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Biomedical subjects

R B Alexander

Publications and source records attributed to R B Alexander.

At least 19 recordsLinked to original sources
PubMed2006

Responsiveness of the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI).

OBJECTIVES: The NIH-Chronic Prostatitis Symptom Index (NIH-CPSI) was developed to assess symptoms and quality of life in men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). We assessed the responsiveness of the NIH-CPSI to change over time and defined thresholds for changes perceptible to patients. METHODS: We studied 174 men with CP/CPPS who participated in a placebo-controlled randomized clinical trial. Changes from baseline to six weeks in the NIH-CPSI total score and pain, urinary, and quality of life subscores were compared to a global response assessment (GRA). Effect sizes and Guyatt statistics were calculated to evaluate responsiveness; 95% confidence intervals were produced using bootstrapping. RESULTS: All scores decreased over time with the largest decrease in subjects who reported on the GRA that they were markedly improved. The NIH-CPSI total, pain, and quality of life scores were highly responsive in the improved groups; the urinary score showed minimal responsiveness. There was no evidence of responsiveness among those subjects who worsened on the trial. ROC curves identified a 6-point decline in the NIH-CPSI total score as the optimal threshold to predict treatment response. CONCLUSIONS: The NIH-CPSI total score and pain and quality of life subscores are responsive to change over time.

Adult↗
PubMed2004

Estimates of diffuse phosphorus sources in surface waters of the United States using a spatially referenced watershed model.

The statistical watershed model SPARROW (SPAtially Referenced Regression On Watershed attributes) was used to estimate the sources and transport of total phosphorus (TP) in surface waters of the United States. We calibrated the model using stream measurements of TP from 336 watersheds of mixed land use and spatial data on topography, soils, stream hydrography, and land use (agriculture, forest, shrub/grass, urban). The model explained 87% of the spatial variability in log transformed stream TP flux (kg yr(-1)). Predictions of stream yield (kg ha(-1) yr(-1)) were typically within 45% of the observed values at the monitoring sites. The model identified appreciable effects of soils, streams, and reservoirs on TP transport. The estimated aquatic rates of phosphorus removal declined with increasing stream size and rates of water flushing in reservoirs (i.e. areal hydraulic loads). A phosphorus budget for the 2.9 million km2 Mississippi River Basin provides a detailed accounting of TP delivery to streams, the removal of TP in surface waters, and the stream export of TP from major interior watersheds for sources associated with each land-use type.

Agriculture↗
PubMed2001

Generation of CD4(+) and CD8(+) T lymphocyte responses by dendritic cells armed with PSA/anti-PSA (antigen/antibody) complexes.

Dendritic cells (DC) acquire antigens through a number of cell surface structures including receptors for the Fc portion of immunoglobulins and mannose. Little is known about the effects of antigen uptake via these receptors on antigen processing and presentation. We compared the capacity of DC to generate CD4(+) and CD8(+) T cell responses after exposure to prostate-specific antigen (PSA) alone, PSA targeted to the mannose receptor (mannosylated PSA (PSA-m)), or PSA targeted to Fc receptors by combining PSA with an anti-PSA antibody (AR47.47). Autologous CD3(+) T cells were added to monocyte-derived immature DC that had been cultured with GM-CSF/IL-4 for 4 days, exposed to antigen, and matured with CD40L or TNFalpha/IFN-alpha. After several rounds of stimulation, T cell responses were assessed by intracellular IFN-gamma production using flow cytometry. Both CD4(+) and CD8(+) T cell responses were observed after stimulation with DC exposed to the PSA/anti-PSA complexes, whereas CD4(+) predominated over CD8(+) T cell responses after stimulation with PSA-armed DC or PSA-m. These CD8(+) T cells responded when rechallenged with DC pulsed with HLA allele-restricted PSA peptides. These results indicate that PSA and PSA-m are processed primarily through pathways that favor HLA Class II presentation, while the PSA/anti-PSA immune complexes are processed through both Class I and Class II pathways in monocyte-derived DC. These findings have potential applications in designing more effective cancer vaccines for prostate cancer.

Antigen Presentation↗
PubMed2000

PSA is a candidate self-antigen in autoimmune chronic prostatitis/chronic pelvic pain syndrome.

BACKGROUND: Previous studies demonstrated that recognition of seminal plasma antigens can occur in patients with chronic prostatitis/chronic pelvic pain syndrome. This suggests that an autoimmune component may contribute to symptoms in some men. To determine if any of the principal secretory proteins of the prostate could be candidate antigens in autoimmune prostatitis, we examined the recall proliferative response of purified CD4 T cells in patients with chronic prostatitis and in normal volunteers using purified seminal plasma antigens and autologous dendritic cells. METHODS: Peripheral blood mononuclear cells were harvested from 14 patients with chronic prostatitis and 12 normal volunteers by density gradient centrifugation. The stimulating cells were irradiated autologous dendritic cells produced by culture of monocyte-enriched fractions with IL-4 and Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF). Purified CD4 T cells were the responding population. Recall proliferation assays were performed, using purified seminal plasma proteins as antigens. RESULTS: In 14 patients with chronic prostatitis, we detected a greater than 2-fold increase in proliferative response to PSA compared to control in 5 patients (36%). No response to Prostatic Acid Phosphatase (PAP) or beta-microseminoprotein was observed in these 14 patients. In 12 normal volunteer donors with no history of genitourinary disease or symptoms, no proliferative response above background was observed for any prostatic antigen. CONCLUSIONS: The data suggest that some men with symptoms of chronic prostatitis have evidence of a proliferative CD4 T-cell response to PSA. PSA is a candidate antigen in chronic prostatitis/chronic pelvic pain syndrome and may be an appropriate target for immunotherapy for prostatic cancer.

Adult↗
PubMed1999

Developing dendritic cell polynucleotide vaccination for prostate cancer immunotherapy.

Immunotherapy has been successfully used to treat some human malignancies, principally melanoma and renal cell carcinoma. Genetic-based cancer immunotherapies were proposed which prime T lymphocyte recognition of unique neo-antigens arising from specific mutations. Genetic immunization (polynucleotide vaccination, DNA vaccines) is a process whereby gene therapy methods are used to create vaccines and immunotherapies. Recent findings indicate that genetic immunization works indirectly via a bone marrow derived cell, probably a type of dendritic antigen presenting cell (APC). Direct targeting of genetic vaccines to these cells may provide an efficient method for stimulating cellular and humoral immune responses to infectious agents and tumor antigens. Initial studies have provided monocytic-derived dendritic cell (DC) isolation and culture techniques, simple methods for delivering genes into these cells, and have also uncovered potential obstacles to effective cancer immunotherapy which may restrict the utility of this paradigm to a subset of patients.

Antigens, Neoplasm↗
PubMed1999

The National Institutes of Health chronic prostatitis symptom index: development and validation of a new outcome measure. Chronic Prostatitis Collaborative Research Network.

PURPOSE: Chronic abacterial prostatitis is a syndrome characterized by pelvic pain and voiding symptoms, which is poorly defined, poorly understood, poorly treated and bothersome. Research and clinical efforts to help men with this syndrome have been hampered by the absence of a widely accepted, reliable and valid instrument to measure symptoms and quality of life impact. We developed a psychometrically valid index of symptoms and quality of life impact for men with chronic prostatitis. MATERIALS AND METHODS: We conducted a structured literature review of previous work to provide a foundation for the new instrument. We then conducted a series of focus groups comprising chronic prostatitis patients at 4 centers in North America, in which we identified the most important symptoms and effects of the condition. The results were used to create an initial draft of 55 questions that were used for formal cognitive testing on chronic prostatitis patients at the same centers. After expert panel review formal validation testing of a revised 21-item draft was performed in a diverse group of chronic prostatitis patients and 2 control groups of benign prostatic hyperplasia patients and healthy men. Based on this validation study, the index was finalized. RESULTS: Analysis yielded an index of 9 items that address 3 different aspects of the chronic prostatitis experience. The primary component was pain, which we captured in 4 items focused on location, severity and frequency. Urinary function, another important component of symptoms, was captured in 2 items (1 irritative and 1 obstructive). Quality of life impact was captured with 3 items about the effect of symptoms on daily activities. The 9 items had high test-retest reliability (r = 0.83 to 0.93) and internal consistency (alpha = 0.86 to 0.91). All but the urinary items discriminated well between men with and without chronic prostatitis. CONCLUSIONS: The National Institutes of Health chronic prostatitis symptom index provides a valid outcome measure for men with chronic prostatitis. The index is psychometrically robust, easily self-administered and highly discriminative. It was formally developed and psychometrically validated, and may be useful in clinical practice as well as research protocols.

Chronic Disease↗
PubMed1999

Polymerase chain reaction amplification of bacterial 16s rRNA genes in prostate biopsies from men without chronic prostatitis.

OBJECTIVES: A previously reported study using nested polymerase chain reaction (PCR) analysis indicated the presence of DNA from a variety of prokaryotic microorganisms in 77% of transperineal prostate biopsies from patients with chronic nonbacterial prostatitis. Because that study did not include a control group, we investigated whether microbial DNA could also be found in transperineal prostate biopsies obtained from men who did not have a history of prostatitis. METHODS: Transperineal biopsies of both lobes of the prostate were obtained under ultrasound guidance from 9 patients with localized adenocarcinoma of the prostate. DNA was extracted from the prostatic tissue and two-round amplification performed using nested primers from a highly conserved region of the bacterial 16s rRNA gene. Amplified DNA was purified and sequenced, and sequences obtained were compared to bacterial rRNA genes recorded in GenBank. Results. Eleven of 18 biopsy specimens from 8 of 9 patients were positive for bacterial DNA by PCR. Sequence data indicated a predominant organism in 8 of 11 specimens, with greater than 95% homology to DNA from several different genera of bacteria, including Escherichia and Bacteroides. All 9 control samples from the instruments before biopsy were negative. CONCLUSIONS: The presence of bacterial 16s rRNA genes in prostatic tissue is not specific for chronic prostatitis and occurred in most of our patients with localized prostate cancer. Whether the presence of such bacteria is related to the development of prostatic diseases such as prostatitis or prostatic cancer will require carefully controlled trials, including appropriate control groups examined identically.

Aged↗
PubMed1998

Specific T cell recognition of peptides derived from prostate-specific antigen in patients with prostate cancer.

OBJECTIVES: To determine if proteins known to be expressed by both benign and malignant prostate epithelium can be recognized by T cells from patients with prostate cancer. We examined 7 HLA-A2 patients with prostate cancer for evidence of T cell reactivity with prostate-specific antigen (PSA). METHODS: Four peptides derived from PSA were chemically synthesized and shown to bind to HLA-A2. As a control, we also examined the immunogenic influenza matrix peptide Flu58-66 that binds to HLA-A2. These peptides were used to stimulate peripheral blood lymphocytes by in vitro stimulation. RESULTS: In 1 patient, specific recognition of peptide PSA141-150 was observed. The remaining 6 patients had no reactivity with any PSA-derived peptide. The T cell line with specific recognition of peptide PSA141-150 failed to recognize an autologous B cell blast line expressing endogenous PSA following infection with a recombinant PSA vaccinia virus construct. Three of the 7 patients demonstrated specific reactivity with Flu58-66. CONCLUSIONS: We found specific recognition of one PSA-derived peptide in 1 patient of 7 with prostate cancer. The peptide-specific lymphocyte cell line did not recognize endogenous PSA, suggesting that the peptide may not be produced by prostate cancer cells producing PSA. Specific recognition of PSA peptides was not common in our patients with prostate cancer. Whether such activity can be induced by vaccination strategies or can be therapeutic in men with established prostate cancer remains to be demonstrated.

Antigen-Antibody Reactions↗
PubMed1998

Elevated levels of proinflammatory cytokines in the semen of patients with chronic prostatitis/chronic pelvic pain syndrome.

OBJECTIVES: Chronic prostatitis/chronic pelvic pain syndrome is a common diagnosis, but the disease is poorly understood. The diagnosis is based only on symptoms, and no measurable parameter can help in defining the presence of the disease, its severity, or its cause. Cytokines are soluble proteins secreted by cells of the immune system that principally regulate inflammatory and immune responses. To provide an objective measure of inflammation in the genital tract, we measured levels of the proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) in the semen of men with chronic prostatitis/chronic pelvic pain syndrome and compared these with levels in normal men. METHODS: We obtained semen samples from 18 men with chronic prostatitis/chronic pelvic pain syndrome and from 8 normal male volunteers. Cytokine levels were measured in the seminal plasma by two-antibody enzyme-linked immunosorbent assay. RESULTS: Men with prostatitis had higher mean levels of IL-1 beta and TNF-alpha in seminal plasma (mean +/-SEM) than normal men: TNF-alpha 98+/-39 versus 17+/-8; IL-1 beta 246+/-63 versus 27+/-10, respectively; P <0.05. There was a strong correlation between the levels of TNF-alpha and IL-1 beta in the semen of men with chronic prostatitis/chronic pelvic pain syndrome. There was no correlation between either TNF-alpha or IL-1 beta levels and the number of leukocytes per high power field in expressed prostatic secretions in patients. CONCLUSIONS: Some men with chronic prostatitis/chronic pelvic pain syndrome have elevated levels of TNF-alpha and IL-1 beta in the semen. This suggests that inflammation of the genital tract is a feature of this disease, irrespective of the presence or absence of leukocytes in the expressed prostatic secretions. Seminal cytokine levels may provide an objective measure of disease in these patients and suggest specific therapeutic strategies to treat chronic prostatitis/chronic pelvic pain syndrome in such patients.

Adult↗
PubMed1998

Polymerase chain reaction amplification of bacterial 16S rRNA genes from cold-cup biopsy forceps.

PURPOSE: In looking for a possible infectious cause for interstitial cystitis (IC), we previously determined that bladder tissue specimens from both IC patients and controls were uniformly positive by polymerase chain reaction assay (PCR) for bacterial 16S ribosomal RNA genes from various genera including Escherichia, Propionobacterium, Acinetobacter, and Salmonella. We therefore determined whether the biopsy forceps might be contaminated with bacterial DNA. MATERIALS AND METHODS: A total of 23 samples were obtained following disinfection of 6 cold-cup bladder biopsy forceps (2 to 5 specimens from each forceps over a period of 19 months). DNA was extracted from each sample, and PCR performed using nested primers from a highly conserved region of the bacterial 16S rRNA gene. Amplified DNA was purified and sequenced, and the sequences obtained were compared with bacterial rRNA gene sequences recorded in GenBank. RESULTS: Thirteen of 23 forceps specimens were positive by PCR for bacterial DNA, including at least one rinse from each of the 6 forceps. In comparison, none of 9 negative control specimens (sterile distilled water put into tubes and processed in the same manner as forceps rinses) had detectable bacterial DNA. Sequence data indicated the presence of a predominant organism in 12 of the 13 positive specimens, with >95% homology to DNA from several different genera of bacteria including Escherichia, Propionobacterium, Stenotrophomonas and Pseudomonas. CONCLUSIONS: These data indicate that reusable bladder biopsy forceps are frequently contaminated with bacterial DNA. Tissue specimens procured with such instruments therefore are inappropriate sources to look for the presence of bacterial pathogens by PCR.

Biopsy↗
PubMed1997

Autoimmune prostatitis: evidence of T cell reactivity with normal prostatic proteins.

OBJECTIVES: To determine whether men with chronic prostatitis/chronic pelvic pain syndrome have evidence of an autoimmune response to prostatic proteins. We examined men with a history of chronic prostatitis/ chronic pelvic pain syndrome for evidence of T lymphocyte reactivity to seminal plasma. METHODS: Patients underwent automated leukopheresis to obtain peripheral blood mononuclear cells. We performed a recall antigen proliferation assay to detect specific proliferation of peripheral helper T lymphocytes in men. with chronic prostatitis/chronic pelvic pain syndrome and compared the results with those of normal men. The antigen for these studies consisted of seminal plasma from normal donors and men with seminal vesicle atresia. RESULTS: A specific recall proliferative response to seminal plasma was observed in 3 of 10 men with a history of chronic prostatitis/chronic pelvic pain syndrome compared with none of 15 normal men. The CD4 T cell proliferative response to seminal plasma was statistically significant when compared with medium alone in men with a history of chronic prostatitis/chronic pelvic pain syndrome but it was not statistically significant in normal men. The recall responses of both the chronic prostatitis/chronic pelvic pain syndrome group and normal subjects to the recall antigens tetanus toxoid and Candida extract were equivalent. CONCLUSIONS: The data represent the first direct evidence that some men with chronic prostatitis/chronic pelvic pain syndrome have an autoimmune component to their disease. Autoimmunity is a potential etiology for chronic nonbacterial prostatitis.

Adult↗
PubMed1997

Cryosurgical ablation of the normal ventral prostate plus adjuvant does not protect Copenhagen rats from Dunning prostatic adenocarcinoma challenge.

PURPOSE: We wished to determine if cryosurgical ablation of the normal ventral prostate of Copenhagen rats confers protective immunity against a subsequent challenge with Dunning R3327 MatLyLu prostatic adenocarcinoma. In human melanoma, tumor antigens have been characterized as normal cellular proteins. We reasoned that cryosurgical ablation of the normal prostate along with immunostimulatory adjuvants might release prostatic antigens to the immune system engendering an immune response and rendering rats immune to prostatic cancer cells. MATERIALS AND METHODS: On day 0, Copenhagen rats underwent cryosurgical ablation of the normal ventral prostate, cryosurgery and intraprostatic injection of Complete Freund's Adjuvant (CFA), CFA injection alone, or laparotomy alone. On day 21, animals received a subcutaneous challenge of MatLyLu tumor cells. Tumor dimensions were recorded at regular intervals by a single blinded investigator. RESULTS: Animals receiving cryosurgical ablation of the normal ventral prostate or intraprostatic CFA developed tumors more frequently than animals receiving laparotomy alone and the effect was statistically significant if animals received both cryosurgical ablation of the prostate and intraprostatic CFA (3 experiments, 1 x 10(4) MatLyLu cells), total number with tumors/total number challenged: laparotomy alone 3/17, cryosurgical ablation 7/17, cryosurgery plus CFA 10/16 (p = 0.013 versus laparotomy, Fisher's exact test), CFA alone 9/17. CONCLUSIONS: Cryosurgical ablation of the normal rat ventral prostate and intraprostatic CFA does not protect against and can enhance the tumorigenicity of MatLyLu prostatic cancer cells at distant sites. This could be occurring through specific immunologic effects or non-specific mechanisms induced by cryosurgery and CFA.

Adenocarcinoma↗
PubMed1996

Isolated perfusion of the kidney with tumor necrosis factor for localized renal-cell carcinoma.

Patients with localized renal-cell carcinoma who are candidates for renal parenchymal sparing surgery are being treated with isolated renal perfusion with recombinant human tumor necrosis factor (TNF). Isolated organ perfusion is a surgical technique that allows a cancer-bearing organ or region of the body to be treated with high doses of chemotherapy or biologic, agents that would not be tolerated systemically. In patients with in-transit melanoma or unresectable sarcoma, treatment with hyperthermic isolated limb perfusion using TNF, interferon-gamma, and melphalan has resulted in response rates exceeding 90%. Because preclinical studies suggest that TNF may induce regression of tumors by causing hemorrhagic necrosis mediated by effects on tumor-related vascular endothelium, a vascular tumor such as renal-cell carcinoma could potentially be very responsive. A phase I study of escalating TNF doses delivered via isolated renal perfusion is currently being conducted.

Animals↗
PubMed1996

Chronic prostatitis: results of an Internet survey.

OBJECTIVES: Chronic prostatitis is a common diagnosis, but the etiology of this disease is unknown. We sought to catalog symptoms and etiologic factors for chronic prostatitis to gather epidemiologic data about the disease. We also sought to determine the feasibility of doing this using the Internet. METHODS: A 54-questions survey was designed and posted to several Internet newsgroups dealing with chronic prostatitis. The questions dealt with symptoms, predisposing factors, demographic data, and sexual practices. Responses were collected by electronic mail and tabulated at a central site. RESULTS: We received 163 completed surveys over a 2-month period. Nine percent of responses came from individuals outside the United States or Canada. Only 9.8% of complete surveys contained one or more unreadable answers. The responding population consisted of relatively young men (mean age 43 years) with a chronic, relapsing set of symptoms mostly characterized by pain at various locations in the pelvis, irritative voiding symptoms, and pain associated with ejaculation. Most respondents were potent and had a single sexual partner. CONCLUSIONS: This catalog of symptoms will be useful in the design of a standardized instrument to distinguish the population of men with prostatitis from normal men or men with benign prostatic hyperplasia. The facility of conducting patient surveys by Internet is demonstrated.

Adult↗
PubMed1995

Helper T cells infiltrating human renal cell carcinomas have the phenotype of activated memory-like T lymphocytes.

Human renal cell carcinomas are characterized by an inflammatory infiltrate containing many T lymphocytes. Attempts to grow T cells from such tumors by culture in interleukin (IL)-2 have yielded heterogeneous populations of cells with functional characteristics typical of lymphokine-activated killer cells obtained by similar culture of cells from peripheral blood mononuclear cells. We examined a panel of surface markers expressed on T lymphocytes to determine if the CD4+ T cells infiltrating human renal cell carcinomas are different from those in peripheral blood mononuclear cells. By flow cytometry analysis the CD4+ T cells in a panel of freshly digested human renal cell carcinoma primary and metastatic tumors expressed the activation markers CD69 and HLA-DR and manifested an increase in CD45RO and a reciprocal decrease in CD45RA expression as compared with peripheral blood CD4+ T cells. This suggests that CD4+ T cells infiltrating renal cell carcinomas are activated and have encountered antigen. However, the expression of the IL-2R alpha chain (CD25) was not different in tumor-infiltrating CD4+ T cells and peripheral blood CD4+ T cells, suggesting that T cells infiltrating human renal cell carcinomas may have a block in proliferative capacity. The general failure of cultured tumor-infiltrating lymphocyte (TIL) from renal cell carcinoma to demonstrate tumor-specific reactivity may be due to the failure of such cells to grow in IL-2.

CD4-Positive T-Lymphocytes↗
PubMed1995

Defective major histocompatibility complex class I expression in a sarcomatoid renal cell carcinoma cell line.

We studied major histocompatibility complex (MHC) class I expression in 12 tumor cell culture lines established from patients with metastatic renal cell carcinoma (RCC). In one of these cell culture lines, UOK 123, we found no surface expression of beta 2-microglobulin (beta 2m) and MHC class I by flow cytometry. Immunofluorescence staining using three different monoclonal antibodies to beta 2m revealed no detectable beta 2m in the endoplasmic reticulum (ER), Golgi apparatus, cytoplasm, or on the cell surface. There was no evidence of folded class I molecules inside or on the surface of the cells; however, the ER stained intensively for unfolded class I molecules. Transient expression of beta 2m by UOK 123 after infection with a recombinant vaccinia virus containing the gene for beta 2m resulted in normal expression of both beta 2m and class I (HLA-A, B, C) determinants assessed by flow cytometry analysis. No expression of class I or beta 2m was seen with the recombinant vaccinia vector carrying a control gene. The inability of class I molecules to reach the cell surface is due to the requirement of beta 2m for proper folding and presentation of the class I MHC complex. The failure to assemble and express MHC class I complex on the cell surface renders these cells incapable of antigen presentation to cytotoxic T cells and provides a mechanism for escape from immune recognition by the tumor.

Carcinoma, Renal Cell↗