Communication Deficits and the Motor System: Exploring Patterns of Associations in Autism Spectrum Disorder (ASD).

Many children with autism spectrum disorder (ASD) have notable difficulties in motor, speech and language domains. The connection between motor skills (oral-motor, manual-motor) and speech and language deficits reported in other developmental disorders raises important questions about a potential relationship between motor skills and speech-language deficits in ASD. To this end, we examined data from children with ASD (n = 1781), 2-17 years of age, enrolled in the Autism Speaks-Autism Treatment Network (AS-ATN) registry who completed a multidisciplinary evaluation that included diagnostic, physical, cognitive and behavioral assessments as part of a routine standard of care protocol. After adjusting for age, non-verbal IQ, Attention Deficit Hyperactivity Disorder (ADHD) medication use, and muscle tone, separate multiple linear regression analyses revealed significant positive associations of fine motor skills (FM) with both expressive language (EL) and receptive language (RL) skills in an impaired FM subgroup; in contrast, the impaired gross motor (GM) subgroup showed no association with EL but a significant negative association with RL. Similar analyses between motor skills and interpersonal relationships across the sample found both GM skills and FM skills to be associated with social interactions. These results suggest potential differences in the contributions of fine versus gross motor skills to autistic profiles and may provide another lens with which to view communication differences across the autism spectrum for use in treatment interventions.

C9orf72 is required for proper macrophage and microglial function in mice.

Expansions of a hexanucleotide repeat (GGGGCC) in the noncoding region of the C9orf72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Decreased expression of C9orf72 is seen in expansion carriers, suggesting that loss of function may play a role in disease. We found that two independent mouse lines lacking the C9orf72 ortholog (3110043O21Rik) in all tissues developed normally and aged without motor neuron disease. Instead, C9orf72 null mice developed progressive splenomegaly and lymphadenopathy with accumulation of engorged macrophage-like cells. C9orf72 expression was highest in myeloid cells, and the loss of C9orf72 led to lysosomal accumulation and altered immune responses in macrophages and microglia, with age-related neuroinflammation similar to C9orf72 ALS but not sporadic ALS human patient tissue. Thus, C9orf72 is required for the normal function of myeloid cells, and altered microglial function may contribute to neurodegeneration in C9orf72 expansion carriers.

The Role of Speech and Language Therapy in Assessing and Managing Pharyngo-esophageal Diverticula.

This study explores the contribution of Speech and Language Therapists (SLTs) to the assessment and management of patients presenting on videofluoroscopic swallow studies (VFSS) with a suspected pharyngo-oesophageal diverticulum. Records for all patients who attended for VFSS in an acute hospital over an eleven-year period were examined (N = 1820). Twenty patients were identified on VFSS as having a suspected diverticulum. Symptoms suggestive of a diverticulum were found during both bedside clinical examination and radiographic examination e.g. respiratory difficulties (n = 15; 75%), voice changes (n = 14; 70/0). VFSS confirmed a reduced risk of aspiration for 14 patients (70%) using a combination of fluid modification (n = 9; 45%), food modification (n = 13; 65%) and swallow strategies (n = 14; 70%). VFSS confirmed aspiration directly related to the diverticulum in 11 patients (55%). Findings indicate that SLTs have the opportunity to identify potential diverticula and implement behavioural management to reduce associated health risks. This is of particular importance to patients who are awaiting, or cannot undergo, surgical repair of their diverticulum.

Organ donation following the circulatory determination of death (DCD): an audit of donation and outcomes following renal transplantation.

Organ Donation following the Circulatory determination of Death was introduced in Beaumont Hospital during 2011. The Intensive Care Society of Ireland formally endorsed a national DCD clinical practice guideline in 2012. This retrospective audit covers a 2-year period during which eleven patients were considered suitable for DCD and where consent was obtained. Nine patients died within the ninety-minute period following the withdrawal of life sustaining therapies and subsequently donated organs (82%). Eighteen kidneys were recovered and seventeen patients received renal transplants--one patient received a nephron-dosing dual renal transplant. Lungs were recovered on two occasions and one patient received a lung transplant. Heart valves were recovered on one occasion. To date sixteen of seventeen recipient patients have functioning renal transplants (94%). In conclusion, this model of deceased donation has proven acceptable to families, nursing and medical staff and the outcomes reported are consistent with international best practice.

External fluorescence retention of calcein-marked juvenile brown trout Salmo trutta raised in natural and artificial environments.

The fluorescence retention and intensity of juvenile brown trout Salmo trutta marked during their first summer were monitored in a hatchery and in four natural streams. A handheld detector was used for direct examination. In the hatchery, three marking treatments (T) were compared: 3·5 min in a 0·5% calcein solution (T0·5-3·5), 7 min in a 0·5% calcein solution (T0·5-7) and 3·5 min in a 1% calcein solution (T1-3·5). The fish were raised indoors for 11 months and then outdoors until 18 months. The fluorescence retention rate was 100% in all treatments at 11 months, although T1-3·5 showed the highest mean fluorescence intensity, followed by T0·5-7 and T0·5-3·5. The fluorescence intensity was not correlated with the final total length (L(T)) of the fish in two treatments, although it significantly decreased with increasing L(T) in T1-3·5. At 18 months, <30% of the fish were still slightly fluorescent, suggesting a negative effect of sunlight exposure. In stream studies, the fluorescence intensity did not significantly differ according to final L(T); an overall mean ± s.d. retention rate of 70·7 ± 26·6% was measured at 12 months with a decrease to 48·6 ± 24·6% at 24 months. Significant differences amongst streams and within reaches of the same stream were observed. Because of a significant positive effect of the shading index on the fluorescence intensity, the use of calcein should be restricted to streams unexposed to direct sunlight. Consequently, the marking method would be reliable for 1 year monitoring studies in shaded streams.

Non heart beating organ donation in adults: a clinical practice guideline.

Non heart beating organ donation (NHBD) occurs when a patient donates organs following the determination of death by cardiorespiratory criteria. It is also know as Donation after Cardiac Death (DCD) or Donation after Circulatory Death (DCD). This is distinct from Donation after Brainstem Death (DBD), which until 2011, accounted for all cadaveric organs (organ from deceased persons) donated within the Republic of Ireland. NHBD is an important initiative that has the potential to be life-saving. When compared to international protocols, the NHBD protocol at Beaumont Hospital is both conservative and restrictive. It offers an alternative when conditions of brainstem death (BSD) cannot be satisfied and, since implementation a number of successful transplants have been performed from NHB donors.

An evaluation of the Cortrak Enteral access system in our intensive care.

Appropriate nutrition is considered a cornerstone of Intensive care; however its successful initiation is frequently impeded by decreased gastric emptying secondary to opiates, sepsis, or ileus. The presence of a postpyloric tube will guarantee delivery of calories while reducing the incidence of reflux and aspiration. Enteral nutrition is approximately 100 fold cheaper than parenteral nutrition. A nasojejunal tube may be placed blindly (success 15%), by direct vision with a gastroscope, or under fluoroscopic guidance in the X-ray department. This study examines the use of the Cortrak Enteral access system (CEAS) in placement of nasojejunal tubes, a method facilitated by the use of an electromagnet. A retrospective review was conducted to evaluate the effectiveness of the CEAS for establishing nasojejunal feeding in the Intensive Care Unit (ICU) between January and December 2010. Our results found that the CEAS was successful in positioning a nasojejunal tube in ten out of twelve patients (83% success rate). Successful placement was confirmed by portable abdominal / chest x-ray. Placement took an average of 30 minutes, and prokinetic agents were used to facilitate two placements. The duration of successful enteral nutrition varied from 2 to 15 days post placement. The CEAS is a simple bedside tool for placing postpyloric tubes. While there is a learning curve associated with its use, it may confer significant benefits to individual patients and also to those responsible for ever shrinking budgets.

Extra-corporeal membrane oxygenation in the management of 2009 influenza A (H1N1) refractory respiratory failure.

Rapidly progressive acute respiratory failure attributed to 2009 H1N1 influenza A infection has been reported worldwide-3. Refractory hypoxaemia despite conventional mechanical ventilation and lung protective strategies has resulted in the use a combination of rescue therapies, such as conservative fluid management, prone positioning, inhaled nitric oxide, high frequency oscillatory ventilation and extracorporeal membrane oxygenation (ECMO)4. ECMO allows for pulmonary or cardiopulmonary support as an adjunct to respiratory and cardiac failure, minimising ventilator-associated lung injury (VALI). This permits treatment of the underlying disease process, while concurrently allowing for recovery of the acute lung injury. This case documents a previously healthy twenty-two year old Asian male patient with confirmed pandemic (H 1N1) 2009 influenza A who was successfully managed with ECMO in the setting of severe refractory hypoxaemia and progressive hypercapnia.

Control of delayed-type hypersensitivity by ocular- induced CD8+ regulatory t cells.

The immunoregulatory pathway from the eye to the peri - pheral immune system is comprised of the iris, ciliary body, circulation, thymus and spleen, and is influenced by the sympathetic nervous system. At the splenic end of this pathway are antigen-specific CD8+ regulatory T cells (Tregs) that mediate directly the suppression of T cells that effect delayedtype hypersensitivity (DTH). Here we review investigations that demonstrate: (i) the injection of antigen into the anterior chamber (AC) attracts circulating monocytic cells to the iris/ciliary body that recirculate to the thymus and spleen. In the thymus, ocular-influenced monocytic cells activate natural killer T (NKT) cells that migrate to the spleen where, in concert with the ocular-influenced monocytic emigrants, they (ii) activate CD4+ and CD8+ immunoregulatory T cells. (iii) The generation of the CD8+ Tregs is dependent on NKT cells in the thymus and the periphery that are influenced by the sympathetic nervous system. (iv) The suppression of DTH by the AC-induced CD8+ Tregs is dependent on the cytokines transforming growth factor-Beta and interferon-gamma and is restricted by the expression of major histocompatibility complex-associated Qa-1b antigens. In aggregate, this oculothymic- splenic pathway is a well-controlled response to ocular injury that utilizes a systemic response to antigen that may protect ocular tissue and systemic tissue.

Effects of sequential changes from conventional ventilation to high-frequency oscillatory ventilation at increasing mean airway pressures in an ovine model of combined lung and head injury.

BACKGROUND: The objective of this study was to determine the intracranial, cardiovascular and respiratory changes induced by conversion to high-frequency oscillator ventilation from conventional mechanical ventilation at increasing airway pressures. METHODS: In this study, 11 anaesthetized sheep had invasive cardiovascular and intracranial monitors placed. Lung injury was induced by saline lavage and head injury was induced by inflation of an intracranial balloon catheter. All animals were sequentially converted from conventional mechanical ventilation to high-frequency oscillator ventilation at target mean airway pressures of 16, 22, 28, 34 and 40 cm H(2)O. The mean airway pressure was achieved by adjusting positive end expiratory pressure while on conventional mechanical ventilation, and continuous distending pressures while on high-frequency oscillator ventilation. Cerebral lactate production, oxygen consumption and venous oximetry were measured and analysed in relation to changes in transcranial Doppler flow velocity. Transcranial Doppler profiles together with other physiological parameters were measured at each airway pressure. RESULTS: Cerebral perfusion pressure was significantly lower during high-frequency oscillator ventilation than during conventional mechanical ventilation (CMV: 45, 34, 22, 6, 9 mmHg vs. HFOV: 33, 20, 19, 5, 5 mmHg at airway pressures mentioned above, P = 0.02). Intracranial pressure and cerebrovascular resistance increased with increasing intrathoracic pressures (P = 0.001). Cerebral metabolic indices demonstrated an initial increase in anaerobic metabolism followed by a decrease in cerebral oxygen consumption progressing to cerebral infarction as intrathoracic pressures were further increased in a stepwise fashion. Arterial PaCO(2) increased significantly after converting from conventional mechanical ventilation to high-frequency oscillator ventilation (P = 0.001). However, no difference was observed between conventional mechanical ventilation and high-frequency oscillator ventilation when intracranial pressure, metabolic and transcranial Doppler indices were compared at equivalent mean airway pressures. CONCLUSIONS: The use of high positive end expiratory pressure with conventional mechanical ventilation or high continuous distending pressure with high-frequency oscillator ventilation increased intracranial pressure and adversely affected cerebral metabolic indices in this ovine model. Transcranial Doppler is a useful adjunct to intracranial pressure and intracranial venous saturation monitoring when major changes in ventilation strategy are adopted.

Oncogenic mutations cause dramatic, qualitative changes in the transcriptional activity of c-Myb.

The v-Myb oncoprotein encoded by Avian Myeloblastosis Virus is highly oncogenic, induces leukemias in chickens and mice and transforms immature hematopoietic cells in vitro. The v-Myb protein is a mutated and truncated version of c-Myb, a DNA-binding transcription factor expressed in many cell types that is essential for normal hematopoiesis. Previous studies suggested that two types of differences, DNA binding domain mutations and the deletion of a C-terminal negative regulatory domain were important for increasing the transforming activity of v-Myb. Here, we combined structure-function studies of the v-Myb and c-Myb proteins with unbiased microarray-based transcription assays to compare the transcriptional specificities of the two proteins. In human cells, the v-Myb and c-Myb proteins displayed strikingly different activities and regulated overlapping, but largely distinct sets of target genes. Each type of mutation that distinguished v-Myb from c-Myb, including the N- and C-terminal deletions, DNA binding domain changes and mutations in the transcriptional activation domain, affected different sets of target genes and contributed to the different activities of c-Myb and v-Myb. The results suggest that v-Myb is not just a de-repressed version of c-Myb. Instead, it is a distinct transcriptional regulator with a unique set of activities.

Optimization of equine infectious anemia derived vectors for hematopoietic cell lineage gene transfer.

Gene transfer into hematopoietic cells may allow correction of a variety of hematopoietic and metabolic disorders. Optimized HIV-1 based lentiviral vectors have been developed for improved gene transfer and transgene expression into hematopoietic cells. However, the use of HIV-1 based vectors for human gene therapy may be limited due to ethical and biosafety issues. We report that vectors based on the non-primate equine infectious anemia virus (EIAV) transduce a variety of human hematopoietic cell lines and primary blood cells. To investigate optimization of gene expression in hematopoietic cells, we compared a variety of post-transcriptional elements and promoters in the context of EIAV vectors. We observed cell specific increase in the number of transgene expressing cells with the different post-transcriptional elements, whereas the use of elongation factor alpha 1 (EFalpha1) promoter resulted in significant increases in both the number of transgene expressing cells and the level of transgene protein in all cell types tested. We then demonstrate increased transduction of hematopoietic cells using a second-generation EIAV vector containing a self-inactivating EIAV LTR and the EIAV central polypurine tract (cppt). These data suggest that optimized EIAV vectors may be a suitable alternative to HIV-1 vectors for use in hematopoietic gene therapy.

Autoimmune progesterone dermatitis in a parturient for emergency caesarean section.

A parturient with a 14-year history of autoimmune progesterone dermatitis presented in labour at 36 weeks' gestation. She had suffered recurrent episodes of angioedema over a long period and had been scheduled for elective caesarean hysterectomy and bilateral oophorectomy at 37 weeks' gestation. In most cases surgical oophorectomy provides prolonged relief from the recurrent angioedema and dermatological manifestations that are typical of autoimmune progesterone dermatitis. Spinal anaesthesia was chosen in order to avoid airway manipulation, a factor frequently implicated in the development of angioedema. Delivery was uneventful and the obstetricians proceeded to hysterectomy and oophorectomy. Forty minutes after delivery the patient experienced an attack of angioedema, she was markedly hypotensive and was given fluids, ephedrine and phenylephrine with good effect. As she remained normotensive, she was given intramuscular rather than intravenous epinephrine to provide a slower release. She recovered well and stabilised without the need for intubation or ventilation. This case reinforces the rationale for regional anaesthesia in these patients and demonstrates how intramuscular epinephrine contributed towards a positive outcome.

Gastric B-cell mucosa-associated lymphoid tissue (MALT) lymphoma in an animal model of 'Helicobacter heilmannii' infection.

While Helicobacter pylori is accepted as the dominant human gastric bacterial pathogen, a small percentage of human infections have been associated with another organism, commonly referred to as 'Helicobacter heilmannii', which is more prevalent in a range of animal species. This latter bacterium has been seen in association with the full spectrum of human gastric diseases including gastritis, peptic ulceration, and gastric carcinomas, including gastric B-cell mucosa-associated lymphoid tissue (MALT) lymphoma. This study describes an analysis of the pathogenic potential of a number of 'H heilmannii' isolates in an animal model of gastric MALT lymphoma. BALB/c mice were infected with ten different 'H heilmannii' isolates originating from both human and animal hosts. The animals were examined at various time points for up to 28 months after infection. The infected animals initially developed a chronic inflammatory response within 6 months. This histological response increased in severity with the length of infection, with the development of overt lymphoma in some animals 18 months after infection. MALT lymphomas were detected in up to 25% of the infected animals. The prevalence of lymphoma was dependent on the length of infection and the origin of the infecting isolates. A range of other histological features accompanied the lymphocytic infiltration, including invaginations of the gastric epithelium and associated hyperplastic tissue, mucus metaplasia, and a small number of diffuse large B-cell lymphomas. The ability to manipulate experientially the presence of the bacterium in the animal model will allow further studies examining the role of antigen drive in the development of Helicobacter-associated MALT lymphoma.

Gastritis associated with Helicobacter-like organisms in baboons.

Subclinical gastritis was observed in 10 of 10 baboons (Papio spp.) from a toxicity study in a research facility. The lesions were similar in xenobiotic-treated and control animals, suggesting a spontaneous rather than chemical-induced disease. Histologic examination revealed lymphoplasmacytic gastritis in the antral mucosa. The fundic mucosa contained minor, scattered aggregates of lymphocytes and plasma cells. A Warthin-Starry silver stain and ultrastructural examination revealed numerous spiral-shaped bacteria morphologically resembling Helicobacter pylori in antral glands and numerous spiral-shaped bacteria morphologically consistent with H. heilmannii-like organisms in fundic glands. Polymerase chain reaction assay of paraffin-embedded antral and fundic tissue using primers for the urease gene and 16S ribosomal ribonucleic acid gene amplified deoxyribonucleic acid fragments with a high degree of sequence homology for H. pylori and H. heilmannii. This is the first report of gastritis associated with Helicobacter-like organisms in baboons.

Analysis of gene transfer and expression in skeletal muscle using enhanced EIAV lentivirus vectors.

Skeletal muscle is an attractive target tissue for gene therapy involving both muscle and nonmuscle disorders. HIV-1-based vectors transduce mature skeletal muscle; however, the use of these vectors for human gene therapy may be limited by biosafety concerns. In this study, we investigated gene transfer using lentivirus vectors based on the equine infectious anemia virus (EIAV) in skeletal muscle in vitro and in vivo. EIAV vectors transduce proliferating and differentiating C2C12 mouse muscle cells; furthermore, the addition of the woodchuck hepatitis posttranscriptional element to EIAV vectors markedly increases gene expression in these cells. A single injection of EIAV vectors into skeletal muscle of adult mice led to detectable gene marking and gene expression for the duration of the 3-month study. Use of a second-generation EIAV self-inactivating vector (E-SIN) increased transduction in muscle cells in vitro, and injection of E-SIN vectors into skeletal muscle resulted in increased gene marking and gene expression compared to first-generation EIAV vectors.

Additional evidence that the sympathetic nervous system regulates the vessel wall release of tissue plasminogen activator.

It is established that sympathetic neurons can synthesize, transport and store tissue plasminogen activator (t-PA) within axon terminals in the smooth muscle of vessel walls. Moreover, sympathetic excitations (e.g. physical and mental stress) are known to induce an acute release of t-PA into the circulation. However, relatively little is known about the nature and extent of sympathetic nervous system involvement in the release process. We inquired whether a chemical sympathectomy will alter the release of t-PA into the blood, and the intrinsic release of stored t-PA from isolated whole vessel explants. A long-term sympathectomy was induced in adult Sprague-Dawley rats by injection of guanethidine during a 5-week course. The destruction of ganglion neurons and vessel wall axons was verified immunohistochemically. t-PA release was assayed as the free activity in hind limb plasma and explant culture medium. Following sympathectomy: (i) the basal t-PA activity in plasma was 70% less than controls (2.92 +/- 1.96 versus 9.33 +/- 1.72 IU/ml;

Comparison of gene transfer efficiencies and gene expression levels achieved with equine infectious anemia virus- and human immunodeficiency virus type 1-derived lentivirus vectors.

This report compares gene transfer efficiencies as well as durations and levels of gene expression for human immunodeficiency virus (HIV) and equine infectious anemia virus (EIAV) lentiviral vectors in a variety of human cell types in vitro. EIAV and HIV vectors transduced equivalent numbers of proliferating and G1/S- and G2/M-arrested cells, and both had very low efficiencies of transduction into G0-arrested cells. Analysis of the levels of both the enhanced green fluorescent protein (EGFP) and mRNA demonstrated that the HIV-transduced cells expressed greater levels of EGFP protein and RNA than the EIAV-transduced cells. Measurements of vector-derived EGFP RNA half-lives were fourfold higher with the HIV vector than with the EIAV vector. Long-term culture of EIAV-transduced human cells showed a significant decrease in the number of cells expressing the transgene; however, no corresponding loss was found in EIAV-transduced equine cells. In contrast, only a moderate decrease in the number of transgene-expressing cells was seen with the HIV vectors. Taken together, these results demonstrate that the EIAV vectors transduced human cells with efficiencies similar to those of the HIV vectors. However, our data indicate that transgene expression from EIAV vectors is limited by the instability of vector-derived RNA transcripts and silencing of the EIAV vectors over time.