Immune complex disease consistent with systemic lupus erythematosus in a patient with lysinuric protein intolerance.
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Biomedical subjects
Publications and source records attributed to J Klassen.
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Twenty-six patients with haematological malignancy received cryopreserved but otherwise unmanipulated blood cell transplants (BCT) from five- or six-antigen matched siblings in whom progenitor cells had been mobilized by G-CSF. Outcomes were compared with a historical control group of 26 BMT patients matched for age and disease status. Granulocyte counts recovered to 0.5 x 10(9)/l in a median of 16 days after BCT compared with 21.5 days after BMT (P = 0.0002). Platelet counts, unsupported for 3 days, reached 20 x 10(9)/l in a median of 14 days vs 20.5 days (P = 0.0003) after BCT compared with BMT in those patients who engrafted. In the BCT and BMT groups, respectively, the risk of grade II-IV acute GVHD was 37 vs 21% (P = 0.16) and of chronic GVHD at 1 year 53 vs 48% (P = 0.9). There was no significant difference in red cell transfusions but BCT patients required fewer platelet transfusions (median 3 vs 5, P = 0.015) and fewer days in hospital (20.5 vs 25, P = 0.02). These results indicate that allogeneic BCT from matched and partially mismatched family donors result in faster engraftment than BMT without a significant increase in GVHD. Allogeneic BCT may prove to be a more tolerable procedure than BMT for both donor and recipient and there are indications of improved cost-effectiveness.
The role of high-dose therapy and autologous stem cell transplantation (ASCT) in the treatment of patients with Ewing's sarcoma (EWS) remains uncertain. From November 1985 to September 1994, 13 patients aged 16-30 years (median 20.5) received high-dose melphalan (HDM) 140-200 mg/m2 +/- 500 cGy TBI followed by ASCT for relapsed/refractory (n = 4), metastatic (n = 2), or non-metastatic (n = 6) EWS, or for peripheral neuroectodermal tumor (PNET) (n = 1). This regimen was well tolerated with no transplant-related mortality and no toxicity requiring life sustaining measures. Three of the four patients treated for relapsed/refractory EWS had progression-free survivals (PFS) less than 5 months. The only long-term survivor of these four patients received HDM while in complete remission following pulmonary irradiation. Both patients with pulmonary metastases at presentation died just 5 and 6 months post-ASCT. All four patients with non-metastatic, bulky (> 8 cm) osseous EWS progressed at a median of 11 months (range 7-22 months) while the two patients with non-bulky EWS remain progression-free 25+ and 28+ months post-HDM/TBI + ASCT. The 19-year-old patient with a PNET of the thoracoabdominal wall relapsed 4 months post-ASCT. Overall, only three of these 13 patients remain progression-free at 25+, 28+, and 108+ months following HDM +/- TBI and ASCT. In conclusion, HDM +/- TBI did not obviously improve the outcome of these 13 patients relative to that expected following conventional dose therapy alone.
There is increasing interest in blood cell transplants (BCT) from normal donors as an alternative to BMT. Ten patients with relapsed or persistent leukemia after BMT received intensive cytotoxic conditioning followed by allogeneic BCT. Three BCT were from single-antigen mismatched donors; two of the corresponding recipients had rejected a BMT from the same donor. Two patients received BCT from a different donor (one matched, one single-antigen mismatched). The other six BCT were from the same, fully matched, bone marrow donors. Donors were given G-CSF to mobilize progenitor cells which were collected by a single 2-4 h leukapheresis. Methotrexate, CsA and folinic acid were used for GVHD prophylaxis for all transplants but CsA was discontinued sooner after BCT than after BMT. One patient died without engraftment having rejected a BMT from the same single-antigen mismatched donor 4 years previously. Nine patients had granulocyte recovery at a median of 14 days, up to 6 days faster than with their previous BMT. Platelet recovery was also 2-6 days faster than with BMT in four previously engrafting patients. Four patients died without platelet recovery after BCT within a year of BMT, three of treatment-related toxicity and one of relapse. Two patients developed grade II acute GVHD. Of six patients given BCT more than a year from BMT, four, all with acute leukemia, survive 7, 14, 29 and 29 months after BCT and one relapsed at 7 months. All four survivors developed chronic GVHD. These results indicate that BCT may be useful therapy for relapse occurring more than a year after BMT.
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Platelet-derived growth factor (PDGF) BB is secreted by most human breast carcinoma cells; however, only recently have PDGF beta receptors been demonstrated in malignant breast tissue. In the present study, the tissue localization of PDGF beta receptor expression was studied in human breast carcinoma and nonmalignant breast tissues stained using both immunofluorescence and immunoperoxidase techniques. We examined a total of 29 cases of breast carcinomas, which showed both in situ and invasive components. PDGF beta receptor staining was localized in the periepithelial stroma and was particularly intense in regions immediately adjacent to carcinoma in situ components in all tumors examined. A diffuse low level of PDGF beta receptor staining was seen throughout the stroma of eight nonmalignant breast tissues as well as of nonmalignant regions of tumor tissues. Image analysis was used to assess the coincidence of staining of PDGF beta receptor with epithelial or stromal cells in 13 of the 29 tumor tissues studied. Less than 5% of malignant ductal epithelium or myoepithelium showed PDGF beta receptor staining. Analysis with stromal cell type-specific markers indicated significant localization of PDGF beta receptor primarily within alpha smooth muscle actin-staining cells (32%) and vascular endothelial cells (41%) in the periepithelial stroma. PDGF beta receptor positivity was strongly associated with periepithelial stromal cells adjacent to the basement membrane surrounding regions of carcinoma in situ but was less intense in regions of invasive carcinoma where basement membrane was degraded. The absence of PDGF beta receptors on carcinoma cells and their presence in the surrounding stroma suggest a paracrine stimulation of adjacent stromal tissue by malignant epithelial cells in human breast tumors.
The effects of dexamethasone (0.2 mg/kg of body weight; IV, IM, and PO) and methylprednisolone acetate (120 mg given intra-articularly) on serum osteocalcin and cortisol concentrations were studied in 6 horses. Serum osteocalcin and cortisol concentrations were serially monitored after each treatment. A significant (P < 0.05) decrease in serum osteocalcin and cortisol concentrations was observed from 12 to 24 and 2 to 48 hours, respectively, after IV and IM administrations of dexamethasone. Serum osteocalcin and cortisol concentrations were significantly decreased from 6 to 48 and 3 to 72 hours, respectively, after oral administration. In contrast, a change in serum osteocalcin concentration was not detected after intra-articular administration of methylprednisolone. Oral, IV, or IM treatment with 0.2 mg of dexamethasone/kg caused a decrease in serum osteocalcin concentration in horses.
Fourteen donors were given recombinant G-CSF to mobilize progenitor cells. Circulating CD34+ cells were monitored daily and leukapheresis was performed at 3-5 days when the level exceeded 20 x 10(6)/L. Monitoring of CD34+ cells collected at intervals during apheresis gave results within 20 min. Yields of 2.6-7.4 x 10(6) per kg recipient body weight were achieved in single aphereses of 2-4 h in all but two cases where the donor was substantially smaller than the recipient. These products were sufficient to establish engraftment, at least of granulocytes, in 11 five or six antigen matched recipients with high risk malignancy. Despite some complications donors tolerated the procedure well and the five individuals who had previously given marrow preferred these manoeuvres to bone marrow harvest. The ability to monitor CD34+ cells rapidly in the circulation and leukapheresis product facilitates an efficient collection technique for allogeneic BCT donors. Adequate yields could probably be achieved by a single harvest on days 2-4 in most donors.
Polyuria is usually the result of a water diuresis or an osmotic diuresis. Traditionally, the assessment of the extracellular fluid (ECF) volume and the concentration of Na+ in plasma is sufficient to differentiate between the two. We present a case and our approach, which is based on calculations and quantitation of osmoles, to demonstrate the utility of this approach. A patient with diabetes mellitus, human T-cell lymphocyte virus, type 1 (HTLV-1) associated lymphoma, and hypercalcemia presented with marked ECF volume contraction and polyuria. A spot urine osmolality was 567 mOsm/kg H2O in the face of urine output of approximately 6 L/d. The initial diagnosis was an osmotic diuresis. However, a quantitative analysis revealed the enormous number of osmoles could not be accounted for physiologically. Hence, we postulated a water diuresis to be the cause of the polyuria. To confirm this hypothesis, we found that at different times during his hospitalization, the urine specific gravity ranged from 1.005 to 1.022, and urine output varied markedly over 8-h periods. Despite a plasma sodium of 147 mmol/L, the patient did not complain of thirst. Taken together, this suggested the presence of a hypothalamic lesion which caused central diabetes insipidus with variable output of antidiuretic hormone together with a blunted thirst response. Illustration of the utility of a quantitative approach to polyuria is the focus of the discussion.
The benefits of long-term cyclosporin (CyA) therapy are not yet established and must be weighed against its toxicity. We studied cardiovascular risk factors in 25 patients who received a kidney transplant between 1985 and 1989 and in whom CyA was discontinued. The protocol for discontinuing CyA involved starting azathioprine (Aza) and then weaning CyA over 6 weeks without changing the prednisone dose. Parameters collected from the patients' charts 3 months before (pre) and 3 months after conversion (post) and at the most current follow-up (cur) included serum creatinine, cholesterol, blood pressure, and anti-hypertensive medication. The severity of the hypertension was graded, based on a hypertension index reflecting the nature and dose of the anti-hypertensive medication. Of the 25 patients in whom CyA was discontinued, 2 experienced a rejection episode during conversion and were switched back to CyA; 1 patient had a rejection episode after conversion but remained on Aza. Converted patients demonstrated improved renal function (1/Cr pre 0.69 +/- 0.20, post 0.84 +/- 0.23, P < 0.05), lower serum cholesterol levels (pre 6.8 +/- 1.0, post 5.8 +/- 1.2, P < 0.05), lower mean arterial pressure (pre 111 +/- 14, post 102 +/- 8, P < 0.05) and a lower hypertension index (pre 2.45 +/- 2.77, cur 1.62 +/- 1.70, P < 0.05). Although conversion may carry some risk of acute rejection, it improves graft function and the cardiovascular risk profile significantly.
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Eleven pediatric patients with nephrosis and focal segmental glomerulosclerosis were treated with long-term (8-38 months) ciclosporin A in combination with steroids. All had abnormal height-velocity curves and multiple hospitalizations for complications of nephrosis. Eight patients attained remission with a dramatic improvement in growth and decrease in necessity for hospitalization for therapy of nephrosis complications, while maintaining adequate renal function. Three nonresponders developed end-stage renal disease. Long-term ciclosporin A therapy may be of benefit in steroid-resistant nephrosis in childhood.
Investigated the degree to which chronic, life-threatening illness and its treatment interfere with continued involvements in valued activities and interests--that is, illness intrusiveness--and its impact on quality of life in end-stage renal disease. Data were collected on two occasions separated by a lag of 6 weeks. Mixed analyses of variance indicated that life domains were affected differentially across treatments. Perceived illness intrusiveness correlated significantly with treatment time requirements, uremic symptoms, intercurrent nonrenal illnesses, fatigue, and difficulties in daily activities. Significant quality-of-life differences were observed across treatment modalities for satisfaction/happiness and pessimism/illness-related concerns but not for depression/distress. Perceived illness intrusiveness correlated significantly with each of these quality-of-life measures. Results were stable over time. These findings substantiate the construct of illness intrusiveness as a mediator of the psychosocial impact of chronic, life-threatening illness.
Microscopic colitis associated with gluten-resistant partial villous atrophy was documented in a 21-year-old woman with chronic nonbloody diarrhea. Electron microscopic examination of the colonic and duodenal biopsies showed focal separations of basal lamina from cryptal epithelial cells forming subepithelial blebs in which were mast cells and fibroblasts. These morphologic features have not been previously described in any inflammatory bowel disease and are reminiscent of bullous pemphigoid of the skin. The findings suggest that not all cases of microscopic colitis lie within the spectrum of collagenous colitis.
Sixty-nine patients receiving Cs after cadaveric or LRD renal transplants were randomly allocated to receive prednisone or no prednisone beginning on the day of transplant. There were 36 in the prednisone group and 33 in the group assigned to no prednisone. Of these latter, only seven (21%) never received prednisone and an additional four had one short course for rejection episodes (11%). Of the remaining 22 who were placed on continuous steroids, only 12 met rejection criteria and either some or all of the remainder probably had Cs nephrotoxicity. The patient and graft survival were better but not statistically so in the no-prednisone group (97% v 89%) and (88% v 78%), and the number of infections was only half that of the prednisone-treated group (22% v 42%). A policy of withholding steroids except for rejection episodes does not prejudice graft or patient survival in Cs-treated patients.
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Familial hypopituitarism in the Hutterite Brethren is an autosomal recessive disorder involving sequential loss of anterior pituitary tropic hormones. Five individuals from two closely related families have been followed for 19 years. Both families are well integrated into the Hutterite community. Three sibs elected not to be treated with growth hormone and sex steroids. These sibs developed growth hormone and gonadotropin deficiency in the first decade of life, with subsequent loss of TSH function and finally ACTH deficiency in the third decade. The pattern of hormone loss differed in the second family, in that deficiency of growth hormone, gonadotropins, and TSH was evident in the first decade. A third family has been reported to have the same disorder and is from a different endogamous subdivision from that of the two families described here. Genealogical analysis of the three families shows that there are four ancestral couples common to the six parents. Thus all affected individuals are likely to be identical by descent for the same ancestral allele. The gene for hypopituitarism is not closely linked to the gene for growth hormone nor to the HLA region.
Angiomatoid vascular changes in lungs and pulmonary hemorrhage are described in a woman in whom mitomycin C-associated hemolytic-uremiclike syndrome developed. These changes represent part of the spectrum of vascular damage that may complicate mitomycin therapy. Patients receiving mitomycin C chemotherapy require careful monitoring for possible development of these complications.