Brain natriuretic peptide is a potentially useful screening tool for the detection of cardiovascular disease in patients with rheumatoid arthritis.
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Adult↗
Biomedical subjects
S Donnelly
Publications and source records attributed to S Donnelly.
Ordered-subset analysis of savant skills in autism for 15q11-q13.
Autism is a complex disorder characterized by genetic and phenotypic heterogeneity. Analysis of phenotypically homogeneous subtypes has been used to both confirm and narrow potential autism linkage regions such as the chromosomal region 15q11-q13. Increased evidence for linkage in this region had been found in a subgroup of 21 autism families (total families = 94) stratified based on a savant skill factor (SSF) from the Autism Diagnostic Interview, Revised (ADI-R). We examined the savant phenotypic finding in our sample of 91 multiplex autism families. Using two-point parametric analysis in stratification with a cutoff point of a savant skill score of 0.16, our families failed to demonstrate linkage to 15q11-q13. In addition, ordered subset analysis (OSA) using SSF as a covariate also failed to show evidence for linkage. Our findings do not support savant skills as an informative phenotypic subset for linkage in our sample.
Adolescent↗
Optimized clinical-scale culture conditions for ex vivo selective depletion of host-reactive donor lymphocytes: a strategy for GvHD prophylaxis in allogeneic PBSC transplantation.
BACKGROUND: Ex vivo selective depletion (SD) is a strategy to prevent GvHD, in which host-reactive donor lymphocytes are selectively eliminated from a PBSC allograft while conserving useful donor immune function. Prior to testing this strategy in patients, our goal was to develop a clinical-scale SD process, which involves co-culture of donor lymphocytes and irradiated recipient cells, followed by the addition of an immunotoxin (IT) directed against the alpha-chain of the IL-2 receptor (CD25), expressed on activated donor T cells. METHODS: Stimulator cells were generated from immunomagnetically selected and expanded recipient T lymphocytes. Donor PBMCs from G-CSF-mobilized peripheral blood were co-cultured for 72 h with irradiated stimulator cells. Alloreactive T cells were targeted for elimination by the addition of the anti-CD25 IT, RFT5-SMPT-dgA, and the IT enhancer, NH(4)Cl. RESULTS: Stimulator-cell selection/expansion yielded > 2 x 10(10) highly enriched CD3(+) cells (98.9 +/- 2.2%). After SD, cell recovery was 68.5 +/- 23.3% and viability was 84.6 +/- 6.4%. This permitted a potential T-cell dose >/= 1 x 10(8) CD3(+) cells kg(-1) to transplant recipients. Although SD donor lymphocytes retained little proliferative capacity against the original stimulator cells (2.6 +/- 0.6%), responses were conserved against third party cells (107.6 +/- 18.6%), the bacterial superantigen staphylococcus enterotoxin B (108.2 +/- 4.2%), and CMV Ag (72.1 +/- 3.8%). DISCUSSION: We have demonstrated that ex vivo SD is feasible in clinical-scale culture conditions. The ability of this strategy to prevent GvHD is the subject of an ongoing clinical trial, in which the SD lymphocyte product is transplanted in conjunction with a T cell-depleted PBSC allograft.
CD3 Complex↗
Canadian survey of clinical status at dialysis initiation 1998-1999: a multicenter prospective survey.
AIMS: The current growth in end-stage kidney disease populations has led to increased efforts to understand the impact of status at dialysis initiation on long-term outcomes. Our main objective was to improve the understanding of current Canadian nephrology practice between October 1998 and December 1999. METHODS: Fifteen nephrology centers in 7 provinces participated in a prospective data collection survey. The main outcome of interest was the clinical status at dialysis initiation determined by: residual kidney function, preparedness for chronic dialysis as measured by presence or absence of permanent peritoneal or hemodialysis access, hemoglobin and serum albumin. Uremic symptoms at dialysis initiation were also recorded, however, in some cases these symptom data were obtained retrospectively. RESULTS: Data on 251 patients during 1-month periods were collected. Patients commenced dialysis at mean calculated creatinine clearance levels of approximately 10 ml/min, with an average of 3 symptoms. 35% of patients starting dialysis had been known to nephrologists for less than 3 months. These patients are more likely to commence without permanent access and with lower hemoglobin and albumin levels. Even of those known to nephrologists, only 66% had permanent access in place. CONCLUSIONS: Patients commencing dialysis in Canada appear to be doing so in relative concordance with published guidelines with respect to timing of initiation. Despite an increased awareness of kidney disease, a substantial number of patients continues to commence dialysis without previous care by a nephrologist. Of those who are seen by nephrologists, clinical and laboratory parameters are suboptimal according to current guidelines. This survey serves as an important baseline for future comparisons after the implementation of educational strategies for referring physicians and nephrologists.
Adult↗
Quality of life measurement in the palliative management of advanced cancer.
A 4-week quality of life (QOL) study was conducted in 157 consecutive advanced cancer patients to compare five QOL measures and to assess changes in QOL during the course of the study. The study patients were representative of the advanced cancer population in the USA, and were similar to the advanced cancer population with respect to age and gender. Global QOL measures appear to be as effective as multidimensional measures in assessing QOL in patients with advanced cancer. Generally, QOL was rated as satisfactory and did not change markedly during the study period.
Aged↗
Why is erythropoietin made in the kidney? The kidney functions as a critmeter.
Erythropoietin is distinct among the hematopoietic growth factors because it is produced primarily in the kidneys rather than the bone marrow. The kidney functions as a critmeter in that it senses oxygen tension and extracellular volume. By regulating red cell mass through erythropoietin and plasma volume through excretion of salt and water, the kidney sets the hematocrit at a normal value of 45%. This is not a random number, but a value that maximizes oxygen delivery to peripheral tissues. The ability of the kidney to coordinate these two volumes to generate a hematocrit of 45% establishes it as the logical site for erythropoietin production. The kidney has the unique ability to translate a measure of plasma volume as tissue oxygen pressure required to regulate erythropoietin production. I hypothesize that the critmeter is a functional unit that regulates the hematocrit. The critmeter is found at the tip of the juxtamedullary region of the cortical labyrinth in the kidney, where erythropoietin is made physiologically. Renal vasculature and nephron segment heterogeneity in sodium reabsorption generate the marginal tissue oxygen pressure required to trigger the production of erythropoietin. The balance of the oxygen consumption for sodium reabsorption and the oxygen delivery to the proximal tubule is reflected by the tissue oxygen pressure that determines red blood cell mass adjusted to plasma volume. Factors that affect blood supply and sodium reabsorption in a discordant manner may modulate the critmeter (eg, angiotensin II). Examples of clinical disorders caused by dysfunction or resetting of the critmeter are described.
Anemia↗
Whole-cell but not acellular pertussis vaccines induce convulsive activity in mice: evidence of a role for toxin-induced interleukin-1beta in a new murine model for analysis of neuronal side effects of vaccination.
Immunization with the whole-cell pertussis vaccine (Pw), while effective at preventing whooping cough in infants, has been associated with local, systemic, and neuronal reactions, including fevers and convulsions in children. In contrast, the new acellular pertussis vaccines (Pa) have a considerably improved safety profile. The lack of an appropriate animal model has restricted investigations into the mechanisms by which neurological reactions are induced by vaccination. Here we describe a novel murine model wherein seizure-like behavioral changes are induced following parenteral administration of Pw. The proinflammatory cytokine interleukin-beta (IL-1beta), production of which has been associated with many neurodegenerative conditions, was significantly increased in the hippocampus and hypothalamus of vaccinated animals. Accompanying this change was a decrease in release of the inhibitory neurotransmitters gamma-aminobutyric acid and adenosine in the hippocampus. Seizure-like behavioral changes were significantly reduced following inhibition of IL-1beta production by the administration of an inhibitor of IL-1beta-converting enzyme and were almost completely abrogated in IL-1 receptor type I knockout mice. These results suggest a causal relationship between IL-1beta induction and convulsive behavior following Pw vaccination. Significantly, Pa neither increased IL-1beta nor induced behavioral changes in mice, but did induce the anti-inflammatory cytokine IL-10. In contrast, administration of active pertussis toxin and lipopolysaccharide, residual in Pw but absent from Pa, also induced convulsive activity. Our findings provide the first direct evidence of an immunological basis for pertussis vaccine reactogenicity and suggest that active bacterial toxins are responsible for the neurologic disturbances observed in children immunized with Pw.
Animals↗
Interleukin-1beta-dependent changes in the hippocampus following parenteral immunization with a whole cell pertussis vaccine.
Neurological side effects are a major cause of concern following immunization with a number of vaccines, especially the whole cell pertussis vaccine (Pw). In this study we report that IL-1beta concentrations were significantly increased in the hippocampus following subcutaneous (s.c.) injection of Pw, and that this was accompanied by increased activity of the stress-activated kinase, c-Jun-N-terminal kinase (JNK) and a decrease in glutamate release. These effects were mimicked by s.c injection of active pertussis toxin (PT) or lipopolysaccharide (LPS). Incubation of hippocampal synaptosomes in the presence of Pw, PT or LPS also resulted in increased JNK activation and decreased glutamate release, effects which were mimicked by IL-1beta and blocked by the IL-1 receptor antagonist (IL-ra). Our observations are consistent with the hypothesis that IL-1beta induced by active bacterial toxins present in vaccine preparations, mediate the neurochemical and perhaps the neurological effects of Pw.
Animals↗
Induction of inflammatory cytokines in the brain following respiratory infection with Bordetella pertussis.
Parenteral injection of endotoxin has been used as a model to examine the role of pro-inflammatory cytokines in the centrally controlled responses to Gram-negative bacterial infection. However, the events that occur following mucosal exposure to live bacteria have received little attention. In this study, we have used a murine model to demonstrate that respiratory infection with Bordetella pertussis, which is associated with a number of systemic complications including fever, seizure and encephalopathy in children, resulted in persistent expression of mRNA transcripts for IL-1beta and TNFalpha and transient expression of IL-6 in the hippocampus and hypothalamus. These changes correlated with elevated levels of cytokine protein in the same brain areas. The results demonstrate that infection at a mucosal surface can result in the induction of pro-inflammatory cytokine production in the brain and suggest that these locally synthesized mediators may contribute to the centrally controlled clinical manifestations of B. pertussis infection.
Animals↗
Ultrasound-based stereotactic guidance in prostate cancer--quantification of organ motion and set-up errors in external beam radiation therapy.
OBJECTIVE: A mobile transabdominal ultrasound-based targeting system (BAT(R)) has been developed which can stereotactically localize the position of the prostate each treatment day and directly integrate this information into the treatment planning system. Daily target verification facilitates a marked reduction in planning treatment margins by correcting potential organ-motion and set-up errors. Previous studies have been performed to establish the precision of ultrasound localization. This report quantifies the magnitude of the patient isocenter shift parameters encountered during clinical implementation of this system. MATERIAL AND METHODS: After five weeks of conformal external beam radiation therapy, 54 patients underwent a second CT simulation. Prostate-only fields based on this scan were created with no PTV margin beyond the CTV. For each of the final conedown treatments (2-4 fractions), patients underwent ultrasound-based stereotactic prostate localization at the treatment machine. The portable system, which electronically imports the CT simulation target-contour and isocenter information, is situated adjacent to the treatment couch. Transverse and sagittal suprapubic ultrasound images are captured, and the system electronically couples this data to the baseline isocenter. The CT contours are maneuvered in three dimensions by a touch-screen menu to visually overlay the ultrasound images. The system then displays the three-dimensional (3D) couch shifts required to produce field alignment. RESULTS: One hundred and eighty-nine daily ultrasound prostate position shifts were recorded for 54 patients. The isocenter field misalignment between the baseline CT and ultrasound ranged from -26.8 to 33.8 mm in the anterior/posterior (A/P) dimension, -10.2 to 30.9 mm in the lateral dimension, and -24.6 to 9.0 mm in the superior/inferior (S/I) dimension. The corresponding directed average disagreements were -3.0 mm (SD 8.3 mm) A/P, 1.86 mm (SD 5.7 mm) lateral, and -2.6 mm (SD 6.5 mm) S/I. The magnitudes of undirected misalignments were frequently larger than 5 mm (51% of A/P, 31% of lateral, and 35% of superior measurements) and oftentimes larger than 10 mm (21% of A/P, 7% of lateral, and 12% of superior measurements). CONCLUSIONS: Organ motion and set-up uncertainties limit optimization of 3D treatment planning by expanding the width of PTV margins required to ensure target coverage. Transabdominal ultrasound-based stereotactic guidance is a safe and direct method for correcting patient positioning. Our experience with the BAT system in a large cohort of prostate cancer patients revealed that substantial daily isocenter corrections were encountered in a large percentage of cases. This data would suggest that daily clinical isocenter misalignments are greater than would be expected from published data on organ motion and set-up variations encountered in the study setting.
Cohort Studies↗
The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients.
A multivariate analysis of the data was conducted to evaluate the effects of age, gender, and performance status on symptom profile. A comprehensive prospective analysis of symptoms was conducted in 1,000 patients on initial referral to the Palliative Medicine Program of the Cleveland Clinic. The median number of symptoms per patient was 11 (range 1-27). The ten most prevalent symptoms were pain, easy fatigue, weakness, anorexia, lack of energy, dry mouth, constipation, early satiety, dyspnea, and greater than 10% weight loss. The prevalence of these 10 symptoms ranged from 50% to 84%. Younger age was associated with 11 symptoms: blackout, vomiting, pain, nausea, headache, sedation, bloating, sleep problems, anxiety, depression, and constipation. Gender was associated with 8 symptoms. Males had more dysphagia, hoarseness, >10% weight loss and sleep problems; females, more early satiety, nausea, vomiting, and anxiety. Performance status was associated with 14 symptoms. Advanced cancer patients are polysymptomatic. Ten symptoms are highly prevalent. Symptom prevalence for 24 individual symptoms differs with age, or gender, or performance status.
Adolescent↗
Quality-of-life assessment in advanced cancer.
In the past 5 years, quality-of-life (QOL) assessment measures such as the McGill, McMaster, Global Visual Analogue Scale, Assessment of QOL at the End of Life, Life Evaluation Questionnaire, and Hospice QOL Index have been devised specifically for patients with advanced cancer. The developers of these instruments have tried to respond to the changing needs of this specific population, taking into account characteristics including poor performance status, difficulty with longitudinal study, rapidly deteriorating physical condition, and change in relevant issues. Emphasis has been placed on patient report, ease and speed of completion, and the existential domain or meaning of life. Novel techniques in QOL measurement have also been adapted for palliative care, such as judgment analysis in the Schedule for the Evaluation of Individual Quality of Life. It is generally agreed that a single tool will not cover all QOL assessment needs.
Health Status Indicators↗
High multidrug resistance (P-glycoprotein 170) expression in inflammatory bowel disease patients who fail medical therapy.
BACKGROUND & AIMS: The multidrug resistance (MDR) gene codes for a drug efflux pump P-glycoprotein 170 (Pgp-170) expressed on the surface of lymphocytes and intestinal epithelial cells. Inflammatory bowel disease (IBD) poorly responsive to medical therapy may relate to MDR expression because glucocorticoids are known Pgp-170 substrates. METHODS: Using flow cytometry, we measured peripheral blood lymphocyte (PBL) MDR in 153 IBD patients and 50 healthy volunteers, and assessed the relationship between PBL, mucosal intraepithelial lymphocyte (IEL), and mucosal epithelial cell (EC) MDR expression in a further 20 IBD patients and 19 controls. RESULTS: Compared with controls, PBL MDR was significantly elevated in patients with Crohn's disease who required bowel resection for failed medical therapy (mean +/- SEM, 26.7 +/- 2.8 vs. 11.9 +/- 1.0; P <0.0001) and patients with ulcerative colitis who required proctocolectomy for failed medical therapy (20.3 +/- 2.5 vs. 11.9 +/- 1.0; P = 0.001). PBL MDR remained stable over time and was not influenced by disease activity or glucocorticoid therapy. Both PBL and mucosal MDR expression appeared independent of disease activity, and there was a significant correlation between PBL MDR expression and both IEL expression (r = 0.92; P < 0.0001) and EC expression (r = 0.54; P < 0.001). CONCLUSIONS: PBL and mucosal MDR expression may play an important role in determining the response of IBD patients to glucocorticoid therapy.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Gender disparity in living renal transplant donation.
Numerous studies document that women constitute the majority of living kidney donors, but the reasons behind the disparity in donation rates between men and women remain obscure. We studied this issue by gathering data on family members of living donor allograft recipients at a single large center over a 5-year period (n = 144). By considering all potential donors (spouses and first-degree relatives) within each recipient's immediate family, we determined that men and women are excluded as donors at approximately similar rates on the basis of medical condition or known blood group type A, type B, type O incompatibility, and that a greater percentage of acceptable female donors (28.3%) compared with men (20.3%) go on to donate a kidney (P: = 0.027). However, when only first-degree relatives are considered, the difference in donation rate between men and women becomes nonsignificant (26.9% of women versus 22.2% of men; P = 0.229). Among spouses, the gender disparity in donation rate is greater (36% of wives versus 6.5% of husbands who are acceptable donors go on to donate a kidney; P = 0.003). Evidence that economic factors may contribute to the overall gender disparity is also presented. In conclusion, the gender disparity among living kidney donors observed in our population can be largely attributed to an overwhelming predominance of wives among spousal donors. Possible explanations and potential interventions to address underrepresentation of male donors are discussed.
Adult↗
Recovery of Candida dubliniensis from non-human immunodeficiency virus-infected patients in Israel.
Candida dubliniensis is a recently discovered yeast species principally associated with carriage and disease in the oral cavities of human immunodeficiency virus (HIV)-infected individuals. To date the majority of isolates of this species have been identified in Europe and North America. In this study, five Candida isolates recovered from separate HIV-negative hospitalized patients in Jerusalem, Israel, were presumptively identified as C. dubliniensis on the basis of their dark green coloration when grown on CHROMagar Candida medium. Their identification was confirmed by a variety of techniques, including carbohydrate assimilation profiles, absence of growth at 45 degrees C, positive reaction with C. dubliniensis-specific antibodies as determined by indirect immunofluorescence analysis, and positive amplification with C. dubliniensis-specific PCR primers. All five strains were shown to be susceptible to a range of antifungal agents, including fluconazole. One of the five isolates was recovered from urine specimens, while the remaining four were recovered from upper respiratory tract and oral samples. While none of the patients was HIV positive, all were receiving broad-spectrum antibacterials at the time isolates of C. dubliniensis were obtained from clinical specimens. This study describes the first isolates of C. dubliniensis from the Middle East and confirms that this yeast can be associated with carriage and infection in the absence of HIV infection.
Adult↗
Is hyaluronic acid effective in patients with osteoarthritis of the knee?
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Adjuvants, Immunologic↗
Plasma-volume contraction and exercise-induced hypoxaemia modulate erythropoietin production in healthy humans.
This study examined exercise-induced hypoxaemia (EIH) and plasma volume contraction as modulators of serum erythropoietin (Epo) production. Five athletes cycled for 3 min at supra-maximal power outputs, at each of two different elevations (1,000 m and 2,100 m). Five subjects were exposed to normobaric hypoxia (F(I)O(2)=0.159), seven subjects underwent plasmapheresis to reduce plasma volume and eight subjects were time controls for Epo levels. Oxyhaemoglobin saturation was significantly reduced during exercise and during normobaric hypoxia. The time period of haemoglobin oxygen saturation <91% was 24+/-29 s (mean+/-S.D., n=5) for exercise at 1000 m, 136+/-77 s (mean+/-S.D., n=5) for exercise at 2100 m and 178+/-255 s (mean+/-S.D., n=5) with resting hypoxic exposure. However, significantly increased serum Epo levels were observed only following exercise (24+/-3%; mean+/-S.D., n=5 at 1,000 m and 36+/-5%; mean+/-S.D., n=5 at 2,100 m). Volume contraction also resulted in increased serum Epo (35+/-6%; mean+/-S.D., n=7) in spite of a significant rise in haematocrit of 2.2%. Despite similar degrees of arterial desaturation, only the hypoxaemia induced by exercise was associated with an increase in serum Epo. This finding indicates that other factors, in addition to hypoxaemia, are important in modulating the production of Epo in response to exercise. Volume depletion in the absence of exercise resulted in increases in Epo levels that were comparable with those observed in response to exercise. The paradoxical responses of the increased haematocrit and the increase in Epo in subjects undergoing plasmapheresis suggests that plasma volume may also modulate the production of Epo.
Adult↗
Euthanasia and assisted suicide.
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Conscience↗