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PubMed1985

Cyclosporine-associated renal arteriopathy resulting in loss of allograft function.

Cyclosporine-associated arteriopathy was the cause of graft loss in 40 percent of all allografts that failed in a series of 200 consecutive cadaveric renal transplants. Arteriopathy was diagnosed by biopsy and renal uptake of indium 111m labeled platelets in the face of acute renal deterioration. A moderate thrombocytopenia and microangiopathic picture of hemolytic uremia was also present on peripheral blood smear. Immunofluorescence and histologic characteristics of the allograft biopsy specimens failed to show evidence for acute rejection: immunoglobulin M, immunoglobulin A, immunoglobulin G, C1q, C3, and C4 were not present, and there was no evidence of an interstitial or vascular mononuclear cellular infiltrate. Two clinical presentations have been described. In Group I (seven patients), anuria occurred rapidly within the first 2 weeks after transplantation. In Group II (nine patients) renal function gradually diminished 1 to 5 months after starting cyclosporine therapy. Fifteen of the 16 recipients had progressive and irreversible loss of renal function which was pathologically associated with fibrin deposition, intimal proliferation, and thrombotic occlusion of the cortical interlobular and arcuate arteries, with subsequent focal glomerular ischemia and cortical infarction. One recipient with rapid loss of renal function received an intraarterial allograft infusion of streptokinase and subsequent systemic heparinization, which resulted in return of normal allograft function. The syndrome of cyclosporine-associated arteriopathy has been linked to a lack of or reduced amounts of prostacyclin-stimulating factor or prostacyclin.

Arterial Occlusive Diseases↗

PubMed1996

[Biomechanical changes in the hip, femur and knee joint after removal of a tensor fasciae latae flap].

The TFI-musculofasciocutaneous flap has become a standard procedure in recent years. Donor-site problems of this method, especially the biomechanical changes of the hip, the proximal femur and the knee joint are evaluated, employing biomechanical techniques. Harvesting of a TFL-flap leads to functional loss of the M. tensor fasciae latae and the iliotibial tract and band. This might lead to a weakening of active and passive stabilising structures of the hip and the knee joint. Loss of the iliotibial tract causes a loss of the lateral tension-band of the proximal femur and leads to a significant increase of shear forces on the proximal femoral shaft. The functionally important structures of the iliotibial tract for knee biomechanics are not influenced by harvesting of the TFL flap. Loss of the M. tensor fasciae latae leads to a mild reduction of hip flexion and internal rotation. The indication for a TFL-flap should consider the patient's activity to prevent overload damage of the proximal femoral shaft. In childhood, harvesting of the TFL flap is likely to influence the growing axial skeleton due to the loss of the iliotibial tract.

Biomechanical Phenomena↗

PubMed1983

Neuronal loss from cervical dorsal root ganglia in adriamycin induced peripheral neuropathy--a quantitative study.

The neurotoxic effects of some of the more recent chemotherapeutic drugs are not well studied. Adriamycin is such a drug, used in the treatment of some cancers in both children and adults. An examination of its effects on the peripheral nervous system was therefore undertaken particularly in view of its use in children. Sprague-Dawley rats, 1 week of age, were injected with a subcutaneous injection of adriamycin (10 mg/kg/wt.). Cervical dorsal root ganglia were removed and prepared for quantitative study at the light microscopic level. Quantitative analysis of neuronal counts of the ganglia showed a statistically significant loss (P less than 0.001) of sensory neurons in the treated rats. The remaining neurons displayed many abnormal morphological features suggestive of a degenerative process. From this study, functional loss cannot be correlated to neuronal type but the significant loss of neurons and numbers of affected cells observed would have a serious effect on sensory function.

Animals↗

PubMed1994

[Cohort studies of effects of long-term toluene diisocyanate (TDI) exposure on pulmonary function].

Toluene diisocyanates (C6H3CH3 (NCO)2, TDIs) are synthetic low molecular-weight organic chemicals with two highly reactive isocyanate groups (-NCO). Exposure to TDI can cause irritation of the eyes, nose, and upper and lower respiratory tract, asthma-like responses, sensitive pneumonitis, and obstructive pulmonary function loss. In this paper, the exposure-effect relationships between long-term TDI exposure and its effect on pulmonary function are summarized by evaluating the results of cohort studies, including 2 cohort studies conducted by the author's research team, which were specially devoted to the exposure-effect relationships and were published at the end of 1992. By assessing the exposure-effect relationships, the current occupational exposure limit of TDI in Japan is discussed and a framework for the health checks on TDI-exposed workers is proposed.

Animals↗

PubMed1998

[Myxoid liposarcoma surrounding non-functioning transplanted kidney after living renal transplantation: a case report].

A 19-year-old male visited our clinic with the complaint of lower abdominal distention, January 1992. He had undergone living renal transplantation from his mother as a donor on June 15, 1988. But the transplanted kidney had become functional loss by chronic rejection 3 years after transplantation. The computed tomography showed huge low density mass around the non-functioning transplanted kidney. En block resection of the tumor and the transplanted kidney was performed. The tumor was pathologically diagnosed as mixoid liposarcoma. It was proved that the tumor cells were derived from recipient cells by the investigation of HLA-DRB1 DNA typing.

Adult↗

PubMed2005

Deconditioning in the hospitalized elderly.

Deconditioning is a complex process of physiological change following a period of inactivity, bedrest or sedentary lifestyle. It results in functional losses in such areas as mental status, degree of continence and ability to accomplish activities of daily living. It is frequently associated with hospitalization in the elderly. The most predictable effects of deconditioning are seen in the musculoskeletal system and include diminished muscle mass, decreases of muscle strength by two to five percent per day, muscle shortening, changes in periarticular and cartilaginous joint structure and marked loss of leg strength that seriously limit mobility. The decline in muscle mass and strength has been linked to falls, functional decline, increased frailty and immobility. The authors describe a three-pronged strategy to combat deconditioning that includes a model of care appropriate to the growing population of elderly clients, the creation of an "elder-friendly" hospital environment and an exercise program.

Activities of Daily Living↗

PubMed1994

[Comparison of a trabeculotomy and trabeculectomy combined with phacoemulsification and foldable lens implantation].

Combined phacoemulsification, foldable lens implantation, and trabeculotomy (12 eyes, LOTOMY group) or trabeculectomy (22 eyes, LECTOMY group) were performed. At 6 months after the operation the visual acuity improvement (over 0.5 improvement, 83.3% in the LOTOMY group, and 95.5% in the LECTOMY group) was not significantly different between the two groups. 9 months postoperatively ocular pressure values (15.6 +/- 3.0 mmHg in the LOTOMY group, and 14.2 +/- 8.0 mmHg in the LECTOMY group) were not significantly different between the two groups. But within 7 days postoperatively average values of the maximal ocular pressure (25.5 +/- 5.9 mmHg in the LOTOMY group, and 11.8 +/- 3.0 mmHg in the LECTOMY group) were significantly higher in the LOTOMY group. The value was higher than the preoperative level. In the follow-up, progressive visual field loss was seen in 17% of the cases in the LOTOMY group. There was no progressive visual field loss in the LECTOMY group. Especially in cases with advanced glaucomatous visual field loss, the occurrence of ocular pressure spikes in the initial postoperative period may be closely related to postoperative progressive visual function loss. Phacotrabeculectomy was effective in avoiding these spikes.

Aged↗

PubMed1987

Lesion size and recovery of function: some new perspectives.

The present article discusses the possibility that functional recovery following brain damage may be to a large degree dependent on the amount of nervous tissue destroyed, such that more neuronal destruction may lead to more and not (as commonly suggested) to less recovery. This assumption may derive from the neuropsychological and neurological literature: many cases with circumscribed brain lesions are implicated with severe functional losses. However, patients with dramatic and severe brain destructions often show astonishingly normal behavior regarding cognition, speech, visuospatial, motor and sensory functions. Animal experimentation as well shows that an extensive lesion of a brain area may be associated with equal or less functional detriment than a small lesion of the same area. Along with the well-known variables of age, lesion growth, or personality and environmental factors, the amount of tissue destroyed should be considered as a potent mediator of functional recovery. At least for some functions and brain regions, the likeliness of recovery may increase with the extent of the lesion and thus the necessity of the brain to fulfill plastic changes.

Animals↗

PubMed2005

Progressive loss of renal function is associated with activation and depletion of naive T lymphocytes.

We hypothesized that progressive loss of renal function specifically affects certain T cell subsets. T lymphocyte subsets of patients with chronic kidney disease and healthy controls were characterized by flow cytometry using heparin-anticoagulated whole blood samples. Plasma interleukin (IL)-7 and IL-15 concentrations were determined as these cytokines are critically involved in T cell homeostasis. The results revealed that a progressive decrease in renal function is associated with activation and selective loss of naive T cells and CD4+ central memory cells and a marked increase in CD8+ memory T cells that lack CD45RO and CCR7. The profile of T cell subsets of patients with CKD 5 with or without hemodialysis treatment was similar except for a pronounced shift to Th1 cells in hemodialysis patients. IL-7 but not IL-15 plasma concentrations were lowered in patients with end-stage renal disease as compared to healthy controls.

Adult↗

PubMed2005

Would blockage of cytokines improve the outcome of pancreatic islet transplantation?

It has been estimated that up to 60% of pancreatic islet tissue undergoes apoptosis within the first several days post-transplantation. This strongly suggests the involvement of an inflammatory event other than alloantigen-specific immune reaction following islet transplantation which contributes to partial destruction of grafts. Inflammatory cytokines including IL-1beta, TNF-alpha and IFN-gamma are implicated in the pancreatic islet beta-cell death and functional loss during autoimmune diabetes and also seem to be involved in early loss of islet mass in islet transplantation. Inflammatory cytokines and free oxygen radicals released in situ could cause apoptosis and the functional impairment of islets after islet transplantation and graft failure. It can be hypothesized that preventing destruction of transplanted islets using cytokine blockade could be helpful in improving islet transplantation outcome. Several approaches have been made based on this hypothesis to examine the effect of inflammatory blockade on the islets survival and functional islet mass. Further investigations are required to identify most efficient way for block of cytokine-induced damage in pancreatic islets transplantation.

Animals↗

PubMed2003

Optimal modes and targets of gene therapy in transplantation.

Genetic modification strategies have the potential to improve outcome following cell/organ transplantation. A unique opportunity in transplantation is that gene therapies need not be restricted to in vivo approaches and that ex vivo genetic modification of cell and/or organs can be of value. Improvements in vector design, production, and delivery should enhance transfection efficiency and optimize gene expression. Herein, we discuss potential modes of gene therapy, focusing on viral, liposome, or naked DNA-based systems for gene delivery. We suggest gene therapy targets taking into consideration the essential constituents of anti-allograft repertory. In addition to strategies that may have salutary effects in mitigating the threat of acute rejection, we suggest genetic strategies for minimizing ischemia/reperfusion injury as well as for the perennial problem of progressive functional loss of the transplanted organ. Data from pre-clinical transplant models support the idea that gene therapy may improve allograft function and survival. We are optimistic that gene therapy will be of clinical value in the near future in the management of recipients of allografts; we believe that genetic strategies would be essential for successful breaching of the formidable challenge of xenotransplantation.

Animals↗

PubMed2002

Ankylosing spondylitis: what is the cost to society, and can it be reduced?

Ankylosing spondylitis is a chronic rheumatic disease leading to functional limitations. This has an important impact on participation in the labour force, with high disease-related work disability. As for cost-of-illness studies, which estimate the costs related to a disease, the cost of lost productivity is the major contributor to the total costs of ankylosing spondylitis. Because of the low prevalence of the disease, the costs related to ankylosing spondylitis are a relatively small part of the costs of all diseases to society. However, given the early and the important long-term functional loss, the lifetime costs and socio-economic impact for the individual patient are likely to be high. Because poor physical function is the major determinant of high direct and productivity costs, new (biological) treatments with effects on long-term functional disability will potentially reduce the economic impact of the disease for society and patients.

Cost of Illness↗

PubMed2005

Screening techniques for detecting chronic kidney disease.

PURPOSE OF REVIEW: As patients with impaired kidney function are at increased risk not only for progressive renal function loss, but also for cardiovascular disease, it is of importance to have accurate techniques to screen patients for the presence of an impaired kidney function. RECENT FINDINGS: Glomerular filtration rate can in mass screenings best be evaluated using a formula based upon a serum creatinine measurement and anthropometric parameters. The Cockcroft-Gault and Modification of Diet in Renal Disease (MDRD) formulas are mostly used. Both are easy to use, but have their limitations. Interpreting the results of such glomerular filtration rate estimates requires a good knowledge of these limitations. Urinary albumin excretion can best be measured from 24 h urine collections. As these collections are difficult to perform, however, an early morning spot urine sample for the measurement of urinary albumin concentration can be applied as preselection for screening purposes. SUMMARY: Mass screening for early kidney function impairment, expressed by an impaired glomerular filtration rate or elevated urinary albumin excretion, may help to detect patients at increased cardiac and renal risk. This can best be done using formulas to estimate glomerular filtration rate and by measuring urinary albumin loss.

Albuminuria↗

PubMed2006

Docosahexaenoic acid protects from amyloid and dendritic pathology in an Alzheimer's disease mouse model.

Genetic data argues that Alzheimer's disease (AD) can be initiated by aggregates of a 42 amino acid beta amyloid peptide (Abeta42). The Abeta aggregates, notably small oligomer species, cause a cascade of events including oxidative damage, inflammation, synaptic toxicity and accumulation of intraneuronal inclusions; notably neurofibrillary tangles. Cognitive deficits are likely to begin with a failure of synaptogenesis and synaptic plasticity with dendritic spine loss and dying back of dendritic arbor. This is followed by neuron loss in key areas involved in learning and memory. Significant prevention or delay of clinical onset may be achievable by modifying environmental risk factors that impact the underlying pathogenic pathways. Because low fish intake and low blood levels of the marine lipid, docosahexaenoic acid (DHA) have been associated with increased AD risk we have tested the impact of depleting or supplementing with dietary DHA on AD pathogenesis in transgenic mice bearing a mutant human gene known to cause AD in people. We reported that even with intervention late in life dietary DHA depletion dramatically enhanced oxidative damage and the loss of dendritic markers, while DHA supplementation markedly reduced Abeta42 accumulation and oxidative damage, corrected many synaptic deficits and improved cognitive function. Loss of brain DHA was exacerbated in mice expressing the mutant human AD transgene, this is consistent with evidence for increased oxidative attack on DHA oxidation in AD. Treatment with the curry spice extract curcumin, a polyphenolic antioxidant that inhibits AP aggregation, has been strongly protective in the same mouse model. Many Western diets are typically deficient in DHA and low in polyphenolic antioxidant intake. These and other data argue that increasing dietary intake of both DHA and polyphenolic antioxidants may be useful for AD prevention.

Alzheimer Disease↗

PubMed2005

Functional outcome and health-related quality of life after surgical repair of full-thickness rotator cuff tear using a mini-open technique.

BACKGROUND: Rotator cuff tear, a common shoulder injury, can lead to shoulder pain and functional loss. HYPOTHESIS: Surgical repair of full-thickness rotator cuff tears using the mini-open surgical technique will improve shoulder function and health-related quality of life. STUDY DESIGN: Cohort study. Level of evidence, 2. METHODS: Patients with a full-thickness rotator cuff tear who underwent a mini-open repair were evaluated for (1) active shoulder range of motion preoperatively, and 6 months and 12 months postoperatively and (2) health-related quality of life preoperatively, 6 months postoperatively, and annually up to 5 years postoperatively. Satisfaction with the repair and return to work status were ascertained 1 year postoperatively. A subgroup analysis of tear size and patient age was also undertaken. RESULTS: Of the subjects, 61 (73%) were men, and the average age was 53.2 ( +/- 9.9) years. According to repeated-measures analysis of variance, shoulder range of motion (flexion and external rotation) improved significantly from before surgery to 1 year after surgery (P <.001). The mean American Shoulder and Elbow Surgeons scores improved from 53.3 ( +/- 20.6) preoperatively to 90.6 ( +/- 11.7) 1 year postoperatively (P <.001). The mean Western Ontario Rotator Cuff scores also improved from 43.2 ( +/- 20.2) preoperatively to 87.2 ( +/- 14.3) 1 year postoperatively (P <.001). No differences were seen in either the American Shoulder and Elbow Surgeons scores or Western Ontario Rotator Cuff scores between the 1-year examination and the last follow-up assessment undertaken at a median of 5 years postoperatively (P >.05). Ninety-six percent of patients were satisfied or very satisfied with the results of their repair; 78% of patients who were working before surgery returned to work without modification by 1 year postoperatively. For the most part, patient age and size of tear did not influence postoperative range of motion or health-related quality of life. CONCLUSION: Mini-open rotator cuff repair led to improved shoulder function and health-related quality of life up to 5 years postoperatively.

Adult↗

PubMed2002

Mutation of the alpha2A-adrenoceptor impairs working memory performance and annuls cognitive enhancement by guanfacine.

Norepinephrine strengthens the working memory, behavioral inhibition, and attentional functions of the prefrontal cortex through actions at postsynaptic alpha2-adrenoceptors (alpha2-AR). The alpha2-AR agonist guanfacine enhances prefrontal cortical functions in rats, monkeys, and human beings and ameliorates prefrontal cortical deficits in patients with attention deficit hyperactivity disorder. The present study examined the subtype of alpha2-AR underlying these beneficial effects. Because there are no selective alpha2A-AR, alpha2B-AR, or alpha2C-AR agonists or antagonists, genetically altered mice were used to identify the molecular target of the action of guanfacine. Mice with a point mutation of the alpha2A-AR, which serves as a functional knock-out, were compared with wild-type animals and with previously published studies of alpha2C-AR knock-out mice (Tanila et al., 1999). Mice were adapted to handling on a T maze and trained on either a spatial delayed alternation task that is sensitive to prefrontal cortical damage or a spatial discrimination control task with similar motor and motivational demands but no dependence on prefrontal cortex. The effects of guanfacine on performance of the delayed alternation task were assessed in additional groups of wild-type versus alpha2A-AR mutant mice. We observed that functional loss of the alpha2A-AR subtype, unlike knock-out of the alpha2C-AR subtype, weakened performance of the prefrontal cortical task without affecting learning and resulted in loss of the beneficial response to guanfacine. These data demonstrate the importance of alpha2A-AR subtype stimulation for the cognitive functions of the prefrontal cortex and identify the molecular substrate for guanfacine and novel therapeutic interventions.

Adrenergic alpha-2 Receptor Agonists↗

PubMed2003

Kernel Cox regression models for linking gene expression profiles to censored survival data.

In functional genomics, one important problem is to relate the microarray gene expression profiles to various clinical phenotypes from patients. The success has been demonstrated in molecular classification of cancer in which gene expression data serve as predictors and different types of cancer are the binary or multi-categorical outcome variable. However, there has been less research in linking gene expression profiles to other types of phenotypes, in particular, the censored survival data such as patients' overall survival or cancer relapse times. In the paper, we develop a kernel Cox regression model for relating gene expression profiles to censored phenotypes in the framework the penalization method in terms of function estimation in reproducing kernel Hilbert spaces. To circumvent the problem of censoring, we use the negative partial likelihood as a loss function in the estimation procedure. The functional combinations of the original gene expression data identified by the method are highly correlated with the patients' survival times and at the same time account for the variability in the gene expression levels. We apply our method to data sets from diffuse large B-cell lymphoma, lung adenocarcinoma and breast carcinoma studies to verify its effectiveness. The results from these analyses indicate that the proposed method works very well in identifying subgroups of patients with different risks of death or relapse and in predicting the risk of relapse or death based on the gene expression profiles measured from the tumor samples taken from the patients.

Artificial Intelligence↗

PubMed2005

Imaging changes and cognitive outcome in primary CNS lymphoma after enhanced chemotherapy delivery.

BACKGROUND AND PURPOSE: In children, MR imaging abnormalities consistent with leukoencephalopathy after treatment for hematologic malignancy do not correlate with neurologic dysfunction and are often overinterpreted with regard to clinical significance. We hypothesized that this would also be true in primary CNS lymphoma (PCNSL) patients who attained a complete response (CR) after treatment with chemotherapy and osmotic blood-brain barrier disruption (BBBD). We hypothesized that cognitive function loss measured after tissue diagnosis but before BBBD-enhanced chemotherapy could be correlated with brain changes visualized by imaging, whereas a correlation would not be present after therapy if the patient attained a complete tumor response, analogous to the findings in children. METHODS: Sixteen primary CNS lymphoma patients were followed after CR (no enhancing tumor) by using a methotrexate-based regimen. Neuropsychological (NP) cognitive testing and MR imaging or CT (when MR imaging was not available) were performed before treatment and at completion of the 12-month treatment for each patient. Thereafter, the same studies were available for nine of these 16 CR patients, who were followed for a median of 55 months. Zone I was defined as enhancing tumor, and zone II as surrounding abnormal MR T2 signal intensity or low-attenuation CT. The cognitive scores were converted to Z scores and the MR T2 signal intensity or CT low-attenuated changes were converted to a summary zone II abnormality score. RESULTS: A significant association between neurocognitive data and zone II abnormality was found at baseline after tissue diagnosis but before chemotherapy (r = -.55; P < .028), but no correlation existed at end of treatment. Imaging studies showed that seven patients developed a new T2 or low-attenuation abnormality by the end of treatment, whereas 15 patients showed a decrease, stable appearance, or complete resolution of their baseline zone II abnormality by end of treatment. Although cognitive loss compared with age-matched control subjects was common before starting therapy, by the end of treatment all patients' cognitive function improved significantly (P < .005). CONCLUSION: The current data suggest that neither enhanced chemotherapy delivery nor changes in MR imaging T2 signal intensity or CT low attenuation, in PCNSL patients who attained a CR, were associated with a decrease in cognitive function.

Adolescent↗