Spinal cord protection in aortic endovascular surgery.

A persistent neurological deficit, such as paraplegia or paraparesis, secondary to spinal cord injury remains one of the most feared complications of surgery on the descending thoracic or abdominal aorta. This is despite sophisticated advances in imaging and the use of less invasive endovascular procedures. Extensive fenestrated endovascular aortic graft prostheses still carry a risk of spinal cord injury of up to 10%; thus, this risk should be identified and strategies implemented to protect the spinal cord and maintain perfusion. The patients at highest risk are those undergoing extensive thoracic aortic stenting including thoracic, abdominal, and pelvic vessels. Although many techniques are available, lumbar cerebrospinal fluid drainage remains the most frequent intervention, along with maintenance of perfusion pressure and possibly staged procedures to allow collateral vessel stabilization. Many questions remain regarding other technical aspects, spinal cord monitoring and cooling, pharmacological protection, and the optimal duration of interventions into the postoperative period.

No evidence for a genetic blueprint: The case of the "complex" mammalian photoreceptor.

Despite the intensity of the search for genes causing inherited retinal degenerations over the past 3 decades, of the approximately 200 disease genes identified to date, all appear to be ordinary housekeeping genes specifying proteins playing basic structural and functional roles in the mature photoreceptor cells. No genes or genetic elements have been identified which can be construed as having a specific morphogenic role, directing the development of the cytoarchitecture of any particular retinal cell. The evidence suggests that the cytoarchitecture of the retinal photoreceptors, although enormously complex, arises from the self-organization of the cells constituents without any regulation or direction from an external genetic blueprint.

CRB1 mutations may result in retinitis pigmentosa without para-arteriolar RPE preservation.

PURPOSE: To report a new phenotype in retinitis pigmentosa (RP) patients with CRB1 mutations at the RP12 locus. PATIENTS: Thirty-seven patients from two Pakistani families with severe retinitis pigmentosa. METHODS: Samples were screened with single-strand conformation polymorphism analysis followed by DNA sequencing of the coding sequence of the CRB1 gene. RESULTS: Two novel CRB1 mutations were discovered. No patients had evidence of preservation of the para-arteriolar retinal pigment epithelium (PPRPE) that has been previously reported in all cases of RP associated with CRB1 mutations. CONCLUSIONS: Patients with severe autosomal recessive (or simplex) RP who lack the finding of PPRPE should not be excluded from molecular analysis of CRB1 purely because they lack the clinical feature of PPRPE. This report illustrates that RP at the RP12 locus is not clinically uniform. The absence of PPRPE cannot be used to exclude CRB1 as a potential molecular explanation for RP.

A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration.

The disks of vertebrate photoreceptors are produced by outgrowths of the plasma membrane. Hence genes that encode retinal proteins targeted to plasma membrane protrusions represent candidates for inherited retinal degenerations. One such candidate is the gene encoding human prominin (mouse)-like 1 (PROML1, previously known as AC133 antigen) which belongs to the prominin family of 5-transmembrane domain proteins. Murine prominin (prom) shows a strong preference for plasma membrane protrusions in a variety of epithelial cells whereas PROML1 is expressed in retinoblastoma cell lines and adult retina. In the present study, molecular genetic analyses of a pedigree segregating for autosomal recessive retinal degeneration indicated that the affected individuals were homozygous for a nucleotide 1878 deletion in PROML1. This alteration is predicted to result in a frameshift at codon 614 with premature termination of translation. Expression of a similar prom deletion mutant in CHO cells indicated that the truncated protein does not reach the cell surface. Immunocytochemistry revealed that prom is concentrated in the plasma membrane evaginations at the base of the outer segments of rod photoreceptors. These findings suggest that loss of prominin causes retinal degeneration, possibly because of impaired generation of the evaginations and/or impaired conversion of the evaginations to disks.

Autosomal recessive retinitis pigmentosa locus RP28 maps between D2S1337 and D2S286 on chromosome 2p11-p15 in an Indian family.

Retinitis pigmentosa (RP) is a group of clinically and genetically heterogeneous disorders characterised by night blindness, constriction of visual field, and dystrophic changes of the retina. Previous genetic studies have shown extensive allelic and non-allelic genetic heterogeneity of RP. Here we describe an Indian family with multiple consanguineous marriages and a total of four patients with autosomal recessive (AR) RP. The homozygosity mapping strategy was successfully used and indicated close linkage between the disease locus and D2S380, D2S441, D2S291, and D2S1394 with maximum lod scores between 1.51-3.07 at theta=0.00. The analysis of multiply informative meioses maps the locus (RP28) for ARRP in this family between D1S1337 and D2S286 on 2p11-p15. The involvement of visinin (VSNL1), a promising candidate gene assigned to chromosome 2p by previous studies, has been excluded by the absence of linkage.

Homozygosity mapping of autosomal recessive retinitis pigmentosa locus (RP22) on chromosome 16p12.1-p12.3.

Autosomal recessive retinitis pigmentosa (arRP) is a genetically and clinically heterogeneous and progressive degenerative disorder of the retina, leading usually to severe visual handicap in adulthood. To date, disease loci/genes have been mapped/identified only in a minority of cases. DNA samples were collected from 20 large consanguineous Indian families, in which arRP segregated and that were suitable for homozygosity mapping of the disease locus. After excluding linkage to all known arRP loci, a genome-wide scan was initiated. In two families, homozygosity mapping, haplotype analysis, and linkage data mapped the disease locus (RP22) in an approximately 16-cM region between D16S287 and D16S420 on the proximal short arm of chromosome 16. No mutation has been found by direct sequencing in the gene (CRYM) encoding micron crystallin, which maps in the critical region.

Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy.

Autosomal recessive childhood-onset severe retinal dystrophy (arCSRD) designates a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis (LCA), while the less aggressive forms are usually considered juvenile retinitis pigmentosa. Recently, mutations in the retinal-specific guanylate cyclase gene were found in patients with LCA. Disease genes implicated in other forms of arCSRD are expected to encode proteins present in the neuroretina or in the retinal pigment epithelium (RPE). The RPE, a monolayer of cells separating the vascular-rich choroid and the neuroretina, is in intimate contact with the outer segments of rods and cones via the microvilli surrounding the photoreceptors. The RPE expresses a tissue-specific and evolutionarily highly conserved 61 kD protein (RPE65) present at high levels in vivo. Although the function of RPE65 is not yet known, an important role in the RPE/photoreceptor vitamin-A cycle is suggested by the fact that RPE65 associates both with serum retinol-binding protein and with the RPE-specific 11-cis retinol dehydrogenase, an enzyme active in the synthesis of the visual pigment chromophore 11-cis retinal. Here we report that the analysis of RPE65 in a collection of about 100 unselected retinal-dystrophy patients of different ethnic origin revealed five that are likely to be pathogenic mutations, including a missense mutation (Pro363Thr), two point mutations affecting splicing (912 + 1G-->T and 65 + 5G-->A) and two small re-arrangements (ins144T and 831del8) on a total of nine alleles of five patients with arCSRD. In contrast to other genes whose defects have been implicated in degenerative retinopathies, RPE65 is the first disease gene in this group of inherited disorders that is expressed exclusively in the RPE, and may play a role in vitamin-A metabolism of the retina.

Mutation of the gene encoding cellular retinaldehyde-binding protein in autosomal recessive retinitis pigmentosa.

Inadequate levels of all-trans-retinol in the blood cause retinal dysfunction; hence, genes implicated in retinal vitamin-A metabolism represent candidates for inherited retinal degenerations. In the current study, molecular genetic analysis of a consanguineous pedigree segregating for non-syndromic autosomal recessive retinitis pigmentosa (arRP) indicated that the affected siblings were homozygous by descent for a G4763A nucleotide substitution in RLBP1, the gene encoding cellular retinaldehyde-binding protein (CRALBP). This substitution is predicted to replace an arginine with glutamine at residue 150. CRALBP is not expressed in photoreceptors but is abundant in the retinal pigment epithelium (RPE) and Müller cells of the neuroretina, where it carries 11-cis-retinol and 11-cis-retinaldehyde. When expressed in bacteria, recombinant CRALBP (rCRALBP) containing the R150Q substitution was less soluble than wild-type rCRALBP. Mutant rCRALBP was purified from the soluble cell lysate and the protein structure was verified by mass spectrometry. The mutant protein lacked the ability to bind 11-cis-retinaldehyde. These findings suggest that arRP in the current pedigree results from a lack of functional CRALBP, presumably leading to disruption of retinal vitamin-A metabolism.

Clinical and vascular laboratory determinants for outcome after infrainguinal atherectomy.

Three surgeons performed 180 atherectomy procedures in 161 patients using the Transluminal Extraction Catheter in 144 and the Auth Rotablator in 36. The primary patency rate was 55% at 1 year and 46% at 2 years, and failure was caused by stenosis in 28 (15.6%) and occlusion in 61 (33.7%) limbs. Multivariate Cox regression analysis showed significantly better outcome if the indication was claudication, the lesion was short or there was associated stenting. Vascular laboratory surveillance was performed in 93 limbs in 83 patients. Cox regression analysis in this subgroup also showed a significant relationship between outcome and the maximum peak systolic velocity from a duplex scan at the last study performed. Receiver operating characteristics curves showed that a raised maximum peak systolic velocity best predicted late failure (sensitivity 84%, specificity 66% for > 200 cm/s; sensitivity 72%, specificity 84% for > 250 cm/s); the velocity ratio at the stenosis to that in the segment above or the resting ankle/brachial pressure index were less predictive. For 50 procedures studied in the vascular laboratory which remained successful to the end of the study, maximum peak systolic velocities were > 250 cm/s from the first postoperative study, suggesting residual stenosis in 6%, or increased to become > 250 cm/s by the last study, suggesting recurrent stenoses in 12%. For 43 procedures which were studied and later failed, velocities were > 250 cm/s from the first test in 26% or increased to > 250 cm/s by the last test before failure in 40%. Vascular laboratory surveillance helps to predict outcome after atherectomy. Failure may be a result of residual disease from the time of the procedure or from restenosis. The apparent high incidence of clinically manifest or developing stenoses raises doubts as to the benefit of atherectomy over balloon dilatation alone.

Endovascular surgery--an overview.

Endovascular surgery is the vascular equivalent of minimally invasive surgery. It offers the benefits of minimal morbidity and mortality rates as well as short hospital stay, with its associated cost curtailment. In spite of many technological innovations, only balloon dilatation and intravascular stenting have established their places in vascular surgery with the newer field of stent grafting for both occlusive and aneurysmal disease still being evaluated.

Oguchi disease: suggestion of linkage to markers on chromosome 2q.

Oguchi disease is a rare autosomal recessive form of congenital stationary night blindness. The condition is associated with fundus discolouration and abnormally slow dark adaptation. Earlier studies suggested that the 48 kD protein S antigen may be involved in the recovery phase of light transduction. Previous cytogenetic and linkage studies have localised the S antigen gene (SAG) to chromosome 2q37.1. In the present study markers which map to distal chromosome 2q were typed in an inbred Oguchi pedigree. The segregation data obtained suggested that the affected subjects are homozygous by descent for a region between D2S172 and D2S345. An intragenic SAG polymorphism was homozygous in all affected people and a recombination event suggested that SAG maps proximal to D2S345. Collectively, these findings support the hypothesis that a defect in S antigen may be responsible for Oguchi disease.

Autosomal recessive retinitis pigmentosa locus maps on chromosome 1q in a large consanguineous family from Pakistan.

A large Pakistani family with several consanguineous marriages is described, in which autosomal recessive retinitis pigmentosa is segregating. Linkage studies revealed close linkage between the disease locus and six loci on chromosome 1q (D1S158, F13B, D1S422, D1S412, D1S413, and D1S53) with maximum lod scores ranging from 0.988-4.657 at theta = 0.065-0.235. However, the analysis of individual nuclear families showed very close linkage without recombination in three branches and several recombinants and negative lod scores throughout in the fourth branch. These results strongly suggest that mutations of two different genes are responsible for the disease in the 'linked' and 'unlinked' branches. Parallel to the linkage heterogeneity, clear phenotypic differences have been observed among the 'linked' and 'unlinked' parts. Our findings demonstrate that in case of recessive disorders the possibility of non-allelic genetic heterogeneity should always be considered, even within the same kindred and in genetic isolates if a largely extended pedigree is analysed.

Infrainguinal atherectomy using the Auth Rotablator: patency rates and clinical success for 36 procedures.

PURPOSE: To determine whether the Auth Rotablator device is suitable for endoluminal atherectomy for infrainguinal occlusive arterial disease. METHODS: Two surgeons used the Auth Rotablator to perform 36 infrainguinal atherectomy procedures in 34 patients for severe intermittent claudication in 21, critical ischemia in 12, or graft stenosis in 3 limbs. There were 24 stenoses and 12 occlusions. Adjuvant balloon dilation was performed in 13 limbs and stenting in 5. RESULTS: There was initial technical and anatomical success in 34 procedures (94%), and 24 technically successful procedures persisted at mean follow-up of 16.5 months, although 1 limb required major amputation. Three failures were due to stenosis requiring further intervention, and 9 were due to occlusion. Failure led to no further intervention in 2, amputation in 1, further endovascular intervention in 5, and open surgical reconstruction in 4 limbs. After further treatment, 29 limbs are patent with no return of symptoms, 3 are occluded, and 4 have required amputation, all for initial presentation with critical ischemia. Life-table analyses calculate primary and secondary patency rates of 61% and 67% and a clinical success rate of 56% at 12 months. CONCLUSIONS: Atherectomy using the Auth Rotablator provides acceptable results, but its role in comparison to other endovascular techniques is still to be defined.

Infrainguinal atherectomy using the transluminal endarterectomy catheter: patency rates and clinical success for 144 procedures.

PURPOSE: To determine if atherectomy using the transluminal endarterectomy catheter (TEC) is an effective endoluminal therapy for infrainguinal occlusive disease. METHODS: Three surgeons used the TEC for 144 infrainguinal atherectomy procedures in 133 patients. The indications were severe claudication in 83, critical ischemia in 56, and graft stenosis in 5 limbs. The pathology was stenosis in 36 and occlusion in 105 limbs. Balloon dilation was also performed in 109 and stenting in 17 limbs. RESULTS: There was initial technical and anatomic success in 124 (86%) procedures. There were 67 technically successful procedures at mean follow-up of 19 months, although 3 of these limbs with gangrene and extensive distal disease required major amputation. There were 26 failures due to stenosis leading to further intervention and 51 due to occlusion. Twenty of these cases were managed conservatively, 21 were treated with repeat endovascular intervention, 31 with bypass grafting, and 5 with amputation. Repeat intervention in 52 limbs resulted in 36 with patent arteries, 10 that are occluded, and 6 that required amputation. Thirteen of the 14 amputations were for limbs with critical ischemia, but 1 was in a patient with claudication. Life-table analysis showed that the primary patency rate was 51%, the assisted primary patency rate was 61%, and the secondary patency rate was 75% at 15 months. The clinical success rate was 49%, and the salvage rate for limbs with critical ischemia was 78% at 12 months. Univariate log-rank testing showing no significant differences according to the clinical presentation of pathology, but results were worse for lesions > 5 cm long due to more frequent immediate failures. However, multivariate Cox regression analysis showed that results were significantly worse for critical ischemia than for claudication, stenosis compared to occlusions, for limbs with poor runoff, for operations performed by percutaneous rather than an open approach, and for those performed more recently. CONCLUSIONS: TEC atherectomy may have a place in selected patients, but the optimal circumstances for its use and long-term efficacy require further study.

Multivariate Cox regression analysis of covariates for patency rates after femorodistal vein bypass grafting.

Multivariate Cox regression analysis of patency rates for 750 consecutive femorodistal autogenous vein graftings for chronic lower limb ischemia showed that significant independent prognostic covariates were the type of graft (long saphenous or arm vein), presence of diabetes, and absence of a past history of myocardial ischemia. Analysis assumes that patients withdrawn with patent grafts due to death or loss to follow-up would have followed the same course as those who remain, and the degree to which this could distort results was studied. Patients who died with patent grafts were more likely to have had past myocardial ischemia and critical lower limb ischemia. Cox regression analysis for 600 operations after excluding patients who died with patent grafts then showed that significant independent covariates were the type of graft (long saphenous or arm vein) and indication (claudication or critical ischemia); then age, sex, hypertension, diabetes, myocardial ischemia, date of operation, surgeon, site of distal anastomosis, or first compared to repeat operations had no significant influence. Cox regression analysis helps determine which covariates influence graft patency rates, but results are affected by censored data, particularly from patients who die with patent grafts.

Therapists' ratings of fundamentalist and nonfundamentalist families in therapy: an empirical comparison.

Using the Family Health Scale, Part I of an instrument developed for this study, two randomly selected groups of certified family therapists rated either nonfundamentalist or fundamentalist families in therapy on eight recognized indicators of family health. Factor analysis yielded eight factors accounting for 66% of the variance between groups. Cannonical discriminant function analysis revealed that therapists rated fundamentalist families as significantly less healthy on three of the eight factors and more healthy on one factor. Part II of this instrument, the Religion Impact Scale assessed the effects of church community and church teachings upon families. For fundamentalists, the church and concomitant belief system had a significant impact upon family organization and functioning. Theoretical and clinical implications of these findings are discussed.