Lipoprotein Lipase Overexpression in Skeletal Muscle Attenuates Weight Regain by Potentiating Energy Expenditure

Moderate weight loss improves numerous risk factors for cardiometabolic disease; however, long-term weight loss maintenance (WLM) is often thwarted by metabolic adaptations that suppress energy expenditure and facilitate weight regain. Skeletal muscle has a prominent role in energy homeostasis; therefore, we investigated the effect of WLM and weight regain on skeletal muscle in rodents. In skeletal muscle of obesity-prone rats, WLM reduced fat oxidative capacity and downregulated genes involved in fat metabolism. Interestingly, even after weight was regained, genes involved in fat metabolism were also reduced. We then subjected mice with skeletal muscle lipoprotein lipase overexpression (mCK-hLPL), which augments fat metabolism, to WLM and weight regain and found that mCK-hLPL attenuates weight regain by potentiating energy expenditure. Irrespective of genotype, weight regain suppressed dietary fat oxidation and downregulated genes involved in fat metabolism in skeletal muscle. However, mCK-hLPL mice oxidized more fat throughout weight regain and had greater expression of genes involved in fat metabolism and lower expression of genes involved in carbohydrate metabolism during WLM and regain. In summary, these results suggest that skeletal muscle fat oxidation is reduced during WLM and regain, and therapies that improve skeletal muscle fat metabolism may attenuate rapid weight regain.     

Longitudinal Impact of a Randomized Clinical Trial to Improve Family Function,Reduce Maternal Stress and Improve Child Outcomes in Families of Children with ADHD

Objective Evaluate the efficacy of a 12 month nursing case-management intervention over a period of 18 months, 6 months after the end of intervention, for families of children attention deficit hyperactivity disorder (ADHD). Methods Mother and child dyads were enrolled to participate in a randomized controlled clinical trial. Children were 4–18 years old. Data were collected at baseline, 6, 12, and 18 months or 6 months after the termination of direct intervention. Longitudinal analyses, using generalized estimating equations, were conducted to assess change in study outcomes relating to family function, maternal stress, and child behavior over the 18 month period. Results Compared to control families, some family function outcomes were moderately improved in the intervention group. In particular, intervention families demonstrated substantial improvement in implementing family behavior controls (p value?=?0.038) and improvement in family satisfaction (not statistically significant p?=?0.062). Although there was improvement in the overall family function measure there was not a statistically significant difference between groups. Maternal stress and child behavior outcomes were not significantly different between control and intervention groups by the end of the intervention. Conclusions for Practice Addressing ADHD is complex and requires the assessment of comorbidities that might exacerbate negative behavior. Our findings support the latest American Academy of Pediatrics guidelines to use behavioral therapy as the first line of treatment in young children. Nursing case-management interventions that provide direct family education and improve family function, especially with respect to providing structure and behavior control, may complement and facilitate behavioral therapy for treatment of ADHD and improving child behavior.     

Cytokeratin phenotypes at the dento-gingival junction in relative health and inflammation, in smokers and non-smokers

OBJECTIVES: The cells of the junctional epithelium (JE) provide and maintain the epithelial attachment, and remain morphologically and phenotypically distinct from oral sulcular (OSE) and external oral epithelia (EOE), from which they may be regenerated de novo. Expression of cytokeratins (CK) in human epithelia has been shown to be highly site-specific, implying a functional role. The aims of this study were to differentiate between the cyto-keratin profiles of JE, OSE, EOE and pocket epithelia (PE) in health and disease, in smokers and non-smokers.
MATERIALS AND METHODS: The cytokeratin profiles of 40 samples of healthy and clinically inflamed human gingival tissue taken from 15 smokers and 25 non-smokers were studied by immunocytochemistry. Cryostat sections of fresh frozen gingival tissues were stained with a panel of monoclonal antibodies (mAb) and visualised by a biotin-Streptavidin-peroxidase complex technique.
RESULTS: JE and PE expressed an identical range of cytokeratins irrespective of the inflammatory or smoking status, with the exception of CK4 expression, which tended to be increased in smokers. The OSE and EOE expressed non-cornifying and cornifying differentiation cytokeratins respectively, but in the presence of inflammation, both these epithelia showed increased expression of CK19 at a basal level in association with expression of one or more of the simple cytokeratins. JE/PE expressed CK17 in external layers only, approximating the tooth surface. All epithelia expressed CK6,16 the markers of high cell turnover.
CONCLUSIONS: CK19 was a consistent differentiation marker for JE and PE.Expression of CK8,18 was enhanced by inflammation. CK4 expression increased in association with smoking. Markers of differentiation were not always co-expressed equally within a pair. Pairs were not always completely mutually exclusive with frequent co-localisation.     

Repair of hollow-bulb maxillary obturator

A technique has been described for the repair of a hollow-bulb obturator when the integrity of the hollow portion has been interrupted.     

Cerebellar Loops: A Review of the Nucleocortical Pathway

Feedback pathways are a common circuit motif in vertebrate brains. Reciprocal interconnectivity is seen between the cerebral cortex and thalamus as well as between basal ganglia structures, for example. Here, we review the literature on the nucleocortical pathway, a feedback pathway from the cerebellar nuclei to the cerebellar cortex, which has been studied anatomically but has remained somewhat obscure. This review covers the work examining this pathway on a number of levels, ranging from its existence in numerous species, its organization within cerebellar circuits, its cellular composition, and a discussion of its potential roles in motor control. Recent interest in cerebellar modular organization raises the profile of this neglected cerebellar pathway, and it is hoped that this review will consolidate knowledge gained over several decades of research into a useful format, spurring new investigations into this evolutionarily conserved pathway.     

A program to educate school nurses about mental health interventions.

Concerned with the increasing incidence of mental health problems in children and adolescents and the impact of these problems on students' school success and predisposition to self- and other-directed violence, the Multnomah Education Service District Department of School Health Services determined to become proactive by providing preventive interventions for students experiencing actual or potential mental health problems. An educational program was designed to assist school nurses in the identification of potential mental health problems. In addition, information about appropriate interventions for students at risk for aggression, violence, and other mental health pathology was presented. The program involved education on mental health assessment and intervention, as well as expert psychiatric clinical support for the development of student support groups. School nurses were then challenged to develop practice improvement projects incorporating this knowledge for a group of students in their work setting. This introductory article describes the project's general rationale and implementation process. The four articles following in this issue of The Journal of School Nursing describe the goals, implementation, and outcomes of the practice improvement projects developed for early intervention with students exhibiting attention disorders, school absenteeism, social withdrawal, and depression.     

THE CHANGING INDICATIONS FOR CAROTID ENDARTERECTOMY IN THE UK

In early series the majority of carotid endarterectomies were performed in patients with amaurosis fugax (AFx) or transient ischaemic attacks (TIAs) who were thought to have atheromatous ulcers of the carotid bifurcation or the internal carotid artery (ICA). The degree of stenosis was considered to be of secondary importance. We compared our own data with two British series undertaken in the early and late 80s/early 90s. This reflects the broadening of indications and the change of practice for carotid endarterectomy over the years, on the one hand towards including patients who are at greater risk of perioperative stroke (previous CVAs vs TIAs, crescendo TIAs and stroke in evolution), and on the other towards patients who have had no symptoms attributable to the carotid lesion (asymptomatic cases, combined carotid and cardiac procedures).     

Preclinical to Clinical Translation of CNS Transporter Occupancy of TD-9855, a Novel Norepinephrine and Serotonin Reuptake Inhibitor

Background:

Monoamine reuptake inhibitors exhibit unique clinical profiles that reflect distinct engagement of the central nervous system (CNS) transporters.

Methods:

We used a translational strategy, including rodent pharmacokinetic/pharmacodynamic modeling and positron emission tomography (PET) imaging in humans, to establish the transporter profile of TD-9855, a novel norepinephrine and serotonin reuptake inhibitor.

Results:

TD-9855 was a potent inhibitor of norepinephrine (NE) and serotonin 5-HT uptake in vitro with an inhibitory selectivity of 4- to 10-fold for NE at human and rat transporters. TD-9855 engaged norepinephrine transporters (NET) and serotonin transporters (SERT) in rat spinal cord, with a plasma EC₅₀ of 11.7ng/mL and 50.8ng/mL, respectively, consistent with modest selectivity for NET in vivo.Accounting for species differences in protein binding, the projected human NET and SERT plasma EC₅₀ values were 5.5ng/mL and 23.9ng/mL, respectively. A single-dose, open-label PET study (4–20mg TD-9855, oral) was conducted in eight healthy males using the radiotracers [¹¹C]-3-amino-4- [2-[(di(methyl)amino)methyl]phenyl]sulfanylbenzonitrile for SERT and [¹¹C]-(S,S)-methylreboxetine for NET. The long pharmacokinetic half-life (30–40h) of TD-9855 allowed for sequential assessment of SERT and NET occupancy in the same subject. The plasma EC₅₀ for NET was estimated to be 1.21ng/mL, and at doses of greater than 4mg the projected steady-state NET occupancy is high (>75%). After a single oral dose of 20mg, SERT occupancy was 25 (±8)% at a plasma level of 6.35ng/mL.

Conclusions:

These data establish the CNS penetration and transporter profile of TD-9855 and inform the selection of potential doses for future clinical evaluation.