Citations

Abstract We have recently shown that effective cytokine gene therapy of solid tumors in HLA-A2 transgenic (HHD) mice lacking murine MHC class I molecule expression results in the generation of HLA-A2–restricted CD8+ T effector cells selectively recognizing tumor blood vessel-associated pericytes and/or vascular endothelial cells. Using an HHD model in which HLA-A2neg tumor (MC38 colon carcinoma or B16 melanoma) cells are not recognized by the CD8+ T cell repertoire, we now show that vaccines on the basis of tumor-associated blood vessel Ags (TBVA) elicit protective Tc1-dependent immunity capable of mediating tumor regression or extending overall survival. Vaccine efficacy was not observed if (HLA-A2neg) wild-type C57BL/6 mice were instead used as recipient animals. In the HHD model, effective vaccination resulted in profound infiltration of tumor lesions by CD8+ (but not CD4+) T cells, in a coordinate reduction of CD31+ blood vessels in the tumor microenvironment, and in the “spreading” of CD8+ T cell responses to alternate TBVA that were not intrinsic to the vaccine. Protective Tc1-mediated immunity was durable and directly recognized pericytes and/or vascular endothelial cells flow-sorted from tumor tissue but not from tumor-uninvolved normal kidneys harvested from these same animals. Strikingly, the depletion of CD8+, but not CD4+, T cells at late time points after effective therapy frequently resulted in the recurrence of disease at the site of the regressed primary lesion. This suggests that the vaccine-induced anti-TBVA T cell repertoire can mediate the clinically preferred outcomes of either effectively eradicating tumors or policing a state of (occult) tumor dormancy.

We undertook this study to determine the minimum amount of coronoid necessary to stabilise an otherwise intact elbow joint. Regan–Morrey types II and III, plus medial and lateral oblique coronoid fractures, collectively termed type IV fractures, were simulated in nine fresh cadavers. An electromagnetic tracking system defined the three-dimensional stability of the ulna relative to the humerus. The coronoid surface area accounts for 59% of the anterior articulation. Alteration in valgus, internal and external rotation occurred only with a type III coronoid fracture, accounting for 68% of the coronoid and 40% of the entire articular surface. A type II fracture removed 42% of the coronoid articulation and 25% of the entire articular surface but was associated with valgus and external rotational changes only when the radial head was removed, thereby removing 67% of the articular surface. We conclude that all type III fractures, as defined here, are unstable, even with intact ligaments and a radial head. However, a type II deficiency is stable unless the radial head is removed. Our study suggests that isolated medial-oblique or lateral-oblique fractures, and even a type II fracture with intact ligaments and a functional radial head, can be clinically stable, which is consistent with clinical observation.

Interleukin- (IL-) 17 is important in the development of asthma and host defense against pneumococci. We determined the role of IL-17 in the risk of pneumococcal pneumonia. We challenged mice intranasally with a bioluminescentStreptococcus pneumoniaestrain after sensitization and challenge with ovalbumin (OVA). We measured the levels of cytokines, including IL-17 (pg/mL), in the lung homogenate in experimental mice with and without OVA sensitization/challenge, as well as those with and without pneumococcal pneumonia. IL-17 levels were significantly lower in OVA-sensitized/challenged mice (9.69±1.49), compared to the control mice (20.92±1.82,P< 0.001). In our overall analysis, including IL-4 and IL-17 levels and OVA sensitization/challenge, IL-4 levels (OR: 81.9, 95%CI: 4.3–1523 per increment of 1.0 pg/mL,P= 0.003) were more significant than IL-17 levels (OR: 1.1, 95%CI: 1.03–1.17 per increment of 1.0 pg/mL,P= 0.003) in determining the risk of pneumococcal pneumonia. IL-17 levels result in a much smaller impact on the risk for pneumococcal pneumonia, compared to IL-4 levels.

Tissue mechanical properties can be obtained by algebraic direct inversion (ADI) of the shear-wave motion differential equation, which is insensitive to reflection and geometry of the pushing beam. Shear waves normally generated by a focused ultrasound pushing beam have limited spatial extent in depth and are transient in time, leading to noisy and unstable ADI results. A comb-shape acoustic radiation force distribution can generate shear waves with longer spatial extent and time duration, facilitating more robust ADI. For 400 μs, a linear array transducer simultaneously transmitted four unfocused pushing beams (12 on elements for each pushing beam, 8 off elements between beams) into a tissue-mimicking phantom (∼1.5 kPa) with a cylindrical inclusion (∼4 kPa). The ultrasound system (Verasonics Inc.) then immediately switched to flash imaging mode (frame rate = 2 kHz, spatial resolution = 0.31 mm) to measure shear-wave displacements in a 38 mm by 30 mm domain that was used for ADI. The reconstructed 2D shear elasticity map provides accurate shear elasticity estimates (background = 1.5 kPa with 7% variance; inclusion = 3.9 kPa with 15% variance) and excellent contrast between the background and inclusion.

The purpose of this study was to describe a modification of the Massachusetts General Hospital (MMGH) tendon repair and to compare it with three other suture techniques. Twenty human flexor digitorum profundus (FDP) tendons were randomly assigned to the modified Pennington (MP) suture and the MMGH suture. These were compared to the modified Kessler (MK) and Massachusetts General Hospital (MGH) sutures, using data from a previous study. All tendons were repaired with a similar epitendinous stitch and core sutures of 4-0 FiberWire. There was no significant difference in the normalized gliding resistance within the two-strand or four-strand core repair groups. The MP suture had significantly higher 2 mm gap force and ultimate load to failure than the MK suture. The MMGH suture had significantly higher 2 mm gap force and maximum failure ultimate load than the MGH suture. All repairs failed by knot unravelling.

Background The etiology of carpal tunnel syndrome (CTS) remains idiopathic in many cases. Noninflammatory fibrosis of the subsynovial connective tissue (SSCT) within the carpal tunnel is common in CTS, and some clinicians have hypothesized that this fibrosis might be a cause rather than an effect of CTS. An animal model in which to test this hypothesis would be useful. The principal objective of this study was to investigate the effect of a surgical injury on SSCT fibrosis and median nerve function within the carpal tunnel in an in vivo rabbit model. Methods Rabbits were sacrificed 12 weeks after surgery and were evaluated by mechanical testing, histology, transmission and scanning electron microscopy, and electrophysiology. Results SSCT fibroblast density ( p<0.0001) and collagen fiber size ( p=0.0004) were significantly higher, and the median nerve distal motor amplitude was significantly lower ( p=0.0018), in the tendon injury group SSCT than in either the sham or control groups. Conclusions Our findings are similar to those seen in patients with carpal tunnel syndrome and suggest that the tendon injury procedure may be the basis of a new animal model of SSCT injury and, possibly, CTS.

Barbed sutures and connecting devices have been historically described and used in flexor tendon tenorrhaphies. With the improvement in biomaterial, we have witnessed recently the resurgence of this concept. In this article, we review the historical use of barbed devices in repairing flexor tendons and explore the available barbed surgical devices that have been described in recent years.

Abstract Background: Taxane-induced peripheral neuropathy is a dose-limiting side effect that leads to suboptimal cancer treatment and diminished quality of life. The mode of taxane neurotoxicity is unclear, but may be through stabilization of microtubules and induction of spindle checkpoint, leading to cell cycle arrest at G2/M. Fanconi Anemia (FA) genes, including FANCD2, and FANCA, appear to be involved in G2/M phase checkpoint maintenance as well as spindle checkpoint in response to internal and external signals, such as taxane treatment. Thus, we hypothesized that variants in FA genes could impact severity of taxane-induced neuropathies.Methods: Using DNA extracted from blood collected from 893 breast cancer patients participating in a trial evaluating metronomic dosing of cyclophosphamide, doxorubicin and paclitaxel (S0221), we genotyped for single nucleotide polymorphisms (SNPs) that represent all of the variability across FANCA (44 SNPs) and FANCD2 (24 SNPs) in all race/ethnicity groups, as well as a panel of ancestry informative markers to control for potential population stratification, using Illumina GoldenGate platform. SNPs with minor allele frequency (MAF) less than 0.10 and those out of Hardy Weinberg Equilibrium (HWE) proportions (p&lt;0.001) were removed from analyses. Ordinal regression was used to test for allelic and haplotypic association with grade 3 or 4 toxicities relative to 0, 1, and 2 toxicities, adjusting for age, genetic admixture index and treatment arm. To adjust for multiple testing, permutation analyses were performed on both single SNP and haplotype models.Results: Eighteen SNPs in FANCD2 and 38 SNPs in FANCA passed MAF and HWE proportion requirements. For FANCD2, 4 SNPs spanning 67.5 Kb (rs7648104, rs2272125 [coding SNP], rs6786638 and rs644215), were significantly associated with taxane-induced neuropathy (p&lt;0.001) after controlling for multiple testing, with each SNP resulting in approximately a twofold increase in odds of severe taxane-induced neuropathy. Haplotype estimation showed that all 18 SNPs comprise a single haplotype. Two major (&gt;1% frequency) haplotypes were found. The frequencies of the risk haplotype in cases (patients with grade 3 or 4 neuropathy) and controls (patients with ≤ grade 2 neuropathy) were 0.25 and 0.15, respectively. Ordinal regression analyses were highly significant (p&lt;0.0005); patients with at least one copy of the risk haplotype had more than a twofold increased risk of grade 3 or 4 taxane-induced neuropathy (OR=2.2, 95% CI 1.44, 3.44). For FANCA, no SNPs or haplotypes were significantly associated with grade 3 or 4 neurotoxicity, either prior to or after correction for multiple testing.Conclusions: These results indicate that the Fanconi-Anemia pathway may be important for neurological sensitivity to taxanes, and that genotypic markers might be able to be used to identify patients at increased risk for severe taxane-induced neuropathy. Further studies will elucidate potential associations with survival outcomes. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2001.

BackgroundDiabetes is a risk factor for mild cognitive impairment (MCI) and dementia. However, the association between high normal fasting blood glucose (FBG) and dementia has not been studied.MethodsPolytomous logistic regression was used to assess the association of dementia and MCI with FBG in an age‐ and sex‐matched sample of 32 dementia patients, 27 amnestic MCI (aMCI) patients, and 31 normal controls (NC). Analyses were repeated for those with normal FBG. Correlations between FBG and cognitive test scores were obtained.ResultsControlling for age, gender, education, body mass index, Hachinski Ischemic Score, magnetic resonance imaging (MRI) stroke, and normalized brain, hippocampal, and white matter hyperintensity MRI volumes; higher FBG was associated with dementia versus aMCI status (OR = 3.13; 95% CI, 1.28–7.69). This association remained (OR = 7.75; 95% CI, 1.10–55.56) when analyses were restricted to subjects with normal FBG. When dementia patients were compared with NC adjusting for age, gender, and education, a significant association with FBG also was seen (OR = 1.83; 95% CI, 1.09–3.08), but it was lost when vascular covariates were added to the model. FBG was not associated with aMCI status versus NC. Higher FBG was correlated with poorer performance on the Trailmaking Test Part B (P = .003). The percentage of dementia patients with high normal FBG (90%) was significantly higher than that of aMCI patients with high normal FBG (32.9%) (χ2 = 13.9, P < .001).ConclusionsHigher FBG was associated with dementia (vs. aMCI) independent of vascular risk factors and MRI indicators of vascular disease, and remained a significant risk factor when analyses were restricted to subjects with normal FBG. The results of this cross‐sectional study suggest that a high normal level of FBG may be a risk factor for dementia.