Citations

This work presents an approach to inversely determine material properties for solids immersed in fluids through the use of steady-state dynamic response. The methodology uses measured acoustic pressure amplitudes in the fluid surrounding a structure being vibrated with a harmonic force to determine the parameters for elastic and viscoelastic material models. Steady-state dynamic finite element analysis is used to compute the frequency response function of homogeneous and heterogeneous solids. The frequency response is then used to inversely estimate material parameters. In order to solve the inverse problem, an optimization method is presented which combines the global search capabilities of the random search method with the reduced computational time of a surrogate model approach. Through numerical and laboratory experiments, this work shows that acoustic emissions hold sufficient information for quantifying both elastic and viscoelastic material behaviors. Furthermore, the examples show that the surrogate model accelerated random search algorithm is an efficient and accurate method for solving these types of inverse problems. This research has direct and important implications in nondestructive evaluation of material properties in general. However, the examples shown in this paper are based on applications related to noninvasive characterization of biological materials through methodologies currently applied to medical imaging.

Intermittent claudication is the most common symptom of peripheral arterial disease (PAD), in part due to an inadequate rise in limb blood flow with exercise. Claudication causes a severe impairment in functional capacity and quality of life in over 3 million Americans. Basic fibroblast growth factor (bFGF) stimulates angiogenesis in vivo and improves limb blood flow in several animal models of hindlimb ischemia. However, the relative safety and efficacy of angiogenic molecules in the treatment of claudication has not been fully evaluated in prospective, blinded clinical trials. In this study, a randomized, double-blind, placebo-controlled, phase II trial of recombinant human bFGF for the treatment of intermittent claudication was performed. bFGF was administered weekly by intravenous infusions of 2 μg/kg for 6 sequential weeks (total dose 12 μg/kg). The primary efficacy endpoint was change in peak walking time (PWT) on a graded exercise treadmill protocol. Secondary efficacy endpoints included changes in functional status as measured by validated questionnaires. The study was stopped prematurely after treatment of the first 24 subjects due to proteinuria in five of the 16 subjects who received systemic bFGF, which exceeded 1000 mg/24 h in four of these five subjects. The small sample size limited evaluation of the predefined efficacy endpoints; however, there was no significant difference between the treatment and control groups for any of the measures of efficacy. In conclusion, intravenous administration of bFGF delivered at low doses weekly for 6 weeks was associated with a high rate of severe proteinuria. It is speculated that bFGF-related proteinuria in this study was primarily related to the systemic route of administration and the frequent dosing schedule. Future clinical trials of bFGF protein should carefully monitor renal function and consider alternative dosing schedules and drug administration routes.

The critical decisions regarding thoracotomy for trauma occur soon after the injury, when decisions have to be made that may influence survival or have an impact on morbidity if operation is delayed. Roadside thoracotomy is impractical, and should not be considered; instead, patients should be taken rapidly to the nearest hospital. Endotracheal intubation prior to transport appears to be beneficial, but the application of MAST trousers and the infusion of large volumes of fluid for hypovolaemia before control of haemorrhage offers no advantage and may be hazardous. On the whole, resuscitative thoracotomy is associated with a low salvage rate, especially for the patient sustaining blunt trauma, but may be worthwhile in the patient with penetrating trauma. Urgent, as opposed to immediate thoracotomy, should be undertaken once the patient has been stabilized. This may occur in most patients with penetrating injuries of the heart who survive to reach hospital, those with continuing, significant haemorrhage through chest drains, and those with tracheal, oesophageal and diaphragmatic injuries. Extensive open chest wounds require considerable ingenuity in closure, often with plastic surgical help. Patients with blunt traumatic rupture of the aorta often have multiple injuries, which may also be life threatening. If bleeding into the abdomen is demonstrated, then laparotomy should precede thoracotomy: musculoskeletal injuries and neurological injuries can usually be dealt with after the aortic rupture has been repaired.

Abstract Background Ileal pouch–anal anastomosis (IPAA) is performed routinely for chronic ulcerative colitis. Methods Using data from a prospective database and annual standardized questionnaires, functional outcome, complications and quality of life (QoL) after IPAA were assessed. Results Some 1885 IPAA operations were performed for chronic ulcerative colitis over a 20-year period (mean follow-up 11 years). The mean age at the time of IPAA was 34·1 years, increasing from 31·2 years (1981–1985) to 36·3 years (1996–2000). The overall rate of pouch success at 5, 10, 15 and 20 years was 96·3, 93·3, 92·4 and 92·1 per cent respectively. Mean daytime stool frequency increased from 5·7 at 1 year to 6·4 at 20 years (P < 0·001), and also increased at night (from 1·5 to 2·0; P < 0·001). The incidence of frequent daytime faecal incontinence increased from 5 to 11 per cent during the day (P < 0·001) and from 12 to 21 per cent at night (P < 0·001). QoL remained unchanged and 92 per cent remained in the same employment. Seventy-six patients were eventually diagnosed with indeterminate colitis and 47 with Crohn's disease. Conclusion IPAA is a reliable surgical procedure for patients requiring proctocolectomy for chronic ulcerative colitis and indeterminate colitis. The clinical and functional outcomes are excellent and stable for 20 years after operation.

Most patients with cystic fibrosis (CF) have a single codon deletion (ΔF508) in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) that impairs assembly of the multidomain glycoprotein. The mutant protein escapes endoplasmic reticulum (ER) quality control at low temperature, but is rapidly cleared from the distal secretory pathway and degraded in lysosomes. CF cells accumulate free cholesterol similar to Niemann-Pick disease type C cells. We show that this lipid alteration is caused by the presence of misassembled mutant CFTR proteins, including ΔF508, in the distal secretory pathway rather than the absence of functional CFTR. By contrast, cholesterol distribution is not changed by either D572N CFTR, which does not mature even at low temperature, or G551D, which is processed normally but is inactive. On expression of the ΔF508 mutant, cholesterol and glycosphingolipids accumulate in punctate endosomal structures and cholesterol esters are reduced, indicating a block in the translocation of cholesterol to the ER for esterification. This is overcome by Rab9 overexpression, resulting in clearance of accumulating intracellular cholesterol. Similar but less pronounced alterations in intracellular cholesterol distribution are observed on expression of a temperature-rescued mutant variant of the related ATP-binding cassette (ABC) protein multidrug resistance-associated protein 1 (MRP1). Thus, on escape from ER quality control, misassembled mutants of CFTR and MRP1 impair lipid homeostasis in endocytic compartments.

AbstractAdoptive T-cell transfer has achieved significant clinical success in advanced melanoma. However, therapeutic efficacy is limited by poor T-cell survival after adoptive transfer and by inefficient trafficking to tumor sites. Here, we report that intratumoral expression of the chemokine CCL21 enhances the efficacy of adoptive T-cell therapy in a mouse model of melanoma. Based on our novel observation that CCL21 is highly chemotactic for activated OT-1 T cells in vitro and down-regulates expression of CD62L, we hypothesized that tumor cell–mediated expression of this chemokine might recruit, and retain, adoptively transferred T cells to the sites of tumor growth. Mice bearing metastatic tumors stably transduced with CCL21 survived significantly longer following adoptive T-cell transfer than mice bearing non–CCL21-expressing tumors. However, although we could not detect increased trafficking of the adoptively transferred T cells to tumors, tumor-expressed CCL21 promoted the survival and cytotoxic activity of the adoptively transferred T cells and led to the priming of antitumor immunity following T-cell transfer. To translate these observations into a protocol of real clinical usefulness, we showed that adsorption of a retrovirus encoding CCL21 to OT-1 T cells before adoptive transfer increased the therapeutic efficacy of a subsequently administered dose of OT-1 T cells, resulting in cure of metastatic disease and the generation of immunologic memory in the majority of treated mice. These studies indicate a promising role for CCL21 in enhancing the therapeutic efficacy of adoptive T-cell therapy. [Cancer Res 2007;67(1):300–8]

Abstract In this study, we observed loss of heterozygosity (LOH) in human chromosomal fragment 6q25.1 in sporadic lung cancer patients. LOH was observed in 65% of the 26 lung tumors examined and was narrowed down to a 2.2-Mb region. Single-nucleotide polymorphism (SNP) analysis of genes located within this region identified a candidate gene, termed p34. This gene, also designated as ZC3H12D, C6orf95, FLJ46041, or dJ281H8.1, carries an A/G nonsynonymous SNP at codon 106, which alters the amino acid from lysine to arginine. Nearly 73% of heterozygous lung cancer tissues with LOH and the A/G SNP also exhibited loss of the A allele. In vitro clonogenic and in vivo nude mouse studies showed that overexpression of the A allele exerts tumor suppressor function compared with the G allele. p34 is located within a recently mapped human lung cancer susceptibility locus, and association of the p34 A/G SNP was tested among these families. No significant association between the less frequent G allele and lung cancer susceptibility was found. Our results suggest that p34 may be a novel tumor suppressor gene involved in sporadic lung cancer but it seems not to be the candidate familial lung cancer susceptibility gene linked to chromosomal region 6q23-25. [Cancer Res 2007;67(1):93–9]