasma.

Characterization of the active site of homogeneous thyroid purine nucleoside phosphorylase.

Purine nucleoside phosphorylase (purine-nucleoside : orthophosphate ribosyltransferase, EC 2.4.2.1) has been purified approx. 4000-fold and to electrophoretic homogeneity from bovine thyroid glands. The isolated enzyme has a specific activity of 17 mumol . min-1 . mg-1. The native enzyme appears to have a molecular weight of 92 000 as determined by sedimentation equilibrum ultracentrifugation and is comprised of three subunits having a molecular weight of 31 000 each as shown by sodium dodecyl sulfate gel electrophoresis. The enzyme is irreversibly denatured below pH 5 and the enzyme-substrate complex is shown to have an ionization constant (pKa) of 9.2 which influences catalytic activity. The pH dependence of the kinetic constants identifies three amino acid ionizable protons. The binding of inosine is effected by an imidazole ring of histidine (pKa 5.65) and a sulfhydryl group of cysteine (pKa 8.5) and the maximal velocity is restricted by an epsilon-amino group which is essential for phosphate binding. The requirement of these residues for activity was confirmed by group-specific chemical modification. The presence of phosphate protected only the lysyl residue while inosine protected all three residues from chemical titration. A model is proposed for the catalytic mechanism of purine nucleoside phosphorylase.

Thyroid purine nucleoside phosphorylase. II. Kinetic model by alternate substrate and inhibition studies.

Nucleoside analog inhibition studies have been conducted on thyroidal purine nucleoside phosphorylase (purine-nucleoside:orthophosphate ribosyltransferase, EC 2.4.2.1) which catalyzed an ordered bi-bi type mechanism where the first substrate is inorganic phosphate and the last product is ribose 1-phosphate. Heterocyclic- and carbohydrate-modified nucleoside inhibitors demonstrate mixed type inhibition suggesting such analogs show an affinity (Ki) for the free enzyme. A kinetic model is proposed which supports the observed inhibition patterns. These studies together with alternate substrate studies indicate that nucleoside binding requires a functional group capable of hydrogen bonding at the 6-position of the purine ring and that the orientation of the bound substrate may be syn. Proper geometry of the phosphate is dependent upon the 3'-substituent to the orientated below the furanose ring. The 5'-hydroxyl group is required for substrate activity. The proposed rate limiting step of the phosphorylase mechanism is the enzymatic protonation of the 7-N position of the nucleoside.

Geological history of the Western north pacific.

A considerable portion of the abyssal floor of the western North Pacific was already receiving pelagic sediment in late Jurassic time. Carbonate sediments were later replaced by abyssal clays as the basin deepened and bottom waters became more aggressive. The resulting facies boundary, which can be recognized on seismic profiles, is broadly transgressive; it ranges in age from mid-Cretaceous in the western Pacific to Oligocene in the central Pacific. Cherts are encountered at and below the major facies boundary and appear to have been formed by postdepositional processes.