Classical conditioning of the nictitating membrane response of the rabbit

Summary We report the connections of cerebellar cortical lobule HVI in the rabbit. We have studied the anterograde and retrograde transport of wheatgerm-agglutinated horseradish peroxidase (WGA-HRP) following its injection into HVI to reveal efferent and afferent connections. All of the cases showed strong anterograde transport to the anterior interpositus nucleus (AIP) — indicating that this is the major efferent target of HVI. Retrogradely labelled cells were found in the inferior olivary, spinal trigeminal, lateral reticular, inferior vestibular and pontine nuclei. Within the olive, the medial part of the rostral dorsal accessory olive (DAO) and the adjacent medial part of the principal olive (PO) were consistently labelled in all cases. This area is known to receive somatosensory information from the face and neck. There was no projection to the hemispheral part of lobule VI from visual parts of the olive within the dorsal cap and medial parts of the medial accessory olive. Likely sources of visual and auditory information to HVI are the dorsolateral basilar pontine nuclei and nucleus reticularis tegmenti pontis, which were densely labelled in all cases. These anatomical findings are consistent whith the suggestion that, during NMR conditioning, information related to the periorbital shock unconditional stimulus (US) may be provided by climbing fibres to HVI and light and white noise conditional stimulus (CS) information may be supplied by pontine mossy fibres.     

Symptomatic treatment of respiratory and nutritional failure in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by death of upper and lower motor neurones. Nutritional and respiratory failure occurs in most patients with ALS. Nutritional failure occurs primarily as a result of dysphagia, although malnutrition may also develop in the absence of clinically apparent dysphagia. The optimal management of nutrition in early ALS has not been established. In later stages of the disease, parenteral nutritional support using percutaneous endoscopic gastrostomy confers a significant survival benefit in selected patients. Respiratory failure occurs as a result of bulbar, cervical and thoracic loss of motor neurones. Inspiratory muscles are preferentially affected. Management of respiratory failure includes the use of strategies that limit aspiration pneumonia, the reduction in secretions, and positioning of the patient to a maximal mechanical advantage. Use of non-invasive positive pressure ventilation in appropriate patients significantly enhances survival. The decision to undertake invasive mechanical ventilation should be made prior to the development of symptoms that might warrant this intervention. The progressive nature of the condition should be taken into account when such a decision is discussed with the patient and carer. Further studies are required to determine the optimal nutritional requirements of patients with ALS, and to elucidate the physiological changes involved in the decline in respiratory function. Received: 13 September 1999/Accepted: 1 October 1999     

Upregulation of alveolar epithelial active Na+ transport is dependent on beta2-adrenergic receptor signaling

Alveolar epithelial beta-adrenergic receptor (betaAR) activation accelerates active Na+ transport in lung epithelial cells in vitro and speeds alveolar edema resolution in human lung tissue and normal and injured animal lungs. Whether these receptors are essential for alveolar fluid clearance (AFC) or if other mechanisms are sufficient to regulate active transport is unknown. In this study, we report that mice with no beta1- or beta2-adrenergic receptors (beta1AR-/-/beta2AR-/-) have reduced distal lung Na,K-ATPase function and diminished basal and amiloride-sensitive AFC. Total lung water content in these animals was not different from wild-type controls, suggesting that betaAR signaling may not be required for alveolar fluid homeostasis in uninjured lungs. Comparison of isoproterenol-sensitive AFC in mice with beta1- but not beta2-adrenergic receptors to beta1AR-/-/beta2AR-/- mice indicates that the beta2AR mediates the bulk of beta-adrenergic-sensitive alveolar active Na+ transport. To test the necessity of betaAR signaling in acute lung injury, beta1AR-/-/beta2AR-/-, beta1AR+/+/beta2AR-/-, and beta1AR+/+/beta2AR+/+ mice were exposed to 100% oxygen for up to 204 hours. beta1AR-/-/beta2AR-/- and beta1AR+/+/beta2AR-/- mice had more lung water and worse survival from this form of acute lung injury than wild-type controls. Adenoviral-mediated rescue of beta2-adrenergic receptor (beta2AR) function into the alveolar epithelium of beta1AR-/-/beta2AR-/- and beta1AR+/+/beta2AR-/- mice normalized distal lung beta2AR function, alveolar epithelial active Na+ transport, and survival from hyperoxia. These findings indicate that betaAR signaling may not be necessary for basal AFC, and that beta2AR is essential for the adaptive physiological response needed to clear excess fluid from the alveolar airspace of normal and injured lungs.     

Variation of the genetic expression pattern after exposure to estradiol-17beta and 4-nonylphenol in male zebrafish (Danio rerio)

There is much concern about the increasing presence in the environment of synthetic chemicals that are able to disrupt the endocrine system. Among these compounds, 4-nonylphenol (4-NP) is one of the most studied xenoestrogens, due to its widespread accumulation in water sediment and consequent presence in fatty acid of aquatic organisms. Here, we have used a zebrafish microarray representing 16,399 genes to study the effects of 4-NP and estradiol-17β (E2) in adult male zebrafish in order to elucidate the mechanism of action of 4-NP compared with that of E2. The microarray results showed that both 4-NP and E2 induced a strong expression of vitellogenin (VTG), the sex related precursor of the yolk proteins in oviparous vertebrates. Both treatments induced elevated protein turnover upregulating genes involved in proteolysis and those that are constituents of the ribosome. Many genes regulated by 4-NP and E2 are involved in energy metabolism, oxidative stress defense mechanisms, xenobiotic metabolism, and lipid metabolism. A different pattern of expression in the two treatments was found for genes involved in oxidative stress, since E2 seems to induce the mechanism of detoxification, while 4-NP seems to inhibit this protective mechanism of the cell.Overall, these findings demonstrate that the microarray approach can contribute significantly to the understanding of expression patterns induced by E2 and 4-NP in male zebrafish. The results also demonstrate that 4-NP is able to act through an alternative pattern to that of estradiol-17β, modulating the expression of the same genes in a different manner.     

Using Reference Databases of Genetic Variation to Evaluate the Potential Pathogenicity of Candidate Disease Variants

The potential pathogenicity of genetic variants identified in disease‐based resequencing studies is often overlooked where variants have previously been reported in dbSNP, the 1000 genomes project, or the National Heart, Lung and Blood Institute Exome Sequencing Project (ESP). In this work, we estimate that collectively, these databases capture ～52% of mutations (dbSNP 50.4%; 1000 genomes 4.8%; and ESP 10.2%) reported as disease causing within phenotype‐based locus‐specific databases (LSDBs). To investigate whether these mutations may simply represent benign population variants, we evaluated whether the carrier frequencies associated with mutations implicated in amyotrophic lateral sclerosis were higher than what could be accounted for by high‐penetrance disease models. In doing so, we have questioned the veracity of 51 mutations, but also demonstrated that each of the three databases included credible disease variants. Our results demonstrate the benefits of using databases such as dbSNP, the 1000 genomes project, and the ESP to evaluate the pathogenicity of putative disease variants, and suggest that many disease mutations reported across LSDBs may not actually be pathogenic. However, they also demonstrate that even in the context of rare Mendelian disorders, the potential pathogenicity of variants reported by these databases should not be overlooked without proper evaluation.     

Measurement of upper limb function in ALS: a structured review of current methods and future directions

Journal of Neurology - Measurement of upper limb function is critical for tracking clinical severity in amyotrophic lateral sclerosis (ALS). The Amyotrophic Lateral Sclerosis Rating Scale-revised...     

Internal carotid-artery response to 5% carbon dioxide in women with polycystic ovaries

Although polycystic ovary syndrome is associated with hypertension, hyperlipidaemia, and insulin resistance, mortality from cerebrovascular disease is not increased. We previously reported lower downstream resistance in the internal carotid artery in women with polycystic ovary syndrome. This study was designed to assess vascular reactivity by measuring the response to inhalation of 5% carbon dioxide. We studied 34 young women with polycystic ovary syndrome, 15 with symptomless polycystic ovaries, and 18 controls.