Axially chiral BODIPYs Lerrick, Reinner I; Winstanley, Thomas P L; Haggerty, Karen ...
Chemical communications,
01/2014, Letnik:
50, Številka:
36
Journal Article
Recenzirano
Odprti dostop
The synthesis and resolution of a class of chiral organic fluorophores, axially chiral 4,4-difluoro-4-bora-3a,4a-diaza-s-indacenes (Ax*-BODIPY), is described. Ax*-BODIPYs were prepared through a ...modular synthesis combined with a late stage Heck functionalisation. Resolution was achieved by preparative chiral HPLC. Absolute stereochemical assignment was performed by comparison of experimental ECD spectra with TD-DFT calculations.
Background & Aims Autoimmune pancreatitis (AIP) is a multisystem disorder that often has extrapancreatic manifestations such as immunoglobulin G4–associated cholangitis (IAC). Patients respond ...rapidly to steroids but can relapse after therapy. We assessed the clinical management of relapse in a group of patients with AIP/IAC. Methods We performed a prospective study of patients diagnosed with AIP from 2004–2007 who received steroids. Treatment outcome was defined clinically, radiologically, and biochemically as response to steroids, remission after steroids, failure to wean steroids, and relapse. Steroids ± azathioprine (AZA) were used to treat patients who failed, relapsed, or could not be weaned from steroids. Results Twenty-eight patients with AIP were studied; 23 (82%) had IAC. All patients responded within 6 weeks to prednisolone therapy. Twenty-three patients achieved remission after a median of 5 months of treatment (range, 1.5–17 months), whereas 5 patients (18%) could not be weaned because of a disease flare. Of the patients who achieved remission, 8 of 23 (35%) subsequently relapsed. Overall, 13 of 23 patients (57%) with AIP/IAC relapsed, compared with 0 of the 5 with isolated AIP ( P = .04, Fisher exact test). Steroids were increased/restarted in all patients who relapsed; 10 also received AZA. Remission was achieved and maintained in 7 patients; they remain on AZA monotherapy at a median of 14 months (range, 1–27 months). Conclusions Relapse or failure to wean steroids occurred in 46% of patients with AIP. Patients with IAC are at particularly high risk of relapse. AZA appears to be effective in patients with post-treatment relapse or who cannot be weaned from steroids. To view this article's video abstract, go to the AGA's YouTube Channel.
OBJECTIVE:This study sought to investigate the impact of histopathologically measured excision margins and SNB on local and locoregional disease control in patients with primary cutaneous melanomas ...more than 4 mm thick.
BACKGROUND:Most current guidelines recommend at least a 2-cm surgical margin (which corresponds to a 16-mm histopathologic margin). These guidelines are based on limited evidence, mostly obtained in patients who did not have an SNB.
METHODS:Histopathologic tumor excision margins for clinically lymph node-negative patients with melanomas more than 4 mm thick, treated at Melanoma Institute Australia (1992–2009), were determined. Clinicopathologic predictors of local and locoregional disease-free survival were investigated.
RESULTS:There were 632 patients eligible for the study; of these, 397 (62.8%) had an SNB. The median histopathologic excision margin was 15 mm (interquartile range, 11.0–19.5 mm). After a median follow-up of 37 months, local and locoregional recurrences were observed in 48 (7.6%) and 159 (25.2%) patients, respectively. Excision margin as a continuous variable was a significant predictor of local hazard ratio (HR), 0.91; P < 0.001) and locoregional (HR, 0.97; P = 0.042) tumor control on multivariate analyses. Patients with histopathologic margins 16 mm or less had worse local disease-free survival (HR, 2.41; P = 0.01). Patients who did not have an SNB were at higher risk of locoregional recurrence (HR, 1.67; P = 0.003).
CONCLUSIONS:Histopathologically determined primary tumor excision margins more than 16 mm, corresponding to 2-cm surgical margins, were associated with better local control in patients with melanomas more than 4 mm thick. Patients achieved the best local and locoregional control when SNB was coupled with a more than 16-mm histologic excision margin.
Gametocytes are responsible for transmission of malaria from human to mosquito. Artemisinin combination therapy (ACT) reduces post-treatment gametocyte carriage, dependent upon host, parasite and ...pharmacodynamic factors. The gametocytocidal properties of antimalarial drugs are important for malaria elimination efforts. An individual patient clinical data meta-analysis was undertaken to identify the determinants of gametocyte carriage and the comparative effects of four ACTs: artemether-lumefantrine (AL), artesunate/amodiaquine (AS-AQ), artesunate/mefloquine (AS-MQ), and dihydroartemisinin-piperaquine (DP).
Factors associated with gametocytaemia prior to, and following, ACT treatment were identified in multivariable logistic or Cox regression analysis with random effects. All relevant studies were identified through a systematic review of PubMed. Risk of bias was evaluated based on study design, methodology, and missing data.
The systematic review identified 169 published and 9 unpublished studies, 126 of which were shared with the WorldWide Antimalarial Resistance Network (WWARN) and 121 trials including 48,840 patients were included in the analysis. Prevalence of gametocytaemia by microscopy at enrolment was 12.1 % (5887/48,589), and increased with decreasing age, decreasing asexual parasite density and decreasing haemoglobin concentration, and was higher in patients without fever at presentation. After ACT treatment, gametocytaemia appeared in 1.9 % (95 % CI, 1.7-2.1) of patients. The appearance of gametocytaemia was lowest after AS-MQ and AL and significantly higher after DP (adjusted hazard ratio (AHR), 2.03; 95 % CI, 1.24-3.12; P = 0.005 compared to AL) and AS-AQ fixed dose combination (FDC) (AHR, 4.01; 95 % CI, 2.40-6.72; P < 0.001 compared to AL). Among individuals who had gametocytaemia before treatment, gametocytaemia clearance was significantly faster with AS-MQ (AHR, 1.26; 95 % CI, 1.00-1.60; P = 0.054) and slower with DP (AHR, 0.74; 95 % CI, 0.63-0.88; P = 0.001) compared to AL. Both recrudescent (adjusted odds ratio (AOR), 9.05; 95 % CI, 3.74-21.90; P < 0.001) and new (AOR, 3.03; 95 % CI, 1.66-5.54; P < 0.001) infections with asexual-stage parasites were strongly associated with development of gametocytaemia after day 7.
AS-MQ and AL are more effective than DP and AS-AQ FDC in preventing gametocytaemia shortly after treatment, suggesting that the non-artemisinin partner drug or the timing of artemisinin dosing are important determinants of post-treatment gametocyte dynamics.
Artemisinin resistance in Plasmodium falciparum manifests as slow parasite clearance but this measure is also influenced by host immunity, initial parasite biomass and partner drug efficacy. This ...study collated data from clinical trials of artemisinin derivatives in falciparum malaria with frequent parasite counts to provide reference parasite clearance estimates stratified by location, treatment and time, to examine host factors affecting parasite clearance, and to assess the relationships between parasite clearance and risk of recrudescence during follow-up.
Data from 24 studies, conducted from 1996 to 2013, with frequent parasite counts were pooled. Parasite clearance half-life (PC1/2) was estimated using the WWARN Parasite Clearance Estimator. Random effects regression models accounting for study and site heterogeneity were used to explore factors affecting PC1/2 and risk of recrudescence within areas with reported delayed parasite clearance (western Cambodia, western Thailand after 2000, southern Vietnam, southern Myanmar) and in all other areas where parasite populations are artemisinin sensitive.
PC1/2 was estimated in 6975 patients, 3288 of whom also had treatment outcomes evaluate d during 28-63 days follow-up, with 93 (2.8 %) PCR-confirmed recrudescences. In areas with artemisinin-sensitive parasites, the median PC1/2 following three-day artesunate treatment (4 mg/kg/day) ranged from 1.8 to 3.0 h and the proportion of patients with PC1/2 >5 h from 0 to 10 %. Artesunate doses of 4 mg/kg/day decreased PC1/2 by 8.1 % (95 % CI 3.2-12.6) compared to 2 mg/kg/day, except in populations with delayed parasite clearance. PC1/2 was longer in children and in patients with fever or anaemia at enrolment. Long PC1/2 (HR = 2.91, 95 % CI 1.95-4.34 for twofold increase, p < 0.001) and high initial parasitaemia (HR = 2.23, 95 % CI 1.44-3.45 for tenfold increase, p < 0.001) were associated independently with an increased risk of recrudescence. In western Cambodia, the region with the highest prevalence of artemisinin resistance, there was no evidence for increasing PC1/2 since 2007.
Several factors affect PC1/2. As substantial heterogeneity in parasite clearance exists between locations, early detection of artemisinin resistance requires reference PC1/2 data. Studies with frequent parasite count measurements to characterize PC1/2 should be encouraged. In western Cambodia, where PC1/2 values are longest, there is no evidence for recent emergence of higher levels of artemisinin resistance.
Bronchiectasis has been a largely overlooked disease area in respiratory medicine. This is reflected by a shortage of large-scale studies and lack of approved therapies, in turn leading to a ...variation of treatment across centres. BronchUK (Bronchiectasis Observational Cohort and Biobank UK) is a multicentre, prospective, observational cohort study working collaboratively with the European Multicentre Bronchiectasis Audit and Research Collaboration project. The inclusion criteria for patients entering the study are a clinical history consistent with bronchiectasis and computed tomography demonstrating bronchiectasis. Main exclusion criteria are 1) patients unable to provide informed consent, 2) bronchiectasis due to known cystic fibrosis or where bronchiectasis is not the main or co-dominant respiratory disease, 3) age <18 years, and 4) prior lung transplantation for bronchiectasis. The study is aligned to standard UK National Health Service (NHS) practice with an aim to recruit a minimum of 1500 patients from across at least nine secondary care centres. Patient data collected at baseline includes demographics, aetiology testing, comorbidities, lung function, radiology, treatments, microbiology and quality of life. Patients are followed up annually for a maximum of 5 years and, where able, blood and/or sputa samples are collected and stored in a central biobank. BronchUK aims to collect robust longitudinal data that can be used for analysis into current NHS practice and patient outcomes, and to become an integral resource to better inform future interventional studies in bronchiectasis.
This study was undertaken to determine cancer survival and describe the unique spectrum of cancers diagnosed among New Zealand's adolescents and young adult (AYA) population.
Registrations for 1606 ...15-24 year olds diagnosed with a new primary malignant tumor between 2000 and 2009 were obtained from the New Zealand Cancer Registry and classified according to AYA diagnostic group and subgroup, age, sex, and prioritized ethnicity. Age-standardized incidence rates (IRs) per million person years and 5-year relative survival ratios were calculated.
Cancer incidence was 228.6 per million for adolescents aged 15-19 years and 325.7 per million for young adults aged 20-24 years. Overall IRs were consistent across all ethnic groups but there were unique ethnic differences by tumor group including a higher incidence of bone tumors, carcinoma of the gastrointestinal tract, and gonadal germ cell tumors among Maori, a higher incidence of leukemia among Pacific peoples, and a higher incidence of melanoma among non-Maori/non-Pacific peoples. Five-year relative survival for adolescents (75.1%) and AYA overall (80.6%) appeared poorer than had been achieved in other high-income countries. Maori (69.5%) and Pacific (71.3%) AYA had lower 5-year survival compared to non-Maori/non-Pacific peoples (84.2%).
The survival disparities observed require further investigation to identify and address the causes of these inferior outcomes. The newly established AYA Cancer Network Aotearoa has been tasked with improving cancer survival and care and ensuring equality of access for New Zealand AYAs with cancer.
Cerebral involvement in IgG4-related disease Joshi, Deepak; Jager, Rolf; Hurel, Steven ...
Clinical medicine,
April 2015, 2015-Apr, 2015-04-00, 20150401, Letnik:
15, Številka:
2
Journal Article
Recenzirano
Odprti dostop
IgG4-related disease is a recently recognised multi-system disease. Common organ involvement includes the pancreas, biliary tree and salivary glands. Central nervous system involvement has been ...infrequently reported. In a single-centre cohort of 84 patients, we report cerebral involvement in three (4%) patients. Details of cerebral involvement in these patients are outlined, including pituitary involvement in two patients and a diffuse autoimmune-like encephalopathy in the other.
The synthesis and resolution of a class of chiral organic fluorophores, axially chiral 4,4-difluoro-4-bora-3
a
,4
a
-diaza-
s
-indacenes (Ax*-BODIPY), is described. Ax*-BODIPYs were prepared through ...a modular synthesis combined with a late stage Heck functionalisation. Resolution was achieved by preparative chiral HPLC. Absolute stereochemical assignment was performed by comparison of experimental ECD spectra with TD-DFT calculations.
The synthesis and resolution of a class of chiral organic fluorophores, axially chiral 4,4-difluoro-4-bora-3
a
,4
a
-diaza-
s
-indacenes (Ax*-BODIPY), is described. Ax*-BODIPYs were prepared through a modular synthesis, resolved by preparative chiral HPLC and absolute stereochemistry assigned by ECD.
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