Diagnostics for the exponential normal growth curve model

The exponential normal regression model provides a flexible parametric approach to constructing growth charts or centile curves. We develop diagnostics for this model, with a special emphasis towards assessing the impact of individual cases on estimated centile curves. We also propose a standardized score residual that assesses the fit of individual cases to the location, scale, and skewness functions, respectively. An application of the proposed diagnostics is presented.     

Clinical pharmacokinetics of atomoxetine

Atomoxetine (Strattera, a potent and selective inhibitor of the presynaptic norepinephrine transporter, is used clinically for the treatment of attention-deficit hyperactivity disorder (ADHD) in children, adolescents and adults. Atomoxetine has high aqueous solubility and biological membrane permeability that facilitates its rapid and complete absorption after oral administration. Absolute oral bioavailability ranges from 63 to 94%, which is governed by the extent of its first-pass metabolism. Three oxidative metabolic pathways are involved in the systemic clearance of atomoxetine: aromatic ring-hydroxylation, benzylic hydroxylation and N-demethylation. Aromatic ring-hydroxylation results in the formation of the primary oxidative metabolite of atomoxetine, 4-hydroxyatomoxetine, which is subsequently glucuronidated and excreted in urine. The formation of 4-hydroxyatomoxetine is primarily mediated by the polymorphically expressed enzyme cytochrome P450 (CYP) 2D6. This results in two distinct populations of individuals: those exhibiting active metabolic capabilities (CYP2D6 extensive metabolisers) and those exhibiting poor metabolic capabilities (CYP2D6 poor metabolisers) for atomoxetine.The oral bioavailability and clearance of atomoxetine are influenced by the activity of CYP2D6; nonetheless, plasma pharmacokinetic parameters are predictable in extensive and poor metaboliser patients. After single oral dose, atomoxetine reaches maximum plasma concentration within about 1-2 hours of administration. In extensive metabolisers, atomoxetine has a plasma half-life of 5.2 hours, while in poor metabolisers, atomoxetine has a plasma half-life of 21.6 hours. The systemic plasma clearance of atomoxetine is 0.35 and 0.03 L/h/kg in extensive and poor metabolisers, respectively. Correspondingly, the average steady-state plasma concentrations are approximately 10-fold higher in poor metabolisers compared with extensive metabolisers. Upon multiple dosing there is plasma accumulation of atomoxetine in poor metabolisers, but very little accumulation in extensive metabolisers. The volume of distribution is 0.85 L/kg, indicating that atomoxetine is distributed in total body water in both extensive and poor metabolisers. Atomoxetine is highly bound to plasma albumin (approximately 99% bound in plasma). Although steady-state concentrations of atomoxetine in poor metabolisers are higher than those in extensive metabolisers following administration of the same mg/kg/day dosage, the frequency and severity of adverse events are similar regardless of CYP2D6 phenotype.Atomoxetine administration does not inhibit or induce the clearance of other drugs metabolised by CYP enzymes. In extensive metabolisers, potent and selective CYP2D6 inhibitors reduce atomoxetine clearance; however, administration of CYP inhibitors to poor metabolisers has no effect on the steady-state plasma concentrations of atomoxetine.     

In vivo expression of RANKL in the rat dental follicle as determined by laser capture microdissection

Tooth eruption is a localized event in which many of the genes required for eruption are expressed in the dental follicle. A major function of the follicle is to recruit mononuclear cells for osteoclastogenesis such that the alveolar bone can be resorbed. Osteoclastogenesis is primarily regulated by receptor activator of nuclear factor-kappa B ligand (RANKL), colony-stimulating factor-one (CSF-1) and osteoprotegerin (OPG). In the rat first mandibular molar, osteoclastogenesis is maximal at day 3 and CSF-1 is maximally expressed in the follicle at this time whereas OPG expression is reduced. Whether or not RANKL is expressed in vivo in the follicle is controversial, however. It is critical to determine this because others have shown that in partially-rescued mice null for RANKL, teeth do not erupt. This suggests that RANKL should be expressed in the follicle for eruption to occur. Thus, to precisely determine if RANKL is expressed in the follicle in vivo, laser capture microdissection (LCM) was used to excise dental follicle tissue from frozen sections followed by RNA isolation and RT-PCR. The results show that RANKL is expressed in the dental follicle at days 1-9 postnatally. The technique was confirmed by controls showing that LCM isolates of the follicle, and alveolar bone, express OPG. Also, LCM isolates of alveolar bone were positive for RANKL. Thus, RANKL has now been shown to be expressed in the follicle and it is probable that interactions between it, CSF-1 and OPG regulate locally the osteoclastogenesis needed for tooth eruption.     

B. T. Whitney. Physician, dentist, inventor, entrepreneur and dedicated figther for dentistry and dental education

In the mid-1850s, Western New York had become one of the most highly industrialized areas of the nation, largely because it was the terminus of the Erie Canal. Buffalo was among the foremost cities in the country; and its dentists were actively establishing a professional association. What was lacking, however, was a dental school to serve the whole area, including the territory to the west. Four leading men in the profession, who also started one of America's greatest and most innovative dental manufacturing companies, struggled to achieve that goal. Foremost among them was Benajah Ticknor Whitney, a physician, who had received his M.D. at the first medical school west of the Hudson River. But his interest in dentistry developed early in his training, and Dr. Whitney went on to become one of the state's outstanding dental leaders. Sadly, he didn't live to see his dream fulfilled. It would take 20 more years--and a hard fight to overcome opposition within the profession--until a university-affiliated school was established in Buffalo.     

Chemotaxis and activation of human peripheral blood eosinophils induced by pollen-associated lipid mediators

BACKGROUND: Eosinophil accumulation at sites of allergic inflammation is largely regulated by chemokines and lipid mediators released by a variety of cells of the local microenvironment. Recent studies have shown that pollen grains, apart from their function as allergen carriers, are a rich exogenous source of eicosanoid-like lipid mediators that are rapidly released on contact with the aqueous phase and thus may contribute to the generation of local inflammatory responses. OBJECTIVE: Here we analyze the biological activity of pollen-associated lipid mediators (PALMs) on peripheral human blood eosinophils. METHODS: Human eosinophils were coincubated with pollen grains and analyzed by electron microscopy. The lipid mediator composition of aqueous pollen extracts (APEs) was analyzed by HPLC. Human eosinophils were exposed to APEs or lipid fractions from pollen. Effects on eosinophils were tested by transwell migration and surface expression of CD11b. RESULTS: In vitro experiments showed adhesion of eosinophils to Phleum pratense pollen. In chemotaxis assays eosinophils displayed significant directed migration to APEs. HPLC analysis of APEs from Phleum pratense and Betula alba pollen demonstrated the occurrence of linoleic and alpha-linolenic acid as well as their monohydroxylated derivatives. Moreover, total lipid extracts from pollen and RP-HPLC fractions containing monohydroxylated derivatives of linoleic and alpha-linolenic acid induced similar migratory responses, although to a lesser degree than APEs. In addition, APEs and lipid extracts induced up-regulation of CD11b surface expression and secretion of eosinophil cationic protein. APE-induced chemotaxis was blocked by the leukotriene B(4) receptor antagonist LY293111, suggesting that PALMs may serve as ligands for LTB(4) receptors. CONCLUSION: Pollen grains release lipid mediators that recruit and activate eosinophils in vitro. Similar mechanisms may be effective under natural exposure conditions, in which PALMs may play a role in the recruitment of eosinophils to the site of allergic inflammation.