Biomedical subjects

C Reynolds

Publications and source records attributed to C Reynolds.

At least 19 recordsLinked to original sources

PubMed2006

Nephrotic syndrome associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Chronic graft-versus-host disease (cGVHD) is the most common late complication of allogeneic hematopoietic cell transplantation (HCT) causing significant morbidity and mortality. The kidneys are not considered a target organ for cGVHD in humans, although animal models show renal damage. Renal involvement in patients with cGVHD, presenting as nephrotic syndrome (NS), has rarely been reported in patients who received allogeneic transplantation. Herein we describe, by far, the largest series of nine patients with NS associated with cGVHD, including two patients who received a reduced-intensity regimen. Pathological features of membranous nephropathy were the most common finding on renal biopsy. The clinical course of the NS was temporally associated with the classical features of cGVHD in all but one of the nine cases. The clinicopathologic features of NS in our series as well as reports in the literature demonstrate an immunopathologic process typical of antibody-mediated damage consistent with cGVHD. Treatment directed against antibody-mediated damage, such as anti-B-cell antibody may play an important role in ameliorating NS associated with cGVHD.

Adult↗

PubMed2006

IFN gamma and CXCR-1 gene polymorphisms in idiopathic bronchiectasis.

Idiopathic bronchiectasis is a disease of chronic, bacterial lung infection, unresolving inflammation and progressive lung damage. Bronchiectasis can be associated with autoimmune diseases including ulcerative colitis. Defects of both innate and adaptive immunity have been proposed. The airway inflammation is characterized by interleukin-8 (IL-8) expression and infiltration by neutrophils and T cells. Here we investigated two candidate gene polymorphisms that may contribute to disease susceptibility: a CXCR-1 (+2607 G/C) gene polymorphism that is implicated in IL-8 binding and neutrophil trafficking as well as the interferon-gamma (IFNgamma) (+874 T/A) polymorphism which is linked to levels of IFNgamma production. These polymorphisms were distributed similarly in the idiopathic bronchiectasis group and controls, suggesting that these two candidate gene polymorphisms are not associated with disease susceptibility.

Alleles↗

PubMed2005

Tumor antigen immunization of sibling stem cell transplant donors in multiple myeloma.

The unique antigenic determinants (idiotype (Id)) of the immunoglobulin secreted by myeloma tumor can serve as a tumor-specific antigen for active immunotherapy. Our objective was to induce tumor-specific T-cell immunity in bone marrow transplant (BMT) donors to enhance antitumor effects of allografts. We vaccinated five HLA-matched sibling donors with myeloma Id proteins isolated from recipient plasma before bone marrow harvest. Recipients were administered booster Id immunizations following transplantation. Vaccination induced donor Id and carrier-specific cellular and/or humoral immune responses. Two recipients died within 30 days of BMT from transplant-related complications. Id and carrier-specific T-cell responses were detected in all three remaining patients post-, but not pre-BMT and persisted for 18 months. All three surviving patients converted from partial to complete responses following BMT. Two of the three patients remain disease-free 7 years and 8 years after BMT, and the third died of renal failure after 5.5 years while in complete remission from myeloma. Our results suggest that myeloma Id vaccination induces specific T-cell immunity in healthy donors which may be transferable by BMT, is associated with prolonged disease-free survival of recipients, and may represent a general strategy to enhance graft-versus-tumor effect in other malignancies for which defined tumor-specific antigens exist.

Adult↗

PubMed2004

Primary breast sarcoma: clinicopathologic series from the Mayo Clinic and review of the literature.

Primary sarcomas of the breast are extremely rare, with less than 0.1% of all malignant tumours of the breast. Mayo Clinic Surgical Pathology database was searched for all breast sarcoma from 1910 to 2000. Pathology reports and slides were reviewed and tumour types were determined. Metaplastic carcinomas and phyllodes tumours were excluded. There were 25 women ranging in age 24-81 years (mean 45 years). All but one patient presented with a palpable lump. Mastectomy was performed in 19 patients and lumpectomy in five patients. Histopathological diagnoses were fibrosarcoma (six), angiosarcoma (six), pleomorphic sarcoma (six), leiomyosarcoma (two), myxofibrosarcoma (three), hemangiopericytoma (one) and osteosarcoma (one). Tumour size ranged from 0.3 to 12 cm (mean 5.7). Low-grade lesions were observed in 10 cases and high-grade in 15. Overall, mean follow-up was 10.5 years. Local recurrence was observed in 11 patients and ranged from 2 to 36 months (mean 15 m), while distant metastasis was observed in 10 patients (40%) affecting lungs, bones, liver, spleen, and skin. Of the 25 patients, 12 have died of disease and six of other causes. Five-year overall (OS) and cause-specific survival (CSS) were 66 and 70%, respectively. OS and DFS at 5 years were 91% for tumours < or =5 cm and 50% for tumours >5 cm. Tumour size was significantly associated with OS (risk ratio=1.3 per 1 cm increase; 95% CI, 1.02-1.7; P=0.036). There was no significant difference in OS or CSS between low- and high-grade lesions. In this series, tumour size was a more valuable prognostic factor than tumour grade.

Adult↗

PubMed2004

West Nile virus encephalitis causing fatal CNS toxicity after hematopoietic stem cell transplantation.

We describe here a patient who died of progressive CNS deterioration following allogeneic stem cell transplant with West Nile virus as the sole pathogen on the cerebrospinal fluid and brain tissue analysis. A 50-year-old male with Philadelphia chromosome-positive acute lymphocytic leukemia (ALL) underwent allogeneic PBSCT from his HLA identical sister. After engraftment, the patient developed fever with progressive and ultimately fatal neurological deterioration. Imaging studies of the brain including CT and MRI scans were remarkable for mild low attenuation lesions of the white matter. CSF analysis was negative for neoplastic cells, bacteria, AFB, CMV, HSV, fungal infections and leukemic relapse. However, serological analysis of both the serum and CSF was positive for West Nile virus-specific IgM antibodies. At autopsy, West Nile virus PCR and cultures were positive in the mid-brain tissue. Electron micrographs showed evidence of viral particles. Given the recent increase in the spread of West Nile virus infections and the increased susceptibility of BMT patients to infectious complications, West Nile virus encephalitis should be considered in patients undergoing transplantation.

Autopsy↗

PubMed2004

Tacrolimus as monotherapy or combined with minidose methotrexate for graft-versus-host disease prophylaxis after allogeneic peripheral blood stem cell transplantation: long-term outcomes.

We report long-term outcomes for allogeneic peripheral blood stem cell (PBSC) recipients, evaluating cumulative incidence (CI) of acute and chronic graft-versus-host disease (GVHD), after use of tacrolimus with or without minidose methotrexate for GVHD prophylaxis. From April 1996 to April 1998, 97 adults underwent allogeneic PBSC transplantation. The first 49 received tacrolimus monotherapy as GVHD prophylaxis and the subsequent 48 received combination therapy. The median follow-up for survivors was 67 months. Compared to combination therapy, tacrolimus monotherapy resulted in enhanced neutrophil engraftment, shortened hospitalization, comparable rates of GVHD, and equivalent 100-day survival. The CI of grades II-IV acute GVHD was 35% with tacrolimus and 23% with the combination (P=0.19). The CI of III-IV GVHD was 22% for tacrolimus and 19% for the combination. CI of chronic GVHD was similar between the two groups (P=0.5). Patients with good-risk disease had superior overall survival (OS) when compared to those with poor-risk features (P<0.001). Within the good-risk disease category, patients receiving methotrexate had a trend towards improved OS (P=0.07). Multivariate analysis indicated good-risk disease status and methotrexate were independently associated with improved OS, progression-free survival (PFS), and relapse. In addition, patients developing chronic GVHD had a significantly reduced risk of relapse and improved PFS.

Acute Disease↗

PubMed2002

Wide spectrum screening keratin as a marker of metaplastic spindle cell carcinoma of the breast: an immunohistochemical study of 24 patients.

AIMS: Metaplastic spindle cell carcinomas may be difficult to distinguish histologically from other spindle cell lesions in the breast. Variable staining with cytokeratin immunomarkers has been reported for metaplastic carcinomas. We evaluated the diagnostic utility of anti-cytokeratin polyclonal antibody, wide spectrum screening keratin, to assess spindle cell breast lesions. METHODS AND RESULTS: Twenty-four patients with spindle cell breast carcinoma and 31 patients with benign or malignant spindle cell tumours were studied using a panel of antibodies directed against multiple cytokeratins (AE1/AE3, CAM5.2, wide spectrum screening keratin), epithelial membrane antigen (EMA), and vimentin. Sites of origin for the 31 controls included breast, bone, and soft tissue. All but one (95.8%) metaplastic carcinomas stained positively with wide spectrum screening keratin. Only rare or focal immunoreactivity was observed with AE1/AE3 in four cases; however, sensitivity of AE1/AE3 was improved in 13 cases using steam EDTA as an antigen retrieval technique. Three cases were immunoreactive with CAM5.2 and eight cases were immunoreactive with EMA. All control cases lacked immunoreactivity with the cytokeratin panel and EMA. The spindle cells in the metaplastic breast tumours (88%) and in the controls (97%) stained with vimentin. CONCLUSIONS: Wide spectrum screening keratin may be the most useful and convenient antibody in differentiating metaplastic spindle cell carcinoma from other spindle cell lesions in the breast.

Aged↗

PubMed2001

Clinical protocol. Purging of autologous stem cell sources with bcl-x(s) adenovirus for women undergoing high-dose chemotherapy for stage IV breast carcinoma.

High-dose chemotherapy (HDCT) and autologous bone marrow transplantation (BMT) is frequently used to treat patients with metastatic cancer including breast cancer and neuroblastoma. However, the bone marrow of such patients is often contaminated with tumor cells. Recently, we have found that a recombinant adenovirus vector that contains a bcl-x, minigene (a dominant negative inhibitor of the bcl-2 family), called the bcl-x(s) adenovirus, is lethal to cancer cells derived from epithelial tissues, but not to normal human hematopoietic cells. To determine the mechanism, by which this virus spares normal hematopoietic cells, we isolated normal mouse hematopoietic stem cells and infected them with an adenovirus that contains a beta-galactosidase minigene. Such cells do not express beta-galactosidase, indicating that hematopoietic stem cells do not express transgene encoded by adenovirus vectors based upon the RSV-AD5 vector system. When breast cancer cells mixed with hematopoietic cells were infected with the bcl-x(s) adenovirus, cancer cells were selectively killed by the suicide adenoviruses. Hematopoietic cells exposed to the suicide vectors were able to reconstitute the bone marrow of mice exposed to lethal doses of y-irradiation. These studies suggest that adenovirus suicide vectors may provide a simple and effective method to selectively eliminate cancer cells derived from epithelial tissue that contaminate bone marrow to be used for autologous BMT. We therefore propose to initiate a phase I clinical trial to test the safety of this virus in women with breast cancer undergoing high does chemotherapy and autologous BMT.

Adenoviridae↗

PubMed2001

Bone formation and inflammation in cardiac valves.

BACKGROUND: For nearly a century, the mechanical failure of calcified heart valves was attributed to a passive degenerative process. Recently, several case reports described bone formation in surgically excised heart valves and suggested an unexpected process of tissue repair. METHODS AND RESULTS: We studied the prevalence and pathology of heterotopic ossification in 347 surgically excised heart valves (256 aortic, 91 mitral) in 324 consecutive patients (182 men, 142 women; mean age 68 years) who underwent cardiac valve replacement surgery between 1994 and 1998. The valves were examined microscopically to determine the prevalence and features of bone formation and remodeling. Two hundred eighty-eight valves (83%) had dystrophic calcification. Mature lamellar bone with hematopoietic elements and active bone remodeling were present in 36 valves (13%) with dystrophic calcification. Endochondral bone formation, similar to that seen in normal fracture repair, was identified in 4 valves. Microfractures were present in 92% of all valves with ossification. Neoangiogenesis was found in all valves with ossification. Bone morphogenetic proteins 2 and 4 (BMP 2/4), potent osteogenic morphogens, were expressed by myofibroblasts and preosteoblasts in areas adjacent to B- and T-lymphocyte infiltration in valves where ossification was identified. Mast cells were present in calcified and ossified valves and were especially prominent in atheromatous regions. CONCLUSIONS: Heterotopic ossification consisting of mature lamellar bone formation and active bone remodeling is a relatively common and unexpected finding in end-stage valvular heart disease and may be associated with repair of pathological microfractures in calcified cardiac valves.

Adult↗

PubMed2001

Benign tumors of the breast with multinucleated stromal giant cells. Immunohistochemical analysis of six cases and review of the literature.

The authors present six cases of benign tumors of the breast with numerous multinucleated stromal giant cells (MSGC). All six patients were women aged 37-70 years (mean 48 years), presenting clinically with a breast mass 1.0-3.8 cm in size (mean 1.9 cm; median 1.5 cm). By standard H&E examination, all cases showed the presence of numerous MSGC haphazardly dispersed within the tumor stroma. Three cases revealed MSGC merging into the surrounding adipose tissue simulating infiltrative growth. The MSGC appeared to have multiple nuclei (5 to 25) with fine chromatin and sporadic small nucleoli. Their cytoplasm was inconspicuous. The MSGC expressed vimentin only and to lesser extent CD34. These cells were negative for muscle markers, keratins, S-100 protein, vascular markers, CD68 and hormone receptors. Interestingly, the majority of MSGC and mononuclear stromal cells showed reactivity for p53 protein and Ki-67 proliferation antigen. All patients were treated by simple excision and remain free of recurrence (mean 70 months, median 48 months.). The reactivity of p53 in MSGC and mononuclear stromal cells may play a key role in linking these two cell types. Nonetheless, the presence of MSGC does not alter prognosis of otherwise typical benign lesions.

Adult↗

PubMed2001

Allogeneic stem cell transplantation reduces disease progression compared to autologous transplantation in patients with multiple myeloma.

This study compares the probability of disease progression, progression-free survival, and overall survival between patients undergoing an allogeneic or autologous transplant for multiple myeloma using an identical preparative regimen. Patients received a preparative regimen of TBI, busulfan, and cyclophosphamide followed by an allogeneic or autologous transplant. In the allogeneic group (n = 21), six patients received bone marrow and 15 received G-CSF mobilized PBSC; all autologous patients (n = 35) received PBSC mobilized with cyclophosphamide and G-CSF. Allogeneic donors were HLA-identical (n = 20) or one-antigen mismatched (n = 1) siblings. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus (n = 10), tacrolimus/methotrexate (n = 6), cyclosporine/methotrexate (n = 4), or cyclosporine (n = 1). The groups were evenly matched for gender, pretransplant therapy, disease status at time of transplant, myeloma subtype, and time from diagnosis to transplant. The median age was significantly lower in the allogeneic group (48 vs 55 years, P < 0.01). In the allogeneic group the probabilities of developing acute GVHD grade II-IV and chronic GVHD were 55% and 82%, respectively. The Kaplan-Meier probability of disease progression was significantly lower in the allogeneic group (11% vs 64%, P < 0.001) compared to the autologous group. Although progression-free (60% vs 30%, P = 0.19) and overall survival at 2 years (60% vs 42%, P = 0.39) favored the allogeneic group, this did not reach statistical significance. Within the allogeneic transplant group, patients age 50 years or under had a 3-year overall survival significantly higher when compared to older patients (79% vs 29%, P = 0.03). Using identical preparative regimens, allogeneic transplantation reduced disease progression compared to autologous transplantation for myeloma. This suggests that allogeneic transplantation induces a graft-versus-myeloma (GVM) effect.

Actuarial Analysis↗

PubMed2001

Double dose-intensive chemotherapy with autologous stem cell support for relapsed and refractory testicular cancer: the University of Michigan experience and literature review.

Testicular cancer patients refractory or in relapse after primary chemotherapy have < or =25% 5-year progression-free survival with salvage. To improve prognosis, patients entered a phase I/II tandem dose-escalation trial of carboplatin (1500-2100 mg/m(2)) and etoposide (1200-2250 mg/m(2)) with ABMT. Patients were eligible for a second cycle if disease progression was absent and performance status allowed. From August 1990 to June 1998, 29 males (25 NSGCT) were treated. At the time of ABMT, 10 were chemosensitive, four were chemoresistant, and 10 were absolutely refractory to platinum. Disease status (no. patients) at transplant: primary refractory disease (six), first relapse (10), second relapse (eight), third relapse (five). Fifteen (52%) received both transplants. Treatment-related mortality was 10%. Best response after ABMT included: two CR, one CR surgically NED, five PR, three PR surgically NED, seven SD, and eight PD. Eight (28%) patients are continuously progression-free a median 60 months (range, 31-93) from first ABMT. Three seminoma patients remain progression-free. Of five long-term NSGCT survivors, four were treated in first relapse with platinum-sensitive disease. Eighteen relapses occurred a median of 4 months after ABMT I (two late relapses at 28 and 44 months). The median PFS and OS for the whole group are 4 and 14 months, respectively. Patients with relapsed/ refractory testicular cancer benefit most from ABMT if they have platinum-sensitive disease in first relapse. Patients who do poorly despite ABMT have a mediastinal primary site, true cisplatin-refractory disease, disease progression prior to ABMT, and/or markedly elevated betaHCG at ABMT. New treatment modalities are needed for the latter group.

Adolescent↗

PubMed2001

Structure, activity and evolution of the group I thiolactone peptide quorum-sensing system of Staphylococcus aureus.

In Staphylococcus aureus, the agr locus is responsible for controlling virulence gene expression via quorum sensing. As the blockade of quorum sensing offers a novel strategy for attenuating infection, we sought to gain novel insights into the structure, activity and turnover of the secreted staphylococcal autoinducing peptide (AIP) signal molecules. A series of analogues (including the L-alanine and D-amino acid scanned peptides) was synthesized to determine the functionally critical residues within the S. aureus group I AIP. As a consequence, we established that (i) the group I AIP is inactivated in culture supernatants by the formation of the corresponding methionyl sulphoxide; and (ii) the group I AIP lactam analogue retains the capacity to activate agr, suggesting that covalent modification of the AgrC receptor is not a necessary prerequisite for agr activation. Although each of the D-amino acid scanned AIP analogues retained activity, replacement of the endocyclic amino acid residue (aspartate) located C-terminally to the central cysteine with alanine converted the group I AIP from an activator to a potent inhibitor. The screening of clinical S. aureus isolates for novel AIP groups revealed a variant that differed from the group I AIP by a single amino acid residue (aspartate to tyrosine) in the same position defined as critical by alanine scanning. Although this AIP inhibits group I S. aureus strains, the producer strains possess a functional agr locus dependent on the endogenous peptide and, as such, constitute a fourth S. aureus AIP pheromone group (group IV). The addition of exogenous synthetic AIPs to S. aureus inhibited the production of toxic shock syndrome toxin (TSST-1) and enterotoxin C3, confirming the potential of quorum-sensing blockade as a therapeutic strategy.

Bacterial Proteins↗

PubMed2001

Calciphylaxis causing necrotizing mastitis: a case report.

Calciphylaxis is a rare condition most commonly related to ESRD and hyperparathyroidism. We report a case of necrotizing mastitis caused by calciphylaxis following routine breast biopsy for microcalcifications. Early recognition of the potential for this condition should help in clinical management of patients with calciphylaxis.

Journal Article↗

PubMed2001

MR imaging of the breast in patients with invasive lobular carcinoma.

OBJECTIVE: Our objective was to assess the usefulness of MR imaging in patients diagnosed with invasive lobular carcinoma of the breast. MATERIALS AND METHODS: Between July 1993 and September 1999, 32 women (33 cases) diagnosed with pure invasive lobular carcinoma of the breast underwent contrast-enhanced MR imaging examination. One woman was excluded because of lack of follow-up. Correlation was made between the mammographic and sonographic findings, the MR imaging findings, and the final pathology results for the remaining 32 cases. RESULTS: In 18 women who did not undergo excisional biopsy before the MR imaging, MR imaging showed more extensive tumor burden or the detection of the primary lesion that was occult on conventional imaging in seven (38.9%) of 18 women. In nine (50%) of 18 women, MR imaging performed equally as well as mammography and sonography. In one case (5.6%), MR imaging and mammography underestimated disease extent. In another patient (5.6%), MR imaging overestimated tumor burden, although mammography failed to show the cancer. In 14 patients who had excisional biopsy before the MR imaging, residual tumor was shown in eight women (57.1%) with extensive tumor or additional separate foci in five of the eight patients. In two cases (14.3%) that were interpreted as equivocal, residual tumor was shown in both cases on reexcision. In three cases (21.4%), the MR imaging was interpreted as negative, but microscopic tumor was shown around seroma on reexcision. False-positive enhancement was seen in one case (7.1%). CONCLUSION: MR imaging showed more extensive tumor than conventional imaging and affected the clinical management in 16 (50%) of 32 patients with invasive lobular carcinoma.

Adult↗

PubMed2001

The effect of salinity on different developmental stages of an endemic annual plant, Aster laurentianus (Asteraceae).

Salinity reduces substrate water potential, thereby restricting water and nutrient uptake by plants; salinity may also cause ionic imbalance and toxicity. Because substrate salinity fluctuates through the growing season, a plant may be exposed to different salinity levels, at various stages of development, with potentially significant consequences on population dynamics. Here, we present the results of a study of the effect of substrate salinity on seed germination, seedling emergence, and growth of Aster laurentianus, an annual marsh plant, endemic to the Gulf of St. Lawrence and potentially threatened. Seed germination was reduced in low salt concentration (10 g sea salt/L) and completely inhibited by salinity levels >/=20 g sea salt/L. However, this inhibiting effect was reversible: seeds from the salt treatments germinated readily after being washed in distilled water. Though seedling emergence was diminished at low salinity levels, postemergence survival was little affected. Plant growth was reduced, but net carbon assimilation rate was not affected by high salinity levels. Increased root respiration and respiratory costs associated with salt tolerance might have contributed to lower C accumulation at higher salinity levels. All developmental processes considered are thus negatively affected by substrate salinity, with potentially significant consequences on population abundance and distribution in salt marshes. Yet, the tolerance of this species to high salinity levels after seedling emergence is remarkable. Seed germination represents a major bottleneck in the species life cycle, potentially controlling local distribution and abundance in the natural habitat.

Journal Article↗

PubMed2001

Early educational and health enrichment at age 3-5 years is associated with increased autonomic and central nervous system arousal and orienting at age 11 years: evidence from the Mauritius Child Health Project.

Little is known about the effects of environmental enrichment on psychophysiological measures of arousal and orienting in humans. This study tests the hypothesis that early educational and health enrichment is associated with long-term increases in psychophysiological orienting and arousal. One hundred children were experimentally assigned to a two-year enriched nursery school intervention at ages 3-5 years and matched at age 3 years on psychophysiological measures, gender, and ethnicity to 100 comparisons who received the normal educational experience. Children were retested 6-8 years later at age 11 years on skin conductance (SC) and electroencephalogram (EEG) measures of arousal and attention during pre- and postexperimental rest periods and during the continuous performance task. Nursery enrichment was associated with increased SC amplitudes, faster SC rise times, faster SC recovery times, and less slow-wave EEG during both rest and CPT conditions. This is believed to be the first study to show that early environmental enrichment is associated with long-term increases in psychophysiological orienting and arousal in humans. Results draw attention to the important influence of the early environment in shaping later psychophysiological functioning.

Arousal↗

PubMed2001

Adding value to clinical data by linkage to a public death registry.

We describe the methodology and impact of merging detailed statewide mortality data into the master patient index tables of the clinical data repository (CDR) of the University of Virginia Health System (UVAHS). We employ three broadly inclusive linkage passes (designed to result in large numbers of false positives) to match the patients in the CDR to those in the statewide files using the following criteria: a) Social Security Number; b) Patient Last Name and Birth Date; c) Patient Last Name and Patient First Name. The results from these initial matches are refined by calculation and assignment of a total score comprised of partial scores depending on the quality of matching between the various identifiers. In order to validate our scoring algorithm, we used those patients known to have died at UVAHS over the eight year period as an internal control. We conclude that we are able to update our CDR with 97% of the deaths from the state source using this scheme. We illustrate the potential of the resulting system to assist caregivers in identification of at-risk patient groups by description of those patients in the CDR who were found to have committed suicide. We suggest that our approach represents an efficient and inexpensive way to enrich hospital data with important outcomes information.

Death Certificates↗