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- Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein. [JOURNAL ARTICLE]
- Blood 2014 Nov 19.
Bone marrow megakaryocytes produce platelets by extending long cytoplasmic protrusions, designated proplatelets, into sinusoidal blood vessels. While microtubules are known to regulate platelet production, the underlying mechanism of proplatelet elongation has yet to be resolved. Here we report that proplatelet formation is a process that can be divided into repetitive phases - extension, pause and retraction - as revealed by differential interference contrast and fluorescence loss after photoconversion time-lapse microscopy. Furthermore we show that microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein under static and physiological shear stress by using fluorescence recovery after photobleaching in proplatelets with fluorescence tagged β1-tubulin. A refined understanding of the specific mechanisms regulating platelet production will yield strategies to treat patients with thrombocythemia or thrombocytopenia.
- Alternative treatment approach to cerebral toxoplasmosis in HIV/AIDS: experience from a resource poor setting. [JOURNAL ARTICLE]
- Int J STD AIDS 2014 Nov 18.
The current standard treatment for cerebral toxoplasmosis (pyrimethamine/sulfadiazine) often encounters problems of poor tolerability, adverse effects, frequent dropouts and non-availability of pyrimethamine/sulfadiazine in some parts of India. We had to use the combination of two effective alternative agents for toxoplasmosis, cotrimoxazole and clindamycin, on compassionate ground. This retrospective observational study reports superior efficacy and better tolerability of cotrimoxazole/clindamycin compared to recommended regimen. Primary end-point (complete response) was defined as more than 50% improvement of clinical status or more than 50% decrease in the size of brain lesions after two weeks of treatment initiation. Complete response occurred more commonly in cotrimoxazole/clindamycin than in pyrimethamine/sulfadiazine (80% vs. 31.25%, respectively, relative risk 2.56, 95% confidence interval: 1.21-5.43). There was a trend towards higher on-treatment mortality in pyrimethamine/sulfadiazine in comparison to cotrimoxazole/clindamycin group (mortality rates 37.5% in pyrimethamine/sulfadiazine vs 12% in cotrimoxazole/clindamycin, p = 0.07, relative risk = 3.125, 95% confidence interval: 0.91-10.75). Overall, 62.5% (10/16) patients in pyrimethamine/sulfadiazine suffered drug-related adverse reactions compared to 24% (6/25) in cotrimoxazole/clindamycin (p = 0.02, relative risk = 2.60, 95% confidence interval: 1.17-5.76). Commonest complication in pyrimethamine/sulfadiazine was severe thrombocytopenia with major bleeding (4/16, 25%). We propose that the new combination chemotherapy, which is widely available, effective and safe, can be practiced in developing countries.
- Effects of Ribavirin on Severe Fever with Thrombocytopenia Syndrome Virus In Vitro. [JOURNAL ARTICLE]
- Jpn J Infect Dis 2014; 67(6):423-427.
Severe fever with thrombocytopenia syndrome (SFTS) is a disease with a high case fatality rate that is caused by infection with the recently identified tick-borne SFTS virus (SFTSV), for which there are no specific countermeasures. We examined the effects of ribavirin and mizoribine, which are nucleoside analogue drugs with broad antiviral activities, on SFTSV proliferation in vitro. When 3 cell lines were treated with these drugs before and during infection with a Chinese SFTSV strain, the 99% effective concentrations (EC99) of ribavirin were 19-64 μg/ml (78-262 μM); in contrast, the EC99 of mizoribine was >500 μg/ml (1,929 μM). Similar levels of inhibitory effects of ribavirin were observed with 4 Japanese SFTSV strains. However, when Vero cells were treated with ribavirin 3 days after inoculation, the inhibitory effect was dramatically decreased, indicating that ribavirin did not effectively reduce virus production in pre-infected cells. These results suggest that ribavirin could be used as post-exposure prophylaxis for the prevention of SFTS.
- Plasma exchange to remove HIT antibodies: dissociation between enzyme-immunoassay and platelet activation test reactivities. [JOURNAL ARTICLE]
- Blood 2014 Nov 18.
Repeated therapeutic plasma exchange (TPE) has been advocated to remove heparin-induced thrombocytopenia (HIT) IgG antibodies prior to cardiac/vascular surgery in patients who have serologically-confirmed acute or subacute HIT; for this situation, a negative platelet activation assay (e.g., platelet serotonin-release assay [SRA]) has been recommended as the target serological endpoint to permit safe surgery. We compared reactivities in the SRA and an anti-PF4/heparin IgG-specific enzyme-immunoassay (EIA), testing serial serum samples in a patient with recent (subacute) HIT who underwent serial TPE pre-cardiac surgery, as well as for 15 other serially-diluted HIT sera. We observed that post-TPE/diluted HIT sera-when first testing SRA-negative-continue to test strongly positive by EIA-IgG. This dissociation between the platelet activation assay and a PF4-dependent immunoassay for HIT antibodies indicates that patients with subacute HIT undergoing repeated TPE prior to heparin re-exposure should be tested by serial platelet activation assays even when their EIAs remain strongly positive.
- Regulator of G-Protein Signaling 18 Controls Both Platelet Generation and Function. [JOURNAL ARTICLE]
- PLoS One 2014; 9(11):e113215.
RGS18 is a myeloerythroid lineage-specific regulator of G-protein signaling, highly expressed in megakaryocytes (MKs) and platelets. In the present study, we describe the first generation of a RGS18 knockout mouse model (RGS18-/-). Interesting phenotypic differences between RGS18-/- and wild-type (WT) mice were identified, and show that RGS18 plays a significant role in both platelet generation and function. RGS18 deficiency produced a gain of function phenotype in platelets. In resting platelets, the level of CD62P expression was increased in RGS18-/- mice. This increase correlated with a higher level of plasmatic serotonin concentration. RGS18-/- platelets displayed a higher sensitivity to activation in vitro. RGS18 deficiency markedly increased thrombus formation in vivo. In addition, RGS18-/- mice presented a mild thrombocytopenia, accompanied with a marked deficit in MK number in the bone marrow. Analysis of MK maturation in vitro and in vivo revealed a defective megakaryopoiesis in RGS18-/- mice, with a lower bone marrow content of only the most committed MK precursors. Finally, RGS18 deficiency was correlated to a defect of platelet recovery in vivo under acute conditions of thrombocytopenia. Thus, we highlight a role for RGS18 in platelet generation and function, and provide additional insights into the physiology of RGS18.
- Factors Associated With Grade 3 or 4 Treatment-Related Toxicity in Women With Advanced or Recurrent Cervical Cancer: An Exploratory Analysis of NRG Oncology/Gynecologic Oncology Group Trials 179 and 204. [JOURNAL ARTICLE]
- Int J Gynecol Cancer 2014 Nov 15.
This study aimed to describe pretreatment patient characteristics and baseline quality-of-life scores as they relate to the development of grade 3 or 4 toxicity in patients receiving chemotherapy for advanced/recurrent cervical cancer.The study sample was drawn from Gynecologic Oncology Group protocols 179 and 204. Grade 3 or 4 toxicities were considered in 4 specified categories as follows: peripheral neuropathy, fatigue, hematological, and gastrointestinal (GI). The data variables explored included age, stage, pretreatment radiation, performance status (PS) at treatment initiation, and baseline Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) score. A logistic regression model was developed with various adverse events as binary (0/1) outcomes.Six hundred seventy-three patient-reported questionnaires were used in the analyses. At baseline, pain was the most severe patient-reported symptom. Baseline line-item patient concerns did demonstrate specific correlations with the development of individual toxicities. In 401 patients who were enrolled on Gynecologic Oncology Group 204 (fatigue not measured on 179), a worse PS predicted the development of grade 3 or 4 fatigue (odds ratio, 2.78; 95% confidence interval, 1.66-4.68). Exposure to previous radiation, treatment regimen, and a worse FACT-Cx score were associated with the reporting of both grade 3 or 4 leukopenia (P < 0.05) and anemia (P < 0.0005). Performance status and treatment regimen (P < 0.05) were associated with the development of grade 3 or 4 thrombocytopenia. Age and treatment regimen (P < 0.05) were associated with the development of grade 3 or 4 neutropenia. The FACT-Cx score (P = 0.0016) predicted grade 3 or 4 GI toxicity.The development of fatigue, hematological, and GI toxicity might be predictable based on factors other than treatment assignment such as age, PS, and patient-reported quality-of-life measurement.
- Interrater agreement for two systems used to determine the probability of heparin-induced thrombocytopenia. [Journal Article]
- Am J Health Syst Pharm 2014 Dec 1; 71(23):2045-52.
The interrater reliability of the 4T's method and the HIT expert probability (HEP) score for clinical evaluation of suspected heparin-induced thrombocytopenia (HIT) was investigated.Patients hospitalized over a three-year period who were tested for HIT via anti-platelet factor 4 (anti-PF4) antigen assay were identified using laboratory data; 127 patient cases met the study inclusion criteria. Nine clinical pharmacists with expertise in HIT management evaluated the 127 cases using two pretest scoring systems: the 4T's score and the HEP score. Each case was independently evaluated using both 4T's and HEP scores. The primary endpoint was interrater agreement of overall 4T's and HEP scores and individual item scores.Raw agreement of values assigned by the two raters for each of the four items comprising the 4T's score ranged from 0.54 to 0.86, with agreement of 0.63 for final patient categorizations. Raw agreement of rater weightings of the eight HEP scoring items ranged from 0.34 to 1.0; for dichotomization of patients at the suggested screening cutoff value (>2.0), agreement was 0.65. Kappa coefficients were 0.15-0.45 for 4T's item scores and 0.17-0.70 for HEP score item scores. With both scoring systems, low rater agreement mainly related to determination of the timing of thrombocytopenia and possible other causes of the disorder.In a retrospective study, inter-rater agreement in scoring of HIT probability via the 4T's and HEP scoring systems was relatively low. The HEP score did not increase interrater reliability or correlation with anti-PF4 antibodies compared with the 4T's score.
- Linezolid versus vancomycin for skin and soft tissue infections. [Journal Article]
- Evid Based Child Health 2014 Mar; 9(1):103-66.
The morbidity and treatment costs associated with skin and soft tissue infections (SSTIs) are high. Linezolid and vancomycin are antibiotics that are commonly used in treating skin and soft-tissue infections, specifically those infections due to methicillin-resistant Staphylococcus aureus (MRSA).To compare the effects and safety of linezolid and vancomycin for treating people with SSTIs.In May 2013 we conducted searches of the following databases: Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. We also contacted manufacturers for details of unpublished and ongoing trials. We scrutinised citations within all obtained trials and major review articles to identify any additional trials.We included all randomised controlled trials (RCTs) comparing linezolid with vancomycin in the treatment of SSTIs.Two review authors independently selected trials, assessed risk of bias and extracted data. The primary outcomes were clinical cure, microbiological cure, and SSTI-related and treatment-related mortality. We performed subgroup analyses according to age, and whether the infection was due to MRSA.We included nine RCTs (3144 participants). Linezolid was associated with a significantly better clinical (RR 1.09, 95% CI 1.03 to 1.16) and microbiological cure rate in adults (RR 1.08, 95% CI 1.01 to 1.16). For those infections due to MRSA, linezolid was significantly more effective than vancomycin in clinical (RR 1.09, 95% CI 1.03 to 1.17) and microbiological cure rates (RR 1.17, 95% CI 1.04 to 1.32). No RCT reported SSTI-related and treatment-related mortality. There was no significant difference in all-cause mortality between linezolid and vancomycin (RR 1.44, 95% CI 0.75 to 2.80). There were fewer incidents of red man syndrome (RR 0.04, 95% CI 0.01 to 0.29), pruritus (RR 0.36, 95% CI 0.17 to 0.75) and rash (RR 0.27, 95% CI 0.12 to 0.58) in the linezolid group compared with vancomycin, however, more people reported thrombocytopenia (RR 13.06, 95% CI 1.72 to 99.22), and nausea (RR 2.45, 95% CI 1.52 to 3.94) when treated with linezolid. It seems, from the available data, that length of stay in hospital was shorter for those in the linezolid group than the vancomycin group. The daily cost of outpatient therapy was less with oral linezolid than with intravenous vancomycin. Although inpatient treatment with linezolid cost more than inpatient treatment with vancomycin per day, the median length of hospital stay was three days shorter with linezolid. Thus, total hospital charges per patient were less with linezolid treatment than with vancomycin treatment.Linezolid seems to be more effective than vancomycin for treating people with SSTIs, including SSTIs caused by MRSA. The available evidence is at high risk of bias and is based on studies that were supported by the pharmaceutical company that makes linezolid. Further well-designed, independently-funded, RCTs are needed to confirm the available evidence.Antibiotic drugs for treating skin and soft tissue infections Skin and soft tissue infections such as impetigo, abscesses, ulcers, and surgical site infections are common infections of the skin. For serious skin and soft tissue infections involving the deeper tissues, the death rate and treatment costs are high. Linezolid and vancomycin are antibiotics that are effective in treating skin and soft tissue infections, particularly infections caused by bacteria that have developed resistance to some antibiotics. This review identified nine RCTs, with a total of 3144 participants, and compared treatment with linezolid against treatment with vancomycin for skin and soft tissue infections. Linezolid was found to be more effective than vancomycin for treating these infections. There were fewer skin complications in the group that were treated with linezolid. There were no differences between the two groups in the number of reported deaths, and those treated with linezolid had shorter lengths of hospital stay than those treated with vancomycin. The daily cost of outpatient therapy was less with oral linezolid than with intravenous vancomycin, although for inpatient treatment, linezolid was more expensive than vancomycin. Well-designed trials will be required in future to confirm these results, as the trials from which these conclusions were drawn were of poor methodological quality, at high risk of bias, and were funded by the pharmaceutical company that makes linezolid.
- A Phase II trial of Belinostat (PXD101) in patients with relapsed or refractory peripheral or cutaneous T-cell lymphoma. [JOURNAL ARTICLE]
- Br J Haematol 2014 Nov 17.
Belinostat is a pan-histone deacetylase inhibitor with antitumour and anti-angiogenic properties. An open label, multicentre study was conducted in patients with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥1 prior systemic therapy and were treated with belinostat (1000 mg/m(2) intravenously ×5 d of a 21-d cycle). The primary endpoint was objective response rate (ORR). Patients with PTCL (n = 24) had received a median of three prior systemic therapies (range 1-9) and 40% had stage IV disease. Patients with CTCL (n = 29) had received a median of one prior skin-directed therapy (range 0-4) and four prior systemic therapies (range 1-9); 55% had stage IV disease. The ORRs were 25% (PTCL) and 14% (CTCL). Treatment-related adverse events occurred in 77% of patients; nausea (43%), vomiting (21%), infusion site pain (13%) and dizziness (11%) had the highest incidence. Treatment-related serious adverse events were Grade 5 ventricular fibrillation; Grade 4 thrombocytopenia; Grade 3 peripheral oedema, apraxia, paralytic ileus and pneumonitis; and Grade 2 jugular vein thrombosis. Belinostat monotherapy was well tolerated and efficacious in patients with recurrent/refractory PTCL and CTCL. This trial was registered at www.clinicaltrials.gov as NCT00274651.
- REVEAL-1, a phase 2 dose regimen optimization study of vosaroxin in older poor-risk patients with previously untreated acute myeloid leukaemia. [JOURNAL ARTICLE]
- Br J Haematol 2014 Nov 17.
This phase 2 study (N = 116) evaluated single-agent vosaroxin, a first-in-class anticancer quinolone derivative, in patients ≥60 years of age with previously untreated unfavourable prognosis acute myeloid leukaemia. Dose regimen optimization was explored in sequential cohorts (A: 72 mg/m(2) d 1, 8, 15; B: 72 mg/m(2) d 1, 8; C: 72 mg/m(2) or 90 mg/m(2) d 1, 4). The primary endpoint was combined complete remission rate (complete remission [CR] plus CR with incomplete platelet recovery [CRp]). Common (>20%) grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anaemia, neutropenia, sepsis, pneumonia, stomatitis and hypokalaemia. Overall CR and CR/CRp rates were 29% and 32%; median overall survival (OS) was 7·0 months; 1-year OS was 34%. Schedule C (72 mg/m(2) ) had the most favourable safety and efficacy profile, with faster haematological recovery (median 27 d) and lowest incidence of aggregate sepsis (24%) and 30-d (7%) and 60-d (17%) all-cause mortality; at this dose and schedule, CR and CR/CRp rates were 31% and 35%, median OS was 7·7 months and 1-year OS was 38%. Overall, vosaroxin resulted in low early mortality and an encouraging response rate; vosaroxin 72 mg/m(2) d 1, 4 is recommended for further study in this population. Registered at www.clinicaltrials.gov: #NCT00607997.