Characterization of bone ingrowth and interface mechanics of a new porous 3D printed biomaterial: an animal study.

AIMS: The purpose of this study was to evaluate the biological fixation of a 3D printed porous implant, with and without different hydroxyapatite (HA) coatings, in a canine model. MATERIALS AND METHODS: A canine transcortical model was used to evaluate the characteristics of bone ingrowth of Ti6Al4V cylindrical implants fabricated using laser rapid manufacturing (LRM). At four and 12 weeks post-implantation, we performed histological analysis and mechanical push-out testing on three groups of implants: a HA-free control (LRM), LRM with precipitated HA (LRM-PA), and LRM with plasma-sprayed HA (LRM-PSHA). RESULTS: Substantial bone ingrowth was observed in all LRM implants, with and without HA, at both time periods. Bone ingrowth increased from 42% to 52% at four weeks, to 60% to 65% at 12 weeks. Mechanical tests indicated a minimum shear fixation strength of 20 MPa to 24 MPa at four weeks, and 34 MPa to 40 MPa at 12 weeks. There was no significant difference in the amount of bone ingrowth or in the shear strength between the three implant types at either time period. CONCLUSION: At four and 12 weeks, the 3D printed porous implants exhibited consistent bone ingrowth and high mechanical shear strength. Based on the results of this study, we confirmed the suitability of this novel new additive manufacturing porous material for biological fixation by bone ingrowth. Cite this article: Bone Joint J 2019;101-B(6 Supple B):62-67.

The impact of cancer development on the risk of mycobacterial diseases among rheumatoid arthritis patients.

Mycobacterial diseases are prevalent in cancer and rheumatoid arthritis (RA) patients, especially those receiving tumor necrosis factor-α inhibitor (TNFi). However, the impact of cancer development on the risk of mycobacterial diseases among RA patients is unknown. Data from the Taiwan National Health Insurance Research Database were used to conduct a retrospective study to assess the occurrence of mycobacterial diseases in RA patients developing cancer (cancer-positive), those using TNFi (TNFi-exposure), those with cancer and using TNFi (cancer-TNFi-comb), and those without cancer and not using TNFi (cancer-TNFi-free). Cancer and TNFi exposure were time-dependent, and independent risk factors of mycobacterial diseases were assessed by Cox regression. Among 1344 RA patients diagnosed during 2000-2013, 68 (5·1%) developed cancer before their end points. The incidence rates of mycobacterial diseases in the cancer-positive (n = 56), TNFi-exposure (n = 290), cancer-TNFi-comb (n = 12), and cancer-TNFi-free (n = 986) subgroups were 6·7, 2·0, 7·6, and 1·3 per 1000 person-years, respectively. As compared with the cancer-TNFi-free group, the risk for mycobacterial diseases increased for the TNFi-exposure group (adjusted HR = 3·6, 95% confidence interval (95% CI) 1·1-11·5, P = 0·032) and remained high for cancer-positive (adjusted HR = 14·6, 95% CI 3·3-63·7, P < 0·001) after adjustment. This study suggested that cancer development increased the risk of mycobacterial diseases in RA patients, and risk assessment for this subgroup should be considered.

Increased risk of incident osteoporosis and osteoporotic fracture in tuberculosis patients: a population-based study in a tuberculosis-endemic area.

The occurrence of osteoporosis in tuberculosis, a chronic infection, has rarely been evaluated. In this study, we found significantly higher incidence rates of osteoporosis (Adjusted hazard ratio (AHR) 1.82) and osteoporotic fracture (AHR 2.33) in tuberculosis patients than matched cohorts, which suggest that osteoporosis screening should be considered in tuberculosis patients' follow-up program. The aim of this study is to determine the occurrence of incident osteoporosis in patients who completed anti-tuberculosis (TB) treatment. INTRODUCTION: Chronic inflammatory disorders are associated with an increased risk of osteoporosis. Although TB is an infectious disease characterized by systemic inflammatory responses, the impact of active TB on incident osteoporosis is unclear. We used the Taiwan National Health Insurance Research Database to investigate the association between history of active TB and incident osteoporosis and osteoporotic fracture. METHODS: In this nationwide retrospective cohort study, active TB patients and their age- and sex-matched controls were identified from the National Health Insurance Research Database in Taiwan during 2000-2012. The occurrence of incident osteoporosis, osteoporotic fractures, and risk factors associated with osteoporosis among TB patients and matched controls were analyzed. RESULTS: We observed incident osteoporosis in 2.2% (n = 86) of the TB patients and in 1.1% (n = 162) of the matched controls. The incidence rate of osteoporosis was 4.31 and 1.80 per 1000 person-years, which was significantly higher in TB patients (p < 0.001). In multivariate analysis, TB was an independent risk factor for osteoporosis. The other independent factors associated with osteoporosis were older age, female sex, chronic obstructive pulmonary disease, asthma, and lower income. Moreover, we demonstrated that the occurrence of osteoporotic fracture was significantly higher in TB patients. CONCLUSIONS: Patients with a history of active TB have a higher incidence rate of osteoporosis and osteoporotic fracture.

Determinants of mortality in elderly patients with tuberculosis: a population-based follow-up study.

Elderly individuals with tuberculosis (TB) are more likely to have a non-specific clinical presentation of TB and high mortality. However, factors associated with mortality in elderly TB patients have not been extensively studied. This retrospective cohort study aimed to identify factors associated with death among elderly Taiwanese with TB. All elderly patients with TB from 2006 to 2014 in Taipei, Taiwan, were included in a study. Multiple logistic regression was used to identify the factors associated with death in elderly TB patients. The mean age of the 5011 patients was 79·7 years; 74·1% were men; 32·7% had mortality during the study follow-up period. After controlling for potential confounders, age ⩾75 years (reference: 65-74 years), male sex, end-stage renal disease (ESRD), malignancy, acid-fast bacilli-smear positivity, TB-culture positivity, pleural effusion on chest radiograph and notification by an ordinary ward or intensive care unit were associated with a higher risk of all-cause death; while high school, and university or higher education, cavity on chest radiograph and directly observed therapy were associated with a lower risk of all-cause death. This study found that the proportion of death among elderly patients with TB in Taipei, Taiwan, was high. To improve TB treatment outcomes, future control programmes should particularly target individuals with comorbidities (e.g. ESRD and malignancy) and those with a lower socio-economic status (e.g. not educated).

Use of cloud radar Doppler spectra to evaluate stratocumulus drizzle size distributions in large-eddy simulations with size-resolved microphysics.

A case study of persistent stratocumulus over the Azores is simulated using two independent large-eddy simulation (LES) models with bin microphysics, and forward-simulated cloud radar Doppler moments and spectra are compared with observations. Neither model is able to reproduce the monotonic increase of downward mean Doppler velocity with increasing reflectivity that is observed under a variety of conditions, but for differing reasons. To a varying degree, both models also exhibit a tendency to produce too many of the largest droplets, leading to excessive skewness in Doppler velocity distributions, especially below cloud base. Excessive skewness appears to be associated with an insufficiently sharp reduction in droplet number concentration at diameters larger than ~200 µm, where a pronounced shoulder is found for in situ observations and a sharp reduction in reflectivity size distribution is associated with relatively narrow observed Doppler spectra. Effectively using LES with bin microphysics to study drizzle formation and evolution in cloud Doppler radar data evidently requires reducing numerical diffusivity in the treatment of the stochastic collection equation; if that is accomplished sufficiently to reproduce typical spectra, progress toward understanding drizzle processes is likely.

Better adherence to antithyroid drug is associated with decreased risk of stroke in hyperthyroidism patients.

BACKGROUND: An increased risk for ischaemic stroke has been reported in young hyperthyroidism patients independent of atrial fibrillation (AF). However, whether the use of antithyroid drugs in hyperthyroidism patients can reduce the occurrence of ischaemic stroke remains unclear. METHODS: A total of 36,510 newly diagnosed hyperthyroidism patients during 2003-2006 were identified from the Taiwan National Health Insurance Research database. Each patient was individually tracked for 5 years from their index date (beginning the antithyroid drugs) to identify those who suffered from new episode of ischaemic stroke. Medication possession ratio (MPR) was used to represent the antithyroid drug compliance. The association between the MPR and the risk of stroke was examined. RESULTS: The stroke incidence rates for hyperthyroidism patients with age < 45 years and age ≥ 45 years were 0.42 and 3.76 per 1000 person-years, respectively. The patients aged < 45 years with MPR < 0.2 (adjusted hazard ratio, HR, 2.30; 95% CI, 1.13-4.70; p = 0.02) and 0.2 ≤ MPR < 0.4 (adjusted HR, 2.24; 95% CI, 1.06-4.72; p = 0.035) had a significantly increased risk of ischaemic stroke as compared to those with ≥ 0.6. In patients of the age ≥ 45 years, only the patients with MPR < 0.2 (adjusted HR, 1.44; 95% CI, 1.03-2.01; p = 0.036) had a significantly higher risk of ischaemic stroke as compared to those with MPR ≥ 0.6. In hyperthyroidism patients without AF, good antithyroid drugs compliance also reduced the incidence of stroke significantly (adjusted HR, range: 1.52-1.61; p = 0.02); but not in hyperthyroidism with AF. CONCLUSION: Hyperthyroidism patients with good antithyroid drug compliance had a lower risk of ischaemic stroke than patients with poor compliance.

Noninvasive assessment of liver fibrosis via spleen stiffness measurement using acoustic radiation force impulse sonoelastography in patients with chronic hepatitis B or C.

Portal hypertension and splenomegaly are common in patients with cirrhosis. However, there is limited previous in vivo research on the correlation between spleen stiffness and stages of liver fibrosis. This study aimed to evaluate the diagnostic value of spleen stiffness measurement (SSM), using acoustic radiation force impulse (ARFI) technology, for liver fibrosis assessment. Eligible patients with chronic hepatitis B or C (n = 163) underwent concurrent liver stiffness measurement (LSM), SSM and percutaneous liver biopsy. Receiver operating characteristic curves estimated the diagnostic performance of SSM, with multiple linear regression models for LSM and SSM determining the significance of explanatory factors. Results indicated significant correlation between LSM and SSM (R(2) = 0.574, P < 0.0001). Using SSM to classify METAVIR fibrosis (METAVIR F) scores, the areas under curves were 0.839 (95% CI: 0.780-0.898) for METAVIR F1 vs F2-4, 0.936 (95% CI: 0.898-0.975) for F1-2 vs F3-4 and 0.932 (95% CI: 0.893-0.971) for F1-3 vs F4, all P < 0.001. Multiple linear regression models identified BMI, spleen stiffness, METAVIR F3 and F4, serum alanine aminotransferase, international normalized ratio of prothrombin time, sodium and platelet count as significant independent explanatory factors for liver stiffness (adjusted R(2) = 0.724, P < 0.001). Male gender, liver stiffness, METAVIR F2, F3 and F4 also significantly and independently explained spleen stiffness (adjusted R(2) = 0.647, P < 0.001). ARFI SSM is potentially useful as a single or adjunct predictor of stages of liver fibrosis.

DOT associated with reduced all-cause mortality among tuberculosis patients in Taipei, Taiwan, 2006-2008.

OBJECTIVE: To determine whether patients receiving directly observed treatment (DOT) had lower all-cause mortality than those treated with self-administered treatment (SAT) and to identify factors associated with mortality among tuberculosis (TB) patients. DESIGN: All TB patients in Taipei, Taiwan, diagnosed between 2006 and 2008 were included in a retrospective cohort study. RESULTS: Among 3624 TB patients, 45.5% received DOT, which was disproportionately offered to older patients and those with more underlying illness and severe TB disease. After controlling for patients' sociodemographic factors, clinical findings and underlying comorbidities, the odds of death were 40% lower (aOR 0.60, 95%CI 0.5-0.8) among patients treated with DOT than those on SAT. After adjusting for DOT, independent predictors of death included non-Taiwan birth, increasing age, male, unemployment, end-stage renal disease requiring dialysis, malignancy, acid-fast bacilli smear positivity and pleural effusion. CONCLUSION: DOT was associated with lower all-cause mortality after controlling for confounding factors. DOT should be expanded in Taiwan to improve critical treatment outcomes among TB patients.

A novel radioresistant mechanism of galectin-1 mediated by H-Ras-dependent pathways in cervical cancer cells.

Galectin-1 is a lectin recognized by galactoside-containing glycoproteins, and is involved in cancer progression and metastasis. The role of galectin-1 in radiosensitivity has not previously been investigated. Therefore, this study tests whether galectin-1 is involved in the radiosensitivity mediated by the H-Ras signaling pathway using cervical carcinoma cell lines. A knockdown of galectin-1 expression in HeLa cells decreased clonogenic survival following irradiation. The clonogenic survival increased in both HeLa and C33A cells with galectin-1 overexpression. The overexpression or knockdown of galectin-1 did not alter radiosensitivity, whereas H-Ras was silenced in both cell lines. Whereas K-Ras was knocked down, galectin-1 restored the radiosensitivity in HeLa cells and C33A cells. The knockdown of galectin-1 increased the high-dose radiation-induced cell death of HeLa cells transfected by constitutively active H-Ras. The knockdown of galectin-1 inhibited the radiation-induced phosphorylation of Raf-1 and ERK in HeLa cells. Overexpression of galectin-1 enhanced the phosphorylation of Raf-1 and ERK in C33A cells following irradiation. Galectin-1 decreased the DNA damage detected using comet assay and γ-H2AX in both cells following irradiation. These findings suggest that galectin-1 mediates radioresistance through the H-Ras-dependent pathway involved in DNA damage repair.

Early serum HBsAg level as a strong predictor of sustained response to peginterferon alfa-2a in HBeAg-negative chronic hepatitis B.

BACKGROUND: The roles remain unclear of early on-treatment quantitative serum HBsAg and hepatitis B virus (HBV) DNA levels in the prediction of a sustained response (SR) to peginterferon alfa-2a therapy in HBeAg-negative chronic hepatitis B (CHB) patients infected with genotype B or C. AIMS: To determine their roles in HBeAg-negative CHB patients infected with genotype B or C. METHODS: Sixty-one patients were treated with peginterferon alfa-2a for 48 weeks. Serum HBsAg levels were quantified using the Abbott Architect HBsAg QT assay throughout treatment. Multiple regression analyses were performed to identify independent predictors of SR. RESULTS: Nineteen patients (31%) achieved SR with serum HBV DNA levels <312 copies/mL at 24 weeks post-treatment. Serum HBsAg levels at 12 (OR 31.9; 95% CI 4.8-209.6; P = 0.0003) and 24 weeks of therapy (OR 8.8; 95% CI 2.0-38.0; P = 0.0035), and HBV DNA levels at baseline (OR 7.0; 95% CI 1.3-36.2; P = 0.0203), 12 (OR 7.9; 95% CI 1.2-48.4; P = 0.0249) and 24 weeks of therapy (OR 22.3; 95% CI 2.2-224.0; P = 0.0083) were early independent predictors of SR. A serum HBsAg cut-off of 150 IU/mL at week 12 had an AUC, sensitivity, specificity and positive and negative predictive values of 0.75, 63%, 95%, 86% and 85% with respect to predicting SR respectively. CONCLUSIONS: A quantitative serum HBsAg level at 12 weeks of therapy can be used for the early prediction of SR to peginterferon therapy in HBeAg-negative CHB patients infected with genotype B or C.

Polytetrafluoroethylene patch venoplasty for outflow reconstruction in living donor liver transplantation: two case reports.

Outflow obstruction may lead to liver congestion and eventual graft failure after living donor liver transplantation. Various methods of venoplasty provide wider outflow tracts. Most series have suggested use of autologous or allogenic grafts for patch venoplasty. We used a polytetrafluorethylene patch in two patients. Both showed good patency of the outflow tract at Doppler ultrasonography at 7 months and 4 months posttransplantation. A polytetrafluoroethylene patch may be a good alternative when no other autologous or allogeneic vascular patch is available or when the situation is critical.

Advanced glycation endproducts induce podocyte apoptosis by activation of the FOXO4 transcription factor.

Advanced glycation endproducts (AGEs) and a receptor for AGEs (RAGE) have been linked in the pathogenesis of diabetic nephropathy. RAGE is usually localized to podocytes and is increased in diabetes. RAGE activation increases reactive oxygen species production, which mediates hyperglycemia-induced podocyte apoptosis in early diabetic nephropathy. Here, we examined the interaction of AGE and RAGE on podocyte apoptosis. When we exposed murine cultured podocytes to bovine serum albumin (BSA) that was modified by AGEs or to carboxymethyl-lysine BSA, more apoptosis was found when compared with unmodified BSA. Similarly, more podocytes underwent detachment and apoptosis when cultured on AGE-modified collagen IV than on native collagen IV. AGEs isolated from sera of patients with chronic kidney disease also caused apoptosis of podocytes. Apoptosis was diminished by small interference RNA (siRNA) for RAGE in podocytes exposed to AGE-BSA, but not to AGE-modified collagen IV. Both AGE- and carboxymethyl-lysine modified-BSA activated p38MAP kinase and inhibition of this kinase reduced the apoptotic effect of AGE-BSA. Exposure to AGE-BSA was associated with Akt dephosphorylation and FOXO4 transcriptional activation leading to an increase in the expression of an effector protein of apoptosis, Bim. siRNA for FOXO4 abolished AGE-BSA-induced apoptosis of podocytes. Our study suggests that an AGE-RAGE interaction contributes to podocyte apoptosis by activation of the FOXO4 transcription factor.

Clobetasol ameliorates aphthous ulceration in renal transplant patients on sirolimus.

Aphthous ulceration is a common side effect of sirolimus. These lesions of the oral mucous membranes are often painful and debilitating, leading to either dose reduction or discontinuation of sirolimus in a significant number of patients. We report that the direct application of clobetasol, a high potency topical steroid, led to prompt resolution of the aphthous ulcers that developed in our renal transplant patients on sirolimus-based immunosuppression.

The hedgehog regulated oncogenes Gli1 and Gli2 block myoblast differentiation by inhibiting MyoD-mediated transcriptional activation.

The mechanism by which activation of the Hedgehog (Hh) pathway modulates differentiation and promotes oncogenesis in specific tissues is poorly understood. We therefore, analysed rhabdomyosarcomas from mice that were haploinsufficient for the Hh-binding protein, Hip1, or for the Hh receptor, Patched 1 (Ptch1). Transfection of the Hh-regulated transcription factor Gli1, which is expressed in a subset of mouse and human rhabdomyosarcomas, suppressed differentiation of myogenic rhabdomyosarcoma lines generated from Hip1+/- and Ptch1+/- mice. The closely related factor, Gli2, had similar effects. Gli1 and Gli2 inhibited myogenesis by repressing the capacity of MyoD to activate transcription. Deletion analysis of Gli1 indicated that multiple domains of Gli1 are required for efficient inhibition of MyoD. Gli1 reduced the ability of MyoD to heterodimerize with E12 and bind DNA, providing one mechanism whereby the Gli proteins modulate the activity of MyoD. This novel activity of Gli proteins provides new insights into how Hh signaling modulates terminal differentiation through inhibition of tissue-specific factors such as MyoD. This mechanism may contribute to the broad role of Hh signaling and the Gli proteins in differentiation decisions and cancer formation.

Glucose and diabetes: effects on podocyte and glomerular p38MAPK, heat shock protein 25, and actin cytoskeleton.

Phosphorylated p38 (pp38) mitogen-activated protein kinase (MAPK) regulates heat shock protein 25 (HSP25), stabilizing fibrillar actin (FA) and preventing cleavage to G-actin (GA). Cultured podocytes (Pods) were exposed to glucose (5.5-50 mM)+/-p38MAPK inhibitor SB202190 (SB) or control SB202474 to assess the effects on FA/GA and Pod structure. The relationship of p38MAPK with in vivo Pod structure and albuminuria (Ualb) was assessed in rats with streptozotocin (SZ)-induced diabetes (DM) for 1 week, 1 month, and 4 months. High glucose induced concentration-dependent increases in pp38MAPK and phosphorylated HSP25 (pHSP25) maintained actin cytoskeleton. Inhibition by SB diminished pp38MAPK and pHSP25, decreased FA/GA, and altered FA and GA immunohistochemical appearance. In SZ-DM, glomerular pp38MAPK and biphosphorylated HSP25 were increased after 1 week, declining at 1 month, and at or below C values at 4 months. Glomerular FA/GA in DM was normal at 1 week, declining at 1 month, and low at 4 months. Ualb/creatinine was similar in DM vs C at 1 week, and increased at 1 and 4 months. Morphometry demonstrated progressively diminishing slit pore density in DM over time, denoting evolving effacement. There were strong correlations between slit membrane density and both glomerular biphosphorylated HSP25 and ln Ualb/cr ratio. The data suggest that increased pp38MAPK and pHSP25 comprise an acute adaptation to glycemic stress. Later depletion of DM may contribute to Pod structural alterations and Ualb.

Predictors of cardiovascular events and associated mortality within two years of kidney transplantation.

BACKGROUND: Cardiovascular disease is the most common cause of death after renal transplantation. Furthermore, acute coronary syndrome (ACS) attributable to coronary artery disease (CAD) accounts for the majority of deaths due to cardiovascular disease posttransplant. While renal transplantation is the treatment of choice for end-stage renal disease, understanding the causes of graft and patient loss is exceedingly important to improve outcomes. METHODS: This observational case-controlled study included 780 patients who underwent a kidney transplant between 1989 and 2001 who experienced early ACS (within 2 years). Patients were compared with controls matched for gender, year of transplant, and age. The primary outcome was the occurrence of an ACS event within 2 years after renal transplantation. RESULTS: Cardiovascular disease was the most common cause of death, with all 13 cardiovascular deaths due to CAD. An additional 15 episodes of nonfatal ACS episodes occurred. Thirty-seven percent of early ACS occurred perioperatively, the majority in the first 3 posttransplant months. On multivariate analysis, diabetes (OR [odds ratio] 5.56; P = .0007), smoking (OR 3.56; P = .034), and prior transplant (OR 2.81; P = .047) were associated with early ACS. CONCLUSIONS: Diabetes, smoking, and prior transplant were significantly associated with early ACS. The majority of events occurred perioperatively or within 3 months of transplant, highlighting the importance of improved screening and perioperative management.

A case review: anticoagulation in hemodialysis patients with heparin-induced thrombocytopenia.

We describe a patient with acute renal failure who subsequently developed heparin-induced thrombocytopenia (HIT) while on hemodialysis. Heparin was immediately discontinued and alternative modes of anticoagulation were considered as further hemodialysis was indicated. With several options available, a review of the current literature was performed to aid in the selection of the most appropriate method. We conclude that there is currently no ideal hemodialysis anticoagulation agent for a patient with HIT. Among the currently available alternatives, no anticoagulation or regional citrate infusion during hemodialysis appears to be the most reliable and safest option for these patients. Based upon its safety, reversibility, low cost and availability, a trial of warfarin also may be attempted for hemodialysis anticoagulation. Both danapranoid and lepirudin have been used effectively in hemodialysis patients with HIT, but have the disadvantage of prolonged half-lives in patients with renal failure and relatively high cost.

Activation of expression of hedgehog target genes in basal cell carcinomas.

Mutations in hedgehog signaling pathway genes, especially PTC1 and SMO, are pivotal to the development of basal cell carcinomas. The study of basal cell carcinoma gene expression not only may elucidate mechanisms by which hedgehog signaling abnormalities produce aberrant tumor cell behavior but also can provide data on in vivo hedgehog target gene control in humans. We have found, in comparison with normal skin, that basal cell carcinomas have increased levels of mRNA for PTC1, GLI1, HIP, WNT2B, and WNT5a; decreased levels of mRNA for c-MYC, c-FOS, and WNT4; and unchanged levels of mRNA for PTC2, GLI2, WNT7B, and BMP2 and 4. These findings suggest that mutations in hedgehog signaling pathway genes may exert both cell autonomous and indirect effects and indicate that basal cell carcinoma tumor cells have a phenotype that at least in some aspects resembles that of epidermal stem cells.