The homogenous alternative to biomineralization: Zn- and Mn-rich materials enable sharp organismal "tools" that reduce force requirements.

We measured hardness, modulus of elasticity, and, for the first time, loss tangent, energy of fracture, abrasion resistance, and impact resistance of zinc- and manganese-enriched materials from fangs, stings and other "tools" of an ant, spider, scorpion and nereid worm. The mechanical properties of the Zn- and Mn-materials tended to cluster together between plain and biomineralized "tool" materials, with the hardness reaching, and most abrasion resistance values exceeding, those of calcified salmon teeth and crab claws. Atom probe tomography indicated that Zn was distributed homogeneously on a nanometer scale and likely bound as individual atoms to more than » of the protein residues in ant mandibular teeth. This homogeneity appears to enable sharper, more precisely sculpted "tools" than materials with biomineral inclusions do, and also eliminates interfaces with the inclusions that could be susceptible to fracture. Based on contact mechanics and simplified models, we hypothesize that, relative to plain materials, the higher elastic modulus, hardness and abrasion resistance minimize temporary or permanent tool blunting, resulting in a roughly 2/3 reduction in the force, energy, and muscle mass required to initiate puncture of stiff materials, and even greater force reductions when the cumulative effects of abrasion are considered. We suggest that the sharpness-related force reductions lead to significant energy savings, and can also enable organisms, especially smaller ones, to puncture, cut, and grasp objects that would not be accessible with plain or biomineralized "tools".

Making enhanced recovery the norm not the exception.

BACKGROUND: Enhanced Recovery After Surgery ("STAAR" in our system) is multimodal care focused on the reduction of physiological and psychological stress. While enhanced recovery is well established in colorectal surgery, and there is evidence for effectiveness in other surgical disciplines, to date widespread use is limited. METHOD: We implemented a Lean process that, within 12 months, expanded STAAR to 13 surgical services lines involving >130 surgeons, and impacting the care of >6000 surgical patients/year. RESULTS: Implementation involved educational and administrative meetings (279 in the first 6 months) and rounding. Use of STAAR was defined as >60% compliance. LOS was reduced up to 40%, mortality index and transfusion decreased 67% and 23% respectively. Case mix index increased 17%. Readmission rates, infections, ER visits were not increased. CONCLUSION: Using a Lean process focused on value, STAAR protocols became the standard rather than the exception. Time investment by senior surgical leadership was extensive.

Overexpression of BLM promotes DNA damage and increased sensitivity to platinum salts in triple-negative breast and serous ovarian cancers.

Background: Platinum-based therapy is an effective treatment for a subset of triple-negative breast cancer and ovarian cancer patients. In order to increase response rate and decrease unnecessary use, robust biomarkers that predict response to therapy are needed. Patients and methods: We performed an integrated genomic approach combining differential analysis of gene expression and DNA copy number in sensitive compared with resistant triple-negative breast cancers in two independent neoadjuvant cisplatin-treated cohorts. Functional relevance of significant hits was investigated in vitro by overexpression, knockdown and targeted inhibitor treatment. Results: We identified two genes, the Bloom helicase (BLM) and Fanconi anemia complementation group I (FANCI), that have both increased DNA copy number and gene expression in the platinum-sensitive cases. Increased level of expression of these two genes was also associated with platinum but not with taxane response in ovarian cancer. As a functional validation, we found that overexpression of BLM promotes DNA damage and induces sensitivity to cisplatin but has no effect on paclitaxel sensitivity. Conclusions: A biomarker based on the expression levels of the BLM and FANCI genes is a potential predictor of platinum sensitivity in triple-negative breast cancer and ovarian cancer.

The exon junction complex in neural development and neurodevelopmental disease.

Post-transcriptional mRNA metabolism has emerged as a critical regulatory nexus in proper development and function of the nervous system. In particular, recent studies highlight roles for the exon junction complex (EJC) in neurodevelopment. The EJC is an RNA binding complex composed of 3 core proteins, EIF4A3 (DDX48), RBM8A (Y14), and MAGOH, and is a major hub of post-transcriptional regulation. Following deposition onto mRNA, the EJC serves as a platform for the binding of peripheral factors which together regulate splicing, nonsense mediated decay, translation, and RNA localization. While fundamental molecular roles of the EJC have been well established, the in vivo relevance in mammals has only recently been examined. New genetic models and cellular assays have revealed core and peripheral EJC components play critical roles in brain development, stem cell function, neuronal outgrowth, and neuronal activity. Moreover, human genetics studies increasingly implicate EJC components in the etiology of neurodevelopmental disorders. Collectively, these findings indicate that proper dosage of EJC components is necessary for diverse aspects of neuronal development and function. Going forward, genetic models of EJC components will provide valuable tools for further elucidating functions in the nervous system relevant for neurodevelopmental disease.

Variation in U.S. traffic safety policy environments and motor vehicle fatalities 1980-2010.

OBJECTIVE: To examine the impact of variation in state laws governing traffic safety on motor vehicle fatalities. STUDY DESIGN: Repeated cross sectional time series design. METHODS: Fixed effects regression models estimate the relationship between state motor vehicle fatality rates and the strength of the state law environment for 50 states, 1980-2010. The strength of the state policy environment is measured by calculating the proportion of a set of 27 evidence-based laws in place each year. The effect of alcohol consumption on motor vehicle fatalities is estimated using a subset of alcohol laws as instrumental variables. RESULTS: Once other risk factors are controlled in statistical models, states with stronger regulation of safer driving and driver/passenger protections had significantly lower motor vehicle fatality rates for all ages. Alcohol consumption was strongly associated with higher MVC death rates, as were state unemployment rates. CONCLUSIONS: Encouraging laggard states to adopt the full range of available laws could significantly reduce preventable traffic-related deaths in the U.S. - especially those among younger individuals. Estimating the relationship between different policy environments and health outcomes can quantify the result of policy gaps.

Bioluminescence assay for the highly sensitive detection of botulinum neurotoxin A activity.

This article describes a novel bioluminescence assay for detecting the proteolytic activity of Botulinum NeuroToxins (BoNT) in complex matrices. The assay is capable of detecting traces of BoNT in blood samples as well as in food drinks. The assay was responsive to BoNT/A subtypes 1 to 5, and serotype E3 in buffered solutions. It was responsive to filtered Clostridium botulinum supernatants and BoNT/A1 in complex with neurotoxin associated proteins in bouillon and milk (3.8% fat) down to 400 fM after 4 h RT incubation and in bouillon at concentrations down to 120 fM after 21 h RT incubation. In combination with an immunocapture/enrichment step it could detect BoNT/A1 in citrated plasma at concentrations down to 30 fM (1.2 mouse LD50 per mL). The simplicity of the assay, combined with a demonstrated ability to lyophilize the reagents, demonstrates its usefulness for detection of BoNT in non-specialised analytical laboratories.

Effect of HIV on liver fibrosis among HCV-infected African Americans.

Degree of liver fibrosis largely determines treatment urgency for hepatitis C virus (HCV). This retrospective study examined fibrosis stages and predictive factors in African Americans with HCV monoinfection and human immunodeficiency virus (HIV)/HCV coinfection. Nearly 50% of patients had early-stage fibrosis in the study, despite the long duration of infection in many patients. HIV was associated with the early fibrosis group. These results indicate that a large proportion of patients with HCV infection, including those with HIV, could possibly await more-effective and better-tolerated treatment.

Synchronous renal malignancy presenting as recurrent urinary tract infections.

Renal cell carcinoma (RCC) and urothelial carcinoma of the upper urinary tract are not uncommon urological malignancies. Their simultaneous occurrence in a patient is, however, extraordinarily rare. We report the case of a patient who underwent unilateral nephrectomy for suspected RCC and diagnosed transitional cell carcinoma of the superior pelvis. Preoperative imaging was suspicious for renal pelvic involvement, which was confirmed upon performing cystoscopy and biopsy of the suspected lesion preoperatively. This preoperative approach was especially appropriate as a nephron saving procedure was being considered prior to the discovery of the synchronous lesion. We discuss this rare simultaneous occurrence of synchronous malignancies in the same kidney.

The measurement of patellar height: a review of the methods of imaging.

Many radiographic techniques have been described for measuring patellar height. They can be divided into two groups: those that relate the position of the patella to the femur (direct) and those that relate it to the tibia (indirect). This article looks at the methods that have been described, the logic behind their conception and the critical analyses that have been performed to test them.

Penetrating injury from laminated glass--a trap for the unwary.

Although the incidence of glass injury following road traffic accidents has been decreasing over the past five decades, the location and source of glass bodies from accidents involving vehicles can prove difficult for the radiologist and surgeon and in medico-legal disputes. This case illustrates the issues with regard to penetrating injuries from different types of glass used in the automotive industry. Shatterproof glass windscreens with a laminated coating have been developed to prevent fragmentation and dispersal. This has led to a significant reduction in glass-related injury. Although laminated glass fitted in front windscreens and in some side windows is designed not to shatter, fragmentation can indeed take place in cases of high impact, resulting in penetrating injury that can be difficult to detect and can lead to injury and morbidity. The attending clinician should therefore consider penetrating injuries in the clinical and radiological assessment of individuals who present after motor vehicle accidents and be aware that laminated glass, although considered to be "safe", can indeed be responsible for penetrating injury. We present a unique case report to illustrate this important point, which may encourage debate in the medical world and motor manufacturing industry.

Intraarticular injection of anakinra in osteoarthritis of the knee: a multicenter, randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the clinical response, safety, and tolerability of a single intraarticular injection of anakinra in patients with symptomatic osteoarthritis (OA) of the knee. METHODS: Patients with OA of the knee were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1:2 to receive a single intraarticular injection of placebo, anakinra 50 mg, or anakinra 150 mg in their symptomatic knee. Patients were evaluated for 12 weeks postinjection. The primary end point was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score from baseline to week 4. Safety assessments included the evaluation of adverse events (AEs), laboratory tests, and vital signs. Pharmacokinetic parameters were assessed in a subset of patients. RESULTS: Of 170 patients who enrolled, 160 (94%) completed the study. The mean improvements from baseline to week 4 in the WOMAC score were not statistically different between the placebo group and the patients who received 50 mg of anakinra (P = 0.67) or 150 mg of anakinra (P = 0.77). Anakinra was well tolerated. No withdrawals due to AEs or serious AEs, and no serious infections or deaths were reported. No clinically significant trends were noted in laboratory values or vital signs. Pharmacokinetic parameters demonstrated that the mean terminal half-life of anakinra in serum after intraarticular injection was approximately 4 hours. CONCLUSION: Anakinra was well tolerated as a single 50-mg or 150-mg intraarticular injection in patients with OA of the knee. However, anakinra was not associated with improvements in OA symptoms compared with placebo.

A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease.

BACKGROUND: The safety and efficacy of istradefylline, a selective adenosine A(2A) receptor antagonist, was evaluated in a 12-week, double-blind study in levodopa-treated Parkinson disease (PD) subjects with motor complications. METHODS: Levodopa-treated PD subjects (n = 395) received istradefylline 20 mg/day (n = 163), istradefylline 60 mg/day (n = 155), or placebo (n = 77) at 40 sites. The primary efficacy variable was the change in the percentage of time per day spent in the OFF state. Secondary measurements assessed change in ON time, Unified Parkinson's Disease Rating Scale, and Clinical Global Impression. Safety monitoring included clinical laboratory, electrocardiograms, vital signs, physical/neurologic examinations, and adverse events (AEs). RESULTS: Changes from baseline to endpoint in the percentage OFF time in the active groups compared with placebo were -4.35% (95% CI -8.16 to -0.54; p = 0.026) for istradefylline 20 mg/day and -4.49% (95% CI -8.35 to -0.62; p = 0.024) for 60 mg/day; these changes were significant (analysis of covariance). For total hours, istradefylline demonstrated mean differences from placebo of -0.64 hours (95% CI -1.30 to 0.01) for 20 mg/day and -0.77 hours (95% CI -1.44 to -0.11) for 60 mg/day (p = 0.065; overall treatment effect). Clinical response occurred by the second week and was maintained throughout the study. Istradefylline was well tolerated. The common AEs were dyskinesia, nausea, dizziness, and hallucinations. CONCLUSIONS: Istradefylline demonstrated a significant reduction in the percentage of awake time per day spent in the OFF state, which resulted in a clinically meaningful reduction in OFF time, without an increase in ON time with troublesome dyskinesia, and was well tolerated as adjunctive treatment to levodopa in Parkinson disease.

Extranodal lymphomas presenting as soft tissue sarcomas to a sarcoma service over a two-year period.

Non-Hodgkin's lymphoma usually presents with lymphadenopathy at multiple sites but can also involve any part of the musculoskeletal system. Occasionally the presentation is with a soft tissue mass. The presentation of large, superficial lymphomatous masses is similar both clinically and radiologically to that of soft tissue sarcomas. The six cases of lymphoma presenting to the Exeter Sarcoma Service as suspected soft tissue sarcomas, over a two-year period (2002-2004), are presented. We describe the clinical and imaging characteristics of these tumours and their subsequent management. Our cases showed variability in presentation. Only one of the six cases presented with pain and one with tenderness. Four of the cases had no lymphadenopathy and the other two had lymphadenopathy restricted to one nodal basin. Overlying soft tissue swelling occurred in four cases and in distal limb swelling beyond the mass in one case. Radiologically, lymphomas are known to be likely to exhibit confluent lymphadenopathy that is rare in patients with soft tissue sarcoma. Confluent lymphadenopathy was demonstrated in only one case of this series of patients. It is thought that lymphomas infiltrate across anatomical fascial planes more readily than sarcomas and in four of our six cases this feature was present. Clinical history, examination and MRI are insufficient to differentiate between soft tissue sarcoma and lymphoma and the importance of obtaining a pathological diagnosis prior to surgery is clear. It is crucial to differentiate lymphoma from sarcoma in order to avoid unnecessary excisional procedures in lymphoma patients.

Neurotized Free Muscle Flaps can Produce MRI Changes Mimicking Tumour Recurrence.

Soft tissue sarcomas are investigated by magnetic resonance imaging (MRI) both for initial staging and follow-up. We describe the presence of increased signal on T2-weighted images caused by a neurotized muscle flap following reconstructive surgery. This raised concern about possible sarcoma recurrence that was not clinically evident. On post-operative imaging of sarcomas the presence of recurrent tumour is indicated by a mass and high signal intensity on T2-weighted images. However, high signal changes in skeletal muscle on T2-weighted images are not specific. In this case, the free functioning muscle transfer with neurotization of the flap mimicked recurrence on MR scan. High signal intensity on T2-weighted images in muscle is an indication of either a physiological change or a pathological condition and must be taken in context of the clinical picture.

An association of multiple well differentiated liposarcomas, lipomatous tissue and hereditary retinoblastoma.

Well differentiated liposarcoma (atypical lipomatous tumour) is a low grade tumour, with no metastatic potential unless dedifferentiation supervenes. When superficial, it recurs locally only occasionally after marginal excision. We present a patient in whom bilateral childhood retinoblastoma was followed by later development of massive confluent areas of low grade liposarcoma and lipomatous tissue affecting the upper extremities and trunk. We discuss the role of mutations in the retinoblastoma gene (RB1) in linking these conditions and demonstrate the surgical management of an extremely unusual and challenging case.

Abnormalities of the inactive X chromosome are a common feature of BRCA1 mutant and sporadic basal-like breast cancer.

As a clinical entity, breast cancer appears to be a series of subforms, each with a relatively specific molecular phenotype. Among the characteristics that differentiate these subforms are sex hormone receptor expression, HER2 expression, p53 mutation, high-grade histopathology, and particular gene expression array patterns. Sporadic basal-like breast cancer is one such form. It is a relatively common, high-grade, hormone receptor and HER2-expression-negative, p53 mutation-bearing tumor and is particularly lethal. Although wild type for BRCA1, it is a sporadic phenocopy of most cases of BRCA1(/) breast cancer. Not only do the cells of the two tumors resemble one another with respect to the above-noted characteristics, they also share a defect in the maintenance of an intact, inactive X chromosome (Xi). Other high-grade and most low-grade tumors are rarely defective at Xi. This evidence suggests that an Xi defect contributes to the evolution of both sporadic and BRCA1(/) basal-like breast tumors.

An open-label evaluation of the tolerability and safety of Stalevo (carbidopa, levodopa and entacapone) in Parkinson's disease patients experiencing wearing-off.

OBJECTIVES: To evaluate the tolerability, safety and efficacy of Stalevo (carbidopa, levodopa and entacapone) in Parkinson's disease (PD). BACKGROUND: Levodopa provides the most effective symptom control for the treatment of Parkinson's disease (PD). However, its long-term use is limited by the development of motor complications such as wearing-off. Catechol-O-methyltransferase (COMT) inhibitors such as entacapone extend the plasma half-life of levodopa and reduce 'off' time. Stalevo is a new levodopa product that combines carbidopa, levodopa and entacapone in one tablet. Clinical studies have not been reported with this compound. DESIGN METHODS: An open-label, multi-center US trial evaluated 169 consecutive PD patients experiencing end-of-dose wearing-off, with (n = 39) and without (n = 130) mild dyskinesia. Patients were switched from immediate-release carbidopa/levodopa to Stalevo and were treated for four weeks. Assessments included tolerability measures, adverse events profile, the disease-specific quality of life instrument PDQ-39, UPDRS parts II, III, and question 39 and investigator and patient global clinical assessments. RESULTS: 14 subjects (8%) discontinued treatment with Stalevo, of which 12 (7%) were due to adverse events. 11/130 (8.5%) subjects developed new onset dyskinesia and 17/39 (43.6%) of patients with existing dyskinesia reported a worsening in their dyskinesia. However, this was managed by a change in dose in 21.4% of patients and in another 10.7% dyskinesias resolved without any need for dose adjustment. Other side effects were infrequent and mild, the most common being nausea (12.4%) dizziness (6.5%) and somnolence (6.5%). Stalevo treatment resulted in significant improvements in PDQ-39 and UPDRS (II + III) scores (p < 0.001). Assessment of 'off' time demonstrated a reduction in off time in 32% of patients, compared with an increase in 7% of patients. Improvements were noted by both investigator (68.1%) and patient (68.6%) assessments. CONCLUSIONS: Switching PD patients experiencing wearing-off from carbidopa/levodopa therapy to Stalevo was safe, well tolerated and resulted in clinical improvement.

Subcutaneous calcification following chest wall and breast irradiation: a late complication.

Subcutaneous calcification as a complication of chest wall irradiation has only been described once before in the literature. Six patients who developed heavy calcification of soft tissue following chest wall and breast irradiation are described here, and relevant literature is reviewed.

Reshaping medical volumetric data for enhanced visualization.

Three dimensional volume datasets are now commonly produced in the medical sciences. These datasets are generated by observational equipment such as CT, MRI, and ultrasound. There is a significant amount of research in techniques to render these datasets quickly and more realistically. However, there is little or no work on intuitive methods to manipulate volume datasets and volume models. For example, one may want to view a colon stretched out or unraveled. While techniques exist to transform polygonal models, similar techniques are not available for volumetric data. In this work, we describe our methodology to "reshape volumes" and remap existing volumetric datasets using volumetric skeletons. We demonstrate our results by unraveling a 3D colon dataset and discuss the many potential uses of this new visualization methodology.