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1.
J Equine Vet Sci ; : 105143, 2024 Jun 28.
Article in English | MEDLINE | ID: mdl-38945460

ABSTRACT

Periods of limited activity during semester break may reduce performance during return to ridden work. This study evaluated fitness and muscling of horses when returning to work, following a 12-week period during which horses either continued (conditioned) or discontinued (non-conditioned) ridden work. It was hypothesized that non-conditioned horses would have a lower level of fitness, resulting in higher resting and peak heart rates and lower levels of muscling. Twelve mature, stock type horses aged 16 ± 5 years were assigned to either a conditioned group that maintained light-to-moderate riding or a non-conditioned group receiving no formal exercise. All horses had access to voluntary exercise for 12-24hr/d on grass pasture (1.5-2.5 hectares). Following the 12-week period, all horses were placed into a light-to-moderate intensity exercise program with resting heart rate, peak heart rate, body condition score, gaskin and forearm circumference, and topline muscle measurements performed on d 0, 14, and 28. Peak and resting heart rates were not different between groups (P > 0.05) but increased for both groups throughout the study (P = 0.04). Gaskin circumference of non-conditioned horses was larger (P = 0.04), although non-conditioned horses tended to be heavier (551.4 versus 491.4 ± 21.4 kg; P = 0.07). Conditioned horses had greater average topline muscling scores (P = 0.02). Horses that were conditioned over a 12-week break had greater muscling, but changes in fitness were not detected. Pasture access could contribute to maintenance of fitness during unridden periods.

2.
Public Health ; 233: 45-53, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38848619

ABSTRACT

OBJECTIVES: Variation exists in the capabilities of electronic healthcare records (EHRs) systems and the frequency of their use by primary care physicians (PCPs) from different settings. We aimed to examine the factors associated with everyday EHRs use by PCPs, characterise the EHRs features available to PCPs, and to identify the impact of practice settings on feature availability. STUDY DESIGN: Cross-sectional study. METHODS: PCPs from 20 countries completed cross-sectional online survey between June and September 2020. Responses which reported frequency of EHRs use were retained. Associations between everyday EHRs use and PCP and practice factors (country, urbanicity, and digital maturity) were explored using multivariable logistic regression analyses. The effect of practice factors on the variation in availability of ten EHRs features was estimated using Cramer's V. RESULTS: Responses from 1520 out of 1605 PCPs surveyed (94·7%) were retained. Everyday EHRs use was reported by 91·2% of PCPs. Everyday EHRs use was associated with PCPs working >28 h per week, having more years of experience using EHRs, country of employment, and higher digital maturity. EHRs features concerning entering, and retrieving data were available to most PCPs. Few PCPs reported having access to tools for 'interactive patient education' (37·3%) or 'home monitoring and self-testing of chronic conditions' (34·3%). Country of practice was associated with availability of all EHRs features (Cramer's V range: 0·2-0·6), particularly with availability of tools enabling patient EHRs access (Cramer's V: 0·6, P < 0.0001). Greater feature availability of EHRs features was observed with greater digital maturity. CONCLUSIONS: EHRs features intended for patient use were uncommon across countries and levels of digital maturity. Systems-level research is necessary to identify the country-specific barriers impeding the implementation of EHRs features in primary care, particularly of EHRs features enabling patient interaction with EHRs, to develop strategies to improve systems-wide EHRs use.

3.
Gan To Kagaku Ryoho ; 50(13): 1931-1933, 2023 Dec.
Article in Japanese | MEDLINE | ID: mdl-38303256

ABSTRACT

A 31-year-old man with a big epigastric mass from pancreas body was completely removed by distal pancreatectomy and segmental gastrectomy. Two years after oral administration of S-1 for 4 courses, peritoneal dissemination on the right subdiaphragmatic space was detected. Laparotomy revealed white colored round nodules were found scattered on the peritoneal surface, and the peritoneal cancer index(PCI)was 18. To achieve complete resection of peritoneal nodules, peritonectomy was performed. After complete removal of macroscopic peritoneal metastasis(PM), intraoperative hyperthermic intraoperative peritoneal chemotherapy using 1 gr of gemcitabine and 60 mg of docetaxel was performed for 40 min with thermal dose of 41.5 min. Postoperative course was uneventful. Drug sensitivity test(HDRA method)showed that gemcitabine that gemcitabine showed the highest inhibition rate. The patient was treated with systemic gemcitabine chemotherapy. He is still alive without recurrence 18 months after peritonectomy plus intraoperative HIPEC. Pathological examination showed pancreatic acinar cell carcinoma(PACC)demonstrating positive for chymotrypsin. In conclusion, we present a PACC-case with PM successfully treated by a comprehensive treatment. Intraoperative HIPEC using gemcitabine may be effective for PACC patients with PM in treating residual micrometastasis after peritonectomy.


Subject(s)
Carcinoma, Acinar Cell , Hyperthermia, Induced , Peritoneal Neoplasms , Male , Humans , Adult , Hyperthermic Intraperitoneal Chemotherapy , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/surgery , Carcinoma, Acinar Cell/drug therapy , Gemcitabine , Hyperthermia, Induced/methods , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy
5.
Clin Radiol ; 76(11): 863.e11-863.e17, 2021 11.
Article in English | MEDLINE | ID: mdl-34120733

ABSTRACT

AIM: To define reference values for the transverse relaxation rate (R2∗) in iron storage organs and to investigate the role of human haemochromatosis protein (HFE) genotype on iron storage. MATERIALS AND METHODS: Whole-body magnetic resonance imaging (MRI) including a five-echo gradient-echo sequence was performed in 483 volunteers (269 men, mean age 59.3 ± 12.2 years) without clinical evidence of an iron storage disease at 1.5 T. R2∗ values were assessed for liver, spleen, pancreas, heart, bones, and brain parenchyma. The HFE genotype was determined regarding the single nucleotide polymorphisms (SNPs) rs74315324, rs1799945, rs41303501, rs1800562, rs1800730. R2∗ values were compared among participants without and with at least one mutation. R2∗ reference values were defined using volunteers without any mutation. RESULTS: Three hundred and one participants had no mutations in any HFE SNP, 182 had at least one mutation. HFE gene mutations were distributed as (heterozygous/homozygous) rs1799945:132/9, rs1800562:33/1, and rs1800730:11/0. Mean R2∗ values ± SD (per second) in the group without mutation were: liver: 33.4 ± 12.7, spleen: 24.1 ± 13.8, pancreas: 27.2 ± 6.6, heart: 32.7 ± 11.8, bone: 69.3 ± 21.0, brain parenchyma: 13.9 ± 1.2. No significant difference in R2∗ values were found between participants with and without the HFE gene mutation for any examined iron storage organ (pliver=0.09, pspleen=0.36, ppancreas = 0.08, pheart = 0.36, pbone = 0.98, pbrain=0.74). CONCLUSION: Reference values of R2∗ in iron storage organs are feasible to support the diagnosis of iron storage diseases. Non-specific mutations in HFE SNPs appear not to affect the phenotype of tissue iron accumulation.


Subject(s)
Hemochromatosis Protein/genetics , Hemochromatosis/diagnosis , Iron/metabolism , Magnetic Resonance Imaging/methods , Polymorphism, Single Nucleotide/genetics , Whole Body Imaging/methods , Cohort Studies , Female , Genotype , Germany , Hemochromatosis/metabolism , Humans , Male , Middle Aged , Reference Values
6.
J Environ Anal Toxicol ; 8(1)2021 Feb 15.
Article in English | MEDLINE | ID: mdl-34094707

ABSTRACT

In 2006, the Agency for Toxic Substances and Disease Registry received a request to determine whether a cluster of polycythemia vera patients existed in a northeast Pennsylvania community. A significant cluster of PV cases was identified at the nexus of three counties near several hazardous waste sites. The current study evaluated the potential for a select number of environmental contaminants previously detected in the cluster area to induce DNA damage using in vitro assays with hematopoietic stem-cell derived progenitor cells. CD34+ cells were isolated from normal cord blood samples and were cultured for 48-72 hours to generate erythroid progenitor cells. Eighteen compounds were chosen for the assay; arsenic trioxide, benzo(a)pyrene, benzene, methylene chloride, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), trichloroethylene, potassium chloride, ethylbenzene, benzo[k]fluoranthene, styrene, cadmium chloride, hydroquinone, 1,1,1-trichloroethane, sodium cyanide, manganese chloride, chromium oxide, lead oxide, and sodium arsenite. Genotoxicity of the compounds was determined using the comet assay, and toxicity determined via the cell viability assay. Using the comet assay, 16 compounds at 10 nM concentration, induced a significant amount of DNA damage compared to the control. When evaluating whether a dose-dependent relationship was present, seventeen of the eighteen compounds led to greater DNA damage with increasing exposure concentrations. 2,3,7,8-TCDD was particularly potent, inducing DNA damage in virtually all cells at 1 µM. In conclusion, most of the toxins evaluated using the comet assay showed potential to induce DNA damage in hematopoietic cells, and the genotoxic effects were dose-dependent.

7.
Leuk Res ; 88: 106272, 2020 01.
Article in English | MEDLINE | ID: mdl-31778911

ABSTRACT

Ruxolitinib, a selective JAK1/JAK2 inhibitor, is the current first line therapy for myelofibrosis (MF), which reduces symptomatology and splenomegaly, but does not clearly modify disease course. Panobinostat, a histone deacetylase inhibitor, was shown to be safe and tolerable in phase I and II trials and demonstrated clinical activity in approximately a third of treated patients. Combination therapy of ruxolitinib and panobinostat showed synergistic activity in a preclinical MF model, which prompted clinical evaluation of this combination in both ruxolitinib naïve and treated MF patients. Herein, we report the results of an investigator-initiated, dose escalation, phase I trial of ruxolitinib and panobinostat in 15 patients with primary MF and post-polycythemia vera/essential thrombocythemia MF. This combination treatment proved to be safe and tolerable without dose limiting thrombocytopenia and a maximum tolerated dose of both agents in combination was not determined. The majority of patients maintained stable disease with this combination treatment and 40 % attained a clinical improvement (spleen n = 5, anemia n = 1) by modified IWG-MRT at the end of 6 cycles. This is one of the first attempts of rationally designed, JAK inhibitor-based, combination therapy studies and exemplifies the feasibility of such an approach in patients with advanced MF.


Subject(s)
Panobinostat/administration & dosage , Panobinostat/adverse effects , Polycythemia Vera/drug therapy , Primary Myelofibrosis/drug therapy , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , Thrombocythemia, Essential/drug therapy , Aged , Cohort Studies , Dose-Response Relationship, Drug , Drug Administration Schedule , Drug Therapy, Combination/adverse effects , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Nitriles , Polycythemia Vera/complications , Primary Myelofibrosis/etiology , Pyrimidines , Thrombocythemia, Essential/complications , Treatment Outcome
8.
Injury ; 50(12): 2318-2323, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31607441

ABSTRACT

PURPOSE: Type B fibula fractures are the most common type of ankle fractures. Generally, surgical repair is advised for unstable fractures and non-operative treatment for stable fractures. However, evidence on long-term functional outcome of both treatment regimens is lacking. Aim of this study is to compare the long-term outcome in function and pain between patients with an isolated type B fibula fracture treated non-operatively and surgically. MATERIAL & METHODS: In this retrospective cohort study, all consecutive patients aged between 18 and 75 years, treated non-operatively or surgically between January 2008 and December 2015 for a distal fibula fracture at the level of the syndesmosis without an additional medial or posterior fracture and with a medial clear space ≤6 mm were included. All eligible patients received a questionnaire, composed of the Olerud-Molander Ankle Score (OMAS), the American Orthopaedic Foot and Ankle Society ankle-hindfoot score (AOFAS), the Euroqol-5D (EQ-5D) for quality of life and the Visual Analogue Scale (VAS) for pain sensation. With a mean follow-up of 5.3 years, 229 patients were included. For all aspects of the questionnaire, there was no significant difference between non-operative and operative treatment in outcome of function and pain: the EQ-5D score was respectively 0.8 vs. 0.9 (p = 0.72), mean VAS score 0.8 vs. 1.3 (p = 0.09), OMA score 84 vs. 84 (p = 0.98) and for the AOFAS 93 vs. 90 (p = 0.28). 33% of the patients who had surgery had revision surgery for implant removal because of persistent pain complaints. In 3% of the surgically treated patients, a wound infection required intravenous antibiotic treatment. In the non-operatively treated cohort, one patient developed a deep venous thrombosis in the fractured leg. CONCLUSION: According to results of this study, in adult patients with an isolated distal fibula and medial clear space ≤6 mm, without proven instability these fractures can safely be treated non-operatively, while avoiding risks and costs of surgery and preserving good long-term outcome in terms of pain and function.


Subject(s)
Ankle Fractures , Conservative Treatment , Fibula , Fracture Fixation, Internal , Long Term Adverse Effects , Pain , Postoperative Complications , Quality of Life , Ankle Fractures/diagnosis , Ankle Fractures/epidemiology , Ankle Fractures/physiopathology , Ankle Fractures/surgery , Ankle Joint/physiopathology , Conservative Treatment/adverse effects , Conservative Treatment/methods , Female , Fibula/injuries , Fibula/surgery , Fracture Fixation, Internal/adverse effects , Fracture Fixation, Internal/methods , Humans , Long Term Adverse Effects/diagnosis , Long Term Adverse Effects/physiopathology , Long Term Adverse Effects/psychology , Male , Middle Aged , Netherlands/epidemiology , Outcome and Process Assessment, Health Care , Pain/diagnosis , Pain/epidemiology , Pain/etiology , Postoperative Complications/diagnosis , Postoperative Complications/epidemiology , Postoperative Complications/surgery , Range of Motion, Articular , Recovery of Function , Reoperation/statistics & numerical data
9.
BMC Fam Pract ; 20(1): 96, 2019 08 09.
Article in English | MEDLINE | ID: mdl-31395016

ABSTRACT

BACKGROUND: General Practice (GP) seems to be perceived as less attractive throughout Europe. Most of the policies on the subject focused on negative factors. An EGPRN research team from eight participating countries was created in order to clarify the positive factors involved in appeals and retention in GP throughout Europe. The objective was to explore the positive factors supporting the satisfaction of General Practitioners (GPs) in clinical practice throughout Europe. METHOD: Qualitative study, employing face-to-face interviews and focus groups using a phenomenological approach. The setting was primary care in eight European countries: France, Belgium, Germany, Slovenia, Bulgaria, Finland, Poland and Israel. A thematic qualitative analysis was performed following the process described by Braun and Clarke. Codebooks were generated in each country. After translation and back translation of these codebooks, the team clarified and compared the codes and constructed one international codebook used for further coding. RESULTS: A purposive sample of 183 GPs, providing primary care to patients in their daily clinical practice, was interviewed across eight countries. The international codebook included 31 interpretative codes and six themes. Five positive themes were common among all the countries involved across Europe: the GP as a person, special skills needed in practice, doctor-patient relationship, freedom in the practice and supportive factors for work-life balance. One theme was not found in Poland or Slovenia: teaching and learning. CONCLUSION: This study identified positive factors which give GPs job satisfaction in their clinical practice. This description focused on the human needs of a GP. They need to have freedom to choose their working environment and to organize their practice to suit themselves. In addition, they need to have access to professional education so they can develop specific skills for General Practice, and also strengthen doctor-patient relationships. Stakeholders should consider these factors when seeking to increase the GP workforce.


Subject(s)
Career Choice , General Practitioners/psychology , Job Satisfaction , Europe , Female , Focus Groups , Humans , Interviews as Topic , Male , Middle Aged , Qualitative Research , Work-Life Balance
10.
J Am Assoc Lab Anim Sci ; 58(5): 597-600, 2019 09 01.
Article in English | MEDLINE | ID: mdl-31362805

ABSTRACT

Female athymic nude rats (Rattus norvegicus; n = 45; age, 6 wk) were used in an IACUC-approved protocol to investigate mechanisms and potential treatments associated with brain, spine, and spinal cord metastases from triple negative breast cancer. The analgesic plan included the use of buprenorphine SR LAB (0.6 mg/kg; 0.11 mL/rat) subcutaneously and an oral NSAID delivered via the water. Thirty-seven rats reached the experimental end point at 3 mo after xenotransplantation and were euthanized for tissue harvest. Grossly, all 37 rats had nodules in the subcutis over the shoulders; these were identified as small, cystic structures (diameter, approximately 0.25 cm). The cysts and haired skin were submitted for LC-MS/MS (liquid chromatography-tandem mass spectrometry) and histopathology. Histologically, the cysts were lined by fibrous connective tissue mildly infiltrated by macrophages, lymphocytes, and plasma cells. Adjacent blood vessels were rimmed by a mild infiltrate of lymphocytes and plasma cells. The cysts contained variable accumulations of a light pink, proteinaceous fluid. The cause for the cysts could not be determined histologically; there was no evidence of neoplasia. LC-MS/MS analysis revealed that the cysts contained buprenorphine. We hypothesize that the lack of T cells and a cell-mediated immune response in these rats prevented the dissolution of the vehicle and absorption of the buprenorphine. The manufacturer provides a cautionary statement regarding the use of this formulation in nude mice due to skin reactions, but to our knowledge, this report is the first description of an apparent lack of absorption of the drug in immunodeficient animals.


Subject(s)
Analgesics, Opioid/pharmacokinetics , Buprenorphine/pharmacokinetics , Rats, Nude , Analgesics, Opioid/administration & dosage , Animals , Buprenorphine/administration & dosage , Chromatography, Liquid , Delayed-Action Preparations , Female , Injections, Subcutaneous , Laboratory Animal Science , Rats , Tandem Mass Spectrometry
12.
J Surg Educ ; 76(5): 1319-1328, 2019.
Article in English | MEDLINE | ID: mdl-30979651

ABSTRACT

OBJECTIVE: The objective of this study was to examine uncommon operations in greater detail given that the outcomes of uncommon operations are largely understudied. This study examines the incidence of postoperative events and the role of the resident following uncommon operations. DESIGN: We identified uncommon general surgical operations using the ACS National Surgical Quality Improvement Program Participant Use file (2008-2011). Death or serious morbidity (DSM) within 30 days of the operation was the primary outcome of interest. Failure to rescue (FTR) and prolonged operative time (PRopt) were evaluated as secondary outcome measures. PRopt was defined as ≥90 percentile of operative time for each procedure type. Independent multivariate logistic regression models were generated to examine the impact of these descriptors on the outcomes of interest. SETTING/PARTICIPANTS: The dataset utilized was the United States National Surgical Quality Improvement Program Participant Use File which leverages data points from over 700 hospitals that range from primary to quaternary care centers. Resident participation was defined as resident involved (RI) or no resident involved (NRI), and stratified by postgraduate year (PGY): 1-3, 4-5, and 6+. RESULTS: Resident participant data was available for 21,453 (84.5%) uncommon operations with NRI in 25.4% (5447). With regard to resident participation, PGY1-3 were found in 12.6% (2699), PGY4-5 in 50.4% (10,817), and PGY6+ in 11.6% (2490). The overall observed DSM rate was 28.6% and the observed FTR rate was 5.8%. Overall, there was no difference in DSM by RI status (NRI: 1528; 28.1% vs RI: 4602; 28.8%; p = 0.324); however, PGY level was associated with DSM (PGY1-3: 774, 28.7%, PGY4-5: 3210, 29.7%, PGY6+: 618, 24.8%; p < 0.001). Any RI was associated with a lower rate of FTR (5.1%) when compared to NRI (8.3%, p < 0.001) with decreasing FTR events by increasing PGY (PGY1-3: 6.4%, PGY4-5: 5.2%, PGY6+: 3.3%; p < 0.001). After adjustment for patient risk factors, any RI remained associated with a lower likelihood of FTR than NRI (odds ratio: 0.65, 95% confidence interval: 0.49-0.87) while only the PGY4-5 and PGY6+ groups were associated with lower likelihood of FTR in comparison to NRI. RI was associated with PRopt in univariate and multivariable analyses. CONCLUSIONS: Uncommon operations were associated with substantial DSM. The involvement of PGY4-5 residents was associated with the greatest likelihood of DSM. With increasing PGY of the involved resident, cases with PGY > 5 demonstrated a lower likelihood of risk-adjusted FTR. The explanation for these findings is not clear; however, the involvement of more senior residents in the technical aspects of uncommon operations may lead to improved results.


Subject(s)
General Surgery/education , Internship and Residency , Postoperative Complications/epidemiology , Surgical Procedures, Operative , Failure to Rescue, Health Care , Humans , Operative Time , Surgical Procedures, Operative/education , Surgical Procedures, Operative/standards
13.
Injury ; 50(2): 579-589, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30630597

ABSTRACT

INTRODUCTION: In isolated Weber B fractures (type B fibular fractures), ruling out instability is critical for safe conservative treatment. In fractures without evident medial injury, additional diagnostics like MRI scan or gravity stress test should be done to differentiate between a stable and unstable fracture. The aim of the current study is to gain more insight in current practice and treatment of type B fractures by Dutch trauma- and orthopaedic surgeons. MATERIALS & METHODS: In December 2017 and January 2018, 559 trauma surgeons were invited by email to join an online survey. This survey consisted of questions regarding diagnostics and treatment of isolated distal fibula fractures. Also, respondents were asked to state their preferred treatment of eight separate cases. RESULTS: In total, 161 surgeons participated, covering 68 different hospitals in the Netherlands. Of them, 32.0% treat more than 30 ankle fractures a year. Based on regular mortise radiographs, 13.6% of the respondents chose surgical treatment in case of a medial clear space (MCS) > 4 mm, 33.8% in case of a MCS > 6 mm and 45.5% in case of a MCS > 4 mm in addition to the MCS ≥ superior clear space + 1 mm. Moreover, 18.2% make use of additional diagnostics (43.9% repeat mortise view after a week, 16.6% weight bearing radiograph, 8.6% gravity stress view, 7.9% exorotation radiograph, 6.5% MRI scan, 0.7% ultrasound, 16.8% other) and 8% establishes their decision not based on the mortise radiograph. Fibular dislocation of ≥ 2 mm was used as an indication for surgical treatment by 69%. Of them, 56% decides to treat surgically in these cases, even with proven medial stability. CONCLUSION: Many surgeons treat type B fibular fractures with a MCS > 4 mm at mortise view surgically, even without proven medial injury. Rarely, additional diagnostics as MRI or gravity stress test are performed in cases with a MCS 4-6 mm. Consequently many stable ankle fractures are treated operatively unnecessarily.


Subject(s)
Ankle Fractures/diagnostic imaging , Ankle Joint/diagnostic imaging , Conservative Treatment , Fibula/injuries , Fracture Fixation, Internal , Fractures, Bone/diagnostic imaging , Joint Instability/diagnostic imaging , Unnecessary Procedures/statistics & numerical data , Ankle Fractures/physiopathology , Ankle Fractures/therapy , Ankle Joint/pathology , Conservative Treatment/statistics & numerical data , Cross-Sectional Studies , Fibula/diagnostic imaging , Fracture Fixation, Internal/statistics & numerical data , Fractures, Bone/physiopathology , Fractures, Bone/therapy , Humans , Joint Instability/physiopathology , Joint Instability/surgery , Ligaments, Articular/injuries , Netherlands/epidemiology , Practice Patterns, Physicians'/statistics & numerical data , Predictive Value of Tests , Radiography , Weight-Bearing
15.
Leuk Res ; 60: 31-35, 2017 09.
Article in English | MEDLINE | ID: mdl-28646676

ABSTRACT

Myelofibrosis is a myeloproliferative neoplasm that is characterized by splenomegaly, profound symptom burden, and cytopenias. JAK inhibitor therapy offers improvements in splenomegaly, symptom burden, and potentially survival; however, cytopenias remain a significant challenge. Danazol has previously demonstrated improvements in myelofibrosis-associated anemia. We conducted a phase II clinical trial evaluating the efficacy and tolerability of combination therapy with ruxolitinib, an oral JAK inhibitor, and danazol. Fourteen intermediate or high-risk MF patients were enrolled at 2 institutions. Responses per IWG-MRT criteria were stable disease in 9 patients (64.2%) clinical improvement in 3 (21.4%) all of which were spleen responses, partial response in 1 (7.1%) and progressive disease in 1 (7.1%). Despite limited IWG-MRT response, stabilization of anemia and thrombocytopenia was demonstrated. In JAK inhibitor naïve patients, 4/5 (80%) had stable or increasing hemoglobin. Of the 9 patients on prior JAK inhibitor, 5 patients (55.5%) and 8 patients (88.9%) had stable or increasing hemoglobin or platelet levels, respectively. Adverse events possibly related included grade 3 or greater hematologic toxicity in ten patients (71.4%) and non-hematologic toxicity in two patients (14.3%). Although combination therapy did not lead to increased hematologic response per IWG-MRT criteria, hematologic stabilization was observed and may be clinically useful.


Subject(s)
Danazol/administration & dosage , Drug Therapy, Combination/methods , Primary Myelofibrosis/drug therapy , Pyrazoles/administration & dosage , Adult , Aged , Anemia/drug therapy , Danazol/pharmacology , Female , Humans , Male , Middle Aged , Nitriles , Primary Myelofibrosis/complications , Pyrazoles/pharmacology , Pyrimidines , Thrombocytopenia/drug therapy , Treatment Outcome
16.
Leukemia ; 31(11): 2458-2467, 2017 11.
Article in English | MEDLINE | ID: mdl-28270692

ABSTRACT

Imetelstat (GRN163L) is a specific telomerase inhibitor that has demonstrated clinical activity in patients with myeloproliferative neoplasms (MPN) and in patients with solid tumors. The antitumor effects were associated with the development of thrombocytopenia, one of the common side effects observed in patients treated with imetelstat. The events underlying these adverse effects are not apparent. In this report, we investigated the potential mechanisms that account for imetelstat's beneficial effects in MPN patients and the manner by which imetelstat treatment leads to a reduction in platelet numbers. Using a well-established system of ex vivo megakaryopoiesis, we demonstrated that imetelestat treatment affects normal megakaryocyte (MK) development by exclusively delaying maturation of MK precursor cells. By contrast, additional stages along MPN MK development were affected by imetelstat resulting in reduced numbers of assayable colony-forming unit MK and impaired MK maturation. In addition, treatment with imetelstat inhibited the secretion of fibrogenic growth factors by malignant but not by normal MK. Our results indicate that the delay observed in normal MK maturation may account for imetelstat-induced thrombocytopenia, while the more global effects of imetelstat on several stages along the hierarchy of MPN megakaryopoiesis may be responsible for the favorable clinical outcomes reported in MPN patients.


Subject(s)
Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Megakaryocytes/drug effects , Niacinamide/analogs & derivatives , Telomerase/antagonists & inhibitors , Humans , Megakaryocytes/cytology , Niacinamide/pharmacology , Oligonucleotides , Polyploidy
17.
Cancer Gene Ther ; 24(2): 45-47, 2017 Feb.
Article in English | MEDLINE | ID: mdl-28106046

ABSTRACT

We previously described the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. The isolated variant is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared with 2 of 12 of the parental cell line. OBP-401 is a telomerase-dependent cancer-specific, green fluorescent protein (GFP)-expressing adenovirus. OBP-401 was used to infect parental MDA-MB-231P cells and high-metastatic MDA-MB-231H and MDA-MB-231HLN isolated from a lymph node metastasis and MDA-MB-231HLM isolated from a lung metastasis. Time-course imaging showed that OBP-401 labeled MDA-MB-231HP, MDA-MB-231HLN, and MDA-MB-231HLM cells more brightly than MDA-MB-231 parental cells. OBP-401 killed MDA-MB-231H, MDA-MB-231HLN, and MDA-MB-231HLM cells more efficiently than MDA-MB-231P parental cells. These results indicate that OBP-401 could infect, label and then kill high-metastatic MDA-MB-231 more efficiently than low-metastatic MDA-MB-231.


Subject(s)
Adenoviridae/genetics , Genetic Vectors/genetics , Green Fluorescent Proteins/genetics , Oncolytic Viruses/genetics , Telomerase/metabolism , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathology , Animals , Cell Line, Tumor , Cell Survival , Gene Expression , Genes, Reporter , Humans , Mice , Neoplasm Metastasis , Triple Negative Breast Neoplasms/therapy
18.
BMC Fam Pract ; 17(1): 133, 2016 09 13.
Article in English | MEDLINE | ID: mdl-27619913

ABSTRACT

BACKGROUND: Looking at what makes General Practitioners (GPs) happy in their profession, may be important in increasing the GP workforce in the future. The European General Practice Research Network (EGPRN) created a research team (eight national groups) in order to clarify the factors involved in GP job satisfaction throughout Europe. The first step of this study was a literature review to explore how the satisfaction of GPs had been studied before. The research question was "Which factors are related to GP satisfaction in Clinical Practice?" METHODS: Systematic literature review according to the PRISMA statement. The databases searched were Pubmed, Embase and Cochrane. All articles were identified, screened and included by two separate research teams, according to inclusion or exclusion criteria. Then, a qualitative appraisal was undertaken. Next, a thematic analysis process was undertaken to capture any issue relevant to the research question. RESULTS: The number of records screened was 458. One hundred four were eligible. Finally, 17 articles were included. The data revealed 13 subthemes, which were grouped into three major themes for GP satisfaction. First there were general profession-related themes, applicable to many professions. A second group of issues related specifically to a GP setting. Finally, a third group was related to professional life and personal issues. CONCLUSIONS: A number of factors leading to GP job satisfaction, exist in literature They should be used by policy makers within Europe to increase the GP workforce. The research team needs to undertake qualitative studies to confirm or enhance those results.


Subject(s)
General Practitioners/psychology , Job Satisfaction , Clinical Competence , Humans , Income , Self Efficacy , Work-Life Balance , Workload
19.
Eur J Clin Nutr ; 70(9): 1089-91, 2016 09.
Article in English | MEDLINE | ID: mdl-27026422

ABSTRACT

This pilot study compared inhibition of the glycaemic response to glucose by a dietary source of quercetin glucosides (onion) in lactose-tolerant adults (n=12) and lactose-intolerant adults (n=12). We hypothesised that lactose-intolerant people (who do not express lactase) will retain intact quercetin glucosides that can inhibit glucose uptake via the glucose transporter SGLT1, whereas lactose-tolerant people (who do express lactase) will hydrolyse quercetin glucosides to free quercetin that does not inhibit glucose uptake. In a glucose tolerance test, reduction in peak glucose levels by an onion meal was higher in lactose-intolerant people than in lactose-tolerant people (44.2 versus 19.3%, P=0.04). Incremental area under the blood glucose curve was reduced more in lactose-intolerant people, but was not statistically significant (54.5 versus 42.1%, P=0.42). A diet containing quercetin glucosides may be of greater benefit for glycaemic control in lactose-intolerant people than in lactose-tolerant people.


Subject(s)
Blood Glucose/metabolism , Diet , Glycemic Load/drug effects , Glycosides/pharmacology , Lactose Intolerance/blood , Onions/chemistry , Quercetin/pharmacology , Adult , Dietary Carbohydrates/blood , Feeding Behavior , Female , Glycosides/metabolism , Humans , Lactase/metabolism , Lactose/adverse effects , Lactose/metabolism , Male , Pilot Projects , Quercetin/metabolism , Reference Values , Young Adult
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