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Biomedical subjects

M Skinner

Publications and source records attributed to M Skinner.

At least 19 recordsLinked to original sources
PubMed1996

Dose-intensive melphalan with blood stem cell support for the treatment of AL amyloidosis: one-year follow-up in five patients.

The morbidity and lethality of AL amyloidosis is caused by the deposition of lg light chains as fibrillar amyloid protein in vital organs, disrupting their function, and not by the generally low burden of clonal plasma cells that produce the paraproteins. Survival of patients with AL amyloidosis is no more than 1 to 2 years from the time of diagnosis with current management approaches. Clearly, more effective therapies are needed for this rapidly lethal disease. Five patients were treated with dose-intensive melphalan and blood stem cell support and followed for a period of 1 year. Patients were diagnosed with AL amyloidosis by tissue biopsy and categorized by performance status and organ involvement. Their plasma cell dyscrasias were evaluated with immunofixation electrophoresis of serum and urine specimens, quantitative serum lgs, and immunohistochemical staining of bone marrow biopsy specimens. After treatment with dose-intensive intravenous melphalan followed by infusion of autologous growth-factor-mobilized blood stem cells, clinical evaluations and plasma cell studies were repeated at 3 and 12 months. Three men and 2 women aged 38 to 53 years were treated. Median performance status (SWOG) was 2 (1 to 3), and clinical presentations included nephrotic syndrome (n = 1), symptomatic cardiomyopathy (n = 1), gastrointestinal involvement with polyneuropathy (n = 2), and hepatomegaly (n = 1). With a median follow-up of 13 months (12 to 17 months), all five patients are well and have shown stable or improved performance status and clinical remission of organ-related dysfunction, including a 50% reduction in daily proteinuria with no change in creatinine, reversal of symptoms of cardiomyopathy and reductions of posterior wall and septal thickening, reversal of polyneuropathy and gastric atony, and resolution of hepatomegaly by computed tomographic scan. In 3 of the 5 patients (60%) at 12 months after treatment, plasma cell dyscrasias could not be detected. Dose-intensive chemotherapy with intravenous melphalan and growth-factor-mobilized blood stem cell support is feasible therapy for patients with AL amyloidosis, even when there is clinical evidence of cardiac involvement. At least some patients with AL amyloidosis achieve complete remission of their plasma cell dyscrasia, improvement in performance status, and clinical remission of organ-specific disease after this form of treatment.

Adult↗
PubMed1996

Resolution of heart failure in patients with AL amyloidosis.

BACKGROUND: Patients with AL amyloidosis and congestive heart failure have a very poor prognosis. To date, the recovery of these patients has not been described in detail. OBJECTIVE: To determine the frequency and characteristics regression of disease in patients with congestive heart failure due to AL amyloidosis. DESIGN: Review of patients with systemic AL amyloidosis. SETTING: An international referral center for amyloidosis in the United States. PATIENTS: 140 patients with congestive heart failure due to Al amyloidosis who were seen between 1983 and 1994. MEASUREMENTS: Functional status, Doppler echocardiography, and objective measurements of disease activity. RESULTS: 3 of 140 patients (2.1%) had marked resolution of congestive heart failure and evidence for remission of disease activity. All 3 had been treated with melphalan. CONCLUSIONS: Melphalan appears to have had a favorable effect in 3 patients with AL amyloidosis and heart failure. The abolition of light chains that was seen in these 3 patients suggests that light-chain toxicity may play a role in the genesis of heart failure in patients with AL amyloidosis.

Amyloidosis↗
PubMed1996

Electrocardiography and Doppler echocardiography in secondary (AA) amyloidosis.

The fibrils in AL and AA amyloidosis, although similar in appearance, have different biochemical composition and staining characteristics. Whereas electrocardiographic and echocardiographic features of heart involvement in AA amyloidosis resemble those for AL amyloidosis, our findings support the concept that the constituent amyloid fibrils may play a decisive role in the clinical pattern and significance of heart infiltration.

Adult↗
PubMed1996

Treatment of 100 patients with primary amyloidosis: a randomized trial of melphalan, prednisone, and colchicine versus colchicine only.

PURPOSE: A clinical trial designed to test whether treatment with melphalan, prednisone, and colchicine (MPC) is superior to colchicine (C) alone was performed in patients with primary amyloidosis (AL), a nonmalignant plasma cell dyscrasia. PATIENTS AND METHODS: Patients were randomized to MPC or C with stratification according to sex, time from diagnosis to study entry (ie, less than 3 months or 3 to 12 months), and dominant organ system involvement (ie, cardiac, renal, neurologic, or others). Data were gathered monthly from patients, quarterly from physicians, and annually in the Clinical Research Center. One hundred consecutive patients with AL amyloidosis admitted between 1987 and 1992 who met eligibility requirements were treated and followed for a minimum of 18 months. Fifty patients (group A) received daily oral colchicine and 50 patients (group B) received cycles of oral melphalan and prednisone every 6 weeks for 1 year as well as colchicine. RESULTS: The principal outcome measure was median survival, which was compared in the two treatment groups and in the subgroups. The overall survival of all patients from study entry was 8.4 months. Comparing group A (C) to group B (MPC), the survival was 6.7 months versus 12.2 months (P = 0.087). Both treatment groups had poor survival for patients in the cardiac subgroup, longest survival in the renal group, and significant differences favoring MPC treatment only in patients whose major system manifestations were neurologic (P = 0.037) or other (P = 0.007). Multivariate analysis showed a strongly significant treatment effect (P = 0.003) and improved survival associated with not having cardiac or gastrointestinal involvement. CONCLUSIONS: MPC was advantageous for patients whose major manifestations of amyloid disease were other than cardiac or renal. Better survival regardless of treatment was noted in patients for whom a satisfactory supportive treatment such as transplant or dialysis exists for their organ failure.

Amyloidosis↗
PubMed1996

Polymerization of normal and intact beta 2-microglobulin as the amyloidogenic protein in dialysis-amyloidosis.

The primary structure of beta 2-microglobulin (beta 2m), the major constituent protein of beta 2-microglobulin amyloidosis (A beta 2m) or dialysis-amyloidosis, was initially shown to be identical to serum beta 2m, thereby strongly suggesting the polymerization of intact beta 2m in tissues. Recent biochemical data have been controversial, showing beta 2m acidic isoforms, fragmentation and amino acid sequence alteration of deposited beta 2m. The aim of this study was to reinvestigate beta 2m amyloid deposits for the presence of beta 2m fragments and/or amino acid sequence alteration. Four amyloid-laden tissues (3 femoral bone amyloid cysts and 1 heart tissue) from dialysis patients were used to isolate amyloidogenic beta 2m. Amyloid fibrils were isolated using the classic water extraction method, and purified in 6 M guanidine on a gel-filtration column. The protein was further purified on 17% SDS-PAGE gel, and transferred to a nitrocellulose membrane for immunostaining with antihuman beta 2m. beta 2m samples were microsequenced using the standard 03RPTH program on a 470A gas-phase sequencer, and HPLC was performed after digestion with trypsin. Two peaks were obtained with the gel filtration column, the second corresponding by molecular weight to beta 2m. SDS-PAGE analysis of this peak under reducing conditions, demonstrated one major band at 12,000 Da and a minor band at 25,000 Da (monomer and dimer), and no lower molecular weight bands were observed. The 12 kDa band was micro-sequenced and the amino acid sequence corresponded to that of normal beta 2m through the 40th residue. Amino acid sequence analysis showed no difference from normal beta 2m in any of the beta 2m proteins contained in the amyloid deposits isolated from the four studied tissues. Also, the HPLC profile of the four protein samples were strictly normal and identical to a commercial preparation of beta 2m. The present study demonstrates that beta 2m molecules polymerized in amyloid fibrils and deposits are intact and have a normal amino acid sequence, and produced by a specific and unique fibrillogenetic mechanism, which does not require proteolytic processing from the precursor protein to the amyloid fibrils.

Amino Acid Sequence↗
PubMed1996

Improvement in the polyneuropathy associated with familial amyloid polyneuropathy after liver transplantation.

OBJECTIVE: To study, following liver transplantation, the neurologic progression or regression of the polyneuropathy in a cohort of patients with familial amyloidotic polyneuropathy (FAP). BACKGROUND: FAP is characterized by the relentless progression of neurologic and cardiac impairment, leading to death within 7 to 15 years after disease onset. No effective treatment to slow or halt the progression of this disease has been found to date. DESIGN/METHODS: Over the past 3 years, our FAP patients were offered liver transplantation as treatment. We report on nine patients who were followed longitudinally with serial neurologic examinations since transplantation. RESULTS: Clinically, all patients evaluated for neurologic progression reported significant improvement in general well being. No patient showed any progression in neurologic disease since receiving a liver transplant. Improvements are documented in symptomatic, autonomic, and sensorimotor neurologic disease in all patients. CONCLUSION: Our experience suggests that liver transplantation may offer hope for arrest of progression and neurologic improvement in patients with FAP.

Adult↗
PubMed1995

Haplotype analysis of common transthyretin mutations.

The most frequent transthyretin (TTR) variant associated with hereditary amyloidosis is TTR Met 30, which has its major focus in Portugal, although it also occurs in many other countries. The distribution of the mutation and its occurrence in a CpG dinucleotide lead us to question the origin of the mutation and the possibility of its having originated in Portugal. In order to investigate these questions, we studied the distribution of haplotypes associated with the Met 30 mutation in families from different European countries. All the analysed Portuguese families presented the same haplotype associated with the Met 30 mutation (haplotype I). The same was found for the Swedish and Spanish families studied. However, a distinct haplotype (haplotype III) was found in three families, one Italian, one English and one Turkish. These results suggest that, although the Portuguese Met 30 carriers might have one founder, the mutation probably recurred in populations in Europe in a similar manner to that reported in Japan. In this study, we have also analysed the haplotypes associated with other TTR variants frequent in the Portuguese population.

Amyloidosis↗
PubMed1995

Atrial thrombi occurring during sinus rhythm in cardiac amyloidosis: evidence for atrial electromechanical dissociation.

Thrombus formation in the left atrium is rare in patients in sinus rhythm. In three patients with extensive cardiac amyloidosis transthoracic echocardiography showed large atrial thrombi in or protruding into the body of the left atrium during sinus rhythm. Doppler studies showed no A wave on mitral inflow. Severe atrial and ventricular infiltration by amyloid may have resulted in mechanical atrial standstill with resultant thrombus formation. These findings suggest that patients with severe cardiac amyloidosis may require anticoagulation when atrial function is impaired.

Adult↗
PubMed1994

Two transthyretin mutations (glu42gly, his90asn) in an Italian family with amyloidosis.

A family with familial amyloidotic polyneuropathy (FAP) was previously found to have a substitution of asparagine for histidine at position 90 of transthyretin. Members with his90asn developed FAP. However, close examination of the transthyretin gene revealed that glu42gly is coinherited with his90asn in this family. Since glu42gly has already been seen in Japanese FAP patients, and his90asn has been found in Portuguese and German individuals without FAP, we conclude that his90asn is a nonpathogenic variant.

Adult↗
PubMed1994

Orthotopic liver transplantation for familial amyloidotic polyneuropathy.

Orthotopic liver transplantation for inborn errors of metabolism has become a standard indication for transplantation in pediatric and adult patients with alpha-1 antitrypsin deficiency, Wilson's disease and tyrosinemia, amongst several less common diseases. Familial amyloidotic polyneuropathy (FAP) is a rare autosomal dominant disease whose metabolic origin lies in an abnormal protein synthesized primarily in the liver. FAP, also discussed as the autosomal dominant form of amyloidosis, is characterized as a hereditary form of amyloidosis. It is the rarest form of amyloidosis affecting kindreds of specific ethnic backgrounds. The true incidence of this disease in the United States is not known. The mutant protein, called transthyretin or prealbumin, forms amyloid fibrils which accumulate in vital tissues ultimately leading to the patient's death. Liver transplantation for this inherited disease leads to the production of normal transthyretin protein. This theoretically should arrest the disease process. The first 5 patients in the United States with FAP who have undergone transplantation are presented.

Adult↗
PubMed1993

Neutrophil proteases associated with amyloid fibrils.

We found significant amounts of enzymatic activity characteristic of the human neutrophil proteases, elastase and cathepsin G, associated with isolated amyloid fibrils from patients with five different types of systemic amyloidosis. Amyloid deposits in tissue sections from the patients with amyloid A, amyloid transthyretin and amyloid beta 2-microglobulin amyloidosis also stained positive with antiserum to elastase and cathepsin G. Elastase and cathepsin G, found in the azurophilic granules of the neutrophil and, to a lesser extent, the monocyte, may become associated with amyloid precursor proteins before or during the formation of amyloid fibrils. This may occur in an extracellular inflammatory microenvironment or in a phagolysosome and play a role in the formation of the fibrils.

Amyloid↗
PubMed1993

Localized amyloidosis of the larynx: evidence for light chain composition.

We report the biochemical characterization of amyloid fibrils from a patient with localized amyloidosis of the epiglottis and larynx. Biopsy specimens showed amorphous material consistent with amyloid deposits with a plasmacytic infiltrate. Both plasma cells and amyloid deposits stained positively by immunohistochemistry for kappa light chains. Amyloid fibrils were isolated. The major constituent resolved as a 13 kd band was sequenced and found to be consistent with a kappa 1 light chain. A tryptic digest was carried out and 3 tryptic peptides were sequenced defining the first 45 residues of the protein and residues 110 through 119. Four amino acid substitutions were found, 3 of which have not been described previously. This study defines the immunoglobulin origin of amyloid deposits in localized amyloidosis. The benign nature of localized amyloidosis suggests that a localized clone of plasma cells producing an amyloidogenic light chain may represent the pathogenetic mechanism of this disease, which appears to be a form of plasma cell dyscrasia.

Amino Acid Sequence↗
PubMed1993

Effects of chloroform and bromodichloromethane on DNA synthesis in male F344 rat kidney.

We have been investigating the actions of chloroform (CHCl3) and bromodichloromethane (BDCM) in rat kidney after different routes of exposure. Male F344 rats were exposed by gavage with corn oil or water as the diluting vehicle. All experiments lasted 30 days with gavage exposures 5 days per week for 4 weeks (20 doses). All animals were injected IP with bromodeoxyuridine (BrdU) 3 times over a 6-day period at 50 mg/kg/injection. Kidney tissue was fixed and slides were stained with hematoxylin and eosin for routine viewing and by the PAP (peroxidase-antiperoxidase) technique using anti-BrdU to label cells in DNA synthesis. There were no significant changes in gross parameters evaluated between the control rats and the rats exposed to CHCl3 or BDCM. Rats exposed via corn oil gavage to CHCl3 displayed a segment-specific epithelial cell necrosis (6/6 high dose, 2/6 low dose). The lesions were primarily localized to the second segment of the proximal tubule, although some spread to cells in the first segment was occasionally observed. No histologic lesions were observed in the kidneys of rats exposed to BDCM. Preliminary results indicate a significant increase in DNA synthesis in the CHCl3-treated rats and a slight increase in DNA synthesis in BDCM-treated rats with corn oil as the diluent. The increase in BrdU labeling was primarily in cells of the S2 segment of the proximal tubule and interstitial cells of CHCl3-exposed animals and in cells of the S3 segment of BDCM-exposed animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1993

Variation in birth timing and location of the neonatal line in human enamel.

The location of the neonatal line in 173 primary teeth from 43 children was investigated and shown to differ significantly among pre-term, term, and post-term births. Approximately 75% of the neonatal lines that lie beyond 2SD of the mean location of the line in term births are from children born outside of 38 to 42 weeks gestation. The duration of pregnancy accounts for about 36% of the variation in location of the neonatal line in non-term births. Based on the small proportion of non-term births whose neonatal line is located beyond 2SD of the mean location of the neonatal line in term births, it is estimated that this technique will provide individualizing information in about 3% of immature skeletonized remains in a forensic context. The relative timing of pre- and postnatal pathological striae in the enamel of primary teeth can be evaluated in terms of the variation, documented here, in the location of the neonatal line due to individual and birth timing differences. Determination of the timing of pathological enamel striae will aid in the identification of both children and adults for whom histological examination of enamel is undertaken.

Child↗
PubMed1993

A clinical laboratory information systems survey. A challenge for the decade.

In 1990, the College of American Pathologists Informatics Committee surveyed 14,785 laboratorians for their experiences with a clinical laboratory information system. A 16.25% response rate was achieved, representing 2402 questionnaires that were analyzed. Despite the perceived satisfaction of the clinical laboratory information system users with more expensive systems, no economy of scale was demonstrated with increasing system cost through either laboratory staff reduction or increased number of specimens per day. The strongest predictors of system satisfaction were (1) vendor success measured by number of installations and (2) a selection process that involved the pathologist/laboratory director and included a formal request for proposal. The need for integration of clinical laboratory information systems with hospital information systems, as well as the universal adoption of standard productivity terminology, including work load units, was evident.

Clinical Laboratory Information Systems↗