Quantification in Patient Urine Samples of Felbamate and Three Metabolites: Acid Carbamate and Two Mercapturic Acids

PURPOSE: Previously we proposed and provided evidence for the metabolic pathway of felbamate (FBM), which leads to the reactive metabolite, 3-carbamoyl-2-phenylpropion-aldehyde. This aldehyde carbamate was suggested to be the reactive intermediate in the oxidation of 2-phenyl-1,3-propanediol monocarbamate to the major human metabolite 3-carbamoyl-2-phenylpropionic acid. In addition, the aldehyde carbamate was found to undergo spontaneous elimination to 2-phenylpropenal, commonly known as atropaldehyde. Moreover, atropaldehyde was proposed to play a role in the development of toxicity during FBM therapy. Evidence for atropaldehyde formation in vivo was reported with the identification of modified N-acetyl-cysteine conjugates of atropaldehyde in both human and rat urine after FBM administration. Identification of the atropaldehyde-derived mercapturic acids in urine after FBM administration is consistent with the hypothesis that atropaldehyde is formed in vivo and that it reacts with thiol nucleophiles. Based on the hypothesis that the potential for toxicity will correlate to the amount of atropaldehyde formed, we sought to develop an analytic method that would quantify the amount of relevant metabolites excreted in patient urine. METHODS: We summarize the results of an LC/MS method used to quantify FBM, 3-carbamoyl-2-phenylpropionic acid and two atropaldehyde-derived mercapturic acids in the patient population. RESULTS: Analysis was performed on 31 patients undergoing FBM therapy. The absolute quantities of FBM and three metabolites were measured. CONCLUSIONS: This method demonstrated sufficient precision for the identification of patients exhibiting "abnormal" levels of atropaldehyde conjugates and may hold potential for patient monitoring.     

Clinical correlation and molecular evaluation confirm that the MLH1 p.Arg182Gly (c.544A>G) mutation is pathogenic and causes Lynch syndrome

Approximately 25 % of mismatch repair (MMR) variants are exonic nucleotide substitutions. Some result in the substitution of one amino acid for another in the protein sequence, so-called missense variants, while others are silent. The interpretation of the effect of missense and silent variants as deleterious or neutral is challenging. Pre-symptomatic testing for clinical use is not recommended for relatives of individuals with variants classified as ‘of uncertain significance’. These relatives, including non-carriers, are considered at high-risk as long as the contribution of the variant to disease causation cannot be determined. This results in continuing anxiety, and the application of potentially unnecessary screening and prophylactic interventions. We encountered a large Irish Lynch syndrome kindred that carries the c.544A>G (p.Arg182Gly) alteration in the MLH1 gene and we undertook to study the variant. The clinical significance of the variant remains unresolved in the literature. Data are presented on cancer incidence within five kindreds with the same germline missense variant in the MLH1 MMR gene. Extensive testing of relevant family members in one kindred, a review of the literature, review of online MMR mutation databases and use of in silico phenotype prediction tools were undertaken to study the significance of this variant. Clinical, histological, immunohistochemical and molecular evidence from these families and other independent clinical and scientific evidence indicates that the MLH1 p.Arg182Gly (c.544A>G) change causes Lynch syndrome and supports reclassification of the variant as pathogenic.     

Treatment of deep cerebral venous thrombosis by local infusion of tissue plasminogen activator

BACKGROUND

Treatment of extensive intracranial venous sinus thrombosis with thrombolytic drugs is described, although the indications for and most efficacious technique for achieving thrombolysis remain uncertain. We report the successful lysis of superficial and deep venous system thrombosis by infusion of recombinant human tissue-type plasminogen activator (rt-PA) into the anterior superior sagittal sinus.

CASE DESCRIPTION

A 34-year-old man presented with headaches followed by decreased level of consciousness and left hemiplegia. Angiography showed thrombosis of the superior sagittal and both transverse and straight sinuses with extension into the internal cerebral veins. The superior sagittal sinus was catheterized via a transfemoral route and rt-PA, 25 mg, was infused. There was no significant change in the thrombosis. The catheter was left in place and rt-PA was infused at 1 mg/minute for 19 hours. Repeat angiography showed resolution of the thrombosis. The patient was placed on heparin and then coumadin. He recovered completely.

CONCLUSIONS

This report suggests that superselective infusion of thrombolytics into thrombosed intracranial venous sinuses can lyse intracranial venous sinus thrombosis. The thrombolytic agent must be infused for hours. The apparent successful lysis of clot in the deep venous system when infusion was into the superior sagittal sinus might be related to diffusion of rt-PA throughout the intracranial venous system or to improved venous outflow caused by lysis of clot in superficial dural sinuses.     

Periprosthetic femoral fractures treated with a long-stem cementless component

Periprosthetic femoral fractures can be a difficult management problem. Proximal femoral fractures with a loose component are managed best with revision arthroplasty. We reviewed the midterm follow-up of 14 proximal femoral fractures managed with a long-stem extensively porous-coated femoral component. The average follow-up in this series was 8.2 years (minimum, 5.3 years). Fractures were treated with open reduction and internal fixation, supplemental cortical strut grafting when required, and a canal-filling implant. All fractures achieved union with an average time to union of 4 months. There have been no component failures requiring revision. Twelve prostheses achieved stable bone ingrowth, 1 component showed stable fibrous ingrowth, and 1 component was not stable but was not symptomatic enough to warrant revision.     

Outpatient Vascular Intervention: A Two-Year Experience

PURPOSE: To retrospectively analyze the outcome of a range of interventional vascular procedures performed on outpatients. METHODS: Suitability for outpatient procedures was assessed according to agreed protocols. An episode was defined as any procedure/s through a single access site at one attendance. Retrospective case-note review was performed. RESULTS: There were 693 outpatient episodes between April 1998 and May 2000 (290 interventional, and 403 diagnostic procedures), comprising 25% (693/2,769) of the total workload. Follow-up is available in 214; 38 of these were transfers from outlying hospitals and were excluded from analysis. One hundred and seventy-six were true outpatients. There were 98 iliac and 46 femoropopliteal interventions, 2 aortic stents, 1 renal and 5 upper-limb angioplasties (PTAs), 5 embolizations, 8 Hickman lines, 1 line stripping, 3 atherectomies, 1 dialysis-graft PTA and 6 bypass-graft PTAs. Sixty-eight closure devices were used. Twelve patients were converted to inpatients (6.8%, 12/176). The readmission rate was 3.4% (6/176). The reattendance rate was 1.1% (2/176), both subsequently attending for outpatient duplex ultrasound examination to exclude pseudoaneurysm. The major complication rate was 3.4% and the delayed major complication rate was 1.7%. CONCLUSION: Outpatient vascular intervention is safe with appropriate protocols and with careful patient selection. Local vascular services benefit from the release of inpatient beds.     

Coronary hemodynamic responses during spontaneous angina in patients with and patients without coronary artery spasm

The mechanisms of spontaneous angina were evaluated during cardiac catheterization in 13 patients who had angina occurring without provocation at rest. Left ventricular and systemic hemodynamics, coronary venous flows (thermodilution technique), electrocardiogram and coronary angiograms were recorded before and during spontaneous angina. Angiography during spontaneous angina showed that 5 patients had coronary spasm (group I) and 8 patients did not (group II). In group II there was a preponderance of multivessel coronary artery disease. Left ventricular end-diastolic pressure increased in all patients in both groups during spontaneous angina. In group I, 4 patients had transient ST elevation and 1 patient had peaked T waves during angina. Transient ST depression occurred during spontaneous angina in all group II patients. Group I patients had decreased coronary sinus flow (4 of 5 patients) or decreased regional flow (5 of 5) during spontaneous angina. Coronary resistance and ratio of double product to coronary blood flow increased in all patients. In group II, coronary hemodynamic responses during spontaneous angina varied. Coronary venous flows, coronary resistance and ratio of double product to coronary blood flow showed no uniform pattern. Thus, patients with severe coronary artery disease can have spontaneous angina without angiographic findings of coronary spasm. After analysis of angiograms and coronary hemodynamics in these patients, no apparent uniform mechanism for spontaneous angina was found.