Replication of microchannel structures in WC-Co feedstock using elastomeric replica moulds by hot embossing process.

Hot embossing is a net shaping process that is able to produce the micro-components of polymers with intrinsic and complex shapes at lower cost compared with machining and injection moulding. However, the emboss of hard metals, such as WC-Co, is more challenging due to their high thermal conductivity and ease of agglomeration. Thus, a WC-Co alloy mixed with a wax-based binder feedstock was selected. The formed feedstock exhibited pseudo-plastic flow and was successfully embossed (green part). Here, we developed a novel process that is used to replicate polymer microfluidic chips while simultaneously reducing the channel surface roughness of the mould insert, yielding optical-grade (less than 100 nm surface roughness) channels and reservoirs. This paper concerns the replication of metallic microfluidic mould inserts in WC-Co and the parameters associated with feedstock formation via a hot embossing process. A suitable formulation for micro-powder hot embossing has been established and characterised by thermogravimetric analyses and measurements of mixing torques to verify and quantify the homogeneity of the proposed feedstocks. The relative density of the samples increased with processing temperature, and almost fully dense materials were obtained. In this work, the effects of the sintering temperature on the physical properties were systematically analysed. The evolution of the metal surface morphology during the hot embossing process was also investigated. The results indicate that the feedstock can be used to manufacture micro-fluidic die mould cavities with a low roughness, proper dimensions and good shape retention. The shrinkage of the sintered part was approximately 19-24% compared with that of the brown part.

Walking performance and health-related quality of life after surgical or endovascular invasive versus non-invasive treatment for intermittent claudication--a prospective randomised trial.

OBJECTIVES: Despite limited scientific evidence for the effectiveness of invasive treatment for intermittent claudication (IC), revascularisation procedures for IC are increasingly often performed in Sweden. This randomised controlled trial compares the outcome after 2 years of primary invasive (INV) versus primary non-invasive (NON) treatment strategies in unselected IC patients. MATERIALS/METHODS: Based on arterial duplex and clinical examination, IC patients were randomised to INV (endovascular and/or surgical, n = 100) or NON (n = 101). NON patients could request invasive treatment if they deteriorated during follow-up. Primary outcome was maximal walking performance (MWP) on graded treadmill test at 2 years and secondary outcomes included health-related quality of life (HRQL), assessed with Short Form (36) Health Survey (SF-36). RESULTS: MWP was not significantly (p = 0.104) improved in the INV versus the NON group. Two SF-36 physical subscales, Bodily Pain (p < 0.01) and Role Physical (p < 0.05) improved significantly more in the INV versus the NON group. There were 7% crossovers against the study protocol in the INV group. CONCLUSIONS: Although invasive treatment did not show any significant advantage regarding MWP, the HRQL improvements associated with invasive treatment tentatively suggest secondary benefits of this regimen. On the other hand, a primary non-invasive treatment strategy seems to be accepted by most IC patients.

Effects of three months of low molecular weight heparin (dalteparin) treatment after bypass surgery for lower limb ischemia--a randomised placebo-controlled double blind multicentre trial.

OBJECTIVES: To test the hypothesis that long-term postoperative dalteparin (Fragmin), Pharmacia Corp) treatment improves primary patency of peripheral arterial bypass grafts (PABG) in lower limb ischemia patients on acetylsalicylic acid (ASA) treatment. DESIGN: Prospective randomised double blind multicenter study. MATERIALS AND METHODS: Using a computer algorithm 284 patients with lower limb ischemia, most with pre-operative ischemic ulceration or partial gangrene, from 12 hospitals were randomised, after PABG, to 5000 IU dalteparin or placebo injections once daily for 3 months. All patients received 75 mg of ASA daily for 12 months. Graft patency was assessed at 1, 3 and 12 months. RESULTS: At 1 year, 42 patients had died or were lost to follow-up. Compliance with the injection schedule was 80%. Primary patency rate, in the dalteparin versus the control group, respectively, was 83 versus 80% (n.s.) at 3 months and 59% for both groups at 12 months. Major complication rates and cardiovascular morbidity were not different between the two groups. CONCLUSIONS: In patients on ASA treatment, long-term postoperative dalteparin treatment did not improve patency after peripheral artery bypass grafting. Therefore, low molecular weight heparin treatment cannot be recommended for routine use after bypass surgery for critical lower limb ischemia.

Multicenter clinical experience with large core soft tissue biopsy without vacuum assistance.

The increasing interest in accurate pretreatment diagnosis of solid tumours by morphology, immunohistochemistry, genetics and molecular biology requires clinicians to obtain undamaged large core biopsies. Simultaneously, medical imaging and surgery give priority to minimal tissue injury, affordable technology and optimal patient compliance. A new large core soft tissue biopsy device has been developed to meet the above criteria. After intensive preclinical testing, 30 patients gave informed consent and 26 underwent the new diagnostic biopsy procedure. The sample was studied by morphology, immunohistochemistry and, where indicated, by molecular biology. Successful diagnosis was considered when in line with clinical follow-up and, as for all malignant lesions, when confirmed by open biopsy or surgery. No difficulties in the technique were encountered in 25 patients. In one patient the procedure was prematurely stopped because of anxiety. In all other 25 procedures a complete diagnosis was reached with regard to morphology, immunohistochemistry and molecular biology. A number of radiologists suggested some automation of the technique. This new large core soft tissue biopsy system performs well in the clinical context without injury to the breast parenchyma or artefacts in the harvested tissue specimen. The system meets almost all of the proposed technical and financial requirements. Automation is underway.

Predictors of treatment outcome in intermittent claudication.

OBJECTIVE: To derive formulae to predict the likely 12-month health-related quality of life outcome following different treatments for intermittent claudication (IC). DESIGN: A prospective, randomized, controlled study. MATERIALS: One hundred and seventy-one unselected patients with stable IC were sequentially randomized to invasive therapy, supervised physical training or observation. Hierarchical analysis was used to identify significant predictors of outcome. RESULTS: The strongest outcome predictors were baseline values of the respective outcome variables in all groups. No more than two significant secondary predictors were identified for each outcome variable and no outcome variable was a predictor of any other outcome variable. Resulting prediction equations achieved between 61 and 90% concordance with improvement (75% considered adequate), with best prediction for invasive therapy and poorest for observation. Suggested cutpoints for the various endpoints in the three groups had sensitivities ranging between 65 and 100% and false positive rates between 5 and 50%. CONCLUSIONS: The derived equations adequately predicted improvement on the various outcome variables in invasive therapy and supervised physical training, and may serve as aids in selecting patients likely to benefit most from a particular treatment strategy. The uniqueness of the outcome variables underscores the importance of implementing a comprehensive set of endpoints relevant to the impacts of the condition.

Treatment efficacy of intermittent claudication by surgical intervention, supervised physical exercise training compared to no treatment in unselected randomised patients I: one year results of functional and physiological improvements.

OBJECTIVES: to compare the effect of surgery, exercise and simple observation on maximum exercise power in claudicants. DESIGN: prospective, randomised study. METHODS: a total of 264 unselected claudicants were randomised to supervised exercise training, invasive treatment (open surgical or endovascular procedures) or observation. One year treatment outcomes were analysed on an intention to-treat basis. RESULTS: invasively treated patients showed a significant improvement in maximum walking power, stopping distance, post-ischaemic blood flow and big toe pressure at one year. Patients randomised to physical exercise training or to the control group did not improve in any outcome measure. CONCLUSION: invasive treatment increased walking capacity, leg blood pressure and flow. Supervised physical exercise training offered no therapeutic advantage compared to untreated controls.

Treatment efficacy of intermittent claudication by invasive therapy, supervised physical exercise training compared to no treatment in unselected randomised patients II: one-year results of health-related quality of life.

OBJECTIVE: to compare the effectiveness of invasive therapy, supervised physical training and no treatment in terms of health-related quality of life (HRQL) in patients with intermittent claudication (IC). DESIGN: a prospective, randomised, controlled study. MATERIALS: a total of 253 unselected patients with stable IC were sequentially randomised into 3 balanced treatment groups. At 1 year follow-up data from a battery of generic and disease specific HRQL questionnaires, and global indices of quality of life and physical condition were available in 171 patients. RESULTS: compared with a non-diseased reference group, claudicants were substantially limited in daily physical functioning, but little affected regarding emotional, cognitive and social functioning, or well-being. Invasive therapy yielded significantly greater improvements in some aspects of physical functioning and walk-related symptoms than training. Training was not superior to invasive therapy on any HRQL dimension and superior to no treatment on only one dimension. Treatment effects, however, were generally small-to-moderate and levels of physical dysfunction in all groups remained higher than reference values. CONCLUSIONS: invasive therapy is more effective than supervised training in alleviating illness-specific symptoms and improving certain aspects of physical functioning - the primary HRQL domains impacted on by IC and the principal goals of its treatment. However, since treatment effect sizes were at most moderate and given that untreated claudicants reported at most small deterioration in HRQL, the level of evidence supporting invasive therapy is modest.

Effect of cyclooxygenase and nitric oxide synthase inhibitors on tumor growth in mouse tumor models with and without cancer cachexia related to prostanoids.

The potential interaction between cyclooxygenase (Cox) and NO metabolic pathways in the control of local tumor growth was evaluated. Mice bearing either a sarcoma-derived tumor (C57B1; MCG 101) or a malignant melanoma (C3H/HeN; K1735-M2) were used. These models were principally different because they demonstrate, in tumor hosts, conditions with and without cancer cachexia, seemingly related to high and low production of prostanoids, respectively. Cox inhibitors (Cox-1 and Cox-2) decreased tumor growth by 35-40% in MCG 101-bearing mice but had no such effect on melanoma-bearing mice, despite the expression of the Cox-2 protein in melanoma cells. Indomethacin reduced prostanoid production in both tumor (MCG 101) and host tissues and reduced tumor cell proliferation, mainly in vivo. Nitric oxide synthase (NOS) inhibitors (N(omega)-nitro-L-arginine methyl ester and N(omega)-nitro-L-arginine) reduced tumor growth in vivo by approximately 50% in both tumor models. Tumor growth reduction, related to NOS inhibition, was unrelated to prostanoid production and was an in vivo phenomenon in both tumor models. Specific inhibitors of inducible NOS activity, unexpectedly, had no effect in any tumor model, although inducible NOS protein was present in tumor tissues in large amounts. A combination of Cox and NOS inhibitors had no additive effect on tumor growth (MCG 101). Cox inhibition increased tumor tissue (MCG 101) expression of cNOS mRNA but had no significant effect on tumor tissue expression of the transferrin receptor, vascular endothelial growth factor, or basic fibroblast growth factor. NOS inhibition increased tumor tissue content of cNOS mRNA but showed as well a trend to increase mRNA content of the transferrin receptor and vascular endothelial growth factor. Our results suggest that NOS inhibitors can decrease the local growth of tumors that are either responsive or unresponsive to Cox inhibition. This effect may reflect cross-talk between Cox and NOS pathways within or among tumor cells, or it may represent unrelated effects on tumor and host cells. Whether NO inhibition may be used therapeutically in clinical tumors that are unresponsive to eicosanoid intervention remains to be evaluated.

Are cytokines possible mediators of cancer cachexia?

The possible role of cytokines in the development of cancer cachexia was reviewed from the literature. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, interferon (IFN)-gamma and leukemia inhibitory factor (LIF) can elicit many but not all host changes seen in cancer cachexia, including loss of appetite, loss of body weight, and the induction of acute-phase protein synthesis. However, these cytokines are not always demonstrated in the circulation of the cancer patients. The inability to detect circulating cytokines may be due to their low rate of production, their short half-life and rapid clearance from plasma, or their mode of action (autocrine or paracrine). Different cytokines are induced to stimulate the same response. This is very different from hormonal regulation, where a hormone acts on a cell directly through a specific receptor without depending on other mediators. Specific antibodies including anti-IFN-gamma, anti-TNF and anti-IL-6 antibodies, as well as the cyclooxygenase inhibitor indomethacin, have been used to reverse cancer cachexia. Overlapping physiologic activities make it unlikely that a single substance is the sole cause of cancer cachexia. It is hoped that further investigation on other cytokines and their possible relationships with hormones will help to clarify the mechanisms of cancer cachexia in the near future.

Effects related to indomethacin prolonged survival and decreased tumor-growth in a mouse-tumor model with cytokine dependent cancer cachexia.

Tumor-bearing mice with two different locally growing malignant tumors (epithelial like, MCG 101; malignant melanoma, K1735-M2) were used to evaluate the putative role of prostaglandins for survival and local tumor growth in experimental cancer. Daily systemic injections of indomethacin (1 mu g/g bw) were used to block prostaglandin production in normal and T-cell deficient tumor-bearing nude mice. Tumor progression was determined by measurements of tumor weight, DNA-synthesis, cell cycle kinetics in vivo and in vitro (flow cytometry), tumor tissue concentrations of polyamines (putrescine, spermidine, spermine) and tumor tissue gene expression of growth regulating factors (IL-1 alpha, IL-6, TNF alpha, A,B-PDGF, EGF, VEGF, bFGF, TGF beta(3), angiogenin and transferrin receptor). Tumor tissue content of von Willebrandt factor VIII was estimated by immunohistochemistry. Indomethacin had no effect on survival, host nutritional state or local tumor growth in mice bearing the malignant melanoma with low PGE(2) production. In contrast, indomethacin prolonged survival, improved cachexia and decreased tumor growth in mice bearing the MCG 101 tumor with hundredfold higher prostaglandin tumor production, leading to elevated liver and muscle tissue as well as plasma concentrations of PGE(2). Indomethacin inhibited almost completely the high tumor PGE(2) production in MCG tumors, leading to prolonged potential doubling time for tumor growth in vivo, and a trend to decreased tumor tissue concentration of polyamines (spermidine). Indomethacin had no inhibitory effect on tumor cell proliferation in vitro, although PGE(2) production was decreased by 75%. The effect of indomethacin in vivo was independent of T-cells and was observed with similar magnitude irrespective of the number of MCG cells (10(4)-10(6)) implanted or the site of implantation (s.c., i.p., liver, lung, skeletal muscles). Tumor growth inhibition by indomethacin was not intrinsically transferable by tumor cells from indomethacin treated tumor-animals. Tumor expression of mRNA for several growth regulating factors were either increased (IL-6, TNF alpha, GM-CSF, TGF beta(3)) unchanged (EGF, VEGF, PDGF A,B, IL-1 alpha, transferrin receptor) or decreased (b-FGF and angiogenin) (p<0.05) by indomethacin treatment of MCG mice. Decreased tumor content of von Willebrandt factor VIII in combination with an attenuated tumor vasculature were associated with decreased tumor growth (p<0.05). Our results confirm that high tumor production of prostaglandins was related to reduced survival. Tumor prostaglandins probably promote local tumor growth by stimulation of tumor surrounding cells to produce growth factor(s) for tumor angiogenesis including tumor and matrix cell proliferation unrelated to immune cells.

Anti-inflammatory treatment may prolong survival in undernourished patients with metastatic solid tumors.

Eicosanoids may be important factors for tumor cell proliferation, metastatic formation, and development of cancer cachexia. The present study has evaluated the effect of anti-inflammatory treatment on tumor progression in clinical cancer. Patients (n = 135) with insidious or overt malnutrition due to generalized malignancy (various kinds of solid tumors) and an expected survival of more than 6 months were randomized by a computer-based algorithm to receive placebo, prednisolone (10 mg twice daily), or indomethacin (50 mg twice daily) p.o. until death. Patient groups were stratified in the randomization procedure for sex, tumor type, stage, nutritional state, and previous tumor treatment, and biochemical, physiological, and some functional variables (Karnowsky index, fatigue and pain score). A majority of these variables was then registered during the follow-up. Indomethacin and prednisolone treatment maintained Karnowsky index, while placebo-treated patients experienced a decreased index. Indomethacin-treated patients suffered less pain and consumed less additional analgetics compared to the other patient groups. Indomethacin prolonged mean survival compared to placebo-treated patients from 250 +/- 28 days to 510 +/- 28 days (P < 0.05). Survival analysis on observations from all patients treated with either indomethacin or prednisolone demonstrated a significantly prolonged survival by anti-inflammatory treatment compared to placebo treatment (log rank, P < 0.03). The results suggest that not only may prostaglandin synthesis inhibition offer palliative support to patients with solid advanced cancer, but it may also impact on pathways that ultimately determine outcome.

Imaging of polypoid endoluminal growing bile duct tumors.

We reviewed the radiological documents and protocols of 196 cases of bile duct tumors examined over a period of 12 years: 20 of them (10.2%) presented with a polypoid endoluminal growth. The aim of this study was to provide a better knowledge about the radiological features of this less frequent kind of tumor. In these 20 cases, the correct diagnosis of bile duct lesion was provided in 100% by E.R.C.P., P.T.C., U.S. as well as C.T., and in 42% by arteriography. The correct diagnosis of tumor was made by E.R.C.P. in 86%, by P.T.C. in 88%, by U.S. in 61%, by C.T. in 63%, and by arteriography in 25%. A correct diagnosis of tumor could be reached in all cases by combination of several examination techniques. The anatomopathological diagnosis was: bile duct adenocarcinoma (7 cases), adenocarcinoma of the ampulla of Vater (4), villous adenoma of Vater's ampulla (2), cystadenoma (1), cystadenocarcinoma (1), hepatocellular carcinoma (1), apudoma (1), and metastases (3).

Expression of interleukin-6 in tumor-bearing mice with cytokine dependent cachexia.

Increased production of IL-6 in tumor-bearing mice occured in a variety of host-tissues including tumor tissue. Elevated IL-6 transcription in tumor-bearing mice occured in the tumor, liver, kidney and the small intestine, and was associated with increased concentration in the circulation of bioactive IL-6 of normal size (almost-equal-to 20 000 kDa) in addition with two larger but biologically inactive serum fractions containing immune-reactive IL-6. These inactive complexes were not explained by circulating inhibitor(s). The occurrence of differently sized tumor and host-tissue IL-6 mRNAs were dependent on the subcellular location (nuclear, ribosomal, cytoplasm). the tissue type and the kind of cellular stimulation. In tumor-tissue, IL-6 was produced to the highest concentration in tumor cells, followed by inflammatory and endothelial cells respectively, but IL-6 did not seem to represent an autocrine growth factor loop as earlier reported by us for both IL-1alpha and TNFalpha in the present tumor model. In contrast, evidence supported that IL-6 acted as a paracrinic factor in this model stimulated by some other host-derived factor(s).

Acute-phase proteins in response to tumor growth.

This study has evaluated the relationship between tumor growth and induction of acute-phase proteins. It has also determined whether an intact cellular immunity is obligatory for a fully expressed acute-phase plasma protein response in the presence of a highly antigenic tumor. Quantitatively, acute-phase responses (protein synthesis, plasma concentrations, hepatic RNA content, anorexia) were proportional to tumor burden. Anti-inflammatory drugs (indomethacin 1 micrograms/g body wt, dexamethasone 0.5 micrograms/g body wt) had no direct effect on the attenuation of the systemic acute-phase responses, but did affect them indirectly by decreasing tumor growth. Immune suppression (cyclosporine A at 20 or 60 micrograms/g body wt) had no effect on either acute-phase reactions or local tumor growth. In endotoxin-stimulated (lipopolysaccharide) normal mice, immune suppression aggravated anorexia and caused high mortality, while dexamethasone partly reversed these effects in endotoxin-stimulated mice. Plasma levels of acute-phase proteins correlated to circulating levels of IL-6 in untreated tumor-bearing mice, but this relationship was not obvious in either drug-treated tumor-bearing or endotoxin-stimulated mice. Tumor tissue induced the synthesis of different acute-phase proteins compared to endotoxin. However, disintegrated normal liver tissue induced the synthesis of serum amyloid protein to the same extent as the growing tumor. This effect was primarily associated with the mitochondrial/lysosomal and microsomal liver cell fractions. In conclusion, the overall acute-phase protein response is not a modulating factor of tumor growth.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of the adrenals in the acute phase response to interleukin-1 and tumor necrosis factor-alpha.

The purpose of this study was to investigate the role of the adrenals, particularly the glucocorticoids, in the acute phase response following daily injections for 5 days of recombinant human interleukin-1 alpha,beta and tumor necrosis factor-alpha (TNF alpha). Adult weight-stable freely fed or pair-fed (to cytokine-injected mice) mice (C57Bl/6J) with and without adrenals were used. Adrenalectomized animals showed a sensitivity to both IL-1 alpha and -1 beta (40 ng IL-1/day) greater than 10-fold higher than that of normal mice (420 ng IL-1/day) in regard to mortality and anorexia. Microscopic examination of tissue specimens from adrenalectomized IL-1 alpha,beta-injected mice did not reveal any histologic alterations in lung, kidney, liver, brain, or gastrointestinal tract to explain the mortality. This mortality was not prevented by physiologic replacement doses of hydrocortisone (10-20 micrograms/day); however, a pharmacological dose of 2.5 mg hydrocortisone/day abolished completely the increased toxicity to IL-1 alpha,beta and the anorectic response to IL-1 alpha,beta and TNF alpha. Increased toxicity (mortality) was not observed in adrenalectomized animals with TNF alpha at the dose interval used (450 ng TNF alpha/day and lower). The hepatic acute phase response (liver weight and RNA and liver protein content) was increased by both IL-1 alpha,beta and TNF alpha in a glucocorticoid-independent way. The cytokine-induced alterations of plasma concentrations of acute phase proteins (serum amyloid P, transferrin, complement C3) were significantly dependent on glucocorticoids, while the decline in plasma albumin was not.(ABSTRACT TRUNCATED AT 250 WORDS)

Co-variation between walking ability and circulatory alterations in patients with intermittent claudication.

Unselected patients (n = 183) with subjective symptoms of intermittent claudication were examined clinically and by various circulatory tests (calf blood-flow, ankle, toe pressures). The aims of the present study were to evaluate to what extent the central or peripheral circulation is limiting in unselected patients with subjective symptoms of intermittent claudication, to determine the co-variation between the maximum walking capacity and traditional haemodynamical measures mentioned above and to evaluate to what extent a traditional bicycle ergometer exercise test and treadmill walking test give similar information regarding maximum performance. Eighty-five per cent of all patients were or had been smokers and 16% were diabetics. The mean ankle/brachial blood pressure index was 0.58 +/- 0.02 and the average post-ischemic maximum calf bloodflow was 13.3 +/- 0.6 ml/min/100 ml tissue. Leg arterial insufficiency was the limiting factor of walking capacity in 90% of all patients at 87 +/- 2 W corresponding to a walking distance of 282 +/- 13 m, while leg exhaustion was the limiting factor in 80% of the patients during test on the bicycle ergometer at maximum 84 +/- 2W. The mean maximum walking capacity for all patients was 86 +/- 3W and the mean maximum capacity on the bicycle ergometer was 87 +/- 2W. The ankle/brachial index showed only a weak correlation (r = 0.30, p < 0.002) to walking capacity. Our results demonstrate that the maximum walking capacity on a treadmill agrees with mean values of maximum exercise capacity on a bicycle ergometer.(ABSTRACT TRUNCATED AT 250 WORDS)