The Resolution Rate of Pulmonary Embolism on CT Pulmonary Angiography: a Prospective Study.

PURPOSE: To prospectively assess the rate of clot resolution from CT pulmonary angiography (CTPA) in patients with acute pulmonary embolism (PE). MATERIALS AND METHODS: This prospective cohort study included 290 patients (136 men, 154 women; mean age, 51.9 years) with acute PE. All patients had a CTPA at the presentation and had at least one follow-up within 6 months (mean 72.7 days). Sixty-four percent of patients had follow-up scans for research purposes within a pre-determined period (between 28 and 184 days; mean, 78.27 days) and 36 % had (between 2 and 184 days; mean, 62.78 days) for a clinical indication. The volume of each clot was measured using a semi-automated quantification program. The resolution rate was evaluated by interval-censored analysis. RESULTS: The overall estimated probability of complete resolution was 42 % at 7 days, 56 % at 10 days, and 71 % at 45 days. Achieving complete resolution was significantly faster in patients with peripheral clots (HR: 1.78; CI: 1.05-3.03, p = 0.032) but slower in patients with consolidation and history of venous thromboembolism (VTE), (HR: 0.37; CI: 0.18-0.79, p = 0.01 and HR: 0.57; CI: 0.35-0.91, p = 0.019, respectively). Although the patients with cancer showed a faster resolution rate (HR: 1.67; CI: 1.05-2.68, p = 0.032), the mortality rate was significantly higher than non-cancer patients. CONCLUSION: The resolution rate of clot burden in acute PE was associated with patients' clinical presentation variables and CTPA imaging biomarkers. This information may be incorporated into designing a prediction rule and determining the appropriate duration of anticoagulation therapy in patients with acute PE.

Synovial fluid interleukin-16, interleukin-18, and CRELD2 as novel biomarkers of prosthetic joint infections.

OBJECTIVES: Prosthetic joint infection (PJI) diagnosis is a major challenge in orthopaedics, and no reliable parameters have been established for accurate, preoperative predictions in the differential diagnosis of aseptic loosening or PJI. This study surveyed factors in synovial fluid (SF) for improving PJI diagnosis. METHODS: We enrolled 48 patients (including 39 PJI and nine aseptic loosening cases) who required knee/hip revision surgery between January 2016 and December 2017. The PJI diagnosis was established according to the Musculoskeletal Infection Society (MSIS) criteria. SF was used to survey factors by protein array and enzyme-linked immunosorbent assay to compare protein expression patterns in SF among three groups (aseptic loosening and first- and second-stage surgery). We compared routine clinical test data, such as C-reactive protein level and leucocyte number, with potential biomarker data to assess the diagnostic ability for PJI within the same patient groups. RESULTS: Cut-off values of 1473 pg/ml, 359 pg/ml, and 8.45 pg/ml were established for interleukin (IL)-16, IL-18, and cysteine-rich with EGF-like domains 2 (CRELD2), respectively. Receiver operating characteristic curve analysis showed that these factors exhibited an accuracy of 1 as predictors of PJI. These factors represent potential biomarkers for decisions associated with prosthesis reimplantation based on their ability to return to baseline values following the completion of debridement. CONCLUSION: IL-16, IL-18, and CRELD2 were found to be potential biomarkers for PJI diagnosis, with SF tests outperforming blood tests in accuracy. These factors could be useful for assessing successful debridement based on their ability to return to baseline values following the completion of debridement.Cite this article: M-F. Chen, C-H. Chang, L-Y. Yang, P-H. Hsieh, H-N. Shih, S. W. N. Ueng, Y. Chang. Synovial fluid interleukin-16, interleukin-18, and CRELD2 as novel biomarkers of prosthetic joint infections. Bone Joint Res 2019;8:179-188. DOI: 10.1302/2046-3758.84.BJR-2018-0291.R1.

The relationship of the anterior articular capsule to the adjacent subscapularis: An anatomic and histological study.

INTRODUCTION: The purpose of this study was to delineate the anatomic relationship between the anterior articular capsule and the adjacent subscapularis by measuring the dimensions of the anterior articular capsule attachment and the subscapularis footprint on the humerus, as well as investigating the interface between the two structures. MATERIALS AND METHODS: Three shoulder specimens underwent histological analysis; for histological analysis, cross-sections through the subscapularis-capsule complex were harvested at the tendinous and muscular insertion sites. The dimensions of the anterior articular capsule attachment and the subscapularis footprint (including the tendinous and muscular insertions) were measured in thirteen cadaveric shoulder specimens. RESULTS: Histologically, the articular capsule has thin and loosely arranged collagen fibers with many interspersing fibroblast nuclei, whereas the outer layer of the articular capsule blends into a layer of more loosely spaced and less organized collagen fibers. This interface between the subscapularis and the underlying articular capsule is filled with more loosely spaced and less organized collagen fibers. The macroscopic evaluation showed that the minimum articular capsule width (4.2mm, SD 2.2mm) was located at its initiation 4.9mm (SD, 2.1mm) inferior to the superior margin of the subscapularis; the corresponding subscapularis footprint width measured 10.1mm (SD, 4.9mm). The maximum articular capsule width was11.1 mm (SD, 3.7mm) and was located 5mm distal to the inferior margin of the tendinous footprint. The maximum subscapularis footprint width was 15.8mm (SD, 2.9mm); the corresponding articular capsule attachment measured 5.2mm (SD, 1.8mm). CONCLUSIONS: Our results suggest that the anterior articular capsule attachment of the glenohumeral joint complements the footprint of the subscapularis and occupies a larger area of the lesser tubercle and metaphysis of the humerus than previously documented. The histological study confirms the presence of a demarcation between the subscapularis and articular capsule, specifically more significant at the region medial to the tendon insertion and at the muscular insertion of the subscapularis.

Risk of age-related macular degeneration in patients with prostate cancer: a nationwide, population-based cohort study.

BACKGROUND: Prostate cancer (PC) can be related to increased systemic oxidative stress and dihydrotestosterone level, which are also reported to be involved in the pathogenesis of age-related macular degeneration (AMD). We conducted a cohort study to determine whether patients with PC have an increased risk of AMD. PATIENTS AND METHODS: Data were collected from the Taiwan Longitudinal Health Insurance Database for the 1999-2010 period. The study PC cohort comprised 22 084 patients aged ≥18 years with a first diagnosis of PC. The comparison cohort consisted of age-, occupation-, and urbanization level-matched patients at a ratio of 1 : 1. The primary outcome was the incidence of AMD, which was evaluated using Kaplan-Meier survival analysis and proportional hazards modeling. RESULTS: The mean follow-up periods (standard deviation) for the patients with AMD in the age-, occupation-, and urbanization level-matched PC cohort and non-PC cohorts were 4.69 (2.90) and 5.51 (2.82) years. The mean age of the PC cohort was 73.9 years and that of the non-PC cohort was 73.2 years, with approximately 85.9% of the patients aged >65 years. The PC cohort had a higher risk of AMD than did the propensity score-matched non-PC cohort with an adjusted hazard ratio of 1.25 (95% confidence interval, 1.12-1.39). Compared with PC cohort receiving no injection hormone therapy, the PC cohort receiving injection hormone therapy had a lower risk of AMD (adjusted hazard ratio, 0.56; 95% confidence interval, 0.41-0.76). CONCLUSION: PC is associated with an increased risk of AMD. Patients with PC receiving injected form of androgen deprivation therapy had a lower risk of AMD than patients with PC not receiving injected form of androgen-deprivation therapy.

Impacts of treatments on the quality of life among esophageal squamous cell carcinoma patients.

This study aims to investigate the effects of treatments on the quality of life for patients with esophageal squamous cell carcinoma patients diagnosed at early and late stages. From a medical center in central Taiwan, patients who had been diagnosed with esophageal squamous cell carcinoma from February 2007 and March 2011 were recruited. Using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Quality of Life Questionnaire Oesophageal 18 (QLQ-OES18), quality of life scores for 105 esophageal squamous cell carcinoma patients were obtained and assessed. Multivariate analysis was performed on the quality of life scores after stratification by cancer stage. Among early-stage esophageal squamous cell carcinoma patients, those received only surgery (S-only) performed better in physical and social functioning compared with patients who underwent surgery and concurrent chemoradiotherapy (S+CCRT) (ß = 9.0, P = 0.03; ß = 12.1, P = 0.04, respectively). For those that received only concurrent chemoradiotherapy (CCRT-only), they performed worse in role and emotional functioning relative to S+CCRT patients (ß = -17.2, P = 0.02; ß = -15.7, P = 0.05, respectively). Among late-stage patients, CCRT-only treatment gave insignificantly better global health status and functional scale scores and less severe symptoms compared to the S+CCRT option. Better functional scores and less aggravated symptoms are observed in early-stage esophageal squamous cell carcinoma patients who received surgery-only treatment relative to those that underwent both surgery and chemoradiotherapy. For late-stage esophageal cancer patients, the measured difference of quality of life is not significant between CCRT-only and S+CCRT treatments.

Association between thyroid dysfunction and dysglycaemia: a prospective cohort study.

AIMS: To compare the incidence of hyperglycaemia among participants with low, elevated and normal serum thyroid-stimulating hormone concentration, as well as the incidence of abnormal thyroid function test results among participants with normal blood glucose and those with hyperglycaemia. METHODS: In a prospective study, a cohort of 72 003 participants with normal, low and elevated serum thyroid-stimulating hormone concentration were followed from the study beginning to the first report of diabetes and prediabetes. A proportional hazards regression model was used to calculate the hazard ratios and 95% CIs for each outcome, adjusting for age, sex, education level, smoking, alcohol consumption and obesity. Analyses for the association between dysglycaemia and incident abnormal thyroid function test were also conducted. RESULTS: During a median 2.6 year follow-up, the incident rates for dysglycaemia, particularly prediabetes, were substantially higher in participants with elevated thyroid-stimulating hormone concentrations at baseline, while the rates for participants with normal and low thyroid-stimulating hormone were similar. After controlling for risk factors, participants with elevated thyroid-stimulating hormone retained a 15% increase in risk of prediabetes (adjusted hazard ratio 1.15, 95% CI 1.04-1.26), but were not at greater risk of diabetes (adjusted hazard ratio 0.96, 95% CI 0.64-1.44). By contrast, participants with normal and low thyroid-stimulating hormone concentrations had similar dysglycaemia risks. Participants with diabetes and prediabetes were not at greater risks of developing abnormal thyroid function test results when compared with participants with euglycaemia. CONCLUSIONS: People with elevated serum thyroid-stimulating hormone concentration are at greater risk of developing prediabetes. Whether this includes a greater risk of developing frank diabetes may require an extended period of follow-up to clarify.

Association between teriparatide treatment persistence and adherence, and fracture incidence in Taiwan: analysis using the National Health Insurance Research Database.

UNLABELLED: Medication persistence and adherence are critical for osteoporosis outcomes. Using the Taiwan National Health Insurance Research Database, we found that persistence and adherence to teriparatide were low in Taiwanese patients with osteoporosis and that greater persistence and adherence were associated with a lower incidence of hip and other nonvertebral fractures. INTRODUCTION: The purpose of this study was to determine the persistence and adherence to teriparatide treatment in Taiwanese patients with osteoporosis, and to examine the association between persistence and adherence to teriparatide with fracture risks. METHODS: Medical and pharmacy claims for 4,692 patients with vertebral or hip fractures and teriparatide prescriptions between 2005 and 2008 were identified (Taiwan National Health Insurance Research Database). Persistence was the time from the start of treatment to the first 90-day gap between two teriparatide prescriptions. Adherence was the number of teriparatide pens (each pen is used over 1 month) prescribed over 24 months. Association of persistence and adherence to teriparatide with fracture incidence was assessed using adjusted Cox proportional hazards models. RESULTS: The proportion of patients persisting with teriparatide for >6 months and >12 months was 44.6 and 24.9 %, respectively. Over 24 months, 53.6 % of patients were adherent for >6 months and 33.9 % were adherent for >12 months. Patients persisting for >12 months had a significantly lower incidence of hip (adjusted hazard ratio [HR], 0.61 [95 % confidence interval (CI), 0.40-0.93], P = 0.0229) and nonvertebral fracture (HR, 0.79 [95 % CI, 0.63-0.99], P = 0.0462) compared with those who persisted for ≤12 months. Patients adherent for >12 months had a lower incidence of hip (HR, 0.66 [95 % CI, 0.46-0.96], P = 0.0286) and nonvertebral fracture (HR, 0.81 [95 % CI, 0.66-0.99], P = 0.0377) compared with those adherent for ≤12 months. CONCLUSIONS: Persistence and adherence to teriparatide over 24 months were low in Taiwanese patients with osteoporosis; greater adherence and persistence were associated with a lower incidence of nonvertebral fractures.

Effect of detrusor botulinum toxin a injection on urothelial dysfunction in patients with chronic spinal cord injury: a clinical and immunohistochemistry study before and after treatment.

OBJECTIVE: The objective of this study is to investigate the changes of urothelial junction proteins, apoptosis and suburothelial inflammation after detrusor injection of botulinum toxin A (BoNT-A) in patients with spinal cord injury (SCI) and neurogenic detrusor overactivity (NDO). METHODS: A total of 26 patients with chronic suprasacral SCI and NDO were enroled. The urothelium was assessed by cystoscopic biopsy at baseline, 3 and 6 months after a single treatment of 300 U BoNT-A into the detrusor. Immunofluorescence staining of E-cadherin, zonula occludens-1 (ZO-1) and tryptase for mast cell activity were performed. Urothelial apoptosis was also evaluated. The differences in urothelial dysfunction were compared between baseline and 3 and 6 months after treatment. Bladder biopsies from patients undergoing anti-incontinence surgery served as controls. RESULTS: A single 300-U BoNT-A injection into the detrusor significantly decreased detrusor pressure and increased bladder compliance at 3 and 6 months after treatment. Significantly lower E-cadherin and ZO-1 expressions and increased mast cell and apoptotic cell counts were noted in SCI bladders compared with controls (all P<0.001). Significantly greater distributions of E-cadherin (P<0.001) and ZO-1 (P=0.05) expressions were noted 3 months after BoNT-A injection. However, these changes had declined by 6 months after treatment. Activated mast cells and urothelial apoptosis showed no significant differences between baseline and 3 or 6 months. CONCLUSION: Urothelial dysfunction and adhesive and junction protein concentrations in SCI patients' bladders recovered after BoNT-A treatment. However, this effect decreased with time. Thus, neurogenic inflammation after SCI was not adequately improved after a single BoNT-A injection.

Cardiovascular risks associated with second-line oral antidiabetic agents added to metformin in patients with Type 2 diabetes: a nationwide cohort study.

AIM: To compare the cardiovascular risks associated with second-line oral antidiabetic agents added to initial metformin therapy in a large nationwide observational study. METHODS: We conducted a nationwide retrospective cohort study using the Taiwan National Health Insurance database. A total of 36 118 users of different add-on oral antidiabetic agents (sulphonylureas, glinides, pioglitazone, α-glucosidase inhibitors and dipeptidyl peptidase-4 inhibitors) after initial metformin therapy were included in the analysis. The reference group was sulphonylureas added to metformin, the most commonly used combination regimen. The main outcomes of interest were hospitalizations for any cardiovascular event including acute myocardial infarction, congestive heart failure and ischaemic stroke. In the main analysis, all patients were followed within their initiation groups until the study end, disregarding any changes in treatment status over time. RESULTS: In intention-to-treat analyses, there was no difference in the risk of any cardiovascular event among the add-on combination treatment groups, but significantly lower risks of acute myocardial infarction were found for the glinides plus metformin treatment group (crude hazard ratio 0.52, adjusted hazard ratio 0.39; 95% CI 0.20-0.75) and for the α-glucosidase inhibitors plus metformin treatment group (crude hazard ratio 0.63, adjusted hazard ratio 0.54; 95% CI 0.31-0.95). No difference in risk of congestive heart failure or ischaemic stroke risk was found among the combination treatment groups. In secondary as-treated analyses, similar but less significant associations were found as compared with the primary intention-to-treat analyses for all treatment groups. CONCLUSION: There were no differences in overall cardiovascular risks among several add-on second-line oral antidiabetic agents; however, glinide plus metformin and α-glucosidase inhibitors plus metformin combination therapies might be associated with lower risks of acute myocardial infarction.

Pulsed radiofrequency inhibited activation of spinal mitogen-activated protein kinases and ameliorated early neuropathic pain in rats.

Background: Pulsed radiofrequency (PRF) has been widely used to treat chronic pain, but the effectiveness and mechanisms in preventing early neuropathic pain have not been well explored. Even fewer knowledge is available in its impact on glia-mediated nociceptive sensitization. This study aims to elucidate the modulation of PRF on nerve injury-induced pain development and activation of spinal mitogen-activated protein kinases (MAPKs). Methods: In a rat spinal nerve ligation (SNL) model, a low-volt PRF treatment was applied to the L5 dorsal root ganglion after nerve injury. Nociceptive behaviours were measured by von Frey and heat withdrawal tests at multiple time points. MAPK activations, including p-ERK and p-p38, as well as TNF-á level in the spinal dorsal horn were assessed and the cell types that expressed MAPK activation were identified by double immuno fluorescence staining.Results: We found that SNL promptly induced neuropathic pain in the affected hind limb for over 1 week as well as increased p-ERK and p-p38 in the spinal dorsal horn. PRF significantly attenuated SNL-induced mechanical allodynia and thermal hyperalgesia for 5­7 days. PRF also inhibited ERK and p38 activations, which were found majorly located within neurons and microglia, respectively. Besides, PRF significantly suppressed expression of TNF-á in the spinal dorsal horn throughout the course. Conclusions: Low-volt PRF significantly ameliorated SNL-induced acute pain. Inferentially, PRF may inhibit spinal sensitization by down-regulating spinal MAPK activations and activation-mediated cytokine release.We demonstrated that early PRF treatment in acute nerve injury helps to ameliorate neuropathic pain development.

Long-term evaluation of mesenchymal stem cell therapy in a feline model of chronic allergic asthma.

BACKGROUND: Mesenchymal stem cells (MSCs) decrease airway eosinophilia, airway hyperresponsiveness (AHR), and remodelling in murine models of acutely induced asthma. We hypothesized that MSCs would diminish these hallmark features in a chronic feline asthma model. OBJECTIVE: To document effects of allogeneic, adipose-derived MSCs on airway inflammation, AHR, and remodelling over time and investigate mechanisms by which MSCs alter local and systemic immunologic responses in chronic experimental feline allergic asthma. METHODS: Cats with chronic, experimentally induced asthma received six intravenous infusions of MSCs (0.36-2.5 × 10E7 MSCs/infusion) or placebo bimonthly at the time of study enrollment. Cats were evaluated at baseline and longitudinally for 1 year. Outcome measures included: bronchoalveolar lavage fluid cytology to assess airway eosinophilia, pulmonary mechanics and clinical scoring to assess AHR, and thoracic computed tomographic (CT) scans to assess structural changes (airway remodelling). CT scans were evaluated using a scoring system for lung attenuation (LA) and bronchial wall thickening (BWT). To assess mechanisms of MSC action, immunologic assays including allergen-specific IgE, cellular IL-10 production, and allergen-specific lymphocyte proliferation were performed. RESULTS: There were no differences between treatment groups or over time with respect to airway eosinophilia or AHR. However, significantly lower LA and BWT scores were noted in CT images of MSC-treated animals compared to placebo-treated cats at month 8 of the study (LA P = 0.0311; BWT P = 0.0489). No differences were noted between groups in the immunologic assays. CONCLUSIONS AND CLINICAL RELEVANCE: When administered after development of chronic allergic feline asthma, MSCs failed to reduce airway inflammation and AHR. However, repeated administration of MSCs at the start of study did reduce computed tomographic measures of airway remodelling by month 8, although the effect was not sustained at month 12. Further study of MSC therapy including repeated MSC administration is warranted to assess impact on remodelling in chronic asthma.

Anticancer benefits of early versus late use of rapamycin in a rat model of urothelial carcinoma.

BACKGROUND: We previously reported both in vivo and in vitro effects of rapamycin on urothelial carcinoma. Clinically, the use of rapamycin could not completely prevent the recurrence of urothelial carcinoma. Therefore, we designed this study to compare the difference of efficacy between early and late use of rapamycin in a rat model of urothelial carcinoma. METHODS: The rat model of urothelial carcinoma was induced by adding 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) to the drinking water for up to 20 weeks in male Fisher-344 rats. Rapamycin was fed orally from the 1st day, 5th week, 9th week, 13th week, and 17th week. The antitumor effects of different periods of rapamycin treatment were assessed grossly and microscopically. RESULTS: Papillary tumors of urinary bladder were successfully induced in the BBN group. Simultaneous use of rapamycin and BBN from the 1st day of treatment significantly reduced the tumor growth in urinary bladder: 80% of the rats had no tumor and 20% had low-grade tumors. Adding rapamycin from the 5th week was associated with more tumor growth: 20% of the rats had no tumors, 20% had low-grade tumors, and 60% had high-grade tumors. Moreover, in the groups with rapamycin treatment from the 9th week, 13th week, and 17th week, all rats developed high-grade papillary tumors in urinary bladder, as did the control group that received no rapamycin. CONCLUSIONS: The study results suggest that the anticancer effect of rapamycin on urothelial carcinoma is stage dependent. Early use of rapamycin provides better anticancer effect, whereas late use of rapamycin fails to inhibit the cancer growth.

The effect of statins on cardiac allograft survival.

PURPOSE: In addition to having a lipid-lowering effect, statins also have an anti-inflammatory effect that may reduce allograft dysfunction by preventing cardiac allograft vasculopathy (CAV) and play an immunomodulatory role. We studied the effect of statins on cardiac allograft survival at the National Taiwan University Hospital (NTUH). MATERIALS AND METHODS: We retrospectively reviewed the patients undergoing heart transplantation at NTUH in the last 6 years. After transplantation, all patients received biochemical monitoring every month and echocardiographic examination regularly at NTUH. Protocol biopsy was performed in all except 18 pediatric patients. All patients received immunosuppressants, including tacrolimus or cyclosporine, everolimus or mycophenolate acid, and prednisolone. They were divided into statin and nonstatin groups according to whether or not a statin was taken. RESULTS: At NTUH, from 2007 to 2012, 168 heart transplantations were performed. The ages of the patients ranged from 6 to 74 years old with male predominance. The etiology was mainly dilated cardiomyopathy (52.4%) and ischemic cardiomyopathy (39.3%), including 7 retransplantations from severe CAV with heart failure. Twenty-three patients (17%) suffered from acute rejection. The overall 1-year actuarial survival rate was 86% ± 2% and the 5-year survival rate was 79% ± 3%. Seventy-eight patients (57.4%) took statins and the statin group has a better 5-year survival rate and freedom from cardiac death survival rate (P < .01). CONCLUSION: Our study showed that the use of statins after transplantation was associated with better survival.

Inhibitory effects of polypeptides derived from a snake venom C-type lectin, aggretin, on tumor cell-induced platelet aggregation.

BACKGROUND AND OBJECTIVES: Podoplanin, a transmembrane sialoglycoprotein, is expressed by lymphatic endothelial cells and many tumor cells, and is involved in tumor cell-induced platelet aggregation and tumor metastasis. A recent study found that C-type lectin-like receptor 2 (CLEC-2) is a physiologic receptor for podoplanin. Previous studies showed that aggretin, a snake venom-derived protein, activates platelets by targeting platelet CLEC-2. We hypothesized that the C-terminal fragment of aggretin may bind to platelet CLEC-2 and displace podoplanin, in turn exerting antitumor metastatic effects. METHODS AND RESULTS: Aggretin α-chain C-terminus (residues 106-136; AACT) prolonged the lag phase of platelet aggregation induced by aggretin in human washed platelets, indicating that AACT may target the binding site of CLEC-2. HepG2 cells, which are podoplanin-expressing hepatoma cells, induced platelet aggregation with a lag phase. Pretreatment with AACT inhibited platelet aggregation and prolonged the lag phase induced by HepG2 cells. This inhibitory effect was also found with another hepatocarcinoma cell line, HuH-7. AACT inhibited the interaction between HuH-7 cells and platelets, and a specific binding assay demonstrated that CLEC-2 was the binding site for AACT on platelets. In addition, the invasive ability of HepG2 cells was abolished by AACT in a chick embryo chorioallantoic membrane model. Furthermore, formation of lung metastases after intravenous administration of HuH-7 cells was significantly reduced when mice were treated with AACT. CONCLUSIONS: AACT interacts with CLEC-2 of platelets, leading to interference with platelet aggregation and the subsequent metastatic potential of tumor cells. These results suggest that aggretin AACT is a potential candidate for the treatment of tumor metastasis through CLEC-2 blockade.

Effects of low amplitude pulsed radiofrequency stimulation with different waveform in rats for neuropathic pain.

Pulsed-radiofrequency (PRF) electrical stimulation has been widely used for chronic pain treatment. It has been demonstrated with advantages of low temperature over traditional continuous radiofrequency (CRF) lesions with higher amplitude and mono polar electrode to treat pain in clinics (frequency 500 KHz, Pulse duration 20 msec, Amplitude 45 V, Treatment 2 min). We compare the effects of different pulse waveforms and PRF parameters (Pulse duration 25 ms, Treatment duration 5 min, low amplitude of 2.5/1.25 V) with a miniature bi-polar electrode on Dorsal root ganglion (DRG). The pain relief effect due to PRF is evaluated by using Von Frey method for the pain threshold index based on behavior response to mechanical stimulus of various strengths. Experimental results of Von Frey Score show that the sinusoidal group has higher responses than the square wave one. Both fast and secondary expressed proteins of c-fos and pp38 are measured from spinal cord tissue sectioning slides to characterize the pain associated inflammatory responses and their responses due to PRF stimulation.

Comparison of direct and indirect bronchoprovocation testing using ventilator-acquired pulmonary mechanics in healthy cats and cats with experimental allergic asthma.

Airway hyperresponsiveness (AHR) is a key feature of asthma and can be measured using bronchoprovocation. Direct (methacholine, MCh) or indirect (adenosine-5-monophosphate, AMP; or mannitol) bronchoprovocants are used in human patients, the latter inducing AHR only with pre-existing airway inflammation. The present study compared the responses to direct (MCh) and indirect (mannitol, AMP) bronchoprovocation in healthy and asthmatic cats (n=6/group). The order of bronchoprovocant was randomized using a published table of random numbers and there was a 1-month washout before crossover to the next treatment. Pulmonary mechanics were measured in anesthetized and mechanically ventilated cats using a critical care ventilator. Saline at baseline and increasing doses of each bronchoprovocant were aerosolized for 30 s, followed by 4 min of data collection between doses. The endpoint for each bronchoprovocant was reached when airway resistance exceeded 200% of baseline values (EC200Raw). There was a significant difference (P<0.001) in the airway response of asthmatic vs. healthy cats over the range of MCh concentrations, despite there being no significant difference in the EC200Raw between the groups. Response to MCh was significantly greater (P<0.05) in asthmatic than in healthy cats at MCh concentrations as low as 0.0625 mg/mL. For AMP, a small subset of asthmatics (n=2/6) responded at low concentrations; four asthmatic cats and all healthy cats failed to respond even to the highest concentrations of AMP. One asthmatic cat but no healthy cats responded to mannitol. In conclusion, MCh discriminated asthmatic from healthy cats but neither AMP nor mannitol was an effective bronchoprovocant in this model.

Development of an imaging-guided CEA-pretargeted radionuclide treatment of advanced colorectal cancer: first clinical results.

BACKGROUND: Radiolabelled antibody targeting of cancer is limited by slow blood clearance. Pretargeting with a non-radiolabelled bispecific monoclonal antibody (bsMAb) followed by a rapidly clearing radiolabelled hapten peptide improves tumour localisation. The primary goals of this first pretargeting study in patients with the anti-CEACAM5 × anti-hapten (HSG) bsMAb, TF2, and the radiolabelled hapten-peptide, IMP288, were to assess optimal pretargeting conditions and safety in patients with metastatic colorectal cancer (CRC). METHODS: Different dose schedules were studied in four cohorts of five patients: (1) shortening the interval between the bsMAb and peptide administration (5 days vs 1 day), (2) escalating the TF2 dose (from 75 to 150 mg), and (3) reducing the peptide dose (from 100 to 25 µg). After confirmation of tumour targeting by (111)In-IMP288, patients were treated with a bsMAb/(177)Lu-IMP288 cycle. RESULTS: Rapid and selective tumour targeting of the radiolabelled peptide was visualised within 1 h, with high tumour-to-tissue ratios (>20 at 24 h). Improved tumour targeting was achieved with a 1-day interval between the administration of the bsMAb and the peptide and with the 25-µg peptide dose. High (177)Lu-IMP288 doses (2.5-7.4 GBq) were well tolerated, with some manageable TF2 infusion reactions, and transient grades 3-4 thrombocytopaenia in 10% of the patients who received (177)Lu-IMP288. CONCLUSION: This phase I study demonstrates for the first time that pretargeting with bsMAb TF2 and radiolabelled IMP288 in patients with CEA-expressing CRC is feasible and safe. With this pretargeting method, tumours are specifically and rapidly targeted.