Combined Spinal-Epidural for Loop Ileostomy in a Patient With End-Stage Amyotrophic Lateral Sclerosis: A Case Report.

Anesthesia can be a challenge for patients with amyotrophic lateral sclerosis (ALS). This progressive neurological disease is associated with a high risk of aspiration and postoperative ventilatory failure. Our patient was a 72-year-old man with ALS, quadriplegia, bulbar symptoms, dysphagia, and dysarthria who underwent palliative exploratory laparotomy and loop ileostomy creation. He received a single-shot spinal anesthetic at L4-L5 and a thoracic T11-12 epidural. He tolerated the procedure well with no perioperative pulmonary complications or worsening of his ALS. To reduce the risks of general anesthesia, we chose a neuraxial approach.

The history of spin ice.

This review is a study of how the idea of spin ice has evolved over the years, with a focus on the scientific questions that have come to define the subject. Since our initial discovery of spin ice in 1997, there have been well over five thousand papers that discuss it, and in the face of such detail, it must be difficult for the curious observer to 'see the wood for the trees'. To help in this task, we go in search of the biggest insight to have emerged from the study of spin ice. On the way, we identify highlights and outstanding puzzles, and celebrate the inspirational role that Roger Cowley played in the early years.

Clinical predictors of postoperative delirium, functional status, and mortality in geriatric patients undergoing non-elective surgery for hip fracture.

STUDY OBJECTIVE: To identify modifiable preoperative factors that might influence the morbidity and mortality associated with non-elective, inpatient hip fracture surgeries in the geriatric surgical population. DESIGN: Retrospective database analysis from the American College of Surgeons National Surgical Quality Improvement Program Geriatric Surgery Pilot Project. SETTING: Inpatient, perioperative. PATIENTS: Geriatric patients undergoing surgery. INTERVENTIONS: Non-elective hip repair surgery. MEASUREMENTS: Preoperative demographic, medical, surgical, and anesthetic variables; post-operative rates of delirium, decline in functional status, and 30-day mortality. MAIN RESULTS: The 1261 patients in this study were predominantly female (74%), white (89%), and non-Hispanic (92%). Ages were distributed across groups from 65 to over 90 years. Most patients were categorized as American Society of Anesthesiologists Physical Status class 3 (64%). General anesthesia (57%) was the most common anesthetic, followed by spinal (38%). Preoperative functional status was recorded in 79% as independent in activities of daily living (ADLs). About one third of patients had baseline dementia. Post-operatively, 42% experienced delirium, and most patients required partial or total assistance with ADLs (72% and 12%, respectively). Reoperation was required in 2.8% of cases. Mortality at 30 days was 5.0%. In the multivariable analysis, risk factors associated with post-operative delirium included dementia and lack of competency to sign consent. In the analysis for postoperative decline in functional status, the major risk factor was a history of falls, while emergently performed surgery was protective. The analysis for mortality at thirty days was under-powered. CONCLUSIONS: Hip fractures remain a major source of morbidity in geriatric patients. Baseline dementia and inability to sign surgical consent are significant risk factors for adverse outcomes after hip fractures and should be considered in the informed consent process. Data from this study and currently ongoing randomized trials will help guide reductions in morbidity and mortality in this population.

Investigating Capnography Innovation for Better Patient Monitoring in the Resource Limited Surgical Setting.

BACKGROUND: Access to basic anesthetic monitoring in the developing world is lacking, which contributes to the 100 times greater anesthesia-related mortality in low- and middle-income countries. We hypothesize that an environmental sensor with a lower sampling rate could provide some clinical utility by providing CO2 levels, respiratory rate, and support in detection of clinical abnormalities. MATERIALS AND METHODS: A bench-top lung simulation was created to replicate CO2 waveforms, and an environmental sensor was compared with industry-available technology. Sensor response time and respiratory rates were compared between devices. Additionally, an in silico model was created to replicate capnography pathology as waveforms would appear using the environmental sensor. RESULTS AND CONCLUSION: Breath simulations using the bench-top lung simulation produced similar results to industry standards with a degree of variability. Respiratory rates did not differ between the environmental sensor and all other devices tested. Finally, pathological waveforms created in silico carried a certain level of detail regarding ventilatory pathology, which could provide some clinical insight to an anesthesiologist. We believe our prototype is the first step toward making low-cost and portable capnography available in the resource-limited setting, and future efforts should focus on bridging the gap to safer anesthesia and surgery globally.

Is there concordance in attitudes and beliefs between parents and scientists about autism spectrum disorder?

There is no reported investigation comparing concordance in attitudes and beliefs about autism spectrum disorder between parents of children with autism spectrum disorder and scientists who research autism spectrum disorder. To investigate the level of concordance between these groups on causes of autism, priorities of research, perceived stigma, and disclosure of genetic test results, telephone interviews were conducted. Parents (n = 502) were recruited from the Simons Simplex Collection, and research scientists (n = 60) were recruited from investigators funded by the Simons Foundation. Response rates were notable (parents 91%, scientists 80%). Parents and scientists differed significantly regarding beliefs of the likely major cause of autism (p = 0.007) and priorities for further research (p < 0.001). Scientists believed in genetic causes while many parents believed in vaccines as the cause of autism. Parents (37%) were more likely to hesitate vaccinating their child (p < 0.001). In contrast, there was strong concordance regarding extent of perceived stigma (95% vs 92%) and preferences for disclosure of genetic test results, including incidental findings. While scientists believed communication important, paradoxically fewer than half reported it important for scientists to communicate directly with parents. Better communication between parents and scientists should improve mutual understanding and ultimately the health and well-being of children with autism spectrum disorder and their families.

Assessing unmet anaesthesia need in Sierra Leone: a secondary analysis of a cluster-randomized, cross-sectional, countrywide survey.

OBJECTIVES: To determine the unmet anaesthesia need in a low resource region. INTRODUCTION: Surgery and anæsthesia services in low- and middle-income countries (LMICs) are under-equipped, under-staffed, and unable to meet current surgical need. There is little objective measure as to the true extent and nature of unmet need. Without such an understanding it is impossible to formulate solutions. Therefore, we re-examined Surgeons OverSeas (SOSAS) unmet surgical need data to extrapolate unmet anaesthesia need. METHODS: For the untreated surgical conditions identified by SOSAS, we assigned anaesthetic technique required to carry out the procedure. The chosen anaesthetic was based on common practice in the region. Procedures were categorized into minimal anaesthesia, spinal anæsthesia, regional anaesthesia, ketamine/monitored anaesthesia care (MAC), and general endotracheal anæsthesia (GETA). DISCUSSIONS: Ninety-two per cent (687 of 745) of untreated surgical conditions in Sierra Leone would require some form of anaesthesia. Seventeen per cent (125 of 745) would require MAC, 22% (167 of 745) would require spinal anaesthesia, and 53% (395 of 745) would require GETA. CONCLUSION: Analyses such as this can provide guidance as to the rational and efficient production and distribution of personnel, drugs and equipment.

Developmental delays and reduced pup ultrasonic vocalizations but normal sociability in mice lacking the postsynaptic cell adhesion protein neuroligin2.

Mutations in neurexin and neuroligin genes have been associated with neurodevelopmental disabilities including autism. Autism spectrum disorder is diagnosed by aberrant reciprocal social interactions, deficits in social communication, and repetitive, stereotyped patterns of behaviors, along with narrow restricted interests. Mouse models have been successfully used to study physiological and behavioral outcomes of mutations in the trans-synaptic neurexin-neuroligin complex. To further understand the behavioral consequences of Neuroligin2 (NLGN2) mutations, we assessed several behavioral phenotypes relevant to autism in neuroligin2 null (Nlgn2(-/-)), heterozygote (Nlgn2(+/-)), and wildtype (Nlgn2(+/+)) littermate control mice. Reduced breeding efficiency and high reactivity to handling was observed in Nlgn2(-/-) mice, resulting in low numbers of adult mice available for behavioral assessment. Consistent with previous findings, Nlgn2(-/-) mice displayed normal social behaviors, concomitant with reduced exploratory activity, impaired rotarod performance, and delays on several developmental milestones. No spontaneous stereotypies or repetitive behaviors were detected. Acoustic, tactile, and olfactory sensory information processing as well as sensorimotor gating were not affected. Nlgn2(-/-) pups isolated from mother and littermates emitted fewer ultrasonic vocalizations and spent less time calling than Nlgn2(+/+) littermate controls. The present findings add to the growing literature on the role of neurexins and neuroligins in physiology and behavior relevant to neurodevelopmental disorders.

Reduced excitatory neurotransmission and mild autism-relevant phenotypes in adolescent Shank3 null mutant mice.

Mutations in the synaptic scaffolding protein gene SHANK3 are strongly implicated in autism and Phelan-McDermid 22q13 deletion syndrome. The precise location of the mutation within the Shank3 gene is key to its phenotypic outcomes. Here, we report the physiological and behavioral consequences of null and heterozygous mutations in the ankyrin repeat domain in Shank3 mice. Both homozygous and heterozygous mice showed reduced glutamatergic transmission and long-term potentiation in the hippocampus with more severe deficits detected in the homozygous mice. Three independent cohorts were evaluated for magnitude and replicability of behavioral endophenotypes relevant to autism and Phelan-McDermid syndrome. Mild social impairments were detected, primarily in juveniles during reciprocal interactions, while all genotypes displayed normal adult sociability on the three-chambered task. Impaired novel object recognition and rotarod performance were consistent across cohorts of null mutants. Repetitive self-grooming, reduced ultrasonic vocalizations, and deficits in reversal of water maze learning were detected only in some cohorts, emphasizing the importance of replication analyses. These results demonstrate the exquisite specificity of deletions in discrete domains within the Shank3 gene in determining severity of symptoms.

Control of anterodorsal thalamic head direction cells by environmental boundaries: comparison with conflicting distal landmarks.

Experiments were conducted to determine whether environmental boundaries exert preferential control over the tuning of head direction (HD) cells. In each experiment, HD cells were recorded in the rat anterodorsal thalamus while they foraged for randomly scattered food in trapezoid- and rectangle-shaped environments. After an initial recording session, each environment was rotated 90°, and changes in the preferred firing directions of HD cells were monitored. Rats were disoriented before each test session to prevent the use of self-movement cues to maintain orientation from one session to the next. In Experiment 1, we demonstrate that HD cell tuning consistently shifted in register with the trapezoid shaped enclosure, but was more variable in the rectangle shaped environment. In Experiments 2 and 3, we show that the strong control by the trapezoid persists in the presence of one clearly visible distal landmark, but not when three or more distal landmarks, including view of the recording room, are present. Together, the results indicate that distinct environmental boundaries exert strong stimulus control over HD cell orientation. However, this geometric control can be overridden with a sufficient number of salient distal landmarks. These results stand in contrast to the view that information from geometric cues usually takes precedence over information from landmark cues.

Haploinsufficiency of the autism-associated Shank3 gene leads to deficits in synaptic function, social interaction, and social communication.

BACKGROUND: SHANK3 is a protein in the core of the postsynaptic density (PSD) and has a critical role in recruiting many key functional elements to the PSD and to the synapse, including components of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA), metabotropic glutamate (mGlu) and N-methyl-D-aspartic acid (NMDA) glutamate receptors, as well as cytoskeletal elements. Loss of a functional copy of the SHANK3 gene leads to the neurobehavioral manifestations of 22q13 deletion syndrome and/or to autism spectrum disorders. The goal of this study was to examine the effects of haploinsufficiency of full-length Shank3 in mice, focusing on synaptic development, transmission and plasticity, as well as on social behaviors, as a model for understanding SHANK3 haploinsufficiency in humans. METHODS: We used mice with a targeted disruption of Shank3 in which exons coding for the ankyrin repeat domain were deleted and expression of full-length Shank3 was disrupted. We studied synaptic transmission and plasticity by multiple methods, including patch-clamp whole cell recording, two-photon time-lapse imaging and extracellular recordings of field excitatory postsynaptic potentials. We also studied the density of GluR1-immunoreactive puncta in the CA1 stratum radiatum and carried out assessments of social behaviors. RESULTS: In Shank3 heterozygous mice, there was reduced amplitude of miniature excitatory postsynaptic currents from hippocampal CA1 pyramidal neurons and the input-output (I/O) relationship at Schaffer collateral-CA1 synapses in acute hippocampal slices was significantly depressed; both of these findings indicate a reduction in basal neurotransmission. Studies with specific inhibitors demonstrated that the decrease in basal transmission reflected reduced AMPA receptor-mediated transmission. This was further supported by the observation of reduced numbers of GluR1-immunoreactive puncta in the stratum radiatum. Long-term potentiation (LTP), induced either with θ-burst pairing (TBP) or high-frequency stimulation, was impaired in Shank3 heterozygous mice, with no significant change in long-term depression (LTD). In concordance with the LTP results, persistent expansion of spines was observed in control mice after TBP-induced LTP; however, only transient spine expansion was observed in Shank3 heterozygous mice. Male Shank3 heterozygotes displayed less social sniffing and emitted fewer ultrasonic vocalizations during interactions with estrus female mice, as compared to wild-type littermate controls. CONCLUSIONS: We documented specific deficits in synaptic function and plasticity, along with reduced reciprocal social interactions in Shank3 heterozygous mice. Our results are consistent with altered synaptic development and function in Shank3 haploinsufficiency, highlighting the importance of Shank3 in synaptic function and supporting a link between deficits in synapse function and neurodevelopmental disorders. The reduced glutamatergic transmission that we observed in the Shank3 heterozygous mice represents an interesting therapeutic target in Shank3-haploinsufficiency syndromes.

Directional learning, but no spatial mapping by rats performing a navigational task in an inverted orientation.

Previous studies have identified neurons throughout the rat limbic system that fire as a function of the animal's head direction (HD). This HD signal is particularly robust when rats locomote in the horizontal and vertical planes, but is severely attenuated when locomoting upside-down (Calton & Taube, 2005). Given the hypothesis that the HD signal represents an animal's sense of directional heading, we evaluated whether rats could accurately navigate in an inverted (upside-down) orientation. The task required the animals to find an escape hole while locomoting inverted on a circular platform suspended from the ceiling. In Experiment 1, Long-Evans rats were trained to navigate to the escape hole by locomoting from either one or four start points. Interestingly, no animals from the 4-start point group reached criterion, even after 29 days of training. Animals in the 1-start point group reached criterion after about six training sessions. In Experiment 2, probe tests revealed that animals navigating from either 1- or 2-start points utilized distal visual landmarks for accurate orientation. However, subsequent probe tests revealed that their performance was markedly attenuated when navigating to the escape hole from a novel start point. This absence of flexibility while navigating upside-down was confirmed in Experiment 3 where we show that the rats do not learn to reach a place, but instead learn separate trajectories to the target hole(s). Based on these results we argue that inverted navigation primarily involves a simple directional strategy based on visual landmarks.

Removal of RNA impurities by tangential flow filtration in an RNase-free plasmid DNA purification process.

Addition of animal-derived ribonuclease A to degrade RNA impurities is not recommended in the manufacture of pharmaceutical-grade plasmid DNA. Tangential flow filtration (TFF) takes advantage of the significant size difference between RNA and plasmid DNA to remove RNA in the permeate while plasmid remains in the retentate, in an RNase-free plasmid purification process. Operating conditions including transmembrane pressure, membrane pore size, conductivity of the diafiltration buffer, and plasmid load on the membrane were investigated to maximize RNA clearance. Although direct TFF of clarified lysate removed substantial amounts of RNA, the RNA levels left in the retentate were still significant. Calcium chloride is a potent precipitant of high-molecular-weight RNA. The addition of calcium chloride to the clarified lysate combined with the clearance of low-molecular-weight RNA by TFF resulted in complete RNA removal and high plasmid recovery.