Extended interval dosing of natalizumab in multiple sclerosis.

BACKGROUND: Natalizumab (NTZ), a monoclonal antibody to human α4ß1/ß7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days. METHODS: A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks. RESULTS: 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort. CONCLUSIONS: Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

Phage display mapping for peptide 11 sensitive sequences binding to laminin-1.

We utilized a 9-mer random phage display library to identify sequences which bind to laminin-1 and elute with heparan sulfate or peptide 11 (CDPGYIGSR). Laminin-1 derivatized plates were used for biopanning. Three consecutive rounds of low pH elutions were carried out, followed by three rounds of specific elutions, each consisting of a heparan sulfate elution followed by a peptide 11 elution. The random sequence inserts were sequenced for phage populations eluted at low pH, by heparan sulfate and by peptide 11. Specifically eluted phage populations exhibited three classes of mimotopes for different regions in the cDNA derived amino acid sequence of the 67 kDa laminin binding protein (LBP). These regions were (1) a palindromic sequence known as peptide G, (2) a predicted helical domain corresponding to LBP residues 205-229, and (3) TEDWS-containing C-terminal repeats. All elution conditions also yielded phage with putative heparin binding sequences. We modeled the LBP(205-229) domain, which is strongly predicted to have a helical secondary structure, and determined that this region likely possesses heparin-binding characteristics located to one side of the helix, while the opposite side appears to contain a hydrophobic patch where peptide 11 could bind. Using ELISA plate assays, we demonstrated that peptide 11 and heparan sulfate individually bound to synthetic LBP(205-229) peptide. We also demonstrated that the QPATEDWSA peptide could inhibit tumor cell adhesion to laminin-1. These data support the proposal that the 67 kDa LBP can bind the beta-1 laminin chain at the peptide 11 region, and suggest that heparan sulfate is a likely alternate ligand for the binding interactions. Our results also confirm previous data suggesting that the most C-terminal region of the LBP, which contains the TEDWS repeats, is involved in cell adhesion to laminin-1, and we specifically implicate the repeat sequence in that activity.

Multiple sequential femoral tibial grafting for severe ischemia.

For the past decade a common procedure used to salvage severely ischemic limbs has been autogenous vein bypass grafting to the distal popliteal artery or, if the popliteal trifurcation is occluded, to one of the tibial-peroneal branches. Reported limb salvage rate and long-term graft function varies considerably but in most series is low. To increase graft flow and to decrease resistance in femoral-poplitical-tibial grafts and thereby to perfuse the ischemic foot more effectively, we have employed multiple sequential anastomoses of a single vein graft to distal branches--a technique similar to that used occasionally in aortocoronary bypass grafting. The autogenous vein graft alone, or in combination with bovine heterograft, has been used in six patients with gangrenous toes or far advanced ischemia and in one patient with severe claudication. Multiple anastomoses below the knee were carried out in each patient. Anastomosis has been to a blind popliteal segment, then to a tibial or peroneal in four patients, to both tibials in another two patients, and to both tibials and the peroneal in one patient. Flow rates measured on the operating table clearly demonstrated a significant increase in flow through the graft with each additional anastomosis. There has been a greater response to surgery with return of pulses, warmth of the foot, and rapid healing as compared with previous patients having single femoral-tibial anastomoses. One failure occurred acutely from a technical problem early in the series; one failed at 3 months in a patient with pancreatic cancer and another patient died 2 weeks after operation of a myocardial infarct.

Compressive neuropathy as a complication of anticoagulant therapy.

Three cases of compressive neuropathy after anticoagulant therapy are reported. The first known description of ulnar and radial nerve involvement in this syndrome is provided. A review of the literature along with a discussion of some of the clinical features, the diagnosis, and the management of this entity are presented.

Transantral transsphenoidal approach to the pituitary. Technical note.

The authors describe the technique of a transantral transsphenoidal approach to the sella turcica. The advantages and potential complications are discussed. This procedure may also be applicable when dealing with tumors of the skull base and orbits.

Carotid artery aneurysm of granulomatous origin.

A native of the Western Caroline Islands presented with a granulomatous aneurysm of the right common carotid artery measuring 7 to 8 cm, which was resected and replaced with a reversed segment of saphenous vein. Adequacy of the collateral circulation to the brain was established by occlusion of the common carotid artery with local anesthesia. This was followed by definitive operation with general endotracheal anesthesia and induced hypertension. Although tuberculosis was the most likely etiologic agent, sarcoid could not be ruled out. Granulomatous aneurysms of the common carotid are extremely rare, and if this case was sarcoid in origin, it is the first such case reported. Only one other similar aneurysm could be found in the literature. Of the various methods of reconstruction of the common carotid artery reported, autogenous reversed saphenous vein is recommended strongly.

Immune monitoring of blood in heart transplant recipients: application of flow cytometry.

In this study, we review the utility of peripheral blood lymphocyte evaluation using commercially available monoclonal antibodies in the diagnosis of rejection or infection in 27 patients undergoing allograft heart transplantation. Double-color staining methods employing fluorescein isothiocyanate (FITC) and phycoerythrin (PE) allowed identification of a variety of lymphocyte subsets and determination of activation or proliferation of lymphocytes. All patients also underwent regular endomyocardial biopsy procedures. A total of 30 rejection episodes were diagnosed by endomyocardial biopsy. The results of immune monitoring profile (IMP) of lymphocytes and endomyocardial biopsies were concordant 76% of the time. Discrepancies were most common when the biopsy showed only mild rejection. The false-positive rate with serial IMP was less than 1%. The IMP was also useful in distinguishing between infection, especially cytomegalovirus infection, and rejection. General guidelines for utilizing IMP in transplant recipients are presented.

A study of the diastolic flow velocity profile of the clinically uncomplicated mitral porcine bioprosthesis using an echo-Doppler technique.

Pulsed Doppler echocardiography was performed in 17 subjects who had clinically uncomplicated porcine bioprosthesis in the mitral position. A positive initial diastolic flow wave was present in all patients; end-diastolic A waves were seen in the sinus rhythm of every patient. The peak of the diastolic wave was delayed when compared with the normals in our laboratory. This wave had clearly demarcated ascending, mid- and descending segments. When contrasted with normal subjects, the slope of the diastolic wave was mildly reduced in all patients. Fine to coarse indentations on the descending and mid-segments were seen in 15/17 (88%) of the patients. We conclude that the diastolic flow profile of the clinically uncomplicated mitral bioprosthesis resembles mild mitral stenosis. Reduced orifice size and/or the physical properties of the bioprosthesis are the likely mechanisms for these alterations.

Concentration of 99mTechnetium polyphosphate in fibrothorax following pneumonectomy.

Following the injection of 99mTechnetium-polyphosphate for bone scanning, a diffuse accumulation of radioactivity in post-pneumonectomy fibrothorax was demonstrated in 3 patients. This substantiates the nonspecificity of the localization of 99mTc-phosphorus compounds, and underlines the need for close clinical correlation in the accurate interpretation of such scans.

Gated cardiac tomographic visualization of coronary artery calcification.

Coronary artery calcification (CAC) is usually detected by fluoroscopy or on cine films during coronary angiography, but measurement of the calcification is not possible. Gated tomography of the heart provides a full sized image with high contrast spatial resolution of 0.1 mm and low contrast spatial resolution of 0.76 mm. The radiation exposure to the heart is between 1-5% of that experienced with coronary cinefluorography . Measurement of the diameter of calcium deposits is possible and calcium that could be related to arterial stenosis may be identified.

Intrarenal reflux and renal damage.

The retrograde flow of dye from the calices into the collecting tubules (intrarenal reflux) seen during cystrography in children and its effect on the kidneys were evaluated. A retrospective analysis was made of 175 patients with excretory urograms revealing cortical atrophy. Of these patients 68 per cent had cystograms revealing vesicoureteral reflux. Intrarenal reflux was seen in 8 patients less than 6 years old, an incidence of 13.5 per cent in that age group. There was a high correlation, 7 of 8 or 87.5 per cent, between the areas of intrarenal reflux, and associated renal cortical atrophy and calicectasis. Intrarenal reflux provides a pathway by which bacteria and hydrostatic pressure may produce injury to the renal parenchyma. The presence of intrarenal reflux is an absolute indication for ureteroneocystostomy.

Eosinophilic fasciitis with porphyria cutanea tarda and progressive destructive arthritis.

The course of arthritis with eosinophilic fasciitis is poorly documented. We report a patient in whom polyarthritis preceded the clinical appearance of eosinophilic fasciitis and progressed over a 14-year period to a destructive process with inflammatory and degenerative characteristics. Porphyria cutanea tarda and transient extramedullary pancytopenia complicated this patient's disease.

Universal spondylodiscitis in a patient with erosive peripheral arthritis and apatite crystal deposition.

A patient with erosive peripheral arthritis in whom vasculitis and monoclonal IgG kappa paraprotein were associated with sacroiliitis and widespread destruction of intervertebral discs is reported. Crystals resembling apatite were identified in intervertebral disc material, and we postulate that the discitis was accelerated by apatite deposition. Our case illustrates a unique example of axial involvement in rapidly progressive joint disease.

Air-contrast barium enema studies after flexible proctosigmoidoscopy: randomized controlled clinical trial.

The authors performed a randomized clinical trial to determine the effect of flexible proctosigmoidoscopy (FPS) on the quality of air-contrast barium enema (ACBE) studies performed on the same day and whether it mattered if air or carbon dioxide was used for endoscopic insufflation. One hundred twenty-one patients were randomly assigned to one of the following groups: Same-day studies were performed, with air used for insufflation, in group 1; same-day studies, with carbon dioxide, in group 2; and separate-day studies in group 3. Scout images obtained before the ACBE study were graded for the amount of air seen, and ACBE studies were graded for overall quality; each was graded on a scale of 0-3 in a blinded fashion. The air score was significantly greater in group 1 (2.69) than in group 2 (2.01) (P less than .001), which in turn was significantly greater than in group 3 (1.53) (P less than .01). The ACBE quality scores in the three groups were not significantly different. The authors conclude that FPS can be done before ACBE examination without impairing the quality of the ACBE study. Although carbon dioxide insufflation results in less intestinal air after FPS, the quality of the ACBE study is not affected.

Bone mineral density and biochemical markers of bone metabolism in ankylosing spondylitis.

OBJECTIVE: To determine (1) bone mineral density (BMD) of the axial and appendicular skeleton in men with moderate and severe ankylosing spondylitis (AS), and (2) associations between BMD and bone metabolism variables. METHODS: Nineteen men with AS and 19 healthy male controls were evaluated for osteoporosis by dual energy x-ray absorptiometry in both the hip and the lateral and posterior-anterior (PA) projections of the lumbar spine. Calcium homeostasis was evaluated by measuring minerals, calcitropic hormones, and markers of remodeling. Total testosterone levels were also measured. RESULTS: Osteopenia was noted in both the hip and spine of the subjects with AS. The lateral projection of L3 was a more sensitive indicator of the vertebral BMD compared to the PA projection. Calciuin homeostasis and testosterone levels were normal in subjects with AS. In most subjects, markers of bone formation and resorption were normal. CONCLUSION: BMD of subjects with AS is decreased, in spite of normal calcium homeostasis and bone remodeling indices.

Left main coronary artery embolism: a case report.

A 27-year-old man had recurrent myocardial infarction found to be due to coronary embolism to the left main coronary artery with downstream embolization. The presumed etiology of thromboembolism was idiopathic cardiomyopathy. A unique method of treatment with Fogarty catheter retrieval was used.

Metacarpophalangeal arthropathy associated with manual labor (Missouri metacarpal syndrome). Clinical radiographic, and pathologic characteristics of an unusual degeneration process.

We describe 7 manual laborers with painful, palpably enlarged metacarpophalangeal joints. Characteristic radiographic changes were joint space loss, prominent osteophytes, and cystic metacarpal heads most prominent in the second and third metacarpophalangeal joints. In 3 of 4 patients, joint biopsy specimens showed subsynovial fibrosis and villous hyperplasia. All 7 patients had similar backgrounds of heavy work demanding sustained gripping motions of both hands, for periods that exceeded 30 years. We designated their condition metacarpophalangeal arthropathy associated with manual labor.