Glucagon- and secretin-related peptides differentially alter ocular growth and the development of form-deprivation myopia in chicks

PURPOSE: Exogenous glucagon inhibits the induction of myopia in chicks, but the endogenous peptide and receptor that regulate eye growth are unknown. The purpose of this study was to determine which peptides and receptors in the glucagon-secretin family play a role in the control of ocular growth. METHODS: The effect of intravitreally injected peptides on the development of form-deprivation (FD) myopia and on the growth of eyes with unrestricted vision was determined by refraction and A-scan ultrasonography. Chicks received three injections, one every 48 hours, of secretin-related peptides (porcine secretin, human peptide histidine-isoleucine-amide-27, vasoactive intestinal peptide [VIP], VIP fragment 6-28, or pituitary adenylate cyclase-activating polypeptide; 10(-8)-10(-4) M in 20 microL) or five injections of proglucagon-derived peptides (human glucagon, oxyntomodulin, miniglucagon, or glucagon-like peptide [GLP]-2 or chicken GLP-1). Immunohistochemistry was used to detect proglucagon-derived peptides in the eye. RESULTS: Secretin-related peptides had no effect on FD myopia, whereas some proglucagon-derived peptides did. Both glucagon and oxyntomodulin dose-dependently inhibited development of myopia, primarily by inhibition of vitreous chamber elongation (EC(50) = 10(-4) M and 10(-5.5) M, respectively). GLP-1 increased deprivation-induced myopic refractive error by altering anterior chamber development. None of the peptides significantly affected refractive error in eyes with unrestricted vision, although changes in anterior and posterior eye growth were observed in response to glucagon, oxyntomodulin, GLP-1, and miniglucagon. Immunoreactivity for miniglucagon and GLP-1 was colocalized in glucagon-immunoreactive amacrine cells. CONCLUSIONS: Prevention of experimental myopia by exogenous glucagon is mediated by receptors selective for glucagon and oxyntomodulin, indicating that glucagon-like peptides and receptors are probable endogenous retinal regulators of the development of myopia.     

Mortality among prisoners: how accurate is the Australian National Death Index?

OBJECTIVE: The effectiveness of the National Death Index (NDI) in identifying deaths among different populations has been studied before. Prisoners represent a segment of the population that might be expected to be difficult to link. The objective of this research was to evaluate the accuracy of the Australian NDI to ascertain the mortality status of prisoners in New South Wales, Australia. METHODS: Data on 311 inmates who had died in custody between January 1988 and March 2003, and on 7,558 inmates known to be alive at the end of May 2003, were matched to the NDI database. Matching was undertaken using a probabilistic linkage method followed by a clerical review. The underlying causes of death reported by the NDI were compared against those reported by the NSW Coroner and held at the Legal Branch of the Department of Corrective Services. RESULTS: Linkage correctly identified 275 of the 311 known deaths (sensitivity: 88.4%). Of the 7,558 prisoners known to be alive in custody at the end of May 2003, linkage to the NDI incorrectly identified 23 as dead (specificity: 99.7%). Cause of death was accurately reported by the NDI for 95.5% of deaths identified by the linkage. CONCLUSION: The results of this study show that the NDI is an accurate and feasible means for evaluating mortality among prisoners. The nature of the prisoner population makes the linkage a difficult task for the NDI. The success of the data linkage depends on the extent and accuracy of information contained in the index file and type and quality of information available.     

The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses

Glutamate release from photoreceptor terminals is controlled by voltage-dependent calcium channels (VDCCs). In humans, mutations in the Cacna1f gene, encoding the alpha1F subunit of VDCCs, underlie the incomplete form of X-linked congenital stationary night blindness (CSNB2). These mutations impair synaptic transmission from rod and cone photoreceptors to bipolar cells. Here, we report anatomical and functional characterizations of the retina in the nob2 (no b-wave 2) mouse, a naturally occurring mutant caused by a null mutation in Cacna1f. Not surprisingly, the b-waves of both the light- and dark-adapted electroretinogram are abnormal in nob2 mice. The outer plexiform layer (OPL) is disorganized, with extension of ectopic neurites through the outer nuclear layer that originate from rod bipolar and horizontal cells, but not from hyperpolarizing bipolar cells. These ectopic neurites continue to express mGluR6, which is frequently associated with profiles that label with the presynaptic marker Ribeye, indicating potential points of ectopic synapse formation. However, the morphology of the presynaptic Ribeye-positive profiles is abnormal. While cone pedicles are present their morphology also appears compromised. Characterizations of visual responses in retinal ganglion cells in vivo, under photopic conditions, demonstrate that ON-center cells have a reduced dynamic range, although their basic center-surround organization is retained; no alteration in the responses of OFF-center cells was evident. These results indicate that nob2 mice are a valuable model in which to explore the pathophysiological mechanisms associated with Cacna1f mutations causing CSNB2, and the subsequent effects on visual information processing. Further, the nob2 mouse represents a model system in which to define the signals that guide synapse formation and/or maintenance in the OPL.     

Sex differences and the role of sex steroids in renal injury

PURPOSE: There is growing evidence that significant sex differences exist in the response of the kidney to injury. In this review we explored the cumulative clinical knowledge and experimental evidence of this phenomenon. MATERIALS AND METHODS: The current clinical evidence of increased male susceptibility to acute and chronic renal injury, and experimental data elucidating potential mechanisms of this phenomenon were reviewed. RESULTS: Renal damage induced by nephron reduction, patient age and renal ischemia is tolerated differently by the sexes. Sex differences in disease susceptibility have historically been attributed to the protective effects of estrogen but recent evidence suggests that male hormones also have an important role in these differences. Vascular mediators, such as endothelin, nitric oxide and angiotensin II, appear to be influenced by sex and sex steroids. Additionally, inflammatory mediators, such as transforming growth factor-beta1, tumor necrosis factor-alpha and p38 mitogen activating protein kinase, similarly show differential expression and activity based on sex and the presence of sex steroids. These mediators have a significant impact on the kidney response to inflammation and injury. CONCLUSIONS: Greater understanding of the specific role of sex steroids in renal injury may provide new therapeutic strategies to protect against inflammatory injury and renal damage in the future.     

A comparison of three measures of upper limb function in Friedreich ataxia

Friedreich Ataxia (FRDA) is the commonest inherited ataxia. Clinical trials of pharmaceuticals are increasingly being conducted in this condition. This requires the most accurate outcome measures to enable trials to be conducted with a minimum number of subjects in the shortest time frame and to minimize the risk of false negative results. Upper limb function is a major area of morbidity in FRDA. We therefore have compared the performance of three tests of upper limb function in FRDA: the Nine Hole Peg Test (9HPT), Box and Blocks Test (BBT) and Jebsen Taylor Hand Function Test (JTHFT). This study was undertaken to ascertain the best test for inclusion in a Friedreich Ataxia Functional Composite (FAFC) test for use in clinical studies and therapeutic trials. The three tests were administered to the dominant and non-dominant upper limbs of 38 individuals with genetically proven FRDA on two occasions, 12 months apart. The results of testing were correlated with the following disease parameters; age at disease onset, disease duration and score for the Friedreich Ataxia Rating Scale (FARS). The responsiveness to change of each test was assessed by measuring the effect size and calculations of the number of subjects required for similarly powered therapeutic trials. Results for all tests correlated significantly with disease duration and FARS score. The only test scores that changed significantly over 12 months were those for the non-dominant 9HPT and BBT. Scores for these two tests also had the largest effect sizes and required the fewest subjects for similarly powered therapeutic trials. We conclude, therefore, that the non-dominant 9HPT and BBT are the best tests for inclusion in a FAFC. Since the 9HPT has already been suggested for inclusion in a FAFC, we recommend that this test is used but that it is the non-dominant limb that is tested.     

A novel deletion–insertion mutation identified in exon 3 of <Emphasis Type="Italic">FXN</Emphasis> in two siblings with a severe Friedreich ataxia phenotype

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease most commonly caused by a GAA trinucleotide repeat expansion in the first intron of FXN, which reduces expression of the mitochondrial protein frataxin. Approximately 98% of individuals with FRDA are homozygous for GAA expansions, with the remaining 2% compound heterozygotes for a GAA expansion and a point mutation within FXN. Two siblings with early onset of symptoms experienced rapid loss of ambulation by 8 and 10 years. Diagnostic testing for FRDA demonstrated one GAA repeat expansion of 1010 repeats and one non-expanded allele. Sequencing all five exons of FXN identified a novel deletion-insertion mutation in exon 3 (c.371_376del6ins15), which results in a modified frataxin protein sequence at amino acid positions 124–127. Specifically, the amino acid sequence changes from DVSF to VHLEDT, increasing frataxin from 211 residues to 214. Using the known structure of human frataxin, a theoretical 3D model of the mutant protein was developed. In the event that the modified protein is expressed and stable, it is predicted that the acidic interface of frataxin, known to be involved in iron binding and interactions with the iron–sulphur cluster assembly factor IscU, would be impaired.     

Superior Cerebellar Peduncle Atrophy in Friedreich��s Ataxia Correlates with Disease Symptoms

Friedreich’s ataxia (FRDA) is the most common early onset inherited ataxia with clinical manifestations, including gradual progression of unremitting cerebellar–sensory ataxia, peripheral sensory loss, loss of lower limb tendon reflexes and hypertrophic cardiomyopathy. Although atrophy of the superior cerebellar peduncle (SCP) has been reported in several magnetic resonance imaging (MRI) studies of FRDA, the relationship of SCP changes to genetic and clinical features of FRDA has not been investigated. We acquired T1-weighted MRI scans in 12 right-handed individuals with FRDA, homozygous for a GAA expansion in intron 1 of FXN, as well as 13 healthy age-matched controls. The corrected cross-sectional areas of the right (left) SCP in the individuals with FRDA (R, 20 ± 7.9 mm²; L, 25 ± 5.6 mm²) were significantly smaller than for controls (R, 68 ± 16 mm²; L, 78 ± 17 mm²) (p < 0.001). The SCP volumes of individuals with FRDA were negatively correlated with Friedreich’s ataxia rating scale score (r = −0.553) and disease duration (r = −0.541), and positively correlated with the age of onset (r = 0.548) (p < 0.05). These findings suggest that structural MR imaging of the SCP can provide a surrogate marker of disease severity in FRDA and support the potential role of structural MRI as a biomarker in the evaluation of neurodegenerative diseases and therapies.     

Split-appendix technique for simultaneous appendicovesicostomy and appendicocecostomy

Purpose

Surgical treatment of urinary and fecal incontinence with appendicocecostomy (AC) and appendicovesicostomy (AV) has high success in achieving continence. Usually, the appendix can only be used for one of these, requiring the second channel to be constructed from alternative tissue. We describe our outcomes using the spilt-appendix technique for simultaneous creation of AC and AV.

Methods

We reviewed records for all patients that underwent simultaneous AC and AV from the appendix alone from 1999 to 2009. When anatomy permitted, the appendix was divided into 2. The proximal end was kept in continuity with the cecum for an AC, whereas the distal end was used for AV. The appendiceal length, continence status, and subsequent need for surgical revision were recorded.

Results

Of 394 children who underwent reconstructive surgery with a Mitrofanoff channel, 43 patients (11%) used the split-appendix technique. After a mean follow-up of 40 months, 43 of 43 ACs and 41 of 43 AVs are continent. Of the 86, 16 (19%) channels created required surgical revision.

Conclusions

The channels created from split-appendix technique have outcomes and revision rates comparable with those of other described techniques. This technique is applicable to a minority of children undergoing continent reconstruction; however, it has the benefit of avoiding a bowel resection and its accompanying risks.