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Background/Objective The deleterious effects of chronic spinal cord injury (SCI) on the skeleton in rats, especially the lower extremities, has been proved previously. However, the long-term skeletal changes after SCI in non-human primates (NHP) have been scarcely studied. This study aimed to evaluate the bone loss in limbs and vertebrae and the bone metabolic changes in NHP after unilateral cervical spinal cord contusion injury. Methods Twelve Macaca fascicularis were randomly divided into the SCI (n=8) and the Sham (n=4) groups. The SCI models were established using hemi-contusion cervical spinal cord injury on fifth cervical vertebra (C5), and were further evaluated by histological staining and neurophysiological monitoring. Changes of bone microstructures, bone biomechanics, and bone metabolism markers were assessed by micro-CT, micro-FEA and serological kit. Results The NHP hemi-contusion cervical SCI model led to consistent unilateral limb dysfunction and potential plasticity in the face of loss of spinal cord. Furthermore, the cancellous bone mass of ipsilateral humerus and radius decreased significantly compared to the contralateral side. The bone volume fraction of humerus and radius were 17.2% and 20.1% on the ipsilateral while 29.0% and 30.1% on the contralateral respectively. Similarly, the thickness of the cortical bone in the ipsilateral forelimbs was significantly decreased, as well as the bone strength of the ipsilateral forelimbs. These changes were accompanied by diminished concentration of osteocalcin and total procollagen type 1 N-terminal propeptide (t-P1NP) as well as increased level of β-C-terminal cross-linking telopeptide of type 1collagen (β-CTX) in serological testing. Conclusions The present study demonstrated that hemi-SCI induced loss of bone mass and compromised biomechanical performance in ipsilateral forelimbs, which could be indicated by both muscle atrophy and serological changes of bone metabolism, and associated with a consistent loss of large-diameter cells of sensory neurons in the dorsal root ganglia. The Translational potential of this Article Our study, for the first time, demonstrated the bone loss in limbs and vertebrae as well as the bone metabolic changes in non-human primates after unilateral spinal cord injury (SCI). This may help to elucidate the role of muscle atrophy, serological changes and loss of sensory neurons in the mechanisms of SCI-induced osteoporosis, which would be definitely better compared with rodent models.

Since December 2019, when coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan and then spread worldwide, there have been ...

Purpose The aim of this study was to explore the effects of an enteral nutrition (EN) feeding protocol in critically ill patients. Methods This was a prospective multi-center before-after study. We compared energy related and prognostic indicators between the control group (pre-implementation stage) and intervention group (post-implementation stage). The primary endpoint was the percentage of patients receiving EN within 7 days after ICU admission. Results 209 patients in the control group and 230 patients in the intervention group were enrolled. The implementation of the EN protocol increased the percentage of target energy reached from day 3 to day 7, and the difference between two groups reached statistical significance in day 6 (P = .01) and day 7 (P = .002). But it had no effects on proportion of patient receiving EN (P = .65) and start time of EN (P = .90). The protocol application might be associated with better hospital survival (89.1% vs 82.8%, P = .055) and reduce the incidence of EN related adverse (P = .004). There was no difference in ICU length of stay, duration of mechanical ventilation and ICU cost. Conclusion The implementation of the enteral feeding protocol is associated with improved energy intake and a decreased incidence of enteral nutrition related adverse events for critically ill patients, but it had no statistically beneficial effects on reducing the hospital mortality rate. Trial registration ClinicalTrials.gov , NCT02976155 . Registered November 29, 2016- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02976155 .

Background BCMA-specific chimeric antigen receptor-T cells (CAR-Ts) have exhibited remarkable efficacy in refractory or relapsed multiple myeloma (RRMM); however, primary resistance and relapse exist with single-target immunotherapy. Bispecific CARs are proposed to mitigate these limitations. Methods We constructed a humanized bispecific BM38 CAR targeting BCMA and CD38 and tested the antimyeloma activity of BM38 CAR-Ts in vitro and in vivo. Twenty-three patients with RRMM received infusions of BM38 CAR-Ts in a phase I trial. Results BM38 CAR-Ts showed stronger in vitro cytotoxicity to heterogeneous MM cells than did T cells expressing an individual BCMA or CD38 CAR. BM38 CAR-Ts also exhibited potent antimyeloma activity in xenograft mouse models. In the phase I trial, cytokine release syndrome occurred in 20 patients (87%) and was mostly grade 1–2 (65%). Neurotoxicity was not observed. Hematologic toxicities were common, including neutropenia in 96% of the patients, leukopenia in 87%, anemia in 43% and thrombocytopenia in 61%. At a median follow-up of 9.0 months (range 0.5 to 18.5), 20 patients (87%) attained a clinical response and minimal residual disease-negativity (≤ 10–4 nucleated cells), with 12 (52%) achieving a stringent complete response. Extramedullary plasmacytoma was eliminated completely in 56% and partially in 33% and of 9 patients. The median progression-free survival was 17.2 months. Two relapsed patients maintained BCMA and CD38 expression on MM cells. Notably, BM38 CAR-Ts cells were detectable in 77.8% of evaluable patients at 9 months and 62.2% at 12 months. Conclusion Bispecific BM38 CAR-Ts were feasible, safe and significantly effective in patient with RRMM. Trial registration: Chictr.org.cn ChiCTR1800018143.

Background Septic shock is characterized by an uncontrolled inflammatory response and microcirculatory dysfunction. There is currently no specific agent for treating septic shock. Anisodamine is an agent extracted from traditional Chinese medicine with potent anti-inflammatory effects. However, its clinical effectiveness remains largely unknown. Methods In a multicentre, open-label trial, we randomly assigned adults with septic shock to receive either usual care or anisodamine (0.1–0.5 mg per kilogram of body weight per hour), with the anisodamine doses adjusted by clinicians in accordance with the patients’ shock status. The primary end point was death on hospital discharge. The secondary end points were ventilator-free days at 28 days, vasopressor-free days at 28 days, serum lactate and sequential organ failure assessment (SOFA) score from days 0 to 6. The differences in the primary and secondary outcomes were compared between the treatment and usual care groups with the χ2 test, Student’s t test or rank-sum test, as appropriate. The false discovery rate was controlled for multiple testing. Results Of the 469 patients screened, 355 were assigned to receive the trial drug and were included in the analyses—181 patients received anisodamine, and 174 were in the usual care group. We found no difference between the usual care and anisodamine groups in hospital mortality (36% vs. 30%; p = 0.348), or ventilator-free days (median [Q1, Q3], 24.4 [5.9, 28] vs. 26.0 [8.5, 28]; p = 0.411). The serum lactate levels were significantly lower in the treated group than in the usual care group after day 3. Patients in the treated group were less likely to receive vasopressors than those in the usual care group (OR [95% CI] 0.84 [0.50, 0.93] for day 5 and 0.66 [0.37, 0.95] for day 6). Conclusions There is no evidence that anisodamine can reduce hospital mortality among critically ill adults with septic shock treated in the intensive care unit. Trial registration ClinicalTrials.gov (NCT02442440; Registered on 13 April 2015).

The angioarchitecture of the spinal cord and microvascular changes after acute and subacute spinal cord injury (SCI) have been reported in rodents. Microvascular changes after chronic SCI have not been explored. We characterized three-dimensional microvascular changes during the chronic phase of cervical hemicontusion SCI in rats.At 12 weeks after 1.2-mm hemicontusion injury, microvascular parameters, including vascular volume, ratio of vascular volume to tissue volume, vascular number, and vascular separation, were measured at the epicenter and each cord segment, and the percentage and volume of spinal vessels with different diameters were measured by micro computed tomography at the injury segment.The 1.2-mm hemicontusion injury applied a compressive force of 1.050 ± 0.103 N to the cord, resulting in a cavity and a significant decrease in microvasculature at the epicenter. The vascular volume, ratio of vascular volume to tissue volume, and vascular number of the C5 cord decreased by 40%, 38%, and 36% at 12 weeks after SCI, whereas vascular separation increased by 54% compared with the control group. In the chronic phase after SCI, the percentage and volume of spinal microvessels at the contusion segment decreased significantly (especially vessels with diameters40 μm).Blood supply to the cervical spinal cord is insufficient during the chronic phase of cervical hemicontusion SCI, especially in microvessels with diameters40 μm. These results may provide a basis to explore microvascular changes of SCI during the chronic phase.

A ketogenic diet (KD) is composed of low-carbohydrate, high-fat and adequate levels of protein. It has been used for decades as a method to treat pediatric refractory epilepsy. However, recently, its side effects on the bones have received increasing attention. In order to comprehensively evaluate the effect of KD on the microstructures and mechanical properties of the skeleton, 14 male Sprague-Dawley rats were equally divided into two groups and fed with a KD (ratio of fat to carbohydrate and protein, 3:1) or a standard diet for 12 weeks. Body weight, as well as blood ketone and glucose levels, were monitored during the experiment. Bone morphometric analyses via micro-computerized tomography were performed on cortical and trabecular bone at the middle L4 vertebral body, the proximal humerus and tibia. The compressive stiffness and strength of scanned skeletal areas were calculated using micro-finite element analysis. The KD led to higher ketone levels and lower glucose levels, with reduced body weight and total bone mineral density (TBMD). After 12 weeks, the diet reduced the bone volume fraction, the trabecular number of cancellous bone, cortical thickness, total cross-sectional area inside the periosteal envelope and the bone area of cortical bone in the tibia and humerus, while increasing trabecular separation. However, KD may not affect the L4 vertebral body. The serum calcium or phosphate concentrations in the blood remained unchanged. In addition, bone stiffness and strength were clearly decreased by the KD, and significantly correlated with the BMD and bone area at all scanned sites. In conclusion, KD led to significant bone loss and reduced biomechanical function in appendicular bones, with a lesser impact on axial bones.

Ketogenic diet (KD) has been used in epilepsy for decades, but previous studies found it may cause severe bone loss. Every-other-day ketogenic diet (EODKD), the combination of KD with intermittent fasting, showed better potential for seizure control recently, while its effects on bone remain unknown. This study aims to establish different ketogenic rat models and compare the influence of EODKD with KD on bone microstructure and metabolism. Thirty male Sprague-Dawley rats were divided into Control, KD and EODKD groups, fed with standard diet, continuous and intermittent ketogenic diet respectively. After 12 weeks, bone mineral density (BMD) and body fat percentage were obtained by dual energy X-ray absorptiometry. Micro-CT and three-point bending test were used to evaluate the bone microstructure and mechanical properties. Activities of serum alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) were measured, together with the osteogenic capabilities of bone marrow stromal cells (BMSCs) tested by ALP activities and alizarin red stain in different osteogenic stage. Both EODKD and KD induced higher ketone and more fat percentage, but led to lower body weight compared with Control group. They both compromised bone mass and mechanical properties. Compared with KD, EODKD demonstrated higher ketone levels, but it also inhibited osteoclastic process as well as early osteogenic differentiation. In general, EODKD accelerated ketosis, but may not deteriorate bone microstructure and strength than KD.

BACKGROUND Although percutaneous disc nucleoplasty (PDN) has been widely applied in treating lumbar disc herniation (LDH) in recent years, the efficacy of surgical levels for PDN on LDH has been reported in limited studies. This study aimed to explore and compare the efficacy of surgical levels (single level vs double level) of PDN in treating LDH. MATERIAL AND METHODS All patients diagnosed with LDH from January 2012 to December 2014 in our hospital who underwent PDN were included in this study. Patients were divided into a single-level group and double-level group based on the number of discs/surgical treatment levels. The improvement of visual analog scale (VAS) score, patient satisfaction, and reoperation occurrence were compared between the 2 groups. RESULTS Of 105 total patients, 75 patients were treated with single-level treatment and 30 patients with double-level treatment. VAS for leg pain and patient satisfaction scores in the double-level group were worse than those in the single-level group at 6 months after surgery (P

Objective To investigate the effects of ketogenic metabolism on macrophage polarization, inflammation inhibition, and function recovery after acute spinal cord injury (SCI) in rats. Methods Sixty-four adult male Sprague-Dawley rats were randomly and equally divided into sham, standard diet (SD), ketone diet (KD), and 1, 3-butanediol (BD) groups. All animals underwent C5 unilateral laminectomy, whereas the SD, KD, and BD groups underwent C5 spinal cord hemi-contusion. The impact rod with a diameter of 1.5 mm was aligned 22.5° to the left and 1.4 mm to the midline, and then triggered to deliver a set displacement of 1.5 mm at a speed of 100 mm/s. The gene expression of inflammatory factors as well as the protein expression of inducible nitric oxide synthase, arginase-1, and inflammatory factors were measured at 1 week post-injury. Serum ketone and behavior were evaluated every second week for 12 weeks. Then, histological analyses of the gray and white matter at the epicenter were conducted at 12 weeks post-injury. Results The serum ketone levels of the KD and BD groups were significantly increased when compared with the SD group. The gene and protein expression of TNF-α and IL-1β tended to increase after the SCI, but were inhibited in the KD and BD groups. The protein expression of inducible nitric oxide synthase, marker of M1 macrophage, was inhibited in the KD and BD groups; on the other hand, the expression of arginase-1, marker of M2 macrophage, was boosted in the KD and BD groups. The usage of the ipsilateral forelimb was higher in the KD group than in the SD group. The hemi-contusive injury resulted in an obvious ipsilateral lesion area at the epicenter, and there was no significant difference between groups regarding the lesion size. However, the spared gray matter area was significantly greater in the KD group than in the SD and BD groups. Conclusion The present study suggests that ketogenic metabolism promotes macrophage polarization to M2, inhibits an inflammatory response, and alleviates the loss of gray matter after SCI. A higher ketone level, such as that induced by the ketogenic diet, seems to benefit function recovery after SCI.

Protecting white matter is one of the key treatment strategies for spinal cord injury (SCI), including alleviation of myelin loss and promotion of remyelination. Rapamycin has been shown neuroprotective effects against SCI and cardiotoxic effects while enhancing autophagy. However, specific neuroprotection of rapamycin for the white matter after cervical SCI has not been reported. Therefore, we aim to evaluate the role of rapamycin in neuroprotection after hemi-contusion SCI in mice. Forty-six 8-week-old mice were randomly assigned into the rapamycin group (n = 16), vehicle group (n = 16), and sham group (n = 10). All mice of the rapamycin and vehicle groups received a unilateral contusion with 1.2-mm displacement at C5 followed by daily intraperitoneal injection of rapamycin or dimethyl sulfoxide solution (1.5 mg⋅kg–1⋅day–1). The behavioral assessment was conducted before the injury, 3 days and every 2 weeks post-injury (WPI). The autophagy-related proteins, the area of spared white matter, the number of oligodendrocytes (OLs) and axons were evaluated at 12 WPI, as well as the glial scar and the myelin sheaths formed by Schwann cells at the epicenter. The 1.2 mm contusion led to a consistent moderate–severe SCI in terms of motor function and tissue damage. Rapamycin administration promoted autophagy in spinal cord tissue after injury and reduced the glial scar at the epicenter. Additionally, rapamycin increased the number of OLs and improved motor function significantly than in the vehicle group. Furthermore, the rapamycin injection resulted in an increase of Schwann cell-mediated remyelination and weight loss. Our results suggest that rapamycin can enhance autophagy, promote Schwann cell myelination and motor function recovery by preserved neural tissue, and reduce glial scar after hemi-contusive cervical SCI, indicating a potential strategy for SCI treatment.

Background: Since late December 2019, the outbreak of the novel coronavirus disease, COVID-19, that began in Wuhan, has become endemic in China and more than 100 countries and regions in the world. There is no report about the prevalence of COVID-19 in CML patients untill now. We aimed to describe the clinical course, outcomes of CML patients with COVID-19 and prevalence of COVID-19 in CML patients. Methods: In this multi-center survey, cross-sectional survey, observational study, the clinical data of CML patients with COVID-19 in each center were collected. Simultaneously, an online survey was conducted for information about the CML patients under the management at each center by asking the CML patients to complete a questionnaire,from February 15, 2020 to February 21, 2020. The questionnaire includes demographic data, place of residence, smoking status, CML diagnosis and treatment, comorbidities, combined medications, epidemiological history, symptoms (fever, cough, shortness of breath, etc) during the epidemic. Additional clinical data was collected on respondents suspected or confirmed to have COVID-19. We described and analyzed the prevalence of COVID-19 in CML patients, and focus on the clinical characteristics and outcomes of COVID-19 patients. Data were compared between the CML patients with optimal response and those with non-optimal response. The primary outcome was prevalence of COVID-19 in CML patients, as of Feb 21, 2020. Secondary outcomes included the history of epidemiology of CML patients, the clinical characteristics and outcomes of CML patients with COVID-19. Findings: Of 392 respondents, 223(56.9%) were males, and 240(61.2%) were 50 years or younger. Only 10 patients took drugs irregularly due to the influence of the epidemic because of traffic control, pharmacies unable to operate normally, etc. In the history of epidemiology, there were 4 patients with definite contact with COVID-19, of which 3 were remote contact and 1 was close contact. 12 respondents had fever, cough or shortness of breath during the epidemic, 1 case (common type) was confirmed with COVID-19 and cured after treatment. 1 patient was clinically diagnosed and succumbed. 1 of 299 (0.3%) patients with an optimal response was diagnosed with COVID-19. Of the 50 patients who failed to respond to CML treatment or had a poor response, 1 patient (2%) had a clinical diagnosis of COVID-19. Interpretation: While the 392 CML respondents required regular referrals to hospitals, they did not have much contact with COVID-19 patients during the outbreak. Patients who failed to achieved an optimal response to CML therapy appear more likely to have a symptomatic infection with SARS-CoV-2. Older patients with comorbidities are at increased risk of death. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China(NSFC)(81873440&81700142). Declaration of Interests: All participants have no competing interests. Ethics Approval Statement: The investigation was approved by the ethics committee of the Union hospital of the Tongji Medical College, which is part of the Huazhong University of Science and Technology.

Aims: Nonvalvular atrial fibrillation often occurs in combination with carotid atherosclerosis, but less is known about it in combination with cerebral artery stenosis. This study investigated the characteristics of cerebral infarction in patients with nonvalvular atrial fibrillation with or without cerebral artery stenosis. Methods: A retrospective analysis was conducted on 172 cerebral infarction patients with nonvalvular atrial fibrillation hospitalized at the Affiliated Ganzhou Hospital of Nanchang University between December 2011 and January 2016. The patients were divided into two groups (stenosis and non-stenosis groups) based on whether the cerebral infarction was combined with cerebral artery stenosis or not. Clinical characteristics, related supplementary examination, and the imaging characteristics of cerebral infarction lesions were compared between the groups. Results: Mean age [(75.73 ± 8.46) years vs. (63.44 ± 9.95) years], National Institute of Health stroke scale (NIHSS) score [(8.66 ± 6.73) vs. (4.59 ± 3.51)], CHA2DS2-VASc score [(2.93 ± 1.40) vs. (0.96 ± 0.98)], history of hypertension (74.4% vs. 30.0%), and history of stroke/ transient ischemic attack (TIA) (55.8% vs. 13.3%) were higher in the stenosis group (n = 107) than in the non-stenosis group (n = 65) (P < 0.01). In the stenosis group, there were different types of cerebral infarction lesions, including multiple infarction (multifocal type), massive infarction, watershed infarction, and lacunar infarction; in the non-stenosis group, the 60.0% lesions were multiple infarction (multifocal type), a significantly higher proportion than the stenosis group (26.2%, P < 0.05). NIHSS score was an independent risk factor for worse prognosis at follow-up (OR (95%CI) 1.251–1.674, P < 0.001). Conclusions: Advanced age, hypertension, and stroke/TIA were increased in patients with cerebral infarction with nonvalvular atrial fibrillation combined with cerebral artery stenosis.

To clarify osteoporotic effects of ketogenic diet (KD) on cancellous and cortical bone compared with ovariectomy (OVX) in mice. Forty female C57BL/6J 8-week-old mice were randomly divided into SD+Sham, SD+OVX, KD+Sham, and KD+OVX groups, and fed for 12 weeks. The distal femur of trabecular bone and the middle femur of cortical bone were evaluated with Micro-CT scanning. The maximum bending force and stiffness of the tibia were calculated using a three-point bending test. Osteoblast and osteoclast expression of femur were identified using tartrate-resistant acid phosphatase (TRAP), collagen type I (CoLI), and osteocalcin (OCN) staining. A 2-factor analysis of variance was used to evaluate effects of KD and OVX on radiological, biomechanical, and histological parameters. KD resulted in not only remarkable cancellous bone decline comparable to OVX, but also unique cortical bone reduction. The maximum bending force and stiffness decreased in the KD+Sham and KD+OVX groups but did not change in the SD+OVX group. The KD+OVX led to significantly higher expression in TRAP and noticeably lower expression in CoLI when compared with other groups. Both KD+Sham and SD+OVX prominently increased expression in TRAP, but decreased expression in CoLI. There was no significant difference in OCN among the four groups. The present results suggest that KD compromises both the cancellous and cortical bone architecture of long bones while OVX only in cancellous bone architecture. A combination of KD and OVX may lead to more bone loss.

Background and Aims: The ENCORE registry aimed at comparing the long-term safety of Crohn’s disease [CD] treatment with infliximab [Remicade®] and with conventional therapies in real-world clinical practice. Methods: The 5-year, prospective, observational ENCORE registry followed patients with CD in nine European countries, who received treatment with infliximab, conventional therapies, or switched to infliximab from conventional therapy. Adverse events [AEs] in pre-specified categories and serious AEs were recorded at least every 6 months of the 5-year observation period. Frequency of events was evaluated, and multivariable analyses using follow-up time [Cox proportion hazards model] and exposure time [Poisson regression] were used to identify risk factors for time to AEs in pre-specified categories. Results: Patients who received infliximab [ N = 1541], conventional therapies [ N = 1121], or switched to infliximab [ N = 298] were followed for medians of 60.4, 55.6, and 42.5 months, respectively. Infliximab median exposure was 18.7 and 19.3 months in the infliximab and switched-to-infliximab groups, respectively. In time-to-event Cox proportion hazards [PH] analyses adjusting for confounders, infliximab [vs conventional therapy] was associated with serious infections (hazard ratio [HR] = 1.64, 95% confidence interval [CI]: 1.17, 2.31] and haematological conditions [HR = 2.91, CI: 1.51, 5.59], and not associated with lymphoproliferative disorders/malignancy [HR = 1.44, CI: 0.86, 2.42] or death [HR = 1.22, CI: 0.63, 2.36]. Prednisone use was associated with higher mortality [HR = 3.58, CI: 1.49, 8.61]. In exposure-adjusted Poisson regression analyses, infliximab was associated with lower mortality (risk ratio [[RR] 0.39, CI: 0.17, 0.88]). Conclusions: Data from 5-year safety follow-up of patients with CD in the ENCORE registry demonstrate that infliximab [Remicade®] exposure is associated with increased risk of serious infections and haematological conditions, whereas mortality may be decreased.

Transfacet screws have been used as an alternative posterior fixation in the cervical spine. There is lack of spinal stability of the transfacet screws either as stand-along constructs or combined with anterior plate. This study was designed to evaluate spinal stability of transfacet screws following posterior ligamentous injury and combined with anterior plate, respectively, and compare transfacet screws to lateral mass screw-rod constructs. Flexibility tests were conducted on eight cadaveric specimens in an intact and injury, and instrumented with the transfacet screw fixation and lateral mass screw-rod construct at C5–C7 levels either after section of the posterior ligamentous complex or combined with an anterior plate and a mesh cage for C6 corpectomy reconstruction. A pure moment of ±2.0 Nm was applied to the specimen in flexion–extension, lateral bending, and axial rotation. Ranges of motion (ROM) were calculated for the C5–C7 segment. ROM with the transfacet screws was 22 % of intact in flexion–extension, 9 % in lateral bending and 11 % in axial rotation, while ROM with the lateral mass screw-rod construct was 9 % in flexion–extension, 8 % in lateral bending and 22 % in axial rotation. The only significant difference between two constructs was seen in flexion–extension (5.8 ± 4.2° vs. 2.4 ± 1.2°, P = 0.002). When combined with an anterior plate and mesh cage, the transfacet screw fixation reduced ROM to 3.0° in flexion–extension, 1.2° in lateral bending, and 1.1° in axial rotation, which was similar to the lateral mass screw-rod construct. This study identified the transfacet screw fixation, as stand-alone posterior fixation, was equivalent to the lateral mass screw-rod constructs in axial rotation and lateral bending except in flexion–extension. When combined with an anterior plate, the transfacet screw fixation was similar to the lateral mass screw-rod construct in motion constraint. The results suggested the transfacet screw fixation a biomechanically effective way as supplementation of anterior fixation.

Study design An experimental animal study of osteoporosis (OP) and intervertebral disc degeneration (IDD). Objective The aim of this study was to clarify the effects of estrogen deficiency and supplement on cervical IDD induced by bilateral facetectomy in rats. Summary of background data The relationship between IDD and OP is still controversy with the wide prevalence in aged people. Methods Seventy-two Sprague-Dawley female rats were randomly divided into ovariectomy (OVX) group, facet joints resection of C4-6 (FR), FR-OVX group, estrogen replacement therapy (ERT, based on the FR-OVX group) group, and sham group. Specimens of C4-6 segment were harvested at 12 and 24 weeks. The microstructures of C5 vertebrae, vertebral endplate lesions and calcification, and IDD of C5/6 disc were evaluated by micro-computed tomography (micro-CT) and histology. The protein and gene levels of aggrecan, Col2α1, matrix metalloprotease (MMP)-3, and MMP-13 in the C5/6 and C4/5 discs were measured. Results Microstructures of C5 vertebral body were weakened significantly after ovariectomy, while restored effectively with estradiol supplementation. The facetectomy led to significant IDD, and the IDD was aggravated when combined with OVX. The IDD of the ERT group was alleviated effectively and similar to that of the FR group in intervertebral disc height, vertebral endplate lesions and calcification, and disc degeneration scores. In addition, the estrogen supplement maintained the extracellular matrix by decreasing MMP-3 and MMP-13, and increasing aggrecan and Col2α1 expression. Conclusion The present study demonstrated that estrogen deficiency exacerbated IDD induced by spinal instability, while estrogen supplementation alleviated the progression of disc degeneration related to osteoporosis. Level of evidence N/A.

Metformin (Met), an anti-diabetes drug, has also shown therapeutic effects for ovariectomy-induced (OVX) osteoporosis. However, similar effects against bone loss induced by a ketogenic diet (KD) have not been tested. This study was aimed to evaluate the microarchitectures and biomechanics of KD-induced osteoporosis with and without administration of Met, and compare the effect of Met on bone loss induced by KD with OVX. Forty female C57BL/6J mice were randomly divided into Sham, OVX, OVX + Met (100 mg/kg/day), KD (3:1 ratio of fat to carbohydrate and protein), and KD + Met (100 mg/kg/day) groups. After 12 weeks, the bone mass and biomechanics were measured in distal cancellous bone and in mid-shaft cortical bone of the femur. The activities of serum alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP), together with immunohistochemistry staining of osteocalcin (OCN) and TRAP, were evaluated. Both OVX and KD induced significant bone loss and compromised biomechanical properties in the cancellous bone, but no effect was found in cortical bone. The administration of Met increased the cancellous bone volume fraction (BV/TV) from 3.78 to 5.23% following the OVX and from 4.04 to 6.33% following the KD, it also enhanced the compressive stiffness from 47 to 160 N/mm following the OVX and from 35 to 340 N/mm with the KD. Met effectively increased serum ALP in the KD group while decreased serum TRAP in the OVX group, but up-regulated expression of OCN and down-regulated expression of TRAP in both OVX and KD groups. The present study demonstrated that Met effectively attenuated the cancellous bone loss induced by KD and maintained the biomechanical properties of long bones, providing evidence for Met as a treatment of by KD-induced osteoporosis in teenage skeleton.

BACKGROUND: Interleukin‐18‐137G/C, ‐607G/T polymorphisms play multiple roles in various cancers. However, studies focused on its involvement in breast cancer remain controversial, and no study has taken the interaction between interleukin‐18 (IL‐18) gene polymorphism and body mass index (BMI), menopause into consideration. The study investigated the association between IL‐18‐137, ‐607 polymorphisms and risk of breast cancer and a possible interaction between the 2 single nucleotide polymorphisms (SNPs) and BMI, menopause in Chinese Han woman. METHODS: A total of 488 participants, including 178 patients with breast cancer, 150 patients with benign breast disease and 160 healthy controls were recruited for this study. Polymerase chain reaction (PCR)‐direct sequencing technology was used to identify the genotypes. RESULTS: 137 G/C genotype can decrease the risk of breast cancer (OR = 0.54, 95% CI: 0.31‐0.93; P = .025). In benign group, subjects with G/C genotype of IL‐18‐137G/C polymorphism had a 1.89‐fold increased risk of developing breast cancer (95% CI = 1.05‐3.41; P = .032). Among postmenopausal subjects, people with G/T genotype of IL‐18‐607 polymorphism had a 7.97‐fold increased risk of lymph node metastasis compared with those with T/T homozygotes (95% CI = 1.95‐32.65; P = .0045). Among Overweight and obese patients with breast cancer (BMI ≥ 24), people with G/T genotype of IL‐18‐607 polymorphism had a 5.45‐fold increased risk of lymph node metastasis compared with those with T/T homozygotes (95% CI = 1.74‐17.06; P = .034). CONCLUSIONS: IL‐18‐137 G/C genotype may be a protective factor for healthy group, but a risk factor for benign group. IL‐18‐607 G/T genotype have an interaction with menopausal and BMI. The synergetic effect can further increase the risk of lymph node metastasis for breast cancer patients.

OBJECTIVE: To study correlation among number(n), diameter (D), and blood reflux time(t) and the left common iliac vein stenosis degree of the expansion of perforating veins, so as to guide the clinical formulation and adjust the treatment plan. METHODS: Retrospective analysis of 45 PVs patients with left common iliac vein in different degrees of compression in our hospital from 2010 to 2012 was performed. Left common iliac vein was divided into 50%‐69%, 70%‐99%, 30%‐49% and occlusion of the stenosis to avoid the error of the left iliac vein stenosis. Pearson's correlation analysis among the number, diameter, and blood reflux time of perforating veins and left common iliac vein was performed. RESULTS: Pearson's correlation analysis among the number, diameter, and blood back flow time of perforating veins, and the degree of stenosis was performed, and these results showed that correlation coefficients among the number, diameter, and blood return the PVs between flow time and the degree of stenosis were rp‐n = 0.784, rp‐d = 0.893, rp‐t = 0.845 (P

Severe aplastic anemia (SAA) is a life-threatening bone marrow failure syndrome characterized by pancytopenia and hypocellular bone marrow. Antithymocyte globulin (ATG) is the drug of choice for immunosuppressive therapy (IST) in patients with SAA ineligible for allogeneic stem cell transplantation. This study aimed to evaluate the efficacy and safety profile of porcine antilymphocyte globulin (p-ALG) plus CsA in the treatment of acquired SAA. Clinical information of 69 SAA patients treated with p-ALG plus CsA was collected and retrospectively analyzed for early mortality, response rate, survival rate, side effects, and other complications. The median age at diagnosis was 27 years (range 14 to 52). The overall response rate was 76.8 % with a 90-day median response time (range 30 ~ 360 days). Overall response rates at 3, 6, 12, 18, and 24 months were 63.8, 73.9, 76.8, 75.4, and 75.4 %, respectively. The median follow-up time for surviving patients was 24 months (range 4 ~ 44 months) and the 2-year overall survival (OS) rate was 88.4 %. The disease-free survival (DFS) rate at 2 years was 85.5 %. Older age (≥45 years), very (v)SAA subgroup, and lower baseline absolute lymphocyte count (1 × 10(9)/L) were independent unfavorable predictors of overall survival (p 0.05). Less than one third of patients had serum sickness or allergic reaction during ALG therapy, but symptoms could easily be relieved by steroid treatment; 27.54 % had mild hepatic impairment. Taken together, p-ALG showed similar efficacy and safety profiles to rabbit or horse ATG in IST of acquired SAA. It can be a suitable alternative preparation for rabbit ATG with the great advantage of lower medical expenses.

The ketone metabolite β-hydroxybutyrate (βOHB), is reported to be neuroprotective after spinal cord injury (SCI) in rats, but the underlying mechanism remains unknown. The present study aims to investigate effects of βOHB on suppression of oxidative stress and inhibition of class I histone deacetylases (HDACs) in in vivo and in vitro models. Rats were fed with ketogenic diet (KD) or standard diet (SD) for 3 weeks. A C5 hemi-contusion injury was applied to these animals on the 14th day of experiment, and spinal cord samples were harvested on the 1st, 3rd and 7th days after SCI, respectively. The blood ketone levels were significantly higher in the KD groups. KD reduced oxidative stress markers and reactive oxygen species (ROS) products, downregulated the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX)2 and NOX4, and upregulated the expression of forkhead box group O (FOXO)3a, mitochondrial superoxide dismutase (MnSOD), and catalase after SCI. The in vitro study, performed on PC12 cells, indicated that βOHB inhibited H

The aim of this study is to investigate the effect of ketogenic metabolism, induced by different diet interventions, on histone acetylation and its potential antioxidant capacity to injured spinal cord tissue in rats. 72 male Sprague–Dawley rats were randomly divided into 4 groups, fed with ketogenic diet (KD), every other day fasting (EODF), every other day ketogenic diet (EODKD) and standard diet (SD) respectively for 2 weeks. β-Hydroxybutyrate (βOHB) concentration was measured both in serum and cerebrospinal fluid (CSF). C5 spinal cord tissue was harvested before, at 3 h and 24 h after injury for analysis of HDAC activity, histone acetylation and oxidative makers. All three dietary interventions resulted in a significant increase of βOHB level in both serum and CSF, and inhibited HDAC activity by 31–43% in spinal cord. Moreover, the expressions of acetylated histone AcH3K9 and AcH3K14 were significantly increased. Anti-oxidative stress genes Foxo3a and Mt2 and related proteins, such as mitochondrial superoxide dismutase (SOD), FOXO3a, catalase were increased in dietary intervention groups. After SCI, high ketogenic metabolism demonstrated significant reduction of the expression of lipid peroxidation factors malondialdehyde (MDA), and this might contribute to the reported neuroprotection of the spinal cord from oxidative damage possibly mediated by increasing SOD. The result of this study suggested that by inhibiting HDAC activity and modifying related gene transcription, ketogenic metabolism, induced by KD, EODF or EODKD, might reduce oxidative damage in the spinal cord tissue after acute injury.

Evidence has shown that osteoporosis or intervertebral disc degeneration (IDD) led to cartilage endplate lesions (CEL), but their combined effects on the lesion remain unknown. This study developed an innovative rat model combined ovariectomy (OVX) and cervical muscle section (CMS), and aimed to evaluate the combined effects of osteoporosis and IDD on cartilage endplate lesions of cervical spine. Fifty-two Sprague–Dawley female rats were assigned randomly into four groups as follows: the sham group (n = 10) underwent sham surgery; the OVX group (n = 14) was subjected to bilateral ovariectomy; the CMS group (n = 14) had posterior paraspinal muscles cut from C2 to C7; the CMS–OVX group (n = 14) underwent the OVX and CMS surgeries consecutively. Samples of C6–C7 segments were harvested at 12, 18 and 24 weeks post-surgery. Micro-CT analysis was performed to evaluate the CEL, intervertebral disc height (IDH) and structural indices. Histological analysis with Safranine O/fast green stain and histological score were used to observe the characteristics of the degenerative discs. Ovariectomy surgery resulted in significant changes of most structural indices of the C6 body, such as decrease of percent bone volume and number of bone trabecula at 12 weeks, and greater changes at 18 and 24 weeks. The CEL following CMS surgery was seen on the ventral, while the CEL in the OVX and sham groups on the peripheral. The CEL was greatest in the CMS–OVX group and significantly greater than that in the CMS and OVX groups at 12 and 18 weeks (P

Background Polyetheretherketone rod constructs provide adequate spinal stability. Kinematics and load sharing of anterior thoracolumbar reconstruction with polyetheretherketone rods under preload remains unknown. Methods Eight human cadaveric specimens (T11-L3) were subjected to a pure moment of 5.0 Nm in flexion-extension, lateral bending and axial rotation, and flexion-extension with a compressive preload of 300 N. An anterior reconstruction of L1 corpectomy was conducted with a surrogate bone graft and anterior rod constructs (polyetheretherketone or titanium rods). An axial load-cell was built in the surrogate bone graft to measure the compressive force in the graft. Range of motion, neutral zone and compressive force in the graft were compared between constructs. Findings The polyetheretherketone rod construct resulted in more motion than the titanium rod construct, particularly in extension (P = 0.011) and axial rotation (P = 0.001), but less motion than the intact in all directions except in axial rotation. There was no difference in range of motion or neutral zone between constructs in flexion-extension under preload. The polyetheretherketone rod construct kept the graft compressed 52 N which was similar to the titanium rod construct (63 N), but allowed the graft compressed more under the preload (203 N vs. 123 N, P = 0.003). The compressive forces fluctuated in flexion-extension without preload, but increased in flexion and decreased in extension under preload. Interpretation The polyetheretherketone rod construct allowed more motion compared to the titanium rod construct, but provided stability in flexion and lateral bending without preload, and flexion and extension under preload. The anterior graft shared higher load under preload, particularly for the polyetheretherketone rod construct. The results of this study suggest that rigidity of rods in the anterior reconstruction affects kinematic behavior and load sharing.

Cysteine (C)-X-C motif chemokine receptor 4 (CXCR4), the primary receptor for stromal cell-derived factor-1 (SDF-1), is involved in bone morphogenic protein 2 (BMP2)-induced osteogenic differentiation of mesenchymal progenitors. To target the in vivo function of CXCR4 in bone and explore the underlying mechanisms, we conditionally inactivated CXCR4 in osteoprecursors by crossing osterix (Osx)-Cre mice with floxed CXCR4 (CXCR4(fl/fl)) mice to generate knock-outs with CXCR4 deletion driven by the Osx promoter (Osx::CXCR4(fl/fl)). The Cre-mediated excision of CXCR4 occurred exclusively in bone of Osx::CXCR4(fl/fl) mice. When compared with littermate controls, Osx::CXCR4(fl/fl) mice developed smaller osteopenic skeletons as evidenced by reduced trabecular and cortical bone mass, lower bone mineral density, and a slower mineral apposition rate. In addition, Osx::CXCR4(fl/fl) mice displayed chondrocyte disorganization in the epiphyseal growth plate associated with decreased proliferation and collagen matrix syntheses. Moreover, mature osteoblast-related expression of type I collagen α1 and osteocalcin was reduced in bone of Osx::CXCR4(fl/fl) mice versus controls, suggesting that CXCR4 deficiency results in arrested osteoblast progression. Primary cultures for osteoblastic cells derived from Osx::CXCR4(fl/fl) mice also showed decreased proliferation and impaired osteoblast differentiation in response to BMP2 or BMP6 stimulation, and suppressed activation of intracellular BMP receptor-regulated Smads (R-Smads) and Erk1/2 was identified in CXCR4-deficient cells and bone tissues. These findings provide the first in vivo evidence that CXCR4 functions in postnatal bone development by regulating osteoblast development in cooperation with BMP signaling. Thus, CXCR4 acts as an endogenous signaling component necessary for bone formation.

Stromal derived factor-1 (SDF-1) is a chemokine signaling molecule that binds to its transmembrane receptor CXC chemokine receptor-4 (CXCR4). While we previously detected that SDF-1 was co-required with bone morphogenetic protein 2 (BMP2) for differentiating mesenchymal C2C12 cells into osteoblastic cells, it is unknown whether SDF-1 is similarly involved in the osteogenic differentiation of mesenchymal stem cells (MSCs). Therefore, here we examined the role of SDF-1 signaling during BMP2-induced osteogenic differentiation of primary MSCs that were derived from human and mouse bone marrow. Our data showed that blocking of the SDF-1/CXCR4 signal axis or adding SDF-1 protein to MSCs significantly affected BMP2-induced alkaline phosphatase (ALP) activity and osteocalcin (OCN) synthesis, markers of preosteoblasts and mature osteoblasts, respectively. Moreover, disrupting the SDF-1 signaling impaired bone nodule mineralization during terminal differentiation of MSCs. Furthermore, we detected that blocking of the SDF-1 signaling inhibited the BMP2-induced early expression of Runt-related factor-2 (Runx2) and osterix (Osx), two “master” regulators of osteogenesis, and the SDF-1 effect was mediated via intracellular Smad and Erk activation. In conclusion, our results demonstrated a regulatory role of SDF-1 in BMP2-induced osteogenic differentiation of MSCs, as perturbing the SDF-1 signaling affected the differentiation of MSCs towards osteoblastic cells in response to BMP2 stimulation. These data provide novel insights into molecular mechanisms underlying MSC osteogenesis, and will contribute to the development of MSC therapies for enhancing bone formation and regeneration in broad orthopaedic situations.

Background and purpose: Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolaemia in humans and deletion of the LDLR induces lesion development in mice fed a high-fat diet. LDLR expression is predominantly regulated by sterol regulatory element-binding protein 2 (SREBP2). Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) ligand, belongs to a drug class used to treat dyslipidaemic patients. We have investigated the effects of fenofibrate on hepatic LDLR expression.

Purpose This study aims to compare the biomechanical properties of the novel pedicle screw and plate system with the traditional rod system in asymmetrical posterior stabilization for minimally invasive transforaminal lumbar interbody fusion (MI-TLIF). We compared the immediate stabilizing effects of fusion segment and the strain distribution on the vertebral body. Methods Seven fresh calf lumbar spines (L3-L6) were tested. Flexion/extension, lateral bending, and axial rotation were induced by pure moments of ± 5.0 Nm and the range of motion (ROM) was recorded. Strain gauges were instrumented at L4 and L5 vertebral body to record the strain distribution under flexion and lateral bending (LB). After intact kinematic analysis, a right sided TLIF was performed at L4-L5. Then each specimen was tested for the following constructs: unilateral pedicle screw and rod (UR); unilateral pedicle screw and plate (UP); UR and transfacet pedicle screw (TFS); UP and TFS; UP and UR. Results All instrumented constructs significantly reduced ROM in all motion compared with the intact specimen, except the UR construct in axial rotation. Unilateral fixation (UR or UP) reduced ROM less compared with the bilateral fixation (UP/UR+TFS, UP+UR). The plate system resulted in more reduction in ROM compared with the rod system, especially in axial rotation. UP construct provided more stability in axial rotation compared with UR construct. The strain distribution on the left and right side of L4 vertebral body was significantly different from UR and UR+TFS construct under flexion motion. The strain distribution on L4 vertebral body was significantly influenced by different fixation constructs. Conclusions The novel plate could provide sufficient segmental stability in axial rotation. The UR construct exhibits weak stability and asymmetrical strain distribution in fusion segment, while the UP construct is a good alternative choice for unilateral posterior fixation of MI-TLIF.

Rates of abdominopelvic surgery, with a particular focus on gallbladder procedures, were measured in patients with irritable bowel syndrome (IBS) (n = 108,936) and compared with those in a general population sample (n = 223,082). The patient sample was selected from persons who were members of a managed care organization during the years 1995-2000. Medical records from a randomly selected subset of IBS patients were reviewed to confirm the diagnosis. Crude and standardized rates and adjusted rate ratios for surgery were calculated. The incidence of abdominopelvic surgery, excluding gallbladder procedures, was 87% higher in patients with IBS than that for the general population. The incidence of gallbladder surgery was threefold higher in IBS patients than the general population. Patients with IBS have an increased risk for abdominopelvic and gallbladder surgery and, thus, an associated risk for experiencing morbidity and mortality associated with these surgical procedures.

Cholesteryl ester transfer protein (CETP) promotes reverse cholesterol transport via exchange of cholesteryl ester and triglyceride among lipoproteins. Here, we focused on HDL metabolism during inhibition of CETP expression by using CETP antisense oligodeoxynucleotides (ODNs) in HepG2 cells. CETP secretion was decreased by 70% in mRNA levels and by 52% in mass 20 h after ODNs against CETP were delivered to HepG2 cells. Furthermore, as a consequence of the downregulation of CETP, the expression of scavenger receptor class B type I (SR-BI), an HDL receptor, was also reduced by ∼50% in mRNA and protein levels, whereas the apolipoprotein A-I (apoA-I) expression and secretion were increased by 30 and 92%, respectively. In a functional study, the selective uptake of125I-[14C]cholesteryl oleate-labeled HDL3was decreased. Cholesterol efflux to apoA-I and HDL3was significantly increased by 88 and 37%, respectively. Moreover, the CE levels in cells after antisense treatment were elevated by 20%, which was related to the about twofold increase of cholesterol esterification and increased acyl-CoA:cholesterol acyltransferase 1 mRNA levels. Taken together, these findings suggest that although acute suppression of CETP expression leads to an elevation in cellular cholesterol stores, apoA-I secretion, and cellular cholesterol efflux to apoA-I, the return of HDL-CE to hepatocytes via an SR-BI pathway was inhibited in vitro. Thus antisense inhibition of hepatic CETP expression manifests dual effects: namely, increased formation of HDL and suppression of catabolism of HDL-CE, probably via the SR-BI pathway.

Cholesteryl ester transfer protein (CETP) is a major determinant of plasma levels of high-density lipoprotein-cholesterol (HDL-C) in humans. The anti-atherogenic effect of lowering CETP levels is dependent not only on HDL-C levels but also on a metabolic background of increased low-density lipoprotein or very-low-density lipoprotein. Here we investigated the effects of JTT-705, a chemical inhibitor of CETP, on the development of atherosclerosis in Japanese white rabbits fed on a high cholesterol diet. After 4 weeks on a diet of 0.25% cholesterol-containing chow, 100mg/kg (low dose) or 300mg/kg (high dose) JTT-705 was given, and the animals were monitored at weeks 0, 4, 8 and 12. Aortic atherosclerotic lesions were determined at the end of this period. JTT-705 induced a significant increase in HDL-C in the high-dose group [from 21±3 to 50±7mg/dl (mean±S.E.M.); P

Background: Low intake of fat and high intake of specific vitamins have been hypothesized to reduce risk of basal cell carcinoma of the skin (BCC). Objective: Our objective was to examine intakes of fat, antioxidant nutrients, retinol, folate, and vitamin D in relation to risk of BCC. Design: In 1986, diet was assessed by a validated food-frequency questionnaire in 43217 male participants of the Health Professionals Follow-up Study who were 40-75 y of age and free of cancer. During 8 y of follow-up, we ascertained 3190 newly diagnosed cases of BCC. Results: Total fat consumption was associated with a lower risk of BCC [relative risk (RR): 0.81; 95% CI: 0.72, 0.90 for the highest compared with the lowest quintile of intake; P for trend

This study examined prospectively the associations of waist circumference and waist:hip circumference ratio with risk of breast cancer. A total of 47,382 US registered nurses who reported their waist and hip circumferences in 1986 were followed up through May 1994 for identification of incident cases of breast cancer. During 333,097 person-years of follow-up, 1,037 invasive breast cancers were diagnosed. In proportional hazards analyses, waist circumference was nonsignificantly related to risk of premenopausal breast cancer but was significantly associated with postmenopausal breast cancer after adjustment for established breast cancer risk factors (for the highest quintile of waist circumference vs. the lowest, relative risk (RR) = 1.34; 95% confidence interval (CI): 1.05, 1.72). When the analysis was limited to postmenopausal women who had never received hormone replacement therapy, a stronger positive association was found (RR = 1.88; 95% CI: 1.25, 2.85). After the data were further controlled for body mass index, the positive association was only slightly attenuated (RR = 1.83; 95% CI: 1.12, 2.99). Among past and current postmenopausal hormone users, no significant associations were found. Similar but slightly weaker associations were observed between waist:hip ratio and breast cancer risk. These data suggest that greater waist circumference increases risk of breast cancer, especially among postmenopausal women who are otherwise at lower risk because of never having used estrogen replacement hormones.

The interrelationships between nutritional status, concurrent bone density, bone dimensions, and risk of subsequent hip fracture were investigated using data from the first National Health and Nutrition Examination Survey and its three follow-up studies. A cohort of 890 White women aged 45 years or older who received nutritional and bone measurements in the baseline survey in 1971-75 were recontacted in 1982-84, 1986, and 1987. Height, weight, serum albumin, total energy intake, bone density, and bone dimensions were measured at baseline. Thirty-three incident hip fractures were identified during 12,190 person-years of follow-up. Total energy intake and serum albumin were little correlated with concurrent bone density and bone dimensions. Serum albumin, total energy intake, and weight tended to be inversely associated with risk of hip fracture. The multivariable relative risks were 0.75 (95% confidence interval [CI] = 0.57-0.98) for one standard deviation increment of serum albumin, 0.67 (95% CI = 0.42-1.07) for dietary energy intake, and 0.61 (95% CI = 0.38-0.97) for weight, respectively. Height was positively, but not significantly associated with risk of hip fracture. Nutritional effects on hip fracture were independent of concurrent bone density and bone dimensions. Higher bone density was protective of subsequent hip fracture (relative risk = 0.55, 95% CI = 0.36-0.83, for one standard deviation increment of bone density) independent of effects related to concurrent nutritional status. Thus, poor nutritional status and reduced bone density appeared to increase the risks of subsequent hip fracture independently. Am. J. Hum. Biol. 10:661-667, 1998. © 1998 Wiley-Liss, Inc.

Advanced oxidation protein products (AOPPs) are novel markers of oxidation-mediated protein damage, and accumulation of AOPPs is involved in many pathophysiological conditions. Our previous studies demonstrated that the serum level of AOPPs negatively correlated with the age-related change in bone mineral density (BMD) in rats and that AOPPs inhibited rat osteoblast-like cell proliferation and differentiation in vitro. However, whether AOPPs are involved in senile osteoporosis is still largely unknown. The present study aimed to test the hypothesis that accumulation of AOPPs might accelerate bone deterioration in aged rats. Seventy 18-month-old male Sprague Dawley (SD) rats were randomized to intravenous injection of vehicle, native rat serum albumin (RSA), AOPPs-modified RSA (AOPPs-RSA) with or without oral administration of apocynin (a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor), or apocynin alone. After treatment for 8 weeks or 16 weeks, seven rats in each group were sacrificed. Bone and blood samples were harvested for BMD measurement, micro-computed tomographic (micro-CT) imaging, and biochemical analysis of circulating bone biomarkers. Compared to RSA- or vehicle-treated rats, AOPPs-RSA-treated animals displayed significantly decreased total vertebral BMD and deteriorated microstructure in both the tibias and the lumbar vertebral bodies, which were associated with down-regulated plasma bone-specific alkaline phosphatase concentration and up-regulated tartrate-resistant acid phosphatase 5b concentration. These AOPPs-induced perturbations in aged rats could be prevented by the oral administration of apocynin. However, no significant differences in BMD were detected in the femurs or the biomechanical parameters tested between the different treatment groups. These data suggest that accumulation of AOPPs accelerates bone deterioration in aged rats, likely via the activation of NADPH oxidase. This study provides new information toward understanding the pathogenic basis of senile osteoporosis and may provide targets for intervention.

This study investigated three aspects of general nutritional status (dietary intake, biochemical markers, and anthropometric measurements) in relation to subsequent hip fracture risk by using prospective data from the First National Health and Nutrition Examination Survey (NHANES I) epidemiologic follow-up studies. A cohort of 2,513 white women 45 years and over who participated in the NHANES I survey in 1971-1975 were subsequently followed in the three follow-up studies in 1982-1984, 1986, and 1987, respectively. Multiple nutritional variables were measured at baseline, and 130 incident hip fractures were identified by hospital records or by death certificates during the follow-up period. Cox regression analyses showed that baseline dietary energy intake; serum albumin; and weight, body mass index, skinfold, and arm muscle area were significantly and inversely related to subsequent hip fracture risk (relative risks for a 1-standard deviation increment in these variables ranged from 0.68 to 0.83). The authors suggest that poor nutritional status, evident in inadequate dietary intake, reduced serum albumin, and decreased body mass and soft tissues, increases the risk for subsequent hip fracture. The study also showed that age and previous fracture history were significant risk factors; however, self-reported physical activity, parity, and alcohol use were not significantly related to subsequent hip fracture.

The LDLR plays a key role in cholesterol homeostasis. LDLR mutations cause familial hypercholesterolemia and premature coronary heart disease. Genetic deletion of the LDLR induces atherosclerosis i...

Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins. TaqIB polymorphism (B2 allele) identified in intron 1 is associated with lower plasma CETP concentrations and higher HDL cholesterol levels and may play an antiatherogenic role in humans. However, its molecular mechanism remains unclear. To evaluate the association between the promoter polymorphisms and CETP/HDL cholesterol levels, ten novel and three previously reported polymorphisms located within 3.3 kb of the CETP gene promoter were investigated in a sample of 357 elderly Japanese men. All the promoter polymorphisms were in linkage disequilibrium with each other and with TaqIB. The -2505A allele, the "S" allele of the [gaaa](n) repeat ("S" denotes [gaaa](n)=329 bp and longer, "L" denotes329 bp) and TaqIB2 allele were significantly associated with both lower plasma CETP concentrations and higher HDL cholesterol levels whereas -971G/A and -629A/C were significantly associated with CETP concentrations but not with HDL-C levels. The 12-polymorphism haplotypes consisting of -2804, -2505, [gaaa](n), -1930, -1674, -1129, -1046, -971, -875, -827, -629, and TaqIB were analyzed. These 12 polymorphisms generated eight main haplotypes, accounting for 86% of the observed haplotypes. The G/A/S/T/T/C/T/A/C/C/A/B2 haplotype was significantly associated with lower CETP concentrations (2.0+/-0.6 micro g/ml) and higher HDL cholesterol levels (55.1+/-12.7 mg/dl) than the other seven main haplotypes. The 5- and 3-polymorphism haplotype analyses consisting of -2505 and the [gaaa](n) repeat indicated the -2505C/A polymorphism might explain the variation in the CETP concentrations best, and the [gaaa](n) repeat and/or the -2505C/A polymorphism may independently determine the variation in HDL cholesterol levels, whereas the -629A/C and TaqIB polymorphisms were not instrumental in determining CETP concentrations as well as HDL cholesterol levels, although the latter has been frequently examined in many association studies.

BACKGROUND: Significant hemorrhage together with blood transfusion has negative impact on postoperative morbidity, mortality, and long-term survival of liver resection. Various techniques of vascular occlusion have been developed to reduce intraoperative blood loss. The objective of this study was to compare the outcomes of Pringle maneuver, hemi-hepatic vascular occlusion, and treatment without vascular occlusion used during liver resection. METHOD: Data of 574 patients with Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), who underwent major hepatectomy between January 2009 to March 2013 by Pringle maneuver (N = 158), hemi-hepatic vascular inflow occlusion (N = 216), or without any vascular occlusion (N = 200), were included in this retrospective study. Perioperative blood transfusion, intraoperative blood loss, and postoperative liver function, and surgical complications were analyzed and compared between the three groups. RESULT: There were no significant difference observed in postoperative bilirubin, liver enzyme, and albumin levels between three groups (P>0.05). 5 patients (2.5%) in no occlusion group, 2 (1.3%) in Pringle group, and 8 (3.7%) in hemi-hepatic group had liver failure; but, there were no differences (P>0.05). The overall postoperative complications rate between three groups did not reach significant differences (33.5% vs 34.2% vs 42.6%, respectively; P>0.05). However, significant differences in intraoperative blood loss between no occlusion group (638.2±426.8 ml) and Pringle group (518.0±451.0 ml) or hemi-hepatic group (513.0±366.7 ml) (P

BACKGROUND: Alendronate (ALE) is a conventional drug used to treat osteoporosis. Low-magnitude whole-body vibration (WBV) exercise has been developed as a potential treatment for osteoporosis. The aim of this study was to investigate whether low-magnitude WBV could enhance the protective effect of ALE on bone properties in ovariectomized rats. METHODS: A total of 128 Sprague-Dawley rats were randomly divided into five groups (SHAM, OVX+VEH, OVX+WBV, OVX + ALE, OVX+WBV+ALE). The level of WBV applied was 0.3 g at 45-55 Hz for 20 min/day, 5 day/week and for 3 months. ALE was administered in dose of 1 mg/Kg once a week. Every four weeks eight rats from each group were sacrificed and their blood and both tibiae were harvested. The expression of osteocalcin and CTX in serum was measured by enzyme-linked immunosorbent assay (ELISA) and the tibiae were subjected to metaphyseal three-point bending and μCT analysis. RESULTS: Osteocalcin rose after ovariectomy and was not appreciably changed by either alendronate or WBV alone or in combination. Alendronate treatment significantly prevented an increase in CTX. WBV alone treatment did not alter this effect. Compared with the OVX+WBV group, nearly all tested indices such as the BV/TV, TV apparent, Tb.N, Tb.Th, and Conn.D were higher in the OVX+ALE group at week 12.Compared with the OVX+WBV group, certain tested indices such as BV/TV, TV apparent, Tb.N, and Con.D, were higher in the OVX+WBV+ALE group at week 12. At week 12, tibiae treated with WBV+ALE exhibited a significantly higher Fmax compared to the OVX+VEH group, and a significant difference was also found in energy absorption between the OVX+WBV+ALE and OVX+VEH groups. CONCLUSIONS: Compared with the WBV, ALE was more effective at preventing bone loss and improved the trabecular architecture. However, WBV enhanced the effect of alendronate in ovariectomized rats by inducing further improvements in trabecular architecture.

The authors examined the relation of constitutional factors and sun exposure to risk of basal cell carcinoma of the skin (BCC) in a prospective cohort of 44,591 predominantly Caucasian US male health professionals, 40-75 years of age and free of cancer at enrollment in 1986. During 8 years of follow-up, 3,273 cases of self-reported BCC were documented. The following variables were each associated with an elevated risk of BCC: having red hair; green, hazel, or blue eyes; a tendency to sunburn; and north European ancestry. The lifetime number of blistering sunburns was also positively associated with BCC risk (p trend < 0.0001). Compared with men who as teenagers had been outside less than once a week, men who had been outside weekly (relative risk (RR) = 1.30; 95% confidence interval (CI): 1.14, 1.47) and daily (RR = 1.42; 95% CI: 1.24, 1.63) had an elevated risk of BCC. Living in a region of residence with high solar radiation as an adult was also associated with an increased risk of BCC (RR = 1.48; 95% CI: 1.36, 1.60), whereas living in such a region only in childhood did not increase BCC risk. These results confirm the role of constitutional factors and suggest that adult sun exposure increases BCC risk.

We examined prospectively the associations of bone density and bone dimensions with risk of hip fracture using data from the first National Health and Nutrition Examination Survey and its three follow-up studies. A cohort of 1,489 white women age 45 years or older who received detailed medical examinations in the baseline survey in 1971-1975 were subsequently contacted in 1982-1984, 1986, and 1987. Bone density and hand bone dimensions at several sites were measured at baseline. Fifty incident hip fractures were identified during the follow-up studies. Using Cox regression analyses, we found a relative risk of 11 for women with bone density below the 5th percentile, compared with those above the 75th percentile (95% confidence interval = 2.2-58). Women with smaller external bone dimensions also faced increased risk of hip fracture (relative risk = 4.6 for dimensions below the 5th percentile vs above the 75th percentile; 95% confidence interval = 1.5-14). On the other hand, internal bone dimensions were not associated materially with hip fracture.

Context. —Breast cancer is a major cause of mortality among women. It is important to identify modifiable risk factors for this disease. Objective. —To examine body mass index (BMI) at the age of 18 years and at midlife and adult weight change in relation to breast cancer incidence and mortality. Design. —Cohort study. Setting. —A cohort of 95256 US female nurses aged 30 to 55 years who were followed up for 16 years. Main Outcome Meausure. —Incident and fatal breast cancer. Results. —During 1 203498 person-years, 2517 incident breast cancers (60% postmenopausal) were documented. Higher current BMI was associated with lower breast cancer incidence before menopause and was minimally associated with incidence after menopause. However, a stronger positive relationship was seen among postmenopausal women who never used hormone replacement (relative risk=1.59 for BMI >31 kg/m2vs ≤20 kg/m2; 95% confidence interval, 1.09-2.32;Pfor trend Conclusions. —Avoiding adult weight gain may contribute importantly to the prevention of breast cancer after menopause, particularly among women who do not use postmenopausal hormones.