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.     

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.     

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.     

Comparing how significantly the pharmacological treatment of genitourinary cancer in a non-curative setting affects endpoints of survival or response

Prevalence of advanced genitourinary cancer is high considering approximately 70,000 patients die annually of prostate, bladder and kidney cancer in the United States. Treatment is non-curative but along with the aim of relieving symptoms and improving quality of life, patients and doctors are driven by the goal of prolonging life. In modern urological practice, with the ever increasing number of novel therapies, clinical benefit to patients has to be measured by evaluating the trial endpoints of response and survival against adverse events. This is especially true as the population with advanced cancer is increasingly older and co-morbid. Currently, we are in a time of exponential drug development, innumerable registered trials and a vast amount of expenditure on pharmacological cancer treatment. In this era of financial uncertainty, it is even more important for clinicians to objectively assess the benefit of these expensive, moderately effective treatments that still have associated adverse sequelae. We aim to highlight the pivotal data available and put into context the survival benefit we can currently achieve with the pharmacological treatment of advanced genitourinary cancer, allowing us to critically judge whether a potentially toxic systemic treatment is worthwhile or whether it is better to defer to best supportive care. The figures presented are from the key publications that form the basis of international guideline recommendations and are the standard that newly developed treatments must emulate.     

A Cross-Cultural Study of Disordered Eating Attitudes Among Filipino and Caucasian Americans

The present study examines the symptom levels of eating disorders among Filipino and Caucasian college students residing in Hawaii. The study also examines what variables are associated with disordered eating. A self-report questionnaire that included measures of anger discomfort, self-dissatisfaction, body dissatisfaction, and symptoms of eating disorders was administered to Filipino and Caucasian college students. As predicted, females reported higher eating disorder symptom scores than males. However, Filipino males reported higher levels of disordered eating, dieting, and body dissatisfaction than Caucasian males. No association was found between disordered eating and anger discomfort among Filipinos. The results support previous findings of females reporting higher disordered eating attitudes than males, however, Filipino males reported higher disordered attitudes than Caucasian males. Anger discomfort was not associated with disordered eating among Filipinos, supporting past studies that suggest anger management may not be an appropriate treatment for disordered eating among some Asian groups.