Maturation of executive function in autism.

BACKGROUND: Executive dysfunction has been reported at different ages in autism. It is not clear however, when this impairment emerges or how its expression is affected by development. METHODS: 61 non-mentally retarded autism participants (AUT) and 61 age, gender, and IQ matched typically developing participants (CON) were assessed with two oculomotor executive function tasks, the oculomotor delayed response task (ODR) and the antisaccade task (AS), as well as a visually-guided saccade sensorimotor task (VGS). RESULTS: The AUT group demonstrated impairments in response inhibition and spatial working memory at all ages tested. Developmental improvements in speed of sensorimotor processing and voluntary response inhibition were similar in both groups indicating sparing of some attentional control of behavior. Developmental progression in the speed of initiating a cognitive plan and maintaining information on line over time, however, was impaired in the AUT group indicating abnormal development of working memory. CONCLUSIONS: These results indicate that while executive dysfunction is present throughout development, there is evidence for both typical and atypical developmental progression of executive functions in autism. The plasticity suggested by the developmental improvements may have implications regarding appropriate developmental epochs and types of interventions aimed at enhancing cognitive capacities in individuals with autism.     

Multimodal Management of Mechanical Neck Pain Using a Treatment Based Classification System

The purpose of this case study was twofold: 1) to illustrate the use of a treatment-based classification (TBC) system to direct the early intervention of a patient with mechanical neck pain, and 2) to show the progression of this patient with multimodal-modal intervention. The patient exhibited axial neck pain with referral into her upper extremity. Her pain peripheralized with cervical range of motion and centralized with joint mobilization placing her primarily in the centralization category. Her poor posture and associated muscle weakness along with the chronicity of symptoms placed her secondarily into the exercise and conditioning group resulting in a multi-modal treatment as the patient progressed. Although the design of this case report prevents wide applicability, this study does illustrate the effective use of the TBC system for the cervical spine as captured by accepted outcomes measures.KEYWORDS: Multi-Modal Intervention, Neck Pain, Treatment-Based ClassificationMechanical neck pain commonly arises insidiously¹ and is generally multifactorial in origin, including one or more of the following: poor posture, anxiety, depression, neck strain, and sporting or occupational activities^2,3. In an estimated 50–80% of cases involving back or neck pain, an underlying pathology cannot be definitively determined⁴. Regardless of the primary source of pain, the prognosis for individuals experiencing chronic neck pain is poor, as many patients continue to suffer from persistent pain and disability following conservative physical therapy intervention^5,6. Chronic neck pain appears to be more persistent than low back pain⁷, and it is second only to lumbar pain as the causal factor for time missed from work.Despite the prevalence, less-than optimal prognosis, associated risk of disability, and economic consequences of individuals suffering from mechanical neck pain, there remains a significant gap in the literature, which fails to provide sufficient, high-quality evidence to effectively guide the conservative treatment of this patient population⁸. This lack of quality evidence largely stems from the poorly understood clinical course of neck pain in conjunction with the inconclusive results related to the efficacy of commonly used interventions^2,9,10. Left with poorer quality trials as a guide, Physical Therapists approach the management of this pathology with a plethora of interventions such as manual therapy (MT), therapeutic exercises, manual/mechanical traction, modalities, massage, and functional training^5,10–12.One reason the outcomes in the PT literature may be less than impressive is that many of the studies looking at conservative treatments for the management of neck pain use a heterogeneous subject population¹³. Many studies also combine some or all of the following clinical manifestations into the same case mix during clinical trials: acute whiplash, subacute and chronic mechanical disorders, and chronic cervical headache. The identification of a homogeneous patient population would likely enhance the potential to initiate targeted interventions and to specifically assess treatment responses¹⁴. One solution to acquiring more homogeneous patient populations is the use of treatment-based classification (TBC) systems.Classification systems are developed with the intent of both directing treatment and improving clinical outcomes by identifying detailed combinations of treatments that specifically benefit a subgroup of patients presenting with certain characteristics^5,15. The principle supporting classification systems centers around the following notion: a decrease in uncertainty concerning appropriate, effective treatments could be observed via the linkage of an impairment diagnosis to a treatment choice¹⁶. Classification systems can also serve to improve clinical research by identifying evidence-based practice patterns for specified subgroups of patients⁵. The goal of this model is to heighten decision-making abilities of clinicians in relation to intervention strategy and prognosis¹⁶.While the classification-based strategy has been shown to yield optimal outcomes for the lumbar spine^17–20, comparatively nominal research has been performed to investigate patient outcomes using a similar classification-based approach for the cervical spine^5,16. Despite this preliminary work, research has not served to confirm the validity of such a system⁵. One recent study reported a 98% between-raters percentage agreement with the use of a proposed treatment-based classification (TBC) system (Figure ​(Figure11)⁵. This indicates that the algorithm could be applied consistently by different examiners who are considering the same patient data. With intent to assist in the validation of the outcomes using the aforementioned strategy, the purpose of this case study is to describe the use of a TBC system approach in the management of a single patient with mechanical neck pain and referred pain into the arm.Open in a separate windowFIGURE 1Proposed classification decision-making algorithm.⁵ MVA= motor vehicle accident, NDI = Neck Disability Index. Used with permission.     

A pragmatic neurological screen for patients with suspected cord compressive myelopathy

Physical therapists commonly use screening tests to identify upper motoneuron lesions such as cord compressive myelopathy (CCM), the presence of which necessitates appropriate medical referral. Signs and symptoms of CCM include sensory and ataxic changes of the lower extremities, poorly coordinated gait, weakness, tetraspasticity, clumsiness, spasticity, hyperreflexia, and primitive reflexes. Clinical tests and measures such as Hoffmann sign, clonus, Lhermitte sign, the grip and release test, the finger escape sign, the Babinski test, and the inverted supinator sign have historically been used as screens for CCM. For effectiveness as a screen, a clinical test or measure should demonstrate high sensitivity. Diagnostic accuracy studies have shown that clinical tests and measures for CCM often display low sensitivity, indicating that a negative finding may falsely suggest the absence of a condition or disease that actually is present. To counter the low levels of sensitivity, screening should include a combination of a thorough patient history, recognition of and appropriate referral for cauda equina symptoms, and clusters of any pertinent contributory tests and measures.     

Vessel co‐option is common in human lung metastases and mediates resistance to anti‐angiogenic therapy in preclinical lung metastasis models

Anti‐angiogenic therapies have shown limited efficacy in the clinical management of metastatic disease, including lung metastases. Moreover, the mechanisms via which tumours resist anti‐angiogenic therapies are poorly understood. Importantly, rather than utilizing angiogenesis, some metastases may instead incorporate pre‐existing vessels from surrounding tissue (vessel co‐option). As anti‐angiogenic therapies were designed to target only new blood vessel growth, vessel co‐option has been proposed as a mechanism that could drive resistance to anti‐angiogenic therapy. However, vessel co‐option has not been extensively studied in lung metastases, and its potential to mediate resistance to anti‐angiogenic therapy in lung metastases is not established. Here, we examined the mechanism of tumour vascularization in 164 human lung metastasis specimens (composed of breast, colorectal and renal cancer lung metastasis cases). We identified four distinct histopathological growth patterns (HGPs) of lung metastasis (alveolar, interstitial, perivascular cuffing, and pushing), each of which vascularized via a different mechanism. In the alveolar HGP, cancer cells invaded the alveolar air spaces, facilitating the co‐option of alveolar capillaries. In the interstitial HGP, cancer cells invaded the alveolar walls to co‐opt alveolar capillaries. In the perivascular cuffing HGP, cancer cells grew by co‐opting larger vessels of the lung. Only in the pushing HGP did the tumours vascularize by angiogenesis. Importantly, vessel co‐option occurred with high frequency, being present in >80% of the cases examined. Moreover, we provide evidence that vessel co‐option mediates resistance to the anti‐angiogenic drug sunitinib in preclinical lung metastasis models. Assuming that our interpretation of the data is correct, we conclude that vessel co‐option in lung metastases occurs through at least three distinct mechanisms, that vessel co‐option occurs frequently in lung metastases, and that vessel co‐option could mediate resistance to anti‐angiogenic therapy in lung metastases. Novel therapies designed to target both angiogenesis and vessel co‐option are therefore warranted. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

A Two-Stage Methodology Using K-NN and False-Positive Minimizing ELM for Nominal Data Classification

This paper focuses on the problem of making decisions in the context of nominal data under specific constraints. The underlying goal driving the methodology proposed here is to build a decision-making model capable of classifying as many samples as possible while avoiding false positives at all costs, all within the smallest possible computational time. Under such constraints, one of the best type of model is the cognitive-inspired extreme learning machine (ELM), for the final decision process. A two-stage decision methodology using two types of classifiers, a distance-based one, K-NN, and the cognitive-based one, ELM, provides a fast means of obtaining a classification decision on a sample, keeping false positives as low as possible while classifying as many samples as possible (high coverage). The methodology only has two parameters, which, respectively, set the precision of the distance approximation and the final trade-off between false-positive rate and coverage. Experimental results using a specific dataset provided by F-Secure Corporation show that this methodology provides a rapid decision on new samples, with a direct control over the false positives and thus on the decision capabilities of the model.     

The natural history of the double pylorus

A study of 11 patients with "double pylorus" revealed that a second channel between the gastric antrum and the duodenal bulb is the result of ulcer penetration. The fistula can be a sign of spontaneous recovery from ulcerative disease; the fistula occurred in conjunction with clinical improvement in the majority of the patients. The advantages of radiological vs. endoscopic diagnostic procedures are discussed.     

Onset of symptom relief with rabeprazole: a community-based, open-label assessment of patients with erosive oesophagitis

BACKGROUND: In numerous clinical trials, proton pump inhibitors have demonstrated potent acid suppression and healing of erosive oesophagitis, as well as successful symptom relief for the entire spectrum of gastro-oesophageal reflux disease. AIM: The 'Future of Acid Suppression Therapy' (FAST) trial evaluated, in actual clinical practice, the timing of symptom relief, changes in symptom severity, health-related quality of life and safety in endoscopically confirmed erosive gastro-oesophageal reflux disease treated with rabeprazole. METHODS: This open-label, multicentre study enrolled 2579 patients to receive rabeprazole treatment using 20 mg once daily for 8 weeks. Between two clinical visits (at enrollment and week 8), patients used an interactive voice response system to rate gastro-oesophageal reflux disease symptoms. Subgroup analyses of efficacy were conducted for gender, age, Hetzel-Dent grade, presence of Barrett's oesophagus and for patients reporting previously ineffective symptom relief with omeprazole or lansoprazole. RESULTS: On day 1, rabeprazole significantly decreased daytime and night-time heartburn severity, regurgitation and belching. Complete relief of daytime and night-time heartburn was achieved in 64.0% and 69.2% of symptomatic patients, respectively, on day 1, and in 81.1% and 85.7% of patients, respectively, on day 7. Patients with moderate or severe heartburn symptoms at baseline achieved an even greater degree of satisfactory symptom relief (none or mild) from day 1 onwards. The median time to satisfactory heartburn relief was 2 days. Subgroup analyses showed no consistent differences in efficacy compared to the overall population treated. Health-related quality of life in patients was significantly lower than that of the US general population and improved significantly after 8 weeks of rabeprazole therapy. Rabeprazole was well tolerated, with headache as the most common adverse event, reported by less than 2% of the study population. CONCLUSIONS: In this large, open-label trial, rabeprazole rapidly and effectively relieved gastro-oesophageal reflux disease symptoms in most patients with erosive oesophagitis. Substantial symptom relief was noted on day 1; improvement continued over the first week and at week 4. By week 8, the health-related quality of life had also improved vs. baseline.     

Elevated plasma nociceptin level in patients with Wilson disease

Plasma level of nociceptin, the endogenous agonist of orphanin FQ/ORL1 receptor was found to be significantly elevated in Wilson disease patients (13.98+/-2.44pg/ml, p<0.001, n=20) compared to age-matched healthy controls (9.18+/-1.63pg/ml, n=25). Wilson disease is an autosomal recessive disorder of copper metabolism caused by mutation of the gene ATP7B leading to toxic copper accumulation in the liver and other organs such as brain, kidney and cornea. Measurements were performed by 125I-radioimmunoassay. Neither sex differences nor correlation between plasma nociceptin levels and liver function test results were found. It is suggested that elevated plasma nociceptin level found in Wilson disease patients is due to inhibition of nociceptin-inactivating Zn-metallopeptidases (aminopeptidase N (APN) and endopeptidase 24.15) by the toxic copper deposits in liver and/or brain.     

Histaminergic neurons in the central and peripheral nervous system of gastropods (Helix, Lymnaea): an immunocytochemical, biochemical, and electrophysiological approach

Distribution, chemical-neuroanatomy, concentration, and uptake-release properties of histamine (HA)-containing neurons and the possible physiological effects of HA in the central and peripheral nervous system of the pulmonate snails, Helix pomatia and Lymnaea stagnalis, are described. In the CNS of both species, the distribution pattern of HA-immunoreactive (HA-IR) neurons was similar. In both species the majority were located in the buccal, cerebral, and pedal ganglia. In Helix, approximately 400 HA-IR neurons were seen, whereas in Lymnaea approximately 130 labeled cells were visualized. The neuropils, connectives, commissures, several peripheral nerves, and a part of the peripheral tissues (lip and foot of both species and the upper tentacles of Helix) were innervated by HA-IR elements. Numerous sensory cells were found in the tentacles, lip, and statocysts. The HA concentration values assayed by HPLC ranged from 4.8 to 47.4 pmol/mg in the different central ganglia of Helix, and from 4.3 to 18.6 pmol/mg in Lymnaea CNS, whereas the peripheral tissues contained 0.33-1 pmol/mg HA in Helix and 0.26-0.46 pmol/mg in Lymnaea. In the Lymnaea CNS, a high-affinity (37.6 microM), single component 3H-HA uptake system was demonstrated. 3H-HA release evoked by either electrical stimulation or 100 mM K+ could be prevented in Ca2+-free physiological solution. Voltage-clamp experiments indicated specific changes caused by HA in the membrane conductance of identified central neurons of Helix and Lymnaea. Exogenously applied 10(-5) M HA resulted in the acceleration of locomotion (gliding by foot cilia) of Lymnaea. The findings suggest an important signaling role of HA, described here for the first time, in the nervous system of higher-order, pulmonate, gastropods, involving efferent, integrative, and sensory functions. The data can also be applied as a background for further specification of HA in the regulation of different behaviors in these species.