Association between the 5q31.1 gene neurogenin1 and schizophrenia

Multiple lines of evidence suggest that schizophrenia results from aberrant neurodevelopment. The neurogenin1 gene (neurog1) consists of a single 1,666 bp exon that encodes a basic helix-loop-helix (bHLH) transcription factor that causes neuronal differentiation and induces cortical and glutamatergic differentiation programs. Because of its function and its location in 5q31.1, which has been linked to schizophrenia in multiple samples, we tested it for association with the disorder. We sequenced neurog1 in 25 affected subjects from the Irish Study of High-Density Schizophrenia Families. We observed a 5'-UTR SNP at position -60, already present in databases as rs8192558, and tested it along with rs2344485, rs8192559, and rs2344484. Narrow, intermediate, and broad diagnostic definitions were used. The major alleles of rs8192558 and rs2344484 were over-transmitted to affected subjects using both Pedigree Disequilibrium Test (PDT) (0.01 <or = P <or = 0.06) and FBAT (0.02 <or = P <or = 0.07). A haplotype consisting of the major alleles of all four SNPs was significantly over-transmitted in FBAT to the broad definition (P = 0.049), with trend significance to the narrow and intermediate definitions, and with trend significance in PDT. In confirmatory tests using 657 cases and 411 controls, this haplotype was slightly but not significantly over-represented in cases (81% vs. 77%, P = 0.21). These results, along with a priori evidence for the involvement of neurog1 in neurodevelopment, suggest that variants in neurog1 might have a small effect on susceptibility to schizophrenia. This gene should be tested in additional and larger samples.

Clinical and experimental links between diabetes and glaucoma

Glaucoma is a leading cause of blindness. It is a multifactorial condition, the risk factors for which are increasingly well defined from large-scale epidemiological studies. One risk factor that remains controversial is the presence of diabetes. It has been proposed that diabetic eyes are at greater risk of injury from external stressors, such as elevated intraocular pressure. Alternatively, diabetes may cause ganglion cell loss, which becomes additive to a glaucomatous ganglion cell injury. Several clinical trials have considered whether a link exists between diabetes and glaucoma. In this review, we outline these studies and consider the causes for their lack of concordant findings. We also review the biochemical and cellular similarities between the two conditions. Moreover, we review the available literature that attempts to answer the question of whether the presence of diabetes increases the risk of developing glaucoma. At present, laboratory studies provide robust evidence for an association between diabetes and glaucoma.

The mend of the bend-flexor pollicis longus tendon has an additional pulley distal to its point of angulation

The tendon of flexor pollicis longus angulates at the trapezio-metacarpal joint level. The degree of angulation varies with extent of radial/ulnar deviation (Rack and Ross [1984] J. Physiol. 351:99–110). We report a fibrous pulley at this level that helps stabilize the tendon and facilitates its action. The morphology of the pulley is described. We believe that it has an important role to play in the unique function of the tendon facilitating the movement of the thumb perpendicular to the plane of the thumbnail. Clin. Anat. 21:427–432, 2008. © 2008 Wiley-Liss, Inc

Speed of processing in the primary motor cortex: A continuous theta burst stimulation study

‘Temporally urgent’ reactions are extremely rapid, spatially precise movements that are evoked following discrete stimuli. The involvement of primary motor cortex (M1) and its relationship to stimulus intensity in such reactions is not well understood. Continuous theta burst stimulation (cTBS) suppresses focal regions of the cortex and can assess the involvement of motor cortex in speed of processing. The primary objective of this study was to explore the involvement of M1 in speed of processing with respect to stimulus intensity. Thirteen healthy young adults participated in this experiment. Behavioral testing consisted of a simple button press using the index finger following median nerve stimulation of the opposite limb, at either high or low stimulus intensity. Reaction time was measured by the onset of electromyographic activity from the first dorsal interosseous (FDI) muscle of each limb. Participants completed a 30 min bout of behavioral testing prior to, and 15 min following, the delivery of cTBS to the motor cortical representation of the right FDI. The effect of cTBS on motor cortex was measured by recording the average of 30 motor evoked potentials (MEPs) just prior to, and 5 min following, cTBS. Paired t-tests revealed that, of thirteen participants, five demonstrated a significant attenuation, three demonstrated a significant facilitation and five demonstrated no significant change in MEP amplitude following cTBS. Of the group that demonstrated attenuated MEPs, there was a biologically significant interaction between stimulus intensity and effect of cTBS on reaction time and amplitude of muscle activation. This study demonstrates the variability of potential outcomes associated with the use of cTBS and further study on the mechanisms that underscore the methodology is required. Importantly, changes in motor cortical excitability may be an important determinant of speed of processing following high intensity stimulation.

Lamina propria: The functional center of the bladder?

The bladder mucosa consists of the urothelium, basement membrane, and lamina propria (LP). Although the urothelium has been given much attention, it may be regarded as one part of a signaling system involving another equally important component of the bladder mucosa, namely, the LP. The LP lies between the basement membrane of the mucosa and the detrusor muscle and is composed of an extracellular matrix containing several types of cells, including fibroblasts, adipocytes, interstitial cells, and afferent and efferent nerve endings. In addition, the LP contains a rich vascular network, lymphatic vessels, elastic fibers, and smooth muscle fascicles (muscularis mucosae). The roles of the LP and its components in bladder function have not been definitively established, though it has been suggested to be the capacitance layer of the bladder, determining bladder compliance and enabling adaptive changes to increasing volumes. However, the bladder LP may also serve as a communication center, with an important integrative role in signal transduction to the central nervous system (nociception, mechanosensation). The LP may also, by means of its different components, make it possible for the urothelium to transmit information to other components of the bladder wall, contributing to activation of the detrusor muscle. In addition, the LP may serve as a source for production of factors influencing the growth of both the overlying urothelium and the underlying detrusor muscle.

Natural Toxicants: Tetrodotoxin

Tetrodotoxin (tetrodotoxin) is a potent neurotoxin, which shuts down electrical signaling in nerves by blocking the voltage-gated sodium channel proteins in nerve cell membranes. It was originally discovered in puffer fish but is found in a range of animal species and thought to be produced by bacteria. The toxin can be lethal to humans being 10 000 times more potent than cyanide. Human fatalities have been attributed to the ingestion of this toxin through consumption of puffer fish, a delicacy in Japan and other regions, and other marine species. The effects of tetrodotoxin poisoning onset quickly and include shortness of breath, numbness, tingling, light-headedness, paralysis, and irregular heartbeat. Treatment usually consists of respiratory assistance as no antidote has been developed. The accepted method of analysis for tetrodotoxin is the mouse bioassay, although recently more ethical assays have been developed including high performance liquid chromatography, biosensor and enzyme-linked immunosorbant assay.

Automatic Analysis of Digital Retinal Images for Glaucoma Detection

In this paper we propose a novel automated glaucoma detection framework for mass-screening that operates on inexpensive retinal cameras. The proposed methodology is based on the assumption that discriminative features for glaucoma diagnosis can be extracted from the optical nerve head structures,
such as the cup-to-disc ratio or the neuro-retinal rim variation. After automatically segmenting the cup and optical disc, these features are feed into a machine learning classifier. Experiments were performed using two different datasets and from the obtained results the proposed technique provides
better performance than approaches based on appearance. A main advantage of our approach is that it only requires a few training samples to provide high accuracy over several different glaucoma stages.

Anatomy and Neurophysiology of Coughing: CHEST Guideline and Expert Panel Report

Bronchopulmonary C-fibers and a subset of mechanically sensitive, acid-sensitive myelinated sensory nerves play essential roles in regulating cough. These vagal sensory nerves terminate primarily in the larynx, trachea, carina and large intrapulmonary bronchi. Other bronchopulmonary sensory nerves, sensory nerves innervating other viscera as well as somatosensory nerves innervating the chest wall, diaphragm and abdominal musculature regulate cough patterning and cough sensitivity. The responsiveness and morphology of the airway vagal sensory nerve subtypes and the extrapulmonary sensory nerves that regulate coughing are described. The brainstem and higher brain control systems that process this sensory information are complex, but our current understanding of them is considerable and increasing. The relevance of these neural systems to clinical phenomena, such as urge to cough and psychological methods for treatment of dystussia, is high and modern imaging methods have revealed potential neural substrates for some features of cough in the human.

Investigation of physiological properties of nerves and muscles using electromyography.

The measurement and representation of the electrical activity of muscles [electromyography (EMG)] have a long history from the Victorian Era until today. Currently, EMG has uses both as a research tool, in noninvasively recording muscle activation, and clinically in the diagnosis and assessment of nerve and muscle disease and injury as well as in assessing the recovery of neuromuscular function after nerve damage. In the present report, we describe the use of a basic EMG setup in our teaching laboratories to demonstrate some of these current applications. Our practical also illustrates some fundamental physiological and structural properties of nerves and muscles. Learning activities include 1) displaying the recruitment of muscle fibers with increasing force development; 2) the measurement of conduction velocity of motor nerves; 3) the assessment of reflex delay and demonstration of Jendrassik's maneuver; and 4) a Hoffman reflex experiment that illustrates the composition of mixed nerves and the differential excitability thresholds of fibers within the same nerve, thus aiding an understanding of the reflex nature of muscle control. We can set up the classes at various levels of inquiry depending on the needs/professional requirements of the class. The results can then provide an ideal platform for a discovery learning session/tutorial on how the central nervous system controls muscles, giving insights on how supraspinal control interacts with reflexes to give smooth, precise muscular activation.

Immunohistochemical study of pig retinal development

PURPOSE: The pig eye is similar to the human eye in terms of anatomy, vasculature, and photoreceptor distribution, and therefore provides an attractive animal model for research into retinal disease. The purpose of this study was to characterize retinal histology in the developing and mature pig retina using antibodies to well established retinal cell markers commonly used in rodents.

METHODS: Eyes were enucleated from fetuses in the 9th week of gestation, 1 week old piglets and 6 months old adult animals. Eyeglobes were fixed and cryosectioned. A panel of antibodies to well established retinal markers was employed for immunohistochemistry. Fluorescently labeled secondary antibodies were used for signal detection, and images were acquired by confocal microscopy. Mouse retina at postnatal day (P) 5 was used as a reference for this study to compare progression of histogenesis. Most of the primary antibodies have previously been used on mouse tissue.

RESULTS: Most of the studied markers were detected in midgestation pig retina, and the majority had a similar distribution in pig as in P5 mouse retina. However, rhodopsin immunolabeling was detected in pig retina at midgestation but not in P5 mouse retina. Contrary to findings in all rodents, horizontal cells were Islet1-positive and cones were calbindin-immunoreactive in pig retina, as has also been shown for the primate retina. Recoverin and rhodopsin immunolabeling revealed an increase in the length of photoreceptor segments in 6 months, compared to 1 week old animals.

CONCLUSIONS: Comparison with the published data on human retina revealed similar marker distribution and histogenesis progression in the pig and human retina, supporting the pig as a valuable animal model for studies on retinal disease and repair. Furthermore, this study provides information about the dynamics of retinal histogenesis in the pig and validates a panel of antibodies that reliably detects developing and mature retinal cell phenotypes in the pig retina.

Efficacy and safety of peri-prostatic local anaesthetic injection in tram-rectal biopsy of the prostrate:A prospective randomised study

Objective: To assess the efficacy and safety of periprostatic lignocaine injection in trans-rectal ultrasound (TRUS) -guided biopsy of the prostate gland.

Methods: Ninety- six men (mean age 65 years, range 47-74) undergoing TRUS biopsy were randomised into the local anaesthetic (LA) or placebo group. Six to twelve biopsy cores were taken, the majority being 10 cores. Patients were asked to fill in the expected pain score on a visual analogue scale (VAS) prior to the procedure. They also completed the actual pain experienced on VAS after the biopsy. The incidence of complications was documented.

Results: The age, mean prostate specific antigen (PSA) were comparable in both groups. The expected pain score was also comparable (5.2 +/- 1.6 in LA, 5.0 +/- 1.4 in Placebo). In the LA group, the mean actual pain score was 3.0 +/- 1.8 and in the placebo group it was 6.5 +/- 2.2 (P = 0.0001). When patients were asked whether they would undergo the procedure again in the same way, 100% of the LA group and only 64% of the placebo group responded 'yes'(P=0.002 using Fisher's test). The complication rates were not significantly different between the two groups.

Conclusion: Peri-prostatic injection of local anaesthetic is safe and reduces discomfort significantly, and should be routinely offered to patients.

Non-invasive antidromic neurostimulation:A simple effective method for improving bladder storage

Patients with intractably diminished bladder storage function are encountered frequently by neurourologists, occasionally requiring reconstructive surgery for appropriate resolution. Although sacral neuromodulation is a recognized effective therapeutic modality, present techniques are technically demanding, invasive, and expensive. This study investigated the effect of non-invasive third sacral nerve (S3) stimulation on bladder activity during filling cystometry. One hundred forty-six patients underwent standard urodynamic filling cystometry that was then immediately repeated. Patients in the study group (n = 74) received antidromic transcutaneous sacral neurostimulation during the second fill and the control group (n = 72) underwent a second fill without neurostimulation. A statistically significant increase in bladder storage capacity without a corresponding rise in detrusor pressure was observed in the neurostimulated patients. This improvement in functional capacity is an encouraging finding that further supports the use of this non-invasive treatment modality in clinical practice. Neurourol. Urodynam. 20:73-84. 2001. (C) 2001 Wiley-Liss, Inc.

Transcutaneous sacral neurostimulation for irritative voiding dysfunction

with refractory irritative voiding dysfunction. Following an initial response, patients may successfully apply this treatment themselves to ensure long-term relief. Objective: Patients with irritative voiding dysfunction are often unresponsive to standard clinical treatment. We evaluated the response of such individuals to transcutaneous electrical stimulation of the third sacral nerve. Methods: 32 patients with refractory irritative voiding dysfunction (31 female and 1 male; mean age 47 years) were recruited to the study. Ambulatory transcutaneous electrical neurostimulation was applied bilaterally to the third sacral dermatomes for 1 week. Symptoms of frequency, nocturia, urgency, and bladder pain were scored by each patient throughout and up to 6 months following treatment. Results: The mean daytime frequency was reduced from 11.3 to 7.96 (p = 0.01). Nocturia episodes were reduced from a mean of 2.6 to 1.8 (p = 0.01). Urgency and bladder pain mean symptom scores were reduced from 5.97 to 4.89 and from 1.48 to 0.64, respectively. After stopping therapy, symptoms returned to pretreatment levels within 2 weeks in 40% of the patients and within 6 months in 100%, Three patients who continued with neurostimulation remained satisfied with this treatment modality at 6 months. Conclusions: Transcutaneous third sacral nerve stimulation may be an effective and noninvasive ambulatory technique for the treatment of patients with refractory irritative voiding dysfunction. Following an initial response, patients may successfully apply this treatment themselves to ensure long-term relief.

Effects of thyroxine treatment on histology and behavior using the methimazole model of congenital hypothyroidism in the rat

The timing of thyroxine (T4) replacement treatment in congenital hypothyroidism (CH) has been suggested to be important for optimizing cognitive recovery in humans; however this has not been fully established using modern animal models of CH. Consequently, the current studies investigated the ameliorating effects of postnatal T4 treatment on neuropathology and behavior in CH rats. Rat dams were administered methimazole to produce CH offspring, then brain tissue from male CH pups was analyzed to determine the effects of postnatal (P3, P7, P14 and P21) T4 treatment on hippocampal dendritic branching and the expression of nerve growth factor (NGF). Two operant behavioral procedures were employed to confirm and extend previous findings obtained using this model, and to investigate timelines for instigating T4 treatment on improved behavioral outcomes. T4 treatment initiated at P14 was protective of a reduction in dendritic branching in the hippocampus, and initiated at P7 was protective of a reduction of NGF expression in the fimbria of the hippocampus. Induction of CH did not affect the acquisition of simple operant response rules but had a significant effect on the acquisition of complex operant rules subsequently imposed. Furthermore, T4 treatment initiated at P3 protected learning deficits seen following the imposition of complex operant response rules. These findings indicate T4 treatment initiated at P7 is sufficient for the protection of hippocampal NGF expression and dendritic branching but for the protection of complex behavioral abilities T4 treatment is necessary prior to or approximating P3.

Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions

Ischaemic strokes evoke blood-brain barrier (BBB) disruption and oedema formation through a series of mechanisms involving Rho-kinase activation. Using an animal model of human focal cerebral ischaemia, this study assessed and confirmed the therapeutic potential of Rho-kinase inhibition during the acute phase of stroke by displaying significantly improved functional outcome and reduced cerebral lesion and oedema volumes in fasudil- versus vehicle-treated animals. Analyses of ipsilateral and contralateral brain samples obtained from mice treated with vehicle or fasudil at the onset of reperfusion plus 4 h post-ischaemia or 4 h post-ischaemia alone revealed these benefits to be independent of changes in the activity and expressions of oxidative stress- and tight junction-related parameters. However, closer scrutiny of the same parameters in brain microvascular endothelial cells subjected to oxygen-glucose deprivation ± reperfusion revealed marked increases in prooxidant NADPH oxidase enzyme activity, superoxide anion release and in expressions of antioxidant enzyme catalase and tight junction protein claudin-5. Cotreatment of cells with Y-27632 prevented all of these changes and protected in vitro barrier integrity and function. These findings suggest that inhibition of Rho-kinase after acute ischaemic attacks improves cerebral integrity and function through regulation of endothelial cell oxidative stress and reorganization of intercellular junctions. Inhibition of Rho-kinase (ROCK) activity in a mouse model of human ischaemic stroke significantly improved functional outcome while reducing cerebral lesion and oedema volumes compared to vehicle-treated counterparts. Studies conducted with brain microvascular endothelial cells exposed to OGD ± R in the presence of Y-27632 revealed restoration of intercellular junctions and suppression of prooxidant NADPH oxidase activity as important factors in ROCK inhibition-mediated BBB protection.