Aripiprazole for the treatment of pediatric bipolar I disorder: a 30‐week,randomized, placebo‐controlled study

Objective: To evaluate the long‐term efficacy, safety, and tolerability of aripiprazole in pediatric subjects with bipolar I disorder. Methods: A randomized, double‐blind, 30‐week, placebo‐controlled study of aripiprazole (10 or 30 mg/day) in youths (10–17 years) with bipolar I disorder (manic or mixed) ± psychotic features (n = 296) was performed. After four weeks, acute treatment completers continued receiving ≤26 weeks of double‐blind treatment (n = 210). The primary outcome was Young Mania Rating Scale (YMRS) total score change. Results: Of the 210 subjects who entered the 26‐week extension phase, 32.4% completed the study (45.3% for aripiprazole 10 mg/day, 31.0% for aripiprazole 30 mg/day, and 18.8% for placebo). Both aripiprazole doses demonstrated significantly (p < 0.001) greater improvements in YMRS total score at endpoint compared with placebo in protocol‐specified last observation carried forward analyses, but not in observed case or mixed‐model repeated measures at week 30. Overall time to all‐cause discontinuation was longer for aripiprazole 10 mg/day (15.6 weeks) and aripiprazole 30 mg/day (9.5 weeks) compared with placebo (5.3 weeks; both p < 0.05 versus placebo). Both aripiprazole doses were significantly superior to placebo regarding response rates, Children’s Global Assessment of Functioning and Clinical Global Impressions‐Bipolar severity of overall and mania scores at endpoint in all analyses. Commonly reported adverse events included headache, somnolence, and extrapyramidal disorder. Conclusions: Aripiprazole 10 mg/day and 30 mg/day were superior to placebo and generally well tolerated in pediatric subjects with bipolar I disorder up to 30 weeks. Despite the benefits of treatment, completion rates were low in all treatment arms.     

No Effect of Hole Geometry in Microfracture for Talar Osteochondral Defects

Background

Débridement and bone marrow stimulation is an effective treatment option for patients with talar osteochondral defects. However, whether surgical factors affect the success of microfracture treatment of talar osteochondral defects is not well characterized.

Questions/purposes

We hypothesized (1) holes that reach deeper into the bone marrow-filled trabecular bone allow for more hyaline-like repair; and (2) a larger number of holes with a smaller diameter result in more solid integration of the repair tissue, less need for new bone formation, and higher fill of the defect.

Methods

Talar osteochondral defects that were 6 mm in diameter were drilled bilaterally in 16 goats (32 samples). In eight goats, one defect was treated by drilling six 0.45-mm diameter holes in the defect 2 mm deep; in the remaining eight goats, six 0.45-mm diameter holes were punctured to a depth of 4 mm. All contralateral defects were treated with three 1.1-mm diameter holes 3 mm deep, mimicking the clinical situation, as internal controls. After 24 weeks, histologic analyses were performed using Masson-Goldner/Safranin-O sections scored using a modified O’Driscoll histologic score (scale, 0–22) and analyzed for osteoid deposition. Before histology, repair tissue quality and defect fill were assessed by calculating the mean attenuation repair/healthy cartilage ratio on Equilibrium Partitioning of an Ionic Contrast agent (EPIC) micro-CT (μCT) scans. Differences were analyzed by paired comparison and Mann-Whitney U tests.

Results

Significant differences were not present between the 2-mm and 4-mm deep hole groups for the median O’Driscoll score (p = 0.31) and the median of the μCT attenuation repair/healthy cartilage ratios (p = 0.61), nor between the 0.45-mm diameter and the 1.1-mm diameter holes in defect fill (p = 0.33), osteoid (p = 0.89), or structural integrity (p = 0.80).

Conclusions

The results indicate that the geometry of microfracture holes does not influence cartilage healing in the caprine talus.

Clinical Relevance

Bone marrow stimulation technique does not appear to be improved by changing the depth or diameter of the holes.     

Convergent access to bis-1,2,4-triazinyl-2,2′-bipyridines (BTBPs) and 2,2′-bipyridines via a Pd-catalyzed Ullman-type reaction

Multidentate, soft-Lewis basic, complexant scaffolds have displayed significant potential in the discrete speciation of the minor actinides from the neutron-absorbing lanthanides resident in spent nuclear fuel. Efforts to devise convergent synthetic strategies to targets of interest to improve liquid–liquid separation outcomes continue, but significant challenges to improve solubility in process-relevant diluents to effectively define meaningful structure–activity relationships remain. In the current work, a synthetic method to achieve the challenging 2,2′-bipyridine bond of the bis-1,2,4-triazinyl-2,2′-bipyridine (BTBP) complexant class leveraging a Pd-catalyzed Ullman-type coupling is reported. This convergent strategy improves upon earlier work focused on linear synthetic access to the BTBP complexant moiety. Method optimization, relevant substrate scope and application, as well as a preliminary mechanistic interrogation are reported herein.

Access to functionalized BTBP complexants through a reductive coupling strategy decreases linearity of common synthetic strategies towards these relevant materials for separations.     

Neuropathic Pain Post Spinal Cord Injury Part 2: Systematic Review of Dorsal Root Entry Zone Procedure

Background:

Pharmacotherapy may not sufficiently reduce neuropathic pain in many individuals post spinal cord injury (SCI). The use of alternative therapies such as surgery may be effective in reducing neuropathic pain in these individuals. However, because of the invasive nature of surgery, it is important to examine the evidence for use of this treatment.

Objective:

The purpose of this study was to conduct a systematic review of published literature on the surgical treatment of neuropathic pain after SCI.

Methods:

MEDLINE, CINAHL, EMBASE, and PsycINFO databases were searched for articles in which surgical treatment of pain after SCI was examined. Articles were restricted to the English language. Article selection was conducted by 2 independent reviewers with the following inclusion criteria: the subjects participated in a surgical intervention for neuropathic pain; at least 50% of the subjects had an SCI; at least 3 subjects had an SCI; and a definable intervention involving the dorsal root entry zone (DREZ) procedure was used to reduce pain. Data extracted included study design, study type, subject demographics, inclusion and exclusion criteria, sample size, outcome measures, and study results. Randomized controlled trials (RCTs) were assessed for quality using the Physiotherapy Evidence Database (PEDro) assessment scale. Levels of evidence were assigned to each intervention using a modified Sackett scale.

Results:

Eleven studies met the inclusion criteria. One study provided level 2 evidence, and the rest provided level 4 evidence. The DREZ procedure was shown to be more effective for segmental pain than for diffuse pain after SCI. Further, individuals with conus medullaris level injury were found to have a higher level of neuropathic pain relief than those with cervical, thoracic, or cauda equina injury.

Conclusions:

The studies demonstrated that the DREZ procedure may be effective in reducing segmental pain. Hence, DREZ may be important in treatment of neuropathic pain in individuals resistant to less invasive treatments. Because the studies lacked control conditions and examination of long-term effects, there is a need for larger trials with more stringent conditions.Key words: pain, spinal cord injury, surgical treatmentPain is a major cause of distress and disability in persons with spinal cord injury (SCI). It has been shown to lead to social isolation, unemployment, decreased function, decreased quality of life, depression, and even suicide.^1,2 More than 77% of individuals with an SCI indicated that pain interfered with one or more of their daily activities including sleep (40%), exercise (34.9%), and work (33.6%).² The International Association for the Study of Pain (IASP) defines neuropathic pain as “pain caused by a lesion or disease of the somatosensory nervous system.”³ After an SCI, individuals often report the onset of chronic neuropathic pain caudal to the level of the lesion or at the same level within the associated spinal cord segment.⁴ Dijkers et al⁵ reported no difference in the prevalence of pain based on level or completeness.The reported incidence of neuropathic pain after SCI varies greatly among studies, but between 10% and 30% of patients with SCI experience pain severe enough to interfere with their activities of daily living^6,7 and may require surgical intervention to relieve persistent and refractory pain.^4,8 Unmanageable neuropathic pain occurs more often in individuals with conus medullaris and cauda equina lesions where damage also involves the peripheral nerve roots.⁸When pharmacological and other noninvasive treatments fail to reduce pain, surgical spinal cord stimulation and dorsal root entry zone (DREZ) ablation treatments, such as DREZ lesioning and microsurgical DREZotomy (MDT), can be considered as options for the management of refractory pain.⁹ Neurosurgical procedures to reduce neuropathic pain should be reserved for cases in which medical therapies have failed to sufficiently reduce pain.⁴ The risks associated with ablative surgeries can be significant for individuals with incomplete neurological deficits; therefore, DREZ ablation is generally only considered a treatment option when neuropathic pain is present after a complete SCI.⁸ The MDT procedure targets for ablation the nociceptive fibers in the lateral bundle of the dorsal rootlet, the deafferented neurons of the dorsal horn, and the medial portion of the Lissauer tract.^4,6 This systematic review was conducted to assess the effectiveness of DREZ ablation therapies in reducing neuropathic pain in individuals following SCI.     

Association Between Smoking and Heart Rate Variability Among Individuals with Depression

Background

Both depression and smoking have been independently associated with lower heart rate variability (HRV), suggesting dysregulation of cardiac autonomic function. However, no studies have systematically explored the effects of smoking on HRV among depressed patients.

Purpose

This study examined differences in HRV based on smoking status among depressed individuals.

Methods

Electrophysiological data were examined among 77 adult outpatients without a history of myocardial infarction, who met criteria for major depressive disorder or dysthymia. Frequency domain [low frequency (LF), high frequency (HF), LF/HF ratio, respiratory sinus arrhythmia (RSA)] parameters of HRV, and heart rate and inter-beat interval (IBI) data were compared between depressed smokers (n?=?34) and depressed nonsmokers (n?=?44).

Results

After controlling for covariates, depressed smokers, compared to depressed nonsmokers, displayed significantly lower LF, HF, and RSA.

Conclusions

Among depressed patients, smoking is associated with significantly lower HRV, indicating dysregulated autonomic modulation of the heart.     

Inhibition of P2X4 function by P2Y6 UDP receptors in microglia

ATP‐gated P2X4 receptor channels expressed in spinal microglia actively participate in central sensitization, making their functional regulation a key process in chronic pain pathologies. P2Y6 metabotropic G_q‐coupled receptors, also expressed in microglia, are involved in the initial response to nerve injury, triggering phagocytosis upon activation by UDP. It has been reported recently that expression of both P2X4 and P2Y6 is upregulated in activated microglia following nerve injury. We show here, in resting as well as LPS‐activated primary microglia, that P2Y6 decreases P2X4‐mediated calcium entry and inhibits the dilation of P2X4 channels into a large‐conductance pore measured with a YO‐PRO‐1 uptake assay. Furthermore, P2Y6 activation modulates the ATP‐dependent migration of microglia, a process likely involved in their shift from migratory to phagocytic phenotype. Reconstituting the P2X4‐P2Y6 interaction in recombinant systems shows that P2Y6 activation decreases P2X4 current amplitude, activation and desensitization rates, and reduces P2X4 channel permeability to the large cation NMDG⁺. Phospholipase C‐mediated hydrolysis of the phosphoinositide PI(4,5)P₂, a necessary cofactor for P2X4 channel function, underlies this inhibitory crosstalk. As extracellular levels of both ATP and UDP are increased in the spinal cord following nerve injury, the control of P2X4 activity by P2Y6 might play a critical role in regulating neuropathic pain‐inducing microglial responses. GLIA 2013;61:2038–2049     

Language and Aggressive Behaviors in Male and Female Youth with Autism Spectrum Disorder

Journal of Autism and Developmental Disorders - Aggressive behaviors are common among youth with autism spectrum disorder (ASD) and correlate with pervasive social-emotional difficulties....