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Immunotherapy strategies aimed at increasing human Valpha24(+)Vbeta11(+) natural killer T (NKT) cell numbers are currently a major focus. To provide further information towards the goal of NKT cell-based immunotherapy, we assessed the effects of age, cancer status and prior anticancer treatment on NKT cell numbers and their expansion capacity following alpha-galactosylceramide (alpha-GalCer) stimulation. The percentage and absolute number of peripheral blood NKT cells was assessed in 40 healthy donors and 109 solid cancer patients (colorectal (n=33), breast (n=10), melanoma (n=17), lung (n=8), renal cell carcinoma (n=10), other cancers (n=31)). Responsiveness to alpha-GalCer stimulation was also assessed in 28 of the cancer patients and 37 of the healthy donors. Natural killer T cell numbers were significantly reduced in melanoma and breast cancer patients. While NKT numbers decreased with age in healthy donors, NKT cells were decreased in these cancer subgroups despite age and sex adjustments. Prior radiation treatment was shown to contribute to the observed reduction in melanoma patients. Although cancer patient NKT cells were significantly less responsive to alpha-GalCer stimulation, they remained capable of substantial expansion. Natural killer T cells are therefore modulated by age, malignancy and prior anticancer treatment; however, cancer patient NKT cells remain capable of responding to alpha-GalCer-based immenotherapies. [ABSTRACT FROM AUTHOR]

Objectives: Little published data exists on whether nurse-recorded end-hour values of intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are representative of continuous monitoring during the hour. There is also no standard method of quantifying the observed perturbations in cerebral hemodynamics. This study compared the level of agreement between end-hour values and computer downloaded observations of ICP and CPP at 15-min intervals. We also developed the intracranial hypertension index and the cerebral hypoperfusion index to quantify perturbations in cerebral hemodynamics. Each of these indices relates the number of abnormal observations to the total number of observations taken.Methods: Prospective, non-interventional study.Results: The bias and precision between the two methods for ICP and CPP were -0.002+/-2.6 mmHg and -1.1+/-6.2 mmHg, respectively. A strong correlation existed between the hourly mean calculated from the 15-min and the end-hour values for both ICP ( r(2)=0.95, p<0.0001) and CPP ( r(2)=0.78, p<0.001). The intracranial hypertension index was 40% from the 15-min measurements and 41% from the hourly observations ( p= NS). The cerebral hypoperfusion indices were 13.4% and 13.1% with the 15-min and end-hour values, respectively ( p= NS).Conclusions: The end-hour values of ICP and CPP are as accurate as more frequent measurements during the hour and are adequate for purposes of epidemiological research and medico-legal audit. The intracranial hypertension and cerebral hypoperfusion indices may be useful in describing cerebral hemodynamics for future interventional studies and for assessing quality in the delivery of neuro-critical care. [ABSTRACT FROM AUTHOR]

Ovarian adenocarcinomas develop as the result of multiple genetic and epigenetic changes in the precursor ovarian surface epithelial (OSE) cells which result in a malignant phenotype. We investigated changes in gene expression in ovarian adenocarcinoma using a cDNA array containing 588 known human genes. We found that intercellular adhesion molecule-1 (ICAM-1) was expressed at lower levels in the ovarian tumour cell lines OAW42, PEO1 and JAM than in the immortalised human ovarian surface epithelial cell line HOSE 17.1. Further investigation revealed ICAM-1 was expressed in the surface epithelium of normal ovaries and both mRNA and protein expression levels were reduced in the majority of ovarian adenocarcinoma cell lines and primary tumours. ICAM-1 expression was increased in 8/8 cell lines treated with the de novo methyltransferase inhibitor 5-aza-2'-deoxycytidine, indicating that methylation of CpG islands may play a role in the down-regulation of its expression in primary tumours. There was a significant association between patients whose tumours expressed ICAM-1 and survival (P = 0.03), suggesting that expression levels of ICAM-1 may have clinical relevance. [ABSTRACT FROM AUTHOR]

Objectives: We studied the association between cigarette smoking and ovarian cancer in a population-based case control study.Methods: A total of 794 women with histologically confirmed epithelial ovarian cancer who were aged 18-79 years and resident in one of three Australian states were interviewed, together with 855 controls aged 18-79 years selected at random from the electoral roll from the same states. Information was obtained about cigarette smoking and other factors including age, parity, oral contraceptive use, and reproductive factors. We estimated the relative risk of ovarian cancer associated with cigarette smoking, accounting for histologic type, using multivariable logistic regression to adjust for confounding factors.Results: Women who had ever smoked cigarettes were more likely to develop ovarian cancer than women who had never smoked (adjusted odds ratio (OR) = 1.5; 95% confidence interval (CI) = 1.2-1.9). Risk was greater for ovarian cancers of borderline malignancy (OR = 2.4; 95% CI = 1.4-4.1) than for invasive tumors (OR = 1.7; 95% CI = 1.2-2.4) and the histologic subtype most strongly associated overall was the mucinous subtype among both current smokers (OR = 3.2; 95% CI = 1.8-5.7) and past smokers (OR = 2.3; 95% CI = 1.3-3.9).Conclusions: These data extend recent findings and suggest that cigarette smoking is a risk factor for ovarian cancer, especially mucinous and borderline mucinous types. From a public health viewpoint, this is one of the few reports of a potentially avoidable risk factor for ovarian cancer. [ABSTRACT FROM AUTHOR]

: Fracture of the distal forearm is one of the most frequent osteoporotic fractures. However, there are few data concerning its incidence in Britain. The aim of this study was to determine the incidence of distal forearm fracture in adult British men and women. Six centers took part in the study: Aberdeen, Hull, Nottingham, Portsmouth, Southampton and Truro. At each center, men and women aged 35 years and over with an incident distal forearm fracture and who resided in the catchment area of the main hospital at that center, were identified during a 12 month period. Incident fractures were identified from all possible point-of-contact sources in each locality, including accident and emergency records, fracture clinics, ward listings and plaster room registers. The population at risk was defined geographically according to postcode and the denominator obtained from 1991 census data mapped to these postcodes. During the 12 month study period, 3161 individuals with distal forearm fracture were identified. The age-adjusted incidence, age 35 years and over, was 36.8/10 000 person-years in women and 9.0/10 000 person-years in men. In women, the incidence of fracture increased progressively with age from the perimenopausal period, while in men the incidence remained low until later life. Fractures were more frequently left-sided (55.6%) and 19.4% of subjects required hospitalization. On the basis of these data we estimate that 71 000 adult men and women sustain a distal forearm fracture in Britain each year. Compared with previous British surveys the pattern of incidence with age appears to have changed in women, the reason for this is unclear. [ABSTRACT FROM AUTHOR]

Objective: To test the effect of liquid feeds on the responses to splanchnic ischaemia of a continuous rapid response PCO2 sensor inserted in the jejunum.Design: Prospective experimental animal study in a university research laboratory.Subjects: Adult male Wistar rats.Interventions: Adult male Wistar rats (285-425 g) were anaesthetised with sodium pentobarbitone 60 mg/kg i.p. and ventilated with 100% oxygen and isoflurane via tracheostomy to a PaCO2 of 30-40 mmHg. A sensor was inserted into the mid-jejunum to record PCO2 every second. Distal aortic pressure was transduced. Four control rats received no feeds whilst in another four rats liquid feed was infused into the proximal jejunum at 3 ml/h. In each rat five episodes of splanchnic ischaemia were induced by 2-min elevations of an aortic sling to a mean distal aortic pressure of 30 mmHg.Measurements and Main Results: PCO2 elevations were always detectable, usually less than a minute from the onset of splanchnic ischaemia in both fed and unfed rats, with no difference in mean times to detectable response. In the fed rats there was a small but significant increase in the time to peak sensor response (196+/-16 vs. 180+/-12 s) and a trend towards an elevated mean baseline luminal PCO2 (67+/-9 vs. 55+/-4 mmHg).Conclusions: Brief episodes of splanchnic ischaemia were tracked successfully by a rapid response jejunal continuous PCO2 sensor during the infusion of a proprietary liquid feed preparation despite minor changes in PCO2 response characteristics and a possible elevation in baseline luminal PCO2. [ABSTRACT FROM AUTHOR]

The molecular events that drive the initiation and progression of ovarian adenocarcinoma are not well defined. We have investigated changes in gene expression in ovarian cancer cell lines compared to an immortalized human ovarian surface epithelial cell line (HOSE) using a cDNA array. We identified 17 genes that were under-expressed and 10 genes that were over-expressed in the cell lines compared to the HOSE cells. One of the genes under-expressed in the ovarian cancer cell lines, Id3, a transcriptional inactivator, was selected for further investigation. Id3 mRNA was expressed at reduced levels in 6 out of 9 ovarian cancer cell lines compared to the HOSE cells while at the protein level, all 7 ovarian cancer cell lines examined expressed the Id3 protein at greatly reduced levels. Expression of Id3 mRNA was also examined in primary ovarian tumours and was found in only 12/38 (32%) cases. A search was conducted for mutations ofId3 in primary ovarian cancers using single stranded conformation polymorphism (SSCP) analysis. Only one nucleotide substitution, present also in the corresponding constitutional DNA, was found in 94 ovarian tumours. Furthermore no association was found between LOH at 1p36 and lack of expression of Id3. These data suggest that Id3 is not the target of LOH at 1p36. [ABSTRACT FROM AUTHOR]

We present high-resolution photoemission data from the Bi(111)-surface. The electronic structure of the semimetal close to the Fermi level has been found to change dramatically with respect to the well established bulk band structure. The Fermi surfaces observed for the electron and hole bands resemble those of the next group-V element, antimony, probably as a consequence of surface relaxation. This results in a relatively high surface charge density. The observed temperature dependence of the electron Fermi energy confirms this result. [ABSTRACT FROM AUTHOR]

Chromosome 1 copy number in the benign breast lesions hyperplasia and atypical duct hyperplasia (ADH) was investigated using fluorescence in situ hybridization on paraffin sections. Progression of chromosome 1 changes occurring in parallel with histological progression from normal through hyperplasia and ADH to ductal carcinoma in situ (DCIS) and invasive carcinoma was also assessed, both overall and within individual patients. The mean signal number for normal cells was 1.14, while that for hyperplasia was 1.56 and ADH was 1.5, while values for DCIS of 1.95 and invasive duct carcinoma of 1.79, were higher (P < 0.001). Six of the seven cases also showed a significant trend towards an increasing proportion of cells with greater than 2 signals per nucleus occurring with histological progression (P < 0.001). These results support the concept that benign proliferative breast disease is a biological precursor of in-situ and invasive ductal carcinoma, the early histological changes possibly indicating a field effect with further genetic changes required for the development of a malignant phenotype. [ABSTRACT FROM AUTHOR]

Presents a photoemission data from a one-dimensional metal constructed on an insulating substrate whose spectra contain structures indicative of the excitation of spin and charge collective modes. Surface crystallography of the system; Low-energy diffraction pattern of the surface; Advantages of using photoemission-based techniques to search for Luttinger-liquid behavior.

It has been suggested that oestrogen replacement therapy is associated with risk of epithelial ovarian cancer of the endometrioid type. Using data from an Australian population-based case-control study, the relation between unopposed oestrogen replacement therapy and epithelial ovarian cancer, both overall and according to histological type, was examined. A total of 793 eligible incident cases of epithelial ovarian cancer diagnosed from 1990 to 1993 among women living in Queensland, New South Wales and Victoria were identified. These were compared with 855 eligible female controls selected at random from the electoral roll, stratified by age and geographic region. Trained interviewers administered standard questionnaires to obtain detailed reproductive and contraceptive histories, as well as details about hormone replacement therapy and pelvic operations. No clear associations were observed between use of hormone replacement therapy overall and risk of ovarian cancer. Unopposed oestrogen replacement therapy was, however, associated with a significant increase in risk of endometrioid or clear cell epithelial ovarian tumours (odds ratio (OR) 2.56; 95% confidence interval (CI) 1.32-4.94). In addition, the risk associated with oestrogen replacement therapy was much larger in women with an intact genital tract (OR 3.00; 95% Cl 1.54-5.85) than in those with a history of either hysterectomy or tubal ligation. Post-menopausal oestrogen replacement therapy may, therefore, be a risk factor associated with endometrioid and clear cell tumours in particular. Additionally, the risk may be increased predominantly in women with an intact genital tract. These associations could reflect a possible role of endometriosis in the development of endometrioid or clear cell ovarian tumours. [ABSTRACT FROM AUTHOR]

Objectives: It has been suggested that increased exposure to galactose, due to high consumption of dairy foods or reduced galactose metabolism, is associated with the development of ovarian cancer. We have investigated this in a large case-control study conducted in three Australian states between 1990 and 1993.Methods: Approximately 800 histologically-confirmed cases, 800 community controls and 300 controls recruited through breast-screening clinics completed dietary questionnaires. Approximately 100 cases and all breast-screening controls also provided a blood sample for analysis of galactose-1-phosphate-uridyltransferase (GALT).Results: Ovarian cancer risk was positively associated with increasing consumption of whole milk and other full-fat dairy foods, but was not associated with consumption of low-fat dairy foods and was inversely related to consumption of skimmed milk. There was no association between ovarian cancer and GALT except among women with abnormally low GALT who had a non-significant 2.5-fold increased risk of ovarian cancer.Conclusions: These data do not support the hypothesis that galactose plays a major role in the development of ovarian cancer and suggest that reported associations between milk consumption and ovarian cancer are due to the fat content of milk and not to lactose or galactose. An increased risk of ovarian cancer in women with abnormally low levels of GALT cannot, however, be ruled out. [ABSTRACT FROM AUTHOR]

In two recent case–control studies premature greying of the hair was associated with a lowering of bone mineral density (BMD) and osteopenia, suggesting that this might be a clinically useful risk marker for osteoporosis. We report a further re-examination of this proposal in 52 prematurely grey-haired women from East Yorkshire who responded to an advertisement inviting them for bone densitometry. Thirty-five had no clinical or drug history that could influence bone density. All were Caucasian with a mean age of 52.8 years. In the group as a whole the mean BMD values at the lumbar spine and femoral neck were no different from those of a young adult, but there was a trend toward a greater than average BMD than that of the local age-matched population ( p= 0.097 and 0.218, respectively). Twenty women were premenopausal, with an average age of 45.3 years. Mean BMD values at the lumbar spine and femoral neck in this group were no different from those of young adults. There was, however, a trend toward a BMD greater than that of the local age-matched population at the femoral neck ( p= 0.117). Fifteen women were postmenopausal with an average age of 62.9 years and an average age at menopause of 51.1 years. Mean BMD values at both the lumbar spine and femoral neck in this group were lower than those of young adults, but no different from those of the local age-matched population. In conclusion, our group of prematurely grey-haired women had average BMD for their age, and we are therefore unable to support the proposed clinical usefulness of premature greying as a risk marker for osteoporosis. [ABSTRACT FROM AUTHOR]

Conventional hormone replacement therapy preserves bone mass predominantly by reducing bone turnover but does not exert significant anabolic skeletal effects. In contrast, high doses of estrogen have been shown to increase bone formation in animals and we have recently reported high bone mineral density values in women treated long-term with estradiol implant therapy. The aim of this study was to investigate the mechanisms by which high doses of estrogen may increase bone mass in postmenopausal women. Iliac crest biopsies were obtained from 12 women who had received long-term treatment with estradiol implants (at least 14 years), on demand, following hysterectomy and bilateral salpingo-oophorectomy. Indices of bone turnover, remodeling balance and cancellous bone structure were assessed by image analysis and compared with those of premenopausal women. Mean wall width was significantly higher in women treated with estradiol therapy than in premenopausal women (44.8 ± 4.8 vs 38.8 ± 2.8 mm; mean ± SD; p = 0.001) and eroded cavity area was significantly lower in the implant-treated women (3612 ± 956 vs 5418 ± 1404 mm2; p = 0.001). Bone formation rate at tissue level and activation frequency were lower in the women treated with implants, although the differences were not statistically significant. Indices of cancellous bone structure were generally similar between the two groups. These results provide the first direct evidence that high-dose estrogen therapy produces anabolic skeletal effects in postmenopausal women and indicate that these are achieved by stimulation of osteoblastic activity. [ABSTRACT FROM AUTHOR]

The objectives of the study were: to determine the prevalence of osteoporosis in women in their seventh decade; to determine the number of women who conformed to at least one of the current East Yorkshire Clinical Referral Criteria for Osteoporosis; and to determine the sensitivity and specificity of these referral criteria in the diagnosis of osteoporosis and to compare this with the receiver operating characteristic (ROC) curve of a logistic regression model incorporating variables that were significantly associated with the risk of osteoporosis. An observational study was carried out at the Centre for Metabolic Bone Disease, Hull Royal Infirmary, on women in their seventh decade from three general practices. Densitometric assessment of lumbar spine and femoral neck was carried out using dual-energy X-ray absorptiometry (DXA) and a detailed medical history taken. The main outcome measures were prevalence of osteoporosis in women in their seventh decade and efficacy of agreed clinical referral criteria at osteoporosis case finding. Of 823 Caucasian women who underwent DXA, 24% proved to have osteoporosis at hip, spine or both according to WHO criteria. A further 49% had osteopenia detected at hip, spine or both. At least one of the referral criteria was present in 47% of the women assessed. The sensitivity of the clinical referral criteria for detection of osteoporosis was 58% with a corresponding specificity of 60%. This point lies below the ROC curve (area under fitted curve, A z= 0.73) of a logistic regression model incorporating weight, age at menopause and current use of hormone replacement therapy. In conclusion, osteoporosis according to WHO criteria was found in almost 25% of women in their seventh decade. A simple logistic regression model provided a more sensitive method of osteoporosis case finding than the selective screening component of the clinical referral criteria employed in our practice. [ABSTRACT FROM AUTHOR]

Type II (non-insulin-dependent) diabetes mellitus has a substantial genetic component; however, its molecular basis remains largely unknown. The mode of inheritance is likely to be polygenic, with penetrance influenced by environmental factors. Although the familial aggregation of Type II diabetes is acknowledged, there is little data concerning the prevalence of diabetes in the relatives of subjects with diabetes in comparison with the general population, and our objective was to address this question in the defined geographic region of Oxfordshire, England. We studied 139 first degree relatives of 90 probands with Type II diabetes who attended routine diabetes clinics in Oxfordshire and documented the fasting plasma glucose, triglyceride and HDL-cholesterol concentrations and BMI of these subjects. The probands were selected without regard to family history of diabetes. The control population data were derived from two large-scale Oxford community studies which documented the prevalences of known and newly diagnosed diabetes. The prevalences of newly diagnosed and known diabetes were calculated for each group. The mean BMI, and concentrations of fasting glucose, triglyceride and HDL-cholesterol were compared and prevalence ratios for obesity (defined as BMI > 30 kg/m2), hyperglycaemia (defined as fasting plasma glucose ≥ 6.1 mmol/l), and dyslipidaemia (defined as triglyceride > 2.0 mmol/l, HDL < 1.0 mmol/l) were calculated. There was a fourfold higher prevalence of hyperglycaemia in the first degree relatives of subjects with Type II diabetes compared with the control population: the prevalence ratio after adjustment for age, sex and BMI was 4.32 (95 % confidence interval 2.29–8.17). The relatives had a considerably higher fasting plasma glucose concentration than the control population (5.18 ± 0.67 mmol/l (mean ± 1 SD) vs 4.76 ± 1.59 mmol/l, p = 0.0001), and this difference remained statistically significant after adjustment for age, sex and obesity. The relatives were significantly more obese, had higher fasting plasma insulin concentrations and had lower HDL-cholesterol concentrations. In conclusion, there is a strong familial aggregation of hyperglycaemia and obesity in the relatives of subjects with Type II diabetes and these subjects have higher fasting plasma insulin concentrations and lower HDL-cholesterol than the general population. These data indicate the particular relevance of screening the first degree relatives of subjects with Type II diabetes, as intervention strategies which aim to improve the metabolic profile are indicated for a large proportion of these subjects. [Diabetologia (1999) 42: 24–27] [ABSTRACT FROM AUTHOR]

Broadband ultrasound attenuation (BUA) was investigated as an inexpensive, simple and radiation-free method of screening for low perimenopausal bone density. A total of 587 women (50-54 years), invited for screening had bone mineral density (BMD) measured at the femoral neck and the lumbar spine by dual-energy X-ray absorptiometry (DXA). At the same visit the BUA of the calcaneus was measured. The correlation between BUA and BMD was approximately 0.4 compared with 0.67 between femoral neck and spinal BMD. Receiver operating characteristic (ROC) curve analysis demonstrated BUA to have the same ability for discriminating between low BMD at either the femoral neck or lumbar spine. BUA with a cut-off for normality at the median (BUA=80) had a sensitivity of 68% and specificity of 67% for low bone density identified by a BMD less than the 25th centile at the femoral neck or lumbar spine. The correlation between BUA and BMD was insufficient to allow identification of the same groups as having low bone density. [ABSTRACT FROM AUTHOR]

Heterostructures formed by stacking layered materials require atomically clean interfaces. However, contaminants are usually trapped between the layers, aggregating into randomly located blisters, incompatible with scalable fabrication processes. Here we report a process to remove blisters from fully formed heterostructures. Our method is over an order of magnitude faster than those previously reported and allows multiple interfaces to be cleaned simultaneously. We fabricate blister-free regions of graphene encapsulated in hexagonal boron nitride with an area ~ 5000 μm2, achieving mobilities up to 180,000 cm2 V−1 s−1 at room temperature, and 1.8 × 106 cm2 V−1 s−1 at 9 K. We also assemble heterostructures using graphene intentionally exposed to polymers and solvents. After cleaning, these samples reach similar mobilities. This demonstrates that exposure of graphene to process-related contaminants is compatible with the realization of high mobility samples, paving the way to the development of wafer-scale processes for the integration of layered materials in (opto)electronic devices. Atomically-clean interfaces are required in heterostructures. Here, authors report a method for fast and parallel removal of contaminants from fully-formed heterostructures, including sample intentionally exposed to polymers and solvent, achieving room temperature mobility over 180,000 cm2/Vs for graphene. [ABSTRACT FROM AUTHOR]

Bone mineral density (BMD) increases during growth until a peak is reached at maturity. The risk of development of postmenopausal osteoporosis depends on the peak bone density and the rate of its subsequent loss. To identify whether low weight at birth could affect the peak bone density, we measured BMD at both the lumbar spine and femoral neck using dual energy X-ray absorptiometry (DXA) in a group of women who had low weight at birth and in a control group of normal birth weight. There was no significant correlation between the weight at birth and the adult BMD. It appears, therefore, that low weight at birth does not influence the peak bone density and that prematurity is not a risk factor for osteoporosis. [ABSTRACT FROM AUTHOR]