Integration of vestibular and gastrointestinal inputs by cerebellar fastigial nucleus neurons: multisensory influences on motion sickness

Previous studies demonstrated that ingestion of the emetic compound copper sulfate (CuSO₄) alters the responses to vestibular stimulation of a large fraction of neurons in brainstem regions that mediate nausea and vomiting, thereby affecting motion sickness susceptibility. Other studies suggested that the processing of vestibular inputs by cerebellar neurons plays a critical role in generating motion sickness and that neurons in the cerebellar fastigial nucleus receive visceral inputs. These findings raised the hypothesis that stimulation of gastrointestinal receptors by a nauseogenic compound affects the processing of labyrinthine signals by fastigial nucleus neurons. We tested this hypothesis in decerebrate cats by determining the effects of intragastric injection of CuSO₄ on the responses of rostral fastigial nucleus to whole-body rotations that activate labyrinthine receptors. Responses to vestibular stimulation of fastigial nucleus neurons were more complex in decerebrate cats than reported previously in conscious felines. In particular, spatiotemporal convergence responses, which reflect the convergence of vestibular inputs with different spatial and temporal properties, were more common in decerebrate than in conscious felines. The firing rate of a small percentage of fastigial nucleus neurons (15 %) was altered over 50 % by the administration of CuSO₄; the firing rate of the majority of these cells decreased. The responses to vestibular stimulation of a majority of these cells were attenuated after the compound was provided. Although these data support our hypothesis, the low fraction of fastigial nucleus neurons whose firing rate and responses to vestibular stimulation were affected by the administration of CuSO₄ casts doubt on the notion that nauseogenic visceral inputs modulate motion sickness susceptibility principally through neural pathways that include the cerebellar fastigial nucleus. Instead, it appears that convergence of gastrointestinal and vestibular inputs occurs mainly in the brainstem.     

Determination of the safety and efficacy of therapeutic neutralization of tumor necrosis factor-α (TNF-α) using AZD9773, an anti-TNF-α immune Fab, in murine CLP sepsis

Objective and design

TNF-α neutralization is associated with increased mortality in mouse cecal ligation puncture (CLP) models. AZD9773 is an ovine polyclonal human TNF-α immune Fab, with pharmacological properties that differ from previously studied anti-TNF-α agents. We explored the safety and efficacy of therapeutically administered AZD9773 in mouse CLP sepsis.

Methods

A moderate/severe-grade CLP model resulting in 20–30 % 5-day survival and a mild-grade CLP model resulting in ~70 % 5-day survival were established in human TNF-α transgene/murine TNF null (Tg1278/?/?) mice.

Treatment

Mice received saline resuscitation and imipenem administration every 12 h (0–72 h post-CLP). AZD9773 (or DigiFab control) was dosed 24, 36, 48 and 60 h post-CLP.

Results

Therapeutic dosing of AZD9773 in moderate/severe-grade CLP resulted in significantly increased survival (>70 %) compared with DigiFab (27 %, P < 0.05). Therapeutic dosing of AZD9773 in mild-grade CLP did not significantly affect survival outcome compared with DigiFab or imipenem alone (~60–70 % survival).

Conclusions

These data demonstrate that TNF-α neutralization can improve survival in moderate/severe CLP sepsis. TNF-α suppression in mild-grade models was not associated with survival benefit and did not increase 5-day mortality. These findings suggest that therapeutic benefit following TNF-α attenuation in models of sepsis may depend on model severity.     

Implementation of the automated Leicester Practice Risk Score in two diabetes prevention trials provides a high yield of people with abnormal glucose tolerance

Aims/hypothesis

The Leicester Practice Risk Score (LPRS) is a tool for identifying those at high risk of either impaired glucose regulation (IGR), defined as impaired glucose tolerance and/or impaired fasting glucose, or type 2 diabetes from routine primary care data. The aim of this study was to determine the yield from the LPRS when applied in two diabetes prevention trials.

Methods

Let’s Prevent Diabetes (LPD) and Walking Away from Diabetes (WAD) studies used the LPRS to identify people at risk of IGR or type 2 diabetes from 54 general practices. The top 10% at risk within each practice were invited for screening using a 75 g OGTT. The response rate to the invitation and the prevalence of IGR and/or type 2 diabetes in each study were calculated.

Results

Of those invited 19.2% (n?=?3,449) in LPD and 22.1% (n?=?833) in WAD attended. Of those screened for LPD 25.5% (95% CI 24.1, 27.0) had IGR and 4.5% (95% CI 3.8, 5.2) had type 2 diabetes, giving a prevalence of any abnormal glucose tolerance of 30.1% (95% CI 28.5, 31.6). Comparable rates were seen for the WAD study: IGR 26.5% (95% CI 23.5, 29.5), type 2 diabetes 3.0% (95% CI 1.8, 4.2) and IGR/type 2 diabetes 29.5% (95% CI 26.4, 32.6).

Conclusions/interpretation

Using the LPRS identifies a high yield of people with abnormal glucose tolerance, significantly higher than those seen in a population screening programme in the same locality. The LPRS is an inexpensive and simple way of targeting screening programmes at those with the highest risk.     

Oldest known dinosaurian nesting site and reproductive biology of the Early Jurassic sauropodomorph Massospondylus

The extensive Early Jurassic continental strata of southern Africa have yielded an exceptional record of dinosaurs that includes scores of partial to complete skeletons of the sauropodomorph Massospondylus, ranging from embryos to large adults. In 1976 an incomplete egg clutch including in ovo embryos of this dinosaur, the oldest known example in the fossil record, was collected from a road-cut talus, but its exact provenance was uncertain. An excavation program at the site started in 2006 has yielded multiple in situ egg clutches, documenting the oldest known dinosaurian nesting site, predating other similar sites by more than 100 million years. The presence of numerous clutches of eggs, some of which contain embryonic remains, in at least four distinct horizons within a small area, provides the earliest known evidence of complex reproductive behavior including site fidelity and colonial nesting in a terrestrial vertebrate. Thus, fossil and sedimentological evidence from this nesting site provides empirical data on reproductive strategies in early dinosaurs. A temporally calibrated optimization of dinosaurian reproductive biology not only demonstrates the primary significance of the Massospondylus nesting site, but also provides additional insights into the initial stages of the evolutionary history of dinosaurs, including evidence that deposition of eggs in a tightly organized single layer in a nest evolved independently from brooding.     

Human induced pluripotent stem cells can reach complete terminal maturation: in vivo and in vitro evidence in the erythropoietic differentiation model

Background

Human induced pluripotent stem cells offer perspectives for cell therapy and research models for diseases. We applied this approach to the normal and pathological erythroid differentiation model by establishing induced pluripotent stem cells from normal and homozygous sickle cell disease donors.

Design and Methods

We addressed the question as to whether these cells can reach complete erythroid terminal maturation notably with a complete switch from fetal to adult hemoglobin. Sickle cell disease induced pluripotent stem cells were differentiated in vitro into red blood cells and characterized for their terminal maturation in terms of hemoglobin content, oxygen transport capacity, deformability, sickling and adherence. Nucleated erythroblast populations generated from normal and pathological induced pluripotent stem cells were then injected into non-obese diabetic severe combined immunodeficiency mice to follow the in vivo hemoglobin maturation.

Results

We observed that in vitro erythroid differentiation results in predominance of fetal hemoglobin which rescues the functionality of red blood cells in the pathological model of sickle cell disease. We observed, in vivo, the switch from fetal to adult hemoglobin after infusion of nucleated erythroid precursors derived from either normal or pathological induced pluripotent stem cells into mice.

Conclusions

These results demonstrate that human induced pluripotent stem cells: i) can achieve complete terminal erythroid maturation, in vitro in terms of nucleus expulsion and in vivo in terms of hemoglobin maturation; and ii) open the way to generation of functionally corrected red blood cells from sickle cell disease induced pluripotent stem cells, without any genetic modification or drug treatment.Key words: human induced pluripotent stem cells, terminal maturation, erythropoietic differentiation     

Preliminary reliability and validity testing of a Self-Efficacy Questionnaire for Chinese Family Caregivers

Objectives: To develop and test preliminary reliability and validity of a Self-Efficacy Questionnaire for Chinese Family Caregivers (SEQCFC).

Methods: A cross-sectional survey of 196 family caregivers (CGs) of people with dementia (CGs) was conducted to determine the factor structure of a SEQCFC of people with dementia. Following factor analyses, preliminary testing was performed, including internal consistency, 4-week test-retest reliability, and construct and convergent validity.

Results: Factor analyses with direct oblimin rotation were performed. Eight items were removed and five subscales (self-efficacy for gathering information about treatment, symptoms and health care; obtaining support; responding to behaviour disturbances; managing household, personal and medical care; and managing distress associated with caregiving) were identified. The Cronbach's alpha coefficients for the whole scale and for each subscale were all over 0.80. The 4-week test-retest reliabilities for the whole scale and for each subscale ranged from 0.64 to 0.85. The convergent validity was acceptable.

Conclusions: Evidence for the preliminary testing of the SEQCFC was encouraging. A future follow-up study using confirmatory factor analysis with a new sample from different recruitment centres in Shanghai will be conducted. Future psychometric property testings of the questionnaire will be required for CGs from other regions of mainland China.     

Development of an Optimally Reliable Short Form for Judgment of Line Orientation

Standard and short forms of Judgment of Line Orientation-Form V (JLO; Benton, Sivan, Hamsher, Varney, & Spreen, 1994) were examined for internal consistency (coefficient alpha) in a diagnostically mixed neuropsychiatric sample (N = 230). Equivalence of internally consistent short forms was assessed by correlating them with the full form of the test. Internal consistency for the full 30-item form of JLO (alpha = .84) approximated the optimal level of .80 (Nunnally, 1978). Two 20-item short forms of JLO (items V1-V20 and items V11-V30) also reached comparable alpha levels (alpha = .75 and .80, respectively). These two JLO short forms correlated .90 and .97, respectively, with the full 30-item form. We recommend the JLO short form based on items V11-V30 for clinical use in situations in which employment of the full form may not be advisable and offer a short-to-long-form conversion table for clinical use.