A randomized clinical trial of Cogmed Working Memory Training in school-age children with ADHD: a replication in a diverse sample using a control condition.

BACKGROUND: Cogmed Working Memory Training (CWMT) has received considerable attention as a promising intervention for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children. At the same time, methodological weaknesses in previous clinical trials call into question reported efficacy of CWMT. In particular, lack of equivalence in key aspects of CWMT (i.e., contingent reinforcement, time-on-task with computer training, parent-child interactions, supportive coaching) between CWMT and placebo versions of CWMT used in previous trials may account for the beneficial outcomes favoring CWMT. METHODS: Eighty-five 7- to 11-year old school-age children with ADHD (66 male; 78%) were randomized to either standard CWMT (CWMT Active) or a well-controlled CWMT placebo condition (CWMT Placebo) and evaluated before and 3 weeks after treatment. Dependent measures included parent and teacher ratings of ADHD symptoms; objective measures of attention, activity level, and impulsivity; and psychometric indices of working memory and academic achievement (Clinical trial title: Combined cognitive remediation and behavioral intervention for the treatment of Attention-Deficit/Hyperactivity Disorder; http://clinicaltrials.gov/ct2/show/NCT01137318). RESULTS: CWMT Active participants demonstrated significantly greater improvements in verbal and nonverbal working memory storage, but evidenced no discernible gains in working memory storage plus processing/manipulation. In addition, no treatment group differences were observed for any other outcome measures. CONCLUSIONS: When a more rigorous comparison condition is utilized, CWMT demonstrates effects on certain aspects of working memory in children with ADHD; however, CWMT does not appear to foster treatment generalization to other domains of functioning. As such, CWMT should not be considered a viable treatment for children with ADHD.

Formulation development and statistical optimization of chronotherapeutic tablets of indometacin.

Chronotherapeutic drug delivery offers a new approach in the pharmacologic interventions design for the effective treatment in the diseases which follows circadian rhythm. In the present study chronotherapeutic tablets of indometacin was designed to match the timing of rheumatoid arthritis treatment with the intrinsic illness timing. The developed chronotherapeutic delivery system consists of a core tablet containing the active ingredient along with osmogents and other excipients, which was coated with a swellable polymer, hydroxyl propyl methyl cellulose by compression coating technique. The time controlled release was achieved by coating the entire system with a combination of pH-independent polymer, Eudragit RS 100 and Eudragit RL 100 (1:1). The optimization technique using Box-Behnken design was employed for the selection of the ideal formula. The optimization procedure was validated, and the observed value of the ideal batch was found to be similar with the predicted values within 5% of predicted error. The formulation when administered at bed time starts releasing the drug after a lag time of 4 h and provides sufficient plasma concentration after 6 h of normal sleep. Thus, the tablets can be successfully used for the chronotherapeutic drug delivery of indometacin in the treatment of rheumatoid arthritis.

Spectrum of malabsorption in India--tropical sprue is still the leader.

INTRODUCTION: Two decades ago tropical sprue, Immunoproliferative Small Intestinal Disease (IPSID) and infections were common causes of malabsorption in India. It is possible that implementation of preventive health measures and improved sanitation may have changed the spectrum of disorders causing malabsorption. The aim of this study therefore was to assess the spectrum of malabsorption seen at our center during the past nine years. METHODOLOGY: Patients seen at our center with malabsorption from January 2000 to December 2008 were included in this study. The etiological, clinical and investigation details were recorded on uniform structured data forms. The data obtained was retrospectively analyzed. RESULTS: Malabsorption was detected in 124 patients during the study period. The mean age of patients was 31.9+16 years and 60.5% were males. Tropical sprue was the commonest etiology (29%) followed by celiac and Crohn's disease (15.3% each). Other important etiologies included parasitic infestations (9.7%) and immune deficiency disorders (5.6%). Intestinal tuberculosis was seen in only 2.4% patients. CONCLUSIONS: We are witnessing a change in etiological spectrum of malabsorption . Celiac disease and inflammatory bowel disorders are emerging as important causes and ImmunoProliferative Small Intestinal Disease (IPSID) and intestinal tuberculosis are on the decline. Tropical Sprue however continues to be the commonest cause as in the past.

Key differences between olfactory ensheathing cells and Schwann cells regarding phagocytosis of necrotic cells: implications for transplantation therapies.

Transplantation of peripheral nervous system glia is being explored for treating neural injuries, in particular central nervous system injuries. These glia, olfactory ensheathing cells (OECs) and Schwann cells (SCs), are thought to aid regeneration by clearing necrotic cells, (necrotic bodies, NBs), as well as myelin debris. The mechanism by which the glia phagocytose and traffic NBs are not understood. Here, we show that OECs and SCs recognize phosphatidylserine on NBs, followed by engulfment and trafficking to endosomes and lysosomes. We also showed that both glia can phagocytose and process myelin debris. We compared the time-course of glial phagocytosis (of both NBs and myelin) to that of macrophages. Internalization and trafficking were considerably slower in glia than in macrophages, and OECs were more efficient phagocytes than SCs. The two glial types also differed regarding their cytokine responses after NB challenge. SCs produced low amounts of the pro-inflammatory cytokine TNF-α while OECs did not produce detectable TNF-α. Thus, OECs have a higher capacity than SCs for phagocytosis and trafficking, whilst producing lower amounts of pro-inflammatory cytokines. These findings suggest that OEC transplantation into the injured nervous system may lead to better outcomes than SC transplantation.

Granzyme B PET Imaging of Immune Checkpoint Inhibitor Combinations in Colon Cancer Phenotypes.

PURPOSE: Immune checkpoint inhibitor (ICI) monotherapy and combination regimens are being actively pursued as strategies to improve durable response rates in cancer patients. However, the biology surrounding combination therapies is not well understood and may increase the likelihood of immune-mediated adverse events. Accurate stratification of ICI response by non-invasive PET imaging may help ensure safe therapy management across a wide number of cancer phenotypes. PROCEDURES: We have assessed the ability of a fluorine-labelled peptide, [18F]AlF-mNOTA-GZP, targeting granzyme B, to stratify ICI response in two syngeneic models of colon cancer, CT26 and MC38. In vivo tumour uptake of [18F]AlF-mNOTA-GZP following ICI monotherapy, or in combination with PD-1 was characterised and correlated with changes in tumour-associated immune cell populations. RESULTS: [18F]AlF-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells; however, overall uptake and response to monotherapy or combination therapies was very different in the CT26 and MC38 tumours, likely due to the immunostimulatory environment imbued by the MSI-high phenotype in MC38 tumours. CONCLUSIONS: [18F]AlF-mNOTA-GZP uptake correlates well with changes in CD8+ T cell populations and is able to stratify tumour response to a range of ICIs administered as monotherapies or in combination. However, tracer uptake can be significantly affected by preexisting phenotypic abnormalities potentially confusing data interpretation.

Gamma oscillatory activity in vitro: a model system to assess pathophysiological mechanisms of comorbidity between autism and epilepsy.

Autism spectrum disorder (ASD) and temporal lobe epilepsy exhibit remarkable comorbidity, but for reasons not clearly understood. To reveal a common pathophysiological mechanism, we here describe and characterize an in vitro epileptiform activity in the rat hippocampus that exhibits common features with in vivo activity in rodent ASD models. We discovered the development of this activity in the CA1 region of horizontal slices after prolonged interictal-like epileptiform activity in the CA3 region that was provoked by incubation in high potassium artificial cerebrospinal fluid. The CA1 epileptiform bursts were insensitive to blockers of glutamatergic transmission, and were carried by synaptic as well as extrasynaptic, tonically activated gamma-aminobutyric acid type A (GABA(A)) receptors. The bursts bear resemblance to in vivo gamma-oscillatory activity found in rat ASD models with respect to their gamma frequency spectrum, their origin (in the CA1), and their sensitivity to blockers of cation-chloride pumps (NKCC1 and KCC2), as well as to oxytocin. Considering this bursting activity as an in vitro model for studying comorbidity between epilepsy and ASD may help to disentangle the intricate interactions that underlie the comorbidity between both diseases and suggests that extrasynaptic tonic GABAergic transmission could represent a potential target for ASD.

Sequenced neurocognitive and behavioral parent training for the treatment of ADHD in school-age children.

The present study examines the potential of sequencing a neurocognitive intervention with behavioral parent training (BPT) to improve executive functions (EFs), psychiatric symptoms, and multiple indices of functional impairment in school-age children aged 7 to 11 years who have been diagnosed with attention-deficit/hyperactivity disorder (ADHD). Specifically, in a randomized controlled trial design, 85 children were assigned to either Cogmed Working Memory Training (CWMT) followed by an empirically supported, manualized BPT intervention, or to a placebo version of CWMT followed by the same BPT intervention. Working memory maintenance (i.e., attention control/short-term memory), working memory processing and manipulation, ADHD and oppositional defiant disorder (ODD) symptoms, impairment in parent-child dynamics, familial impairment, and overall functional compromise were evaluated as outcomes. The results suggest specific effects of the combined CWMT and BPT program on verbal and nonverbal working memory storage and nonverbal working memory processing and manipulation but no incremental benefits in regard to ADHD symptoms, ODD symptoms, and functional outcomes. The present findings do not support the hypothesis regarding the complementary and augmentative benefits of sequenced neurocognitive and BPT interventions for the treatment of ADHD. These results, the study's limitations, and future directions for research are further discussed.

Severe and treatment resistant strongyloidiasis--indicator of HTLV-I infection.

The association between severe and persistent strongyloidiasis with human T cell lymphotropic virus type I (HTLV-1) infection is well documented in reports from HTLV-1 endemic regions like Japan and Jamaica. But there are no reports from non-endemic areas like India. We report a case of severe intestinal strongyloidiasis in a 45-year old Keralite man, living in Sikkim. Despite standard treatment with many courses of albendazole, his stool persistently showed Strongyloides stercoralis larvae. In the absence of other immunosuppressive conditions, human T cell lymphotropic virus type I infection was considered and determined positive. Subsequently, treatment with 2 courses of ivermectin achieved eradication of the infection. On follow-up, 3 years later, his stools again revealed Strongyloides stercoralis larvae.

Solitary fibrous tumor of the lateral ventricle: CT appearances and pathologic correlation with follow-up.

Intracranial solitary fibrous tumors are rare, and intraventricular fibrous tumors are even more unusual. We report a case of solitary fibrous tumor in the region of trigone and body of the left lateral ventricle and discuss the clinical presentation, CT characteristics, and histopathologic features with 1-year follow-up. We speculate that the tumor arose from the perivascular connective tissue of the choroid plexus.

To assess the ability of MRI to predict consistency of pituitary macroadenomas.

We prospectively studied the ability of magnetic resonance imaging (MRI) to predict the consistency of pituitary adenomas. The hypothesis was that firm, fibrous tumours would appear homogeneously hypointense on T2-weighted images. Eighty patients who underwent surgery for pituitary macroadenomas were studied. MR images were evaluated preoperatively by the radiologist. The tumour consistency was reported by the surgeon as soft or firm. There were 68 soft tumours and 12 firm tumours. Of the firm tumours, four (33%) were homogeneously isointense, one (8%) homogeneously hyperintense and seven (59%) were heterogeneous in appearance in T2-weighted images. We conclude that the consistency of pituitary macroadenomas cannot be accurately predicted based on MRI signal intensities.

A rare case of heterotaxy and left ventricular non-compaction in an adult.

Heterotaxy syndrome with left ventricular non-compaction is a rare co-existence of abnormalities with unknown cause. It can be isolated with no other associations, or associated with congenital heart diseases, or it can occur with multiple other congenital abnormalities. We describe the third reported case of heterotaxy syndrome with left ventricular non-compaction presenting in an adult.

Mini posterior lumbar interbody fusion with presacral screw stabilization in early lumbosacral instability.

BACKGROUND: Surgical options for the management of early lumbosacral spondylolisthesis and degenerative disc disease with instability vary from open lumbar interbody fusion with transpedicular fixation to a variety of minimal access fusion and fixation procedures. We have used a combination of micro discectomy and axial lumbosacral interbody fusion with presacral screw fixation to treat symptomatic patients with lumbosacral spondylolisthesis or lumbosacral degenerative disc disease, which needed surgical stabilization. This study describes the above technique along with analysis of results. MATERIALS AND METHODS: Twelve patients with symptomatic lumbosacral (L5-S1) instability and degenerative lumbosacral disc disease were treated by micro discectomy and interbody fusion using presacral screw stabilization. Patients with history of bowel, bladder dysfunction and local anorectal diseases were excluded from this study. Postoperatively all patients were evaluated neurologically and radiologically for screw position, fusion and stability. Oswestry disability index was used to evaluate results. RESULTS: We had nine females and three males with a mean age of 47.33 years (range 26-68 years). Postoperative assessment revealed three patients to have screw placed in anterior 1/4(th) of the 1(st) sacral body, in rest nine the screws were placed in the posterior 3/4(th) of sacral body. At 2 years followup, eight patients (67%) showed evidence of bridging trabeculae at bone graft site and none of the patients showed evidence of instability or implant failure. CONCLUSION: Presacral screw fixation along with micro discectomy is an effective procedure to manage early symptomatic lumbosacral spondylolisthesis and degenerative disc disease with instability.

Absorption of nutrient energy in southern Indian control subjects and patients with tropical sprue.

Fecal energy excretion was measured by bomb calorimetry, in a group of 30 healthy volunteers and 15 patients with tropical sprue, to determine the absorption of nutrient energy. The mean energy absorption in the healthy volunteers (91.6%) was less than in similar subjects in temperate climates. The reduction of energy absorption in the volunteers, who all have tropical enteropathy, suggests that this condition leads to wastage of 5% of energy intake. In patients with tropical sprue the energy absorption was significantly lower. A strict metabolic balance study was not essential to detect energy malabsorbers.

Leiomyoma of terminal ileum producing a false-positive Meckel's scan.

A case of positive Meckel's diverticulum scan caused by a leiomyoma of the terminal ileum is reported. The early appearance of activity on the perfusion study aided in recognition of a false-positive scan.

Myocardial imaging with Cc-99m pyrophosphate in patients on adriamycin treatment for neoplasia.

Technetium-99m pyrophosphate was utilized for myocardial imaging in 15 patients on adriamycin treatment for neoplasia. We have noted abnormal accumulation of the pyrophosphate in several patients, particularly in those in whom the so-called poor-risk factors were operative, namely prior radiation, cyclophosphamide therapy, and ischemic heart disease.

The predictive value of myocardial radioisotope scanning in animals treated with doxorubicin.

Thirty-four New Zealand white rabbits were treated with doxorubicin and imaged weekly with Tc-99m pyrophosphate to define the value of abnormal myocardial images in predicting doxorubicin-induced cardiac toxicity. Increased myocardial uptake was detected in most animals on sustained treatment with doxorubicin. A greater proportion of the heart was involved with doxorubicin-related histologic changes in animals with strongly positive myocardial images than in treated animals with moderately positive or normal scans. The myocardial images returned to normal levels 2--6 wk after doxorubicin was discontinued. Five of seven rabbits that received doxorubicin after they had three moderately positive myocardial scans, died from congestive heart failure. Three rabbits whose doxorubicin was discontinued because of scan findings, survived for 6 wk or more before dying from renal failure. The three rabbits who received the highest total dose of doxorubicin died of renal failure without developing abnormal myocardial scans.

Incidence and methods of diagnosis of musculoskeletal injuries incurred in Operations Desert Shield and Desert Storm.

RATIONALE AND OBJECTIVES: The authors studied the incidence and distribution of orthopedic injuries sustained in Operation Desert Shield and Desert Storm by evaluating whether existing diagnostic imaging modalities were sufficient to diagnose the types of musculoskeletal injuries incurred. The authors also sought to determine if a dedicated extremity MR scanner would provide monetary benefits and enhance military readiness. METHODS: The authors retrospectively reviewed data on all musculoskeletal injuries incurred in Desert Shield/Desert Storm to determine the total number of injuries, proportion of orthopedic injuries, number of soft-tissue orthopedic injuries, and the country where the diagnosis was established. The authors also determined the number of patients, duration, and economic impact of the evacuation process. RESULTS: There were 1011 fractures and 1177 soft-tissue injuries; 408 soft-tissue injuries were diagnosed in the Persian Gulf countries, and 769 diagnosed in the United States and Germany. The average time to evacuate these 769 patients was 21 days with an estimated replacement cost of $836,885. CONCLUSIONS: Musculoskeletal soft-tissue injuries comprised 34% of the overall injuries in the Persian Gulf War, and twice as many patients required evacuation for diagnosis as were diagnosed locally using existing imaging modalities. A dedicated extremity magnetic resonance scanner in the battlefield would obviate many evacuations and hence be of both monetary and military readiness benefit.