Individuals with mild-to-moderate hip osteoarthritis walk with lower hip joint contact forces despite higher levels of muscle co-contraction compared to healthy individuals.

OBJECTIVE: To compare hip joint contact forces (HJCF), hip muscle forces, and hip muscle co-contraction levels between individuals with mild-to-moderate hip osteoarthritis (OA) and healthy controls during walking. DESIGN: Eighteen participants with mild-to-moderate hip OA and 23 healthy controls walked at a self-selected speed while motion capture and electromyographic data were synchronously collected. HJCF were computed using a calibrated electromyography-informed neuromusculoskeletal model. Hip joint contact forces, muscle forces, and co-contraction indices for flexor/extensor and adductor/abductor muscle groups were compared between groups using independent sample t-tests (P < 0.05). RESULTS: There was no between-group difference in self-selected walking speed. On average, participants with hip OA walked with 11% lower first peak (mean difference 235 [95% confidence interval (CI) 57-413] N) and 22% lower second peak (mean difference 574 [95%CI 304-844] N) HJCF compared to controls. Hip muscle forces were also significantly lower in the hip OA compared to control group at first (mean difference 224 [95%CI 66-382] N) and second (mean difference 782 [95%CI 399-1164] N) peak HJCF. Participants with hip OA exhibited higher levels of hip muscle co-contraction in both flexor/extensor and adductor/abductor muscle groups. Consistent with existing literature, hip joint angles (extension, adduction) and external moments (flexion, extension, adduction) were lower in hip OA compared to controls. CONCLUSION: Lower HJCF were detected in mild-to-moderate hip OA, primarily due to lower hip muscle force production, and despite higher levels of hip muscle co-contraction. Findings suggest that lower loading of the hip joint during walking is a feature of mild-to-moderate hip OA, which could have implications for the pathogenesis of hip OA and/or disease progression.

Carbon-based nanomaterials as stimulators of production of pharmaceutically active alkaloids in cell culture of Catharanthus roseus.

Carbon-based nanomaterials (CBNs) were previously described as regulators of plant cell division. Here, we demonstrated the ability of multi-walled carbon nanotubes (MWCNT) and graphene to enhance biomass production in callus culture of the medicinal plant Catharanthus roseus cultivated in dark conditions. Furthermore, both tested CBNs were able to stimulate biosynthesis of total produced alkaloids in CBN-exposed callus culture of Catharanthus. In one case, total alkaloids in CBN-exposed Catharanthus were double that of unexposed Catharanthus. Analysis of metabolites by HPLC revealed that production of the pharmaceutically active alkaloids vinblastine and vincristine was dramatically enhanced in callus exposed to MWCNT or graphene in both dark and light conditions of callus cultivation. In vitro assays (MTT, flow cytometry) demonstrated that total alkaloid extracts derived from Catharanthus callus treated with CBNs significantly reduced cell proliferation of breast cancer (MCF-7) and lung cancer (A549) cell lines compared to the application of extracts derived from untreated Catharanthus callus.

Hip joint moments during walking in people with hip osteoarthritis: a systematic review and meta-analysis.

OBJECTIVE: This systematic review and meta-analysis investigated surrogate measures of hip joint loading during walking in people with hip osteoarthritis (OA). METHODS: Five databases were searched up to January 14th, 2018. Studies that measured hip joint moments in the frontal or sagittal plane during walking in people with hip OA and used either a healthy control group or the unaffected leg to compare hip joint moments were included. Standardised mean differences (SMD) in sagittal and frontal plane moments were pooled as appropriate, using a random effect approach. Methodological quality was assessed using the Downs and Black checklist. RESULTS: Thirteen studies with 1,141 participants were eligible and suitable for meta-analyses. Overall, people with hip OA had lower sagittal (SMD -0.55 (95% confidence interval (CI) -1.00 to -0.10) and frontal plane moments (SMD -0.63 (95% CI -0.92, -0.34) compared to controls. However, substantial heterogeneity was observed (I2 ≤ 89%). Results by disease stage suggest that people with end-stage hip OA have lower sagittal (SMD -0.96; -1.30, -0.61; I2 = 69%) and frontal (SMD -1.17; 95% CI -1.71, -0.64; I2 = 85%) plane moments compared to controls. People with less severe hip OA than end-stage disease have comparable sagittal (SMD 0.37; 95% CI -0.17, 0.90; I2 = 69%) and frontal (SMD -0.24; 95% CI -0.76, 0.27; I2 = 51%) plane moments compared to controls. CONCLUSION: Hip joint loading may be dependent on disease stage. People with end-stage hip OA under-loaded compared to controls, while those who were not awaiting hip joint replacement had comparable hip joint loads to controls.

A systematic review and evidence synthesis of qualitative studies to identify primary care clinicians' barriers and enablers to the management of osteoarthritis.

OBJECTIVE: Primary care management of osteoarthritis (OA) is variable and often inconsistent with clinical practice guidelines (CPGs). This study aimed to identify and synthesize available qualitative evidence on primary care clinicians' views on providing recommended management of OA. DESIGN: Eligibility criteria included full reports published in peer-reviewed journals, with data collected directly from primary care clinicians using qualitative methods for collection and analysis. Five electronic databases (MEDLINE, Cochrane Central Register, EMBASE, CINAHL and PsychInfo) were searched to August 2016. Two independent reviewers identified eligible reports, conducted critical appraisal (based on Critical Appraisal Skills Programme (CASP) criteria), and extracted data. Three reviewers independently, then collaboratively, synthesized and interpreted data through an inductive and iterative process to derive new themes. The Confidence in Evidence from Reviews of Qualitative research (CERQual) approach was used to determine a confidence profile for each finding. RESULTS: Eight studies involving approximately 83 general practitioners (GPs), 24 practice nurses, 12 pharmacists and 10 physical therapists, from Australia, France, United Kingdom, Germany and Mexico were included. Four barriers were identified as themes 1) OA is not that serious, 2) Clinicians are, or perceive they are, under-prepared, 3) Personal beliefs at odds with providing recommended practice, and 4) Dissonant patient expectations. No themes were enablers. Confidence ratings were moderate or low. CONCLUSIONS: Synthesising available data revealed barriers that collectively point towards a need to address clinician knowledge gaps, and enhance clinician communication and behaviour change skills to facilitate patient adherence, enable effective conversations and manage dissonant patient expectations. REGISTRATION: PROSPERO (http://www.crd.york.ac.uk/PROSPERO) [4/11/2015, CRD42015027543].

Childhood cardiometabolic risk factors associated with the perinatal environment of the maternal-paternal-child triad.

INTRODUCTION: Clustering of cardiometabolic risk factors in childhood significantly increases the risk of atherosclerotic cardiovascular disease later in life. Identification of modifiable parental factors that contribute to offspring cardiometabolic health is critical for the prevention of disease. The objective was to identify factors associated with child cardiometabolic risk factors at age 5 years. METHODS: Triads from a longitudinal cohort were recalled at 5 years (n = 68). Dietary intake, anthropometrics, physical activity and serum-based risk factors were collected. Best subset selection, linear and logistic regressions were used to identify triad variables associated with increased risk of cardiometabolic risk factor clustering at age 5 years. RESULTS: In this cohort, best subset modelling revealed that increased paternal fat mass, serum low-density lipoproteins and triglycerides, maternal dietary added sugar and being female were associated with increased odds of offspring having two or more cardiometabolic risk factors at age 5 years. CONCLUSIONS: Dietary and exercise interventions prior to conception targeting paternal adiposity and dyslipidaemia as well as maternal dietary habits could decrease children's cardiometabolic risk in later life.

Machine learning methods to support personalized neuromusculoskeletal modelling.

Many biomedical, orthopaedic, and industrial applications are emerging that will benefit from personalized neuromusculoskeletal models. Applications include refined diagnostics, prediction of treatment trajectories for neuromusculoskeletal diseases, in silico design, development, and testing of medical implants, and human-machine interfaces to support assistive technologies. This review proposes how physics-based simulation, combined with machine learning approaches from big data, can be used to develop high-fidelity personalized representations of the human neuromusculoskeletal system. The core neuromusculoskeletal model features requiring personalization are identified, and big data/machine learning approaches for implementation are presented together with recommendations for further research.

A nonadrenergic vagal inhibitory pathway to feline airways.

In cats anesthetized with chloralose-pentobarbital and artificially ventilated, electrical stimulation of the caudal end of the cut cervical vagus nerve has a biphasic effect on the bronchoconstriction induced by an intravenous infusion of serotonin. The response consists of a brief augmentation of bronchoconstriction followed by relatively prolonged bronchodilation. After muscarinic receptor blockade with atropine, vagal stimulation causes only bronchodilation. Vagally mediated bronchodilation is not affected by beta adrenergic blockade with propranolol, alpha adrenergic blockade with phenoxybenzamine, or adrenergic neuronal blockade with guanethidine, but is abolished by autonomic ganglionic blockade with hexamethonium. These findings support the conclusion that a nonadrenergic inhibitory nervous system is present in the pulmonary airways of the cat and that the system is supplied by preganglionic fibers in the cervical vagus nerves.

Alpha-naphthoflavone: an inhibitor of hydrocarbon cytotoxicity and microsomal hydroxylase.

Alpha-naphthoflavone inhibits the metabolism of 3,4-benzopyrene and 7,12-dimethylbenz(a)anthracene in hamster enlbryo cell cultures and protects the cells against the inhibition of cell multiplication by these carcinogens. Alphla-nalphthoflavone also inhibits the aryl hydrocarbon hydroxylase activity in homogenates of induced hamster embryo cells and in liver microsomes from rats previously treated with polycyclic aromatic hydrocarbons, but not in microsomes from control rats.

Induction of differentiation in human promyelocytic leukemia cells by tumor promoters.

Phorbol diester tumor promoters and the promoter mezerein convert human promyelocytic leukemia cells in culture into adherent, nonproliferating cells with many of the characteristics of macrophages. Other types of promoters such as anthralin, phenobarbital, and saccharin do not have this effect. Various compounds that can inhibit some of the biological and biochemical effects of tumor promoters do not interfere with the induction of cell adherence and differentiation by the effective promoters.

Dimethylbenzanthracene tumorigenesis and aryl hydrocarbon hydroxylase in mouse skin: inhibition by 7,8-benzoflavone.

Mouse skin contains aryl hydrocarbon hydroxylase which is highly inducible. The enzyme system is inhibited when 7,8-benzoflavone is added to homogenates of skin epidermis. 7,8-Benzoflavone also inhibits mouse skin tumorigenesis caused by repeated treatment with 9,10-dimethylbenzanthracene or by a single treatment with this chemical followed by weekly treatment with croton oil. These findings suggest that this enzyme system may be responsible for the activation of 9,10-dimethylbenzanthracene to its carcinogenic form.

Unrecognised cognitive impairment in hospice patients: a pilot study.

The presence of cognitive impairment in patients who are receiving hospice care can affect numerous practical, ethical and legal aspects of their healthcare. A number of factors can contribute to cognitive impairment in these patients. Prevalence rates of cognitive impairment vary widely, but it remains under-recognised and under-treated. The aims of this pilot study were to evaluate the presence and nature of cognitive deficits in patients receiving inpatient hospice care who did not have a known current or past diagnosis of a cognitive disorder or any obvious cognitive impairments. A convenience sample of 30 patients receiving inpatient hospice care underwent bedside cognitive testing. A comprehensive battery of tests was used, including the Mini-Mental State Examination (MMSE) and standardised neuropsychological tests of pre-morbid intellectual functioning, immediate and delayed recall, digit span forward and backward, verbal reasoning and letter and category fluency. On average, subjects were impaired on the MMSE and on tests of learning, verbal reasoning and letter and category fluency. Furthermore, 12 of the 30 subjects met DSM-IV cognitive impairment criteria for dementia based on impaired performance in memory and at least one other cognitive domain on testing. The results of this pilot study suggest that a sizable proportion of patients receiving inpatient hospice care have undetected but clinically significant cognitive impairments. Assessing for and helping patients, families and caregivers deal with cognitive impairment might benefit patients' quality of life, relationships and overall care at the end of life. Future research in this population is needed to evaluate the causes and time course of cognitive impairment over time, as well as any relationship between cognitive impairment and decision-making capacity.

The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants.

Long-term success in xenotransplantation is currently hampered by acute vascular rejection. The inciting cause of acute vascular rejection is not yet known; however, a variety of observations suggest that the humoral immune response of the recipient against the donor may be involved in the pathogenesis of this process. Using a pig-to-baboon heterotopic cardiac transplant model, we examined the role of antibodies in the development of acute vascular rejection. After transplantation into baboons, hearts from transgenic pigs expressing human decay-accelerating factor and CD59 underwent acute vascular rejection leading to graft failure within 5 d; the histology was characterized by endothelial injury and fibrin thrombi. Hearts from the transgenic pigs transplanted into baboons whose circulating antibodies were depleted using antiimmunoglobulin columns (Therasorb, Unterschleisshein, Germany) did not undergo acute vascular rejection in five of six cases. Biopsies from the xenotransplants in Ig-depleted baboons revealed little or no IgM or IgG, and no histologic evidence of acute vascular rejection in the five cases. Complement activity in the baboons was within the normal range during the period of xenograft survival. In one case, acute vascular rejection of a xenotransplant occurred in a baboon in which the level of antidonor antibody rose after Ig depletion was discontinued. This study provides evidence that antibodies play a significant role in the pathogenesis of acute vascular rejection, and suggests that acute vascular rejection might be prevented or treated by therapies aimed at the humoral immune response to porcine antigens.

Concomitant K- and N-ras gene point mutations in clonal murine lymphoma.

We have surveyed a panel of induced murine lymphomas for c-ras gene mutations. The K-ras gene seems to be preferentially activated in our system, and there are at least two examples of concomitant K- and N-ras gene mutations in the same tumor. This indicates that in some cases additional ras mutations may contribute to tumorigenesis and is evidence for a role of ras activation in tumor progression.

Induction of cellular deoxyribonucleic acid synthesis in butyrate-treated cells by simian virus 40 deoxyribonucleic acid.

Sodium butyrate (3 mM) inhibited the entry into the S phase of quiescent 3T3 cells stimulated by serum, but had no effect on the accumulation of cellular ribonucleic acid. Simian virus 40 infection or manual microinjection of cloned fragments from the simian virus 40 A gene caused quiescent 3T3 cells to enter the S phase even in the presence of butyrate. NGI cells, a line of 3T3 cells transformed by simian virus 40, grew vigorously in 3 mM butyrate. Homokaryons were formed between G1 and S-phase 3T3 cells, Butyrate inhibited the induction of deoxyribonucleic acid synthesis that usually occurs in B1 nuclei when G1 cells are fused with S-phase cells. However, when G1 3T3 cells were fused with exponentially growing NGI cells, the 3T3 nuclei were induced to enter deoxyribonucleic acid synthesis. In tsAF8 cells, a ribonucleic acid polymerase II mutant that stops in the G1 phase of the cell cycle, no temporal sequence was demonstrated between the butyrate block and the temperature-sensitive block. These results confirm previous reports that certain virally coded proteins can induce cell deoxyribonucleic acid synthesis in the absence of cellular functions that are required by serum-stimulated cells. Our interpretation of these data is that butyrate inhibited cell growth by inhibiting the expression of genes required for the G0 leads to G1 leads to S transition and that the product of the simian virus 40 A gene overrode this inhibition by providing all of the necessary functions for the entry into the S phase.

The c-myc-regulated gene mrl encodes plasminogen activator inhibitor 1.

The DNA sequence of the c-myc-regulated gene mrl (G. C. Prendergast and M. D. Cole, Mol. Cell. Biol. 9:124-134, 1989) reveals that it encodes plasminogen activator inhibitor 1 (PAI-1), a regulator of extracellular proteolysis. Comparison of the human and mouse PAI-1 promoters and cDNA 3' noncoding regions revealed several highly conserved sequence domains, potential targets for c-myc and other factors influencing PAI-1 expression. We discuss possible roles for PAI-1 in normal and neoplastic cell growth control.

RREB-1, a novel zinc finger protein, is involved in the differentiation response to Ras in human medullary thyroid carcinomas.

An activated ras oncogene induces a program of differentiation in the human medullary thyroid cancer cell line TT. This differentiation process is accompanied by a marked increase in the transcription of the human calcitonin (CT) gene. We have localized a unique Ras-responsive transcriptional element (RRE) in the CT gene promoter. DNase I protection indicates two domains of protein-DNA interaction, and each domain separately can confer Ras-mediated transcriptional inducibility. This bipartite RRE was also found to be Raf responsive. By affinity screening, we have cloned a cDNA coding for a zinc finger transcription factor (RREB-1) that binds to the distal RRE. The consensus binding site for this factor is CCCCAAACCACCCC. RREB-1 is expressed ubiquitously in human tissues outside the adult brain. Overexpression of RREB-1 protein in TT cells confers the ability to mediate increased transactivation of the CT gene promoter-reporter construct during Ras- or Raf-induced differentiation. These data suggest that RREB-1 may play a role in Ras and Raf signal transduction in medullary thyroid cancer and other cells.

Multiwalled Carbon Nanotubes Dramatically Affect the Fruit Metabolome of Exposed Tomato Plants.

Here, we reported that multiwalled carbon nanotubes (MWCNT) added to hydroponics system can enhance fruit production of exposed tomato plants. We quantified the exact amount of MWCNT accumulated inside of fruits collected by MWCNT-exposed plants using an advanced microwave induced heating technique (MIH). We found that absorption of MWCNT by tomato fruits significantly affected total fruit metabolome as was confirmed by LC-MS. Our data highlight the importance of comprehensive toxicological risk assessment of plants contaminated with carbon nanomaterials.

Comparative studies on the interaction of benzo[a]pyrene with cells derived from poikilothermic and homeothermic vertebrates. I. Metabolism of benzo[a]pyrene.

The metabolism of benzo[a]pyrene (BP) to water-soluble derivatives was measured in cell cultures derived from poikilothermic and homeothermic vertebrates. Tritiated BP was added to the cultures and, after 24 hours of incubation, the medium was extracted with chloroform:methanol:water. The amount of BP metabolized per cell (relative efficiency of metabolism) was calculated from the 3H-BP equivalents in the aqueous phase of the extraction mixture. Many poikilothermic vertebrate cell cultures, including those derived from fish, toad, lizard, and turtle, were able to metabolize BP. In some instances, metabolism was as efficient as in rodent cell cultures. Cell multiplication was inhibited by BP, only in those cultures in which the metabolism of BP was highly efficient. Conversely, cytotoxicity was not observed in cell cultures with little or no ability to metabolize the carcinogen.

Validation of lymphatic mapping and sentinel node biopsy in patients with symptomatic breast cancer.

BACKGROUND: Lymphatic mapping and sentinel node biopsy in breast cancer aims to allow lymph node negative women to avoid axillary clearance by providing a minimally invasive means of staging the axilla. However, before its implementation into routine clinical practice, initiating departments must verify their expertise in each of the surgical, radiological and pathological components necessary for its successful performance. Here, we present our validation experience. METHODS: Thirty patients with breast cancer of any stage (but without clinical axillary lymphadenopathy) undergoing definitive resection of their primary tumour underwent lymphatic mapping (using blue dye alone or in combination with radioisotope) and sentinel node biopsy concurrent with standard level II axillary clearance over a ten month period. RESULTS: All patients had sentinel nodes identified intraoperatively. The sentinel node in 29 patients correctly predicted the status of axillary involvement. One patient had non-sentinel nodal disease without metastases being identified in their sentinel node. Such a single false negative out of thirty patients is considered acceptable by current guidelines. CONCLUSION: Validation of expertise in sentinel node identification and analysis is feasible over a relatively short period of time in a regional symptomatic breast unit. We now feel confident in offering this procedure to selected patients with breast cancer in our catchment area in place of routine axillary clearance.

SV40-transfected human melanocyte sensitivity to growth inhibition by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate.

Normal human melanocytes, which require the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) for growth in culture, were transfected with a SV40 T-antigen-containing plasmid by using the technique of electroporation, and were scored for colonies of morphologically altered cells. The frequency of transformed colonies was higher when selection was done in the absence rather than the presence of TPA in the medium. Three cell lines derived from transformed colonies were characterized. All show an enhanced growth rate compared to parental cells, anchorage independence, loss of dependence on medium supplements for growth, chromosomal abnormalities, an extended life span, and growth inhibition by TPA. They express nerve growth factor receptor and Mr 97,000 protein, melanotransferrin, two antigens usually associated with melanocytic cells, but the transformed cells are not pigmented. The three cell lines underwent crisis at about passage 10 posttransfection; one cell line recovered and appears to have unlimited growth potential. None of the cell lines is tumorigenic. They should be interesting models for studying multistage carcinogenesis in human cells and transcriptional activation by TPA.