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Biomedical subjects

N Parfrey

Publications and source records attributed to N Parfrey.

12 recordsLinked to original sources
PubMed2003

Effects of fenoldopam on renal blood flow and its function in a canine model of rhabdomyolysis.

BACKGROUND AND OBJECTIVE: Our hypothesis was that fenoldopam, a selective DA1 agonist, would protect against rhabdomyolysis-induced renal injury. METHODS: We studied the effects of intravenous fenoldopam (0.1-1.0 microg kg(-1) min(-1)) or saline on renal blood flow and function in 10 anaesthetized Labrador dogs in whom rhabdomyolysis and myoglobinuric acute renal failure had been induced by administration of glycerol 50% (10mL kg(-1)) intramuscularly. Haemodynamic measurements including renal blood flow and derived parameters of renal function including creatinine clearance were recorded before and for the 30 min following glycerol injection, and during the 3 h following commencement of each infusion. Serum malondialdehyde concentrations were measured before and 15 min after glycerol intramuscularly, and 30 and 150 min after commencement of the infusion. RESULTS: In the fenoldopam group, creatinine clearance was less than placebo at 1 and 2 h after commencing the infusion (12.7 +/- 11.5 versus 31.3 +/- 9.9 mL min(-1), P = 0.04; 8.5 +/- 5.3 versus 20.1 +/- 7.4 mL min(-1), P = 0.03). A 140-fold increase in serum malondialdehyde concentration occurred in one dog (fenoldopam group). CONCLUSION: Fenoldopam increased the severity of the renal injury in this canine model of myoglobinuric acute renal failure.

Animals↗
PubMed2001

Attenuation of pancreatitis-induced pulmonary injury by aerosolized hypertonic saline.

BACKGROUND: The immunomodulatory effects of hypertonic saline (HTS) provide potential strategies to attenuate inappropriate inflammatory reactions. This study tested the hypothesis that administration of intratracheal aerosolized HTS modulates the development of lung injury in pancreatitis. METHODS: Pancreatitis was induced in 24 male Sprague-Dawley rats by intraperitoneal injection of 20% L-arginine (500 mg/100 g body weight). At 24 and 48 h, intratracheal aerosolized HTS (7.5% NaCl, 0.5 mL) was administered to 8 rats, while a further 8 received 0.5 mL of aerosolized normal saline (NS). At 72 hours, pulmonary neutrophil infiltration (myeloperoxidase activity) and endothelial permeability (bronchoalveolar lavage and wet:dry weight ratios) were assessed. In addition, histological assessment of representative lung tissue was performed by a blinded assessor. In a separate experiment, polymorphonucleocytes (PMN) were isolated from human donors, and exposed to increments of HTS. Neutrophil transmigration across an endothelial cell layer, VEGF release, and apoptosis at 1, 6, 12, 18, and 24 h were assessed. RESULTS: Histopathological lung injury scores were significantly reduced in the HTS group (4.78 +/- 1.43 vs. 8.64 +/- 0.86); p < 0.001). Pulmonary neutrophil sequestration (1.40 +/- 0.2) and increased endothelial permeability (6.77 +/- 1.14) were evident in the animals resuscitated with normal saline when compared with HTS (0.70 +/- 0.1 and 3.57 +/- 1.32), respectively; p < 0.04). HTS significantly reduced PMN transmigration (by 97.1, p = 0.002, and induced PMN apoptosis (p < 0.03). HTS did not impact significantly upon neutrophil VEGF release (p > 0.05). CONCLUSIONS: Intratracheal aerosolized HTS attenuates the neutrophil-mediated pulmonary insult subsequent to pancreatitis. This may represent a novel therapeutic strategy.

Acute Disease↗
PubMed2001

In vitro cold activation of complement shown by an overestimation of total complement 4: a study in patients with hepatitis C virus infection.

Total complement 4 (C4) levels, when analysed on the Beckman Array nephelometer, were found to increase number of serum specimens [predominantly from patients with hepatitis C virus (HCV) infection] after overnight storage at 4 degrees C. In order to investigate whether the phenomenon of in vitro cold-dependent activation of complement (CDAC) was the explanation for this increase, paired specimens were collected from 63 patients with HCV infection in tubes with no anticoagulant (serum) and in tubes containing EDTA (which inhibits complement activation). C4 levels increased after overnight storage at 4 degrees C in 33 serum specimens (52%). In contrast, no increase in C4 levels was observed in any of the 63 EDTA specimens. Immunofixation of intact and activated C4 products confirmed that complement activation had taken place in the serum specimens in which C4 levels had increased after storage. There was a higher frequency of hepatitis C viraemia (P<0.0001), HCV antibody positivity (P<0.05) and the presence of rheumatoid factor (P<0.05) in the group of patients in whose serum samples CDAC had occurred (n = 33) than in the other group (n = 30). As a result of our findings on C4 analysis in stored serum specimens, we would recommend potassium EDTA plasma as the specimen of choice for complement analysis on the Beckman Array.

Blood Chemical Analysis↗
PubMed2000

Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia.

Autosomal dominant hereditary spastic paraplegia (AD-HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by pro- gressive spasticity of the lower limbs. Five AD-HSP loci have been mapped to chromosomes 14q, 2p, 15q, 8q and 12q. The SPG4 locus at 2p21-p22 has been shown to account for approximately 40% of all AD-HSP families. SPG4 encoding spastin, a putative nuclear AAA protein, has recently been identified. Here, sequence analysis of the 17 exons of SPG4 in 87 unrelated AD-HSP patients has resulted in the detection of 34 novel mutations. These SPG4 mutations are scattered along the coding region of the gene and include all types of DNA modification including missense (28%), nonsense (15%) and splice site point (26.5%) mutations as well as deletions (23%) and insertions (7.5%). The clinical analysis of the 238 mutation carriers revealed a high proportion of both asymptomatic carriers (14/238) and patients unaware of symptoms (45/238), and permitted the redefinition of this frequent form of AD-HSP.

Adenosine Triphosphatases↗
PubMed1998

Autosomal dominant hereditary spastic paraparesis with cognitive loss linked to chromosome 2p.

A family initially considered to have 'pure' autosomal dominant hereditary spastic paraparesis (HSP), was found on neuropsychological testing to have evidence of late onset cognitive impairment. This family showed genetic linkage to the SPG4 locus on chromosome 2p previously reported for pure HSP. Of 56 living members, 44 were examined, 30 of whom were > 30 years of age and 12 members were found to be affected with HSP including four asymptomatic cases. One other family member (III-5), aged 62 years, died prior to this study of a 4-year dementing illness. Neuropsychological assessment of 11 affected members and 11 matched, unaffected, family controls showed no significant differences between the two groups. However, the neuropsychological test profile in four of 11 affected members tested (mean age 47.2 years) and one of 11 family controls (mean age 41.5 years) showed global cognitive impairment. The pattern of cognitive dysfunction was the same for all five family members identified and was similar to that found in subcortical dementia. The presence of cognitive impairment appeared to be related to age and not the severity of the paraplegia. Both the severity of the paraplegia and the age of onset (21-60 years) varied considerably in this family.

Adult↗
PubMed1995

Familial hemiplegic migraine and autosomal dominant arteriopathy with leukoencephalopathy (CADASIL).

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently described familial cerebrovascular disorder shown to map to chromosome 19q12. Familial hemiplegic migraine has also been shown in some families to map close to the CADASIL locus. The fully developed CADASIL phenotype consists of recurrent strokes developing in the fourth decade, progressing to a pseudobulbar palsy, spastic quadriparesis, and subcortical dementia. In an Irish family 15 members were fully investigated by magnetic resonance scanning; 10 had typical magnetic resonance features of CADASIL. Five members of this family had familial hemiplegic migraine and 4 of these had magnetic resonance evidence of CADASIL. Two other members had migraine with and without aura as a presenting clinical symptom of CADASIL. This disorder has been shown by linkage analysis to map to the CADASIL locus at chromosome 19. The phenotype at presentation of CADASIL in this family was variable and age related and included familial hemiplegic migraine, migraine with and without aura, transient ischemic attacks, strokes, and spinal cord infarction. This family study increases our understanding of the spectrum of clinical manifestations of this underrecognized familial cerebrovascular disorder.

Adult↗
PubMed1992

Mechanisms of complete Freund's adjuvant protection against diabetes in BB rats: induction of non-specific suppressor cells.

We have previously reported that a single injection of complete Freund's adjuvant (CFA) can prevent diabetes appearance in diabetes-prone (DP) BB rats. In this study, we investigated further the mechanism of CFA-induced protection from diabetes. We found that adoptive transfer of splenic cells from CFA-treated DP rats into young DP rats protected the latter from diabetes development. This suggested that CFA-induced protection from diabetes resulted from activation of regulatory (suppressor) cells. Cell mixing experiments in vitro indicated that CFA activated splenic cells with antigen-nonspecific suppressor activity (suppression of lymphoproliferative responses to lipopolysaccharide and to allogeneic splenic cells). Fractionation of splenic cells on Percoll revealed that the suppressor activity resided in low density cells relatively depleted of T-cells, B-cells, macrophages and NK cells. These results suggest that non-specific (natural) suppressor cells in CFA-treated BB rats may be responsible for suppressing autoimmune responses and preventing insulitis and diabetes development.

Animals↗
PubMed1991

In vivo administration of monoclonal antibodies to the CD3 T cell receptor complex induces cell death (apoptosis) in immature thymocytes.

Some thymocytes, upon activation via the TCR complex in vitro, undergo apoptotic cell death. In this report, we examine the cell death induced in the thymus after administration of anti-CD3 or anti-TCR antibodies. We found that shortly after antibody injection, cortical thymocytes undergo apoptosis as characterized by morphologic changes and DNA fragmentation. Anti-CD3 administration led to depletion of nearly all CD4+CD8+ thymocytes, and approximately 50% of CD4+CD8- thymocytes. This depletion predominantly affected cells bearing low levels of CD3, although some depletion also occurred among cells expressing intermediate and high levels. Administration of an anti-TCR antibody also induced apoptosis, but affected significantly fewer thymocytes than anti-CD3. This effect was probably not due to different binding affinities for the two antibodies, because both antibodies show similar dose response effects in an in vitro model of activation-induced apoptosis. This work demonstrates that findings on activation-induced apoptosis in vitro can be extended to the in vivo situation, and further, that the activation of cortical thymocytes, in situ, results in apoptosis and removal of the activated cells. The possible relationships between this activation-induced cell death in immature thymocytes and the process of negative selection of autoreactive T cells is discussed.

Animals↗
PubMed1990

Prevention of diabetes in the BB rat by early immunotherapy using Freund's adjuvant.

The BB rat spontaneously develops an insulin-dependent diabetes mellitus (IDDM) that closely resembles this disease in man. The pathogenesis involves autoimmune destruction of pancreatic islet beta-cells. In the present study, a single intraperitoneal injection of complete Freund's adjuvant (CFA) in diabetes-prone (DP) BB/Wor rats between 9 and 28 days of age reduced the incidence of diabetes at 120 days from 89% to 10-28%, whereas injection of CFA after 40 days of age was ineffective. The CFA-injected, diabetes-free DP rats had normal levels of pancreatic insulin and little or no mononuclear leukocyte infiltration in the islets. These protective effects of CFA were not associated with any changes in peripheral blood leukocyte counts or monoclonal antibody-defined T cell, B cell, or macrophage subsets in the spleen of the DP rats. These results suggest that it is possible to prevent diabetes by adjuvant treatment in early life without general immunosuppression or sustained therapy.

Adjuvants, Immunologic↗