The role of the albumin-carried fatty acids in the induction of tubulointerstitial injury was studied in protein-overload proteinuria. Rats were injected with fatty acid-carrying BSA FA(+)BSA, fatty ...acid-depleted BSA FA(-)BSA, or saline. Macrophage infiltration was measured by immunohistochemical staining, apoptotic cells were detected by in situ end labeling, and proliferating cells were identified by in situ hybridization for histone mRNA. Macrophage infiltration was significantly greater in the FA(+)BSA group than in the FA(-)BSA and saline groups. The infiltrate was largely restricted to the outer cortex. Apoptosis was greater in the FA(+)BSA group than in the FA(-)BSA and saline groups. Compared with the saline group, apoptosis was significantly increased in the FA(+)BSA group but not in the FA(-)BSA group. Cortical cells proliferated significantly more in the FA(+)BSA and FA(-)BSA groups than in the saline group. FA(+)BSA is therefore a more potent inducer of macrophage infiltration and cell death than FA(-)BSA. The fatty acids carried on albumin may be the chief instigators of tubulointerstitial injury in protein-overload proteinuria.
Hemochromatosis and Wilson disease (WD), characterized by the excess hepatic deposition of iron and copper, respectively, produce oxidative stress and increase the risk of liver cancer. Because the ...frequency of p53 mutated alleles in nontumorous human tissue may be a biomarker of oxyradical damage and identify individuals at increased cancer risk, we have determined the frequency of p53 mutated alleles in nontumorous liver tissue from WD and hemochromatosis patients. When compared with the liver samples from normal controls, higher frequencies of G:C to T:A transversions at codon 249 (P < 0.001) and C:G to A:T transversions and C:G to T:A transitions at codon 250 (P < 0.001 and P < 0.005) were found in liver tissue from WD cases, and a higher frequency of G:C to T:A transversions at codon 249 (P < 0.05) also was found in liver tissue from hemochromatosis cases. Sixty percent of the WD and 28% of hemochromatosis cases also showed a higher expression of inducible nitric oxide synthase in the liver, which suggests nitric oxide as a source of increased oxidative stress. A high level of etheno-DNA adducts, formed from oxyradical-induced lipid peroxidation, in liver from WD and hemochromatosis patients has been reported previously. Therefore, we exposed a wild-type p53 TK-6 lymphoblastoid cell line to 4-hydroxynonenal, an unsaturated aldehyde involved in lipid peroxidation, and observed an increase in G to T transversions at p53 codon 249 (AGG to AGT). These results are consistent with the hypothesis that the generation of oxygen/nitrogen species and unsaturated aldehydes from iron and copper overload in hemochromatosis and WD causes mutations in the p53 tumor suppressor gene.
To compare the rate of provision of longer consultations per head of population across practice locations categorised by socioeconomic status.
Retrospective analysis of Medicare data for all ...consultations for all general practitioners in Australia for the 1998-99 and 1999-2000 financial years, grouped by postcode of practice location. Postcodes were categorised by the Socio-Economic Indexes for Areas, Index of Relative Socio-Economic Disadvantage score.
Number of consultations and number of brief, standard, long and prolonged consultations per capita in each postcode grouping.
The absolute number of long plus prolonged consultations showed no trend across postcode groups, but the rate ratio per person was significantly higher in more advantaged postcode areas. This represents an example of care provision in inverse relationship to need.
Despite higher rates of chronic disease and lower rates of preventive care uptake, patients in low socioeconomic status areas receive longer GP consultations at a lower rate than patients in more advantaged areas. Possible strategies to overcome this inverse care provision include increased numbers of GPs in disadvantaged communities, removal of financial disincentives to longer consultations, and strengthening health promotion and community health services in disadvantaged areas.
p53 mutations are common in lung cancer. In smoking-associated lung cancer,the occurrence of G:C to T:A transversions at hotspot codons, e.g., 157, 248, 249,and 273, has been linked to the presence ...of carcinogenic chemicalsin tobacco smoke including polycyclic aromatic hydrocarbons suchas benzo(a)pyrene (BP). In the present study, we have used a highly sensitive mutation assay to determine the p53 mutation load in nontumorous human lung and to study the mutability of p53 codons 157, 248, 249, and 250 to benzo(a)pyrene-diol-epoxide (BPDE), an active metabolite of BP in human bronchial epithelial BEAS-2B cells. We determined the p53 mutational load at codons 157, 248, 249, and 250 in nontumorous peripheral lung tissue either from lung cancer cases among smokers or noncancer controls among smokers and nonsmokers. A 5-25-fold higher frequency of GTC(val) to TTC(phe) transversions at codon 157 was found in nontumorous samples (57%) from cancer cases (n = 14) when compared with noncancer controls (n = 8; P < 0.01). Fifty percent (7/14) of the nontumorous samples from lung cancer cases showed a high frequency of codon 249 AGG(arg) to AGT(ser) mutations (P < 0.02). Four of these seven samples with AGT(ser) mutations also showed a high frequency of codon 249 AGG(arg) to ATG(met) mutations, whereas only one sample showed a codon 250 CCC to ACC transversion. Tumor tissue from these lung cancer cases (38%) contained p53 mutations but were different from the above mutations found in the nontumorous pair. Noncancer control samples from smokers or nonsmokers did not contain any detectable mutations at codons 248, 249, or 250. BEAS-2B bronchial epithelial cells exposed to doses of 0.125, 0.5, and 1.0 microM BPDE, showed G:C to T:A transversions at codon 157 at a frequency of 3.5 x 10(-7), 4.4 x 10(-7), and 8.9 x 10(-7), respectively. No mutations at codon 157 were found in the DMSO-treated controls. These doses of BPDE induced higher frequencies, ranging from 4-12-fold, of G:C to T:A transversions at codon 248, G:C to T:A transversions and G:C to A:T transitions at codon 249, and C:G to T:A transitions at codon 250 when compared with the DMSO-treated controls. These data are consistent with the hypothesis that chemical carcinogens such as BP in cigarette smoke cause G:C to T:A transversions at p53 codons 157, 248, and 249 and that nontumorous lung tissues from smokers with lung cancer carry a high p53 mutational load at these codons.
Hepatitis C virus (HCV) cannot be grown in vitro, making biochemical identification of new drug targets especially important. HCV p7 is a small hydrophobic protein of unknown function, yet necessary ...for particle infectivity in related viruses Harada, T. et al., (2000) J. Virol. 74, 9498–9506. We show that p7 can be cross-linked in vivo as hexamers. Escherichia coli expressed p7 fusion proteins also form hexamers in vitro. These and HIS-tagged p7 function as calcium ion channels in black lipid membranes. This activity is abrogated by Amantadine, a compound that inhibits ion channels of influenza Hay, A.J. et al. (1985) EMBO J. 4, 3021–3024; Duff, K.C. and Ashley, R.H. (1992) Virology 190, 485–489 and has recently been shown to be active in combination with current HCV therapies.
We used field studies and imaging spectroscopy to investigate the effect of grazing on vegetation cover in historically grazed and ungrazed high-mesa rangelands of the Grand Staircase-Escalante ...National Monument, Utah, USA. Airborne hyperspectral remote sensing data coupled with spectral mixture analysis uncovered subtle variations in the key biogeophysical properties of these rangelands: the fractional surface cover of photosynthetic vegetation (PV), nonphotosynthetic vegetation (NPV), and bare soil. The results show that a high-mesa area with long-term grazing management had significantly higher PV (26.3%), lower NPV (54.5%), and lower bare soil (17.2%) cover fractions in comparison to historically ungrazed high-mesa pinyon-juniper rangelands. Geostatistical analyses of remotely sensed PV, NPV, and bare soil were used to analyze differences in ecosystem structure between grazed and ungrazed regions. They showed that PV was spatially autocorrelated over longer distances on grazed areas, whereas NPV and bare soil were spatially autocorrelated over longer distances on ungrazed areas. Field data on the fractional cover of PV, NPV, and bare soil confirmed these remote sensing results locally. Field studies also showed a significantly higher percentage composition of shrubs (27.3%) and forbs (30.2%) and a significantly lower composition of grasses (34.4%) and cacti (1.1%) in grazed areas. No significant difference between grazed and ungrazed mesas was found in percentage composition of trees or in the number of canopies per hectare. Our combined remote sensing and field-based results suggest that grazing has contributed to woody thickening in these pinyon-juniper ecosystems through an increase in shrubs in the understory and intercanopy spaces. These results improve our understanding of broad-scale changes in pinyon-juniper ecosystem structural composition and variability due to longterm grazing.
Objectives: To compare the prevalence of anxiety and affective disorders among employed and unemployed patients and to compare the type of treatment received between the two groups for these ...disorders.
Method: A secondary analysis of the 1997 National Survey of Mental Health and Wellbeing of Adults cross-sectional study was undertaken.
Results: Unemployed adults were more likely to have symptoms of anxiety (OR = 3.09, 95% CI = 2.80–3.41) or an affective disorder (OR = 2.11, 95% CI = 1.95–2.27) or anxiety and/or affective disorders (OR = 2.53, 95% CI = 2.37–2.69). Unemployed participants with symptoms were less likely to have seen a general practitioner for treatment but when they did they received similar care to employed participants.
Conclusions: These results confirm studies reported elsewhere that the prevalence of symptoms of anxiety and/or affective disorders is higher for unemployed people. The data provide further evidence that people with an anxiety and/or affective disorder who are unemployed are not seeking medical treatment. However, unlike previous research undertaken by our group, these results indicate that symptomatic adults who seek help receive comparable treatment in general practice irrespective of their employment status.
The objectives of this trial were to estimate the response rate, progression-free survival, and overall survival of patients who received therapy with etoposide and high-dose ifosfamide, and to ...define the toxicity of this combination when provided with standard chemotherapy in patients with newly diagnosed metastatic osteosarcoma.
Eligible patients received infusions of 100 mg/m(2) per day of etoposide and 3.5 g/m(2) per day of ifosfamide for 5 days. Therapy with granulocyte colony-stimulating factor was begun on day 6. This was repeated 3 weeks after therapy was begun. Response was determined at week 6 by both standard World Health Organization response criteria and by pathologic determination of tumor necrosis of the primary tumor.
Forty-three patients were registered; 39 were assessable for response and 41 for toxicity and survival. Twenty-eight (68%) of 41 had metastatic sites only in the lung; 12 (29%) had metastatic sites in other bones with or without lung involvement. Four patients (10%) experienced complete response, and 19 patients (49%) experienced partial response, for an overall response rate of 59% +/- 8%. The projected 2-year progression-free survival (PFS) for the 28 patients with metastases to lungs was 39% +/- 11%. The projected 2-year PFS for the 12 patients with metastases to other bones (with or without pulmonary metastases) was 58% +/- 17%. Two patients died as a result of therapy toxicity. Eighty-three percent of patients had grade 4 neutropenia, and 29% had grade 4 thrombocytopenia. Ten patients (24%) had sepsis. Fanconi's syndrome was observed in five patients.
The combination of etoposide and high-dose ifosfamide is effective induction chemotherapy for patients with metastatic osteosarcoma, despite significant associated myelosuppression sometimes complicated by infection and renal toxicity.
Relapse remains a significant problem in patients with metastatic osteosarcoma. The response to carboplatin of patients with newly diagnosed metastatic or unresectable osteosarcoma was assessed in an ...upfront phase II window, which was followed-up by surgery and intensive multiagent chemotherapy.
Thirty-seven patients, ages 3 to 23 years with histologically confirmed diagnoses of osteosarcoma, were treated between January 1992 and November 1994 with carboplatin 1,000 mg/m2 per dose administered as a 48-hour continuous infusion. Two courses were administered in 3-week intervals, depending on marrow recovery. After radiographic reevaluation, patients underwent surgical removal of tumor (if feasible) and then 40 weeks of chemotherapy with high-dose methotrexate, ifosfamide, doxorubicin, and cisplatin.
One of the 37 evaluable patients demonstrated a partial response to carboplatin; there were no complete responses. Patients were additionally analyzed by the response of pulmonary metastases to therapy and the extent of tumor necrosis of the primary lesion. By these criteria, 8 of 37 (22%) of patients showed a response at one or more sites, whereas 20 of 37 (54%) had unequivocal disease progression. Severe myelosuppression was the major toxicity. The projected 3-year event-free and overall survival rates were 23.9% and 31.9%, respectively. Only 1 of 17 patients with unresectable disease or distant bone metastases remains alive, in contrast to 6 of 17 patients with the lung as their only metastatic site and two of three patients with resected regional bone metastases.
Continuous-infusion carboplatin demonstrated limited activity as an upfront agent in patients with metastatic osteosarcoma at diagnosis, even at doses that result in severe and prolonged myelosuppression. Patients with isolated pulmonary metastases or resectable bone metastases have a longer median survival time and greater chance of long-term survival than do patients with unresectable bone disease, for whom the prognosis remains dismal.
This clinical and anatomic study was undertaken to see if the skin paddle of the osteocutaneous fibula flap could be made more reliable. Eighty cadaver limbs were dissected to evaluate the type, ...number, and location of the cutaneous perforators supplying the lateral leg. Three types of perforators were identified: septocutaneous, musculocutaneous, and a type we termed septomuscular, which does not actually run within the muscle substance but is adherent to the muscle. Although not a true musculocutaneous perforator, it should be treated as such clinically. Musculocutaneous perforators were found to be more numerous and more proximal than the septocutaneous perforators. Eighteen clinical cases demonstrate a 33 percent skin paddle survival when dissected as a septocutaneous flap and a 93 percent skin paddle survival when dissected as a septomusculocutaneous flap. In using the osteocutaneous fibula flap, it is recommended that a cuff of soleus and flexor hallucis longus be incorporated into the flap to help ensure flap viability.
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