A multimodality intervention to improve musculoskeletal health, function, metabolism, and well-being in spinal cord injury: study protocol for the FIT-SCI randomized controlled trial.

BACKGROUND: A spinal cord injury (SCI) is a devastating, life-changing event that has profoundly deleterious effects on an individual's health and well-being. Dysregulation of neuromuscular, cardiometabolic, and endocrine organ systems following an SCI contribute to excess morbidity, mortality and a poor quality of life. As no effective treatments currently exist for SCI, the development of novel strategies to improve the functional and health status of individuals living with SCI are much needed. To address this knowledge gap, the current study will determine whether a Home-Based Multimodality Functional Recovery and Metabolic Health Enhancement Program that consists of functional electrical stimulation of the lower extremity during leg cycling (FES-LC) plus arm ergometry (AE) administered using behavioral motivational strategies, and testosterone therapy, is more efficacious than FES-LC plus AE and placebo in improving aerobic capacity, musculoskeletal health, function, metabolism, and wellbeing in SCI. METHODS: This single-site, randomized, placebo-controlled, parallel group trial will enroll 88 community-dwelling men and women, 19 to 70 years of age, with cervical and thoracic level of SCI, ASIA Impairment Scale grade: A, B, C, or D, 6 months or later after an SCI. Participants randomized to the multimodality intervention will undergo 16 weeks of home-based FES-LC and AE training plus testosterone undecanoate. Testosterone undecanoate injections will be administered by study staff in clinic or by a visiting nurse in the participant's home. The control group will receive 16 weeks of home-based FES-LC and AE exercise plus placebo injections. The primary outcome of this trial is peak aerobic capacity, measured during an incremental exercise testing protocol. Secondary outcomes include whole body and regional lean and adipose tissue mass; muscle strength and power; insulin sensitivity, lipids, and inflammatory markers; SCI functional index and wellbeing (mood, anxiety, pain, life satisfaction and depressive symptoms); and safety. DISCUSSION: We anticipate that a multimodality intervention that simultaneously addresses multiple physiological impairments in SCI will result in increased aerobic capacity and greater improvements in other musculoskeletal, metabolic, functional and patient-reported outcomes compared to the control intervention. The findings of this study will have important implications for improving the care of people living with an SCI. TRIAL REGISTRATION: ClinicalTrials.gov :  ( NCT03576001 ). Prospectively registered: July 3, 2018.

Treatment of male breast cancer: meta-analysis of real-world evidence.

BACKGROUND: Breast cancer is rare in men and managed by extrapolating from breast cancer in women. The clinicopathological features of male breast cancer, however, differ from those of female breast cancer. Because clinical trials are rare, the synthesis of real-world data is one method of integrating sufficient evidence on the optimal treatment for this patient population. METHODS: PubMed, Embase, and Cochrane Library databases were searched. Clinical studies were included if they evaluated the treatments of interest in male breast cancer; these evaluations included breast-conserving surgery (BCS) versus mastectomy, postmastectomy radiation therapy versus no radiation, the accuracy of sentinel lymph node biopsy (SLNB), and a comparison of various endocrine therapies. RESULTS: Forty studies were retrieved. The pooled estimate of overall survival (OS) revealed no difference between BCS and mastectomy groups. Postmastectomy radiation to the chest wall significantly increased OS relative to no postmastectomy radiation (hazard ratio (HR) 0.67, 95 per cent confidence interval 0.54 to 0.84). The pooled estimates of identification and false-negative rates of SLNB were 97.4 and 7.4 per cent respectively. Tamoxifen treatment was associated with significantly increased OS compared with no tamoxifen intake (HR 0.62, 0.41 to 0.95). CONCLUSION: Identification and false-negative rates for SLNB were comparable to those in female breast cancer. Breast-conserving surgery can be effective and safe; postmastectomy radiation to the chest wall and 5-year tamoxifen treatment improves survival.

A microRNA-mediated regulatory loop modulates NOTCH and MYC oncogenic signals in B- and T-cell malignancies.

Growing evidence suggests that microRNAs (miRNAs) facilitate the cross-talk between transcriptional modules and signal transduction pathways. MYC and NOTCH1 contribute to the pathogenesis of lymphoid malignancies. NOTCH induces MYC, connecting two signaling programs that enhance oncogenicity. Here we show that this relationship is bidirectional and that MYC, via a miRNA intermediary, modulates NOTCH. MicroRNA-30a (miR-30a), a member of a family of miRNAs that are transcriptionally suppressed by MYC, directly binds to and inhibits NOTCH1 and NOTCH2 expression. Using a murine model and genetically modified human cell lines, we confirmed that miR-30a influences NOTCH expression in a MYC-dependent fashion. In turn, through genetic modulation, we demonstrated that intracellular NOTCH1 and NOTCH2, by inducing MYC, suppressed miR-30a. Conversely, pharmacological inhibition of NOTCH decreased MYC expression and ultimately de-repressed miR-30a. Examination of genetic models of gain and loss of miR-30a in diffuse large B-cell lymphoma (DLBCL) and T-acute lymphoblastic leukemia (T-ALL) cells suggested a tumor-suppressive role for this miRNA. Finally, the activity of the miR-30a-NOTCH-MYC loop was validated in primary DLBCL and T-ALL samples. These data define the presence of a miRNA-mediated regulatory circuitry that may modulate the oncogenic signals originating from NOTCH and MYC.

Metabolic imaging of mild traumatic brain injury.

Traumatic brain injury results in a metabolic cascade of changes that occur at the molecular level, invisible to conventional imaging methods such as computed tomography or magnetic resonance imaging. Non-invasive metabolic imaging tools such as single photon emission computed tomography (SPECT), positron emission tomography (PET), and magnetic resonance spectroscopy (MRS) are the ideal methods for providing insight to these changes by measuring regional cerebral blood flow, glucose metabolism, and brain metabolite concentrations, respectively, after mild traumatic brain injury (mTBI). The purpose of this review is to provide an overview of the different methodologies and provide an up-to-date summary of recent findings with SPECT, PET, and MRS technologies, specifically after mTBI, as defined by standardized criteria. Given that the different physiological and pathological responses are heterogeneous, efforts will be made to separate studies at different time points after injury (acute, subacute, and chronic stages) as well as to the different types of mTBI such sports-related head injury where repetitive head injuries are much more common and may present a unique signature.

A review of magnetic resonance imaging and diffusion tensor imaging findings in mild traumatic brain injury.

Mild traumatic brain injury (mTBI), also referred to as concussion, remains a controversial diagnosis because the brain often appears quite normal on conventional computed tomography (CT) and magnetic resonance imaging (MRI) scans. Such conventional tools, however, do not adequately depict brain injury in mTBI because they are not sensitive to detecting diffuse axonal injuries (DAI), also described as traumatic axonal injuries (TAI), the major brain injuries in mTBI. Furthermore, for the 15 to 30 % of those diagnosed with mTBI on the basis of cognitive and clinical symptoms, i.e., the "miserable minority," the cognitive and physical symptoms do not resolve following the first 3 months post-injury. Instead, they persist, and in some cases lead to long-term disability. The explanation given for these chronic symptoms, i.e., postconcussive syndrome, particularly in cases where there is no discernible radiological evidence for brain injury, has led some to posit a psychogenic origin. Such attributions are made all the easier since both posttraumatic stress disorder (PTSD) and depression are frequently co-morbid with mTBI. The challenge is thus to use neuroimaging tools that are sensitive to DAI/TAI, such as diffusion tensor imaging (DTI), in order to detect brain injuries in mTBI. Of note here, recent advances in neuroimaging techniques, such as DTI, make it possible to characterize better extant brain abnormalities in mTBI. These advances may lead to the development of biomarkers of injury, as well as to staging of reorganization and reversal of white matter changes following injury, and to the ability to track and to characterize changes in brain injury over time. Such tools will likely be used in future research to evaluate treatment efficacy, given their enhanced sensitivity to alterations in the brain. In this article we review the incidence of mTBI and the importance of characterizing this patient population using objective radiological measures. Evidence is presented for detecting brain abnormalities in mTBI based on studies that use advanced neuroimaging techniques. Taken together, these findings suggest that more sensitive neuroimaging tools improve the detection of brain abnormalities (i.e., diagnosis) in mTBI. These tools will likely also provide important information relevant to outcome (prognosis), as well as play an important role in longitudinal studies that are needed to understand the dynamic nature of brain injury in mTBI. Additionally, summary tables of MRI and DTI findings are included. We believe that the enhanced sensitivity of newer and more advanced neuroimaging techniques for identifying areas of brain damage in mTBI will be important for documenting the biological basis of postconcussive symptoms, which are likely associated with subtle brain alterations, alterations that have heretofore gone undetected due to the lack of sensitivity of earlier neuroimaging techniques. Nonetheless, it is noteworthy to point out that detecting brain abnormalities in mTBI does not mean that other disorders of a more psychogenic origin are not co-morbid with mTBI and equally important to treat. They arguably are. The controversy of psychogenic versus physiogenic, however, is not productive because the psychogenic view does not carefully consider the limitations of conventional neuroimaging techniques in detecting subtle brain injuries in mTBI, and the physiogenic view does not carefully consider the fact that PTSD and depression, and other co-morbid conditions, may be present in those suffering from mTBI. Finally, we end with a discussion of future directions in research that will lead to the improved care of patients diagnosed with mTBI.

Ultra-fast three dimensional imaging of hyperpolarized 13C in vivo.

OBJECTIVE: PASADENA, a chemical method of enhancing nuclear spin polarization has demonstrated 13C polarizations of order unity for the nascent products of molecular addition by parahydrogen. The extreme brevity of signal enhancement obtained by hyperpolarization requires improved 13C MR in vivo imaging techniques for their optimum utility. MATERIALS AND METHODS: 13C imaging sequences, including 13C 3D FIESTA, were compiled for a GE LX 1.5 T clinical MR scanner. Two water soluble 13C imaging agents were hyperpolarized utilizing parahydrogen and an automated polarizer. 13C polarization was quantified in flow phantoms and in rats with jugular vein catheters. RESULTS: Fast 3D FIESTA 13C MR imaging technique acquired sequential 3D images (3.66 s/acquisition) with superior SNR. Hyperpolarized 13C solutions and vascular phantoms achieved a maximum signal of 26,624+/-593. In vivo 13C MR images of the cardiopulmonary circulation showed maximum 13C signal of 2,402+/-158. 13C images acquired within 3.66 s showed signal enhancement over 10,000 compared to equilibrium polarization. CONCLUSION: 3D-FIESTA was effective for sub-second in vivo imaging of hyperpolarized 13C reagents produced in a custom-built parahydrogen polarizer. Application to 13C hyperpolarized by parahydrogen is demonstrated in vitro and in vivo.

Chemo- and radio-protective effects of polysaccharide of Spirulina platensis on hemopoietic system of mice and dogs.

AIM: To observe polysaccharide of Spirulina platensis (PSp) on the hematopoietic system of mouse and dogs which were damaged by injection of cyclophosphamide (CTX) and 60Co-gamma irradiation. METHODS: CTX and 60Co gamma ray were used to induce bone marrow damage, and the experimental animals were ig with different dose of PSp in vivo, after 12-d and 21-d administration, the whole blood cells and nucleated cells in bone marrow were measured, and the DNA in bone marrow were inspected by UV-spectrophotometer. RESULTS: CTX and 60Co-gamma irradiation induced hemopoietic system damage in mice and dogs, respectively. PSp 30, 60 mg/kg increased the level of the white cells in blood and nucleated cells and DNA in bone marrow in mice but had no effects on red cells and hemoglobins. PSp 12 mg/kg increased the level of red cells, white cells, and hemoglobins in blood and nucleated cells in bone marrow in dogs (P < 0.01), and the effects of PSp 60 mg/kg were better than that of berbamine hydrochloride 60 mg/kg. CONCLUSION: PSp has chemo-protective and radio-protective capability, and may be a potential adjunct to cancer therapy.

Kinetic and physiological effects of alterations in homologous isocitrate-binding sites of yeast NAD(+)-specific isocitrate dehydrogenase.

Yeast NAD(+)-specific isocitrate dehydrogenase is an allosterically regulated octameric enzyme composed of four each of two homologous but nonidentical subunits designated IDH1 and IDH2. Models based on the crystallographic structure of Escherichia coli isocitrate dehydrogenase suggest that both yeast subunits contain isocitrate-binding sites. Identities in nine residue positions are predicted for the IDH2 site whereas four of the nine positions differ between the IDH1 and bacterial enzyme sites. Thus, we speculate that the IDH2 site is catalytic and that the IDH1 site may bind but not catalytically alter isocitrate. This was examined by kinetic analyses of enzymes with independent and concerted replacement of residues in each yeast IDH subunit site with the residues that differ in the other subunit site. Mutant enzymes were expressed in a yeast strain containing disrupted IDH1 and IDH2 loci and affinity-purified for kinetic analyses. The primary effects of various residue replacements in IDH2 were reductions of 30->300-fold in V(max) values, consistent with the catalytic function of this subunit. In contrast, replacement of all four residues in IDH1 produced a 17-fold reduction in V(max) under the same assay conditions, suggesting that the IDH1 site is not the primary catalytic site. However, single or multiple residue replacements in IDH1 uniformly increased half-saturation concentrations for isocitrate, implying that isocitrate can be bound at this site. Both subunits appear to contribute to cooperativity with respect to isocitrate, but AMP activation is lost only with residue replacements in IDH1. Overall, results are consistent with isocitrate binding by IDH2 for catalysis and with isocitrate binding by IDH1 being a prerequisite for allosteric activation by AMP. The effects of residue substitutions on enzyme function in vivo were assessed by analysis of various growth phenotypes. Results indicate a positive correlation between the level of IDH catalytic activity and the ability of cells to grow with acetate or glycerol as carbon sources. In addition, lower levels of activity are associated with increased production of respiratory-deficient (petite) segregants.

Short-echo time proton MR spectroscopy in the presence of gadolinium.

PURPOSE: The purpose of this work was to quantify the impact of contrast agents on short-TE single-voxel 1H MR spectroscopy (MRS) diagnosis of recurrent brain tumors. METHOD: Short-TE 1H MRS was performed in 49 patients with biopsy-proven brain tumors and 14 control subjects. Eight patients (nine paired exams) were examined before and after administration of Gd-DTPA (interval approximately 5-7 min). RESULTS: Tumor spectra showed increased choline/creatine ratio (Cho/Cr; p < 0.009) and Cho concentrations (p < 0.02). Receiver operator characteristic for Cho/Cr = 0.93 differentiated 100% of tumors from control in the absence or presence of contrast agent. Repeated 1H MRS varied <3%. Cho T2 was significantly longer than Cr T2 (p < 0.02). CONCLUSION: Proton MRS with TE of 30 ms may safely be used in combined contrast-enhanced MRI/MRS protocols. Further study is required with long-TE MRS because of the prolonged T2 of Cho.

Vandellia cordifolia regulated cell proliferation and cytokines production in human mononuclear cells.

Vandellia cordifolia (V. cordifolia) used for treatment inflammation in traditional Chinese medicine was selected for immunopharmacological activity test. The effects of V. cordifolia extracted fractions on human mononuclear cells (HMNC) proliferation were determined by tritiated thymidine uptake. The results indicated that VC-ME fraction suppressed HMNC proliferation activated with phytohemagglutinin (PHA) and stimulated cell cycle progression was arrested at the G0/G1 stage. The inhibitory mechanisms may involve the blocking of interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production, since VC-ME suppressed IL-2 and IFN-gamma production of HMNC in a dose-dependent manner. Therefore, it is suggested that immunomodulatory agents are contained in V. cordifolia.

Optimizing vascular gene transfer of plasminogen activator inhibitor 1.

The vessel wall fibrinolytic system plays an important role in maintaining the arterial phenotype and in regulating the arterial response to injury. Plasminogen activator inhibitor type 1 (PAI-1) regulates tissue fibrinolysis and is expressed in arterial tissue; however, its biological role remains uncertain. To help elucidate the role of PAI-1 in the artery wall, and to begin to clarify whether manipulation of vascular PAI-1 expression might be a target for gene therapy, we used adenoviral vectors to increase expression of rat PAI-1 in rat carotid arteries. Infusion of an adenoviral vector in which PAI-1 expression was driven by a promoter derived from the Rous sarcoma virus (RSV) did not increase PAI-1 expression above endogenous levels. To improve PAI-1 expression, we modified the vector by (1) truncating the 3' untranslated region of PAI-1 to increase the mRNA half-life, (2) substituting the SRalpha or the cytomegalovirus (CMV) promoter for the RSV promoter, (3) including an intron in the expression cassette, and (4) altering the direction of transcription of the transgene cassette. The optimal expression vector, revealed by in vitro studies, contained the CMV promoter, an intron, and a truncated PAI-1 mRNA. This vector increased PAI-1 expression by 30-fold over control levels in vitro and by 1.6 to 2-fold over endogenous levels in vivo. This vector will be useful for elucidating the role of PAI-1 in arterial pathobiology. Because genes that are important in maintaining the vascular phenotype are likely to be expressed in the vasculature, the technical issues of how to increase in vivo expression of endogenous genes are highly relevant to the development of genetic therapies for vascular disease.

[Pharmacognostic studies on Sanguis lignum Dracaenae cochinchinensis].

The resin of Dracaena cochinchinensis has been used as the substitute for Chinese drug Xuejie (Sanguis Draconis) for 20 years in China. The pharmacological, toxicological and clinical studies have shown that the former is similar to the latter in effects, and can be used as a substitute for the latter. This paper deals with the resources, morphological and histological characters, chemical and physical analysis of Sanguis Lignum Dracaenae Cochinchinensis.

[Comparative study on the anti-free-radical damage by vital energy-reinforcing method and blood-tonifying method].

A comparative study has been conducted on the anti-free-radical damage by the vital energy-reinforcing and blood-tonifying methods. The results shows that Sijunzi decoction and Siwu decoction can increase the vitality of SOD, accelerate the elimination of free-radical and inhibit the growth of LPO and MAO-B. This means that both these two methods help to delay senility and the vital energy-reinforcing one is more effective.

[A comparative identification of four Gynostemma spp. herbs and their various species from Guangxi].

In this paper, the authors have described the morphological and histological character of the four herbs of Gynostemma spp. and their confused species from Guangxi viz Gynostemma pentaphyllum, G. guangxiense, G. laxum and G. longipes, and their confused species of four Hemsleya daxienensis, H. chinensis, Cayratia japonica and C. japonica var. pubifolia. The description is illustrated with line-drawings for comparative identification.