Phantom calibration method for improved temporal characterization of hemodynamic response in event-related fMRI

In event-related functional MRI, there exist limits on the time length of the experiments on human subjects and the imaging speed. Due to these limitations, data truncation and undersampling have to be used in functional MRI signal acquisition. The effect of these factors on the hemodynamic deconvolution is investigated experimentally and a phantom calibration method to improve the hemodynamic response is developed. It is observed that the high frequency components generated due to data truncation can fold back into low frequencies when the sampling rate is not sufficiently high. This aliasing can introduce significant noise in hemodynamic deconvolution and can reduce the accuracy of the temporal characterization of hemodynamic response. A SMARTPHANTOM BOLD simulator is used to calibrate the aliasing effect in an event-related functional MRI experiment. With the calibration, an anti-aliasing method is used to suppress the aliasing and this resulted in an improved temporal characterization of hemodynamic response in event-related fMRI.     

Stimulation of cAMP accumulation and superoxide production in human neutrophils and monocytes

The effect of sodium fluoride (NaF) on superoxide generation and cyclic adenosine monophosphate (cAMP) levels in human neutrophils and monocytes was investigated. NaF (greater than 10 mM) stimulated superoxide (O2-) production in both cell types in a time dependent manner. NaF (0.5 to 20 mM) increased cAMP levels by 1.5- to 3.-fold in both neutrophils and monocytes. Increases in cAMP levels were time-dependent; the maximal level was attained within 5 minutes after the addition of NaF, and cAMP levels remained elevated for up to 10 minutes. Only high concentrations of NaF (10 and 20 mM) increased both cAMP levels and O2- production. Therefore, a direct role of cAMP in O2- generation is not likely. It is speculated that since NaF (greater than 10 mM) can complex with extracellular Ca++, and thus reduce free Ca++ concentration required for O2- generation, a NaF-dependent increase in cAMP may restore cytosolic free Ca++ by mobilizing intracellular stores of Ca++. Further, in view of the proposed involvement of a phosphorylation-dephosphorylation mechanism in the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, we speculate that NaF, by inhibiting phosphoprotein phosphatase activity, may indirectly activate the NADPH oxidase system and thus superoxide generation.     

Mutation analysis of the parkin and PINK1 genes in American Caucasian early-onset Parkinson disease families

Mutations in the parkin gene and the PTEN-induced putative kinase 1 gene (PINK1) have been identified as the most common causes of autosomal recessive early-onset Parkinson disease (EOPD). To investigate the presence of the parkin and PINK1 gene mutation(s) and to explore genotype-phenotype correlations in American Caucasian families with EOPD from North American, we screened these two genes in probands of six families by direct sequencing, semi-quantitative PCR and RT-PCR. No PINK1 gene mutation was found in any of the probands, but compound heterozygous mutations (EX 3 del and EX 3_4 del) in the parkin gene were identified in one family. Extended analysis of the parkin-positive family showed the phenotype of patients was that of classic autosomal recessive EOPD, characterized by early age at onset, slow progression, beneficial response to levodopa, and levodopa-related motor complications. Three heterozygous mutation carriers (EX 3 del or EX 3_4 del) were free of any neurological symptoms. None of 62 healthy controls harbored EX 3 del or EX 3_4 del mutation. Our data suggest that compound heterozygous mutations (EX 3 and EX 3_4 del) in the parkin gene were the cause of EOPD in one of six Caucasian families; heterozygous EX 3 del and heterozygous EX 3_4 del forms were insufficient to cause this disorder, consistent with a loss-of-function mechanism of the parkin mutations. The results may provide new insights into the cause and diagnosis of PD and have implications for genetic counseling.     

Organ donation after cardiac death in amyotrophic lateral sclerosis

Patients with amyotrophic lateral sclerosis (ALS) are often told that solid organ donation is not possible following death, although the reasons for exclusion are not evidence based. Because ALS patients typically remain sentient until death, organs may be procured under donation after cardiac death protocols. Anticipating this need, our institution created a process for organ donation in ventilator-dependent ALS patients that was subsequently implemented. To our knowledge, this is the first report of organ donation in a patient with rapidly progressive ventilator-dependent ALS.     

Clinical Outcomes of Patients With Recurrent Lung Cancer Reirradiated With Proton Therapy on the Proton Collaborative Group and University of Florida Proton Therapy Institute Prospective Registry Studies

PurposeWe sought to assess clinical outcomes and toxicities of patients with recurrent lung cancer reirradiated with proton beam therapy (PBT) who were enrolled in 2 prospective registry trials.Methods and MaterialsSeventy-nine consecutive patients were reirradiated with PBT at 8 institutions. Conventionally fractionated radiation therapy was used to treat the previous lung cancer in 68% of patients (median equivalent dose in 2 Gy fractions [EQD₂], 60.2 Gy) and hypofractionated/stereotactic body radiation therapy in 32% (median EQD₂, 83.3 Gy). Nine patients (11%) received ≥2 courses of thoracic irradiation before PBT. Eastern Cooperative Oncology Group (ECOG) performance status was 2 to 3 in 13%. Median time from prior radiation therapy to PBT was 19.9 months. PBT was delivered with conventional fractionation in 58% (median EQD₂, 60 Gy), hyperfractionation in 3% (median EQD₂, 62.7 Gy), and hypofractionation in 39% (median EQD₂, 60.4 Gy). Twenty-four patients (30%) received chemotherapy concurrently with PBT.ResultsAll patients completed PBT as planned. At a median follow-up of 10.7 months after PBT, median overall survival (OS) and progression-free survival (PFS) were 15.2 months and 10.5 months, respectively. Acute and late grade 3 toxicities occurred in 6% and 1%, respectively. Three patients died after PBT from possible radiation toxicity. On multivariate analysis, ECOG performance status ≤1 was associated with OS (hazard ratio, 0.35; 95% confidence interval, 0.15-0.80; P = .014) and PFS (hazard ratio, 0.32; 95% confidence interval, 0.14-0.73; P = .007).ConclusionsThis is the largest series to date of PBT reirradiation for recurrent lung cancer and indicates that reirradiation with PBT is well tolerated with acceptable toxicity and encouraging efficacy. ECOG performance status was associated with OS and PFS.     

A Retrospective Study of Comorbidities and Complications in Elderly Acute Myeloid Leukemia Patients in the United States

BackgroundComorbidities in acute myeloid leukemia (AML) patients have been shown to increase with age. However, few studies have described the disease burden in elderly AML patients, a population generally underrepresented in clinical trials. We aimed to characterize the comorbidities and complications in elderly AML patients.Patients and MethodsPatients aged ≥ 65 years with a primary diagnosis of AML were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (2000-2013) and were followed until the end of 2014. AML patients were matched 1:1 to noncancer patients by age, sex, geographic region, and race. A subset of patients with relapsed and/or refractory (R/R) AML was identified by modifying a previously validated algorithm. Baseline comorbidities and complications (eg, infectious, hematologic, cardiovascular) during follow-up were assessed using ICD-9 codes. Cox proportional hazards models were used to determine associations between AML and developing select complications.ResultsCompared to matched noncancer controls, AML patients (n = 3911) had higher baseline National Cancer Institute comorbidity index scores (1.81 vs. 1.63, P < .01), higher incidence rates (per 100 person-years) for all events of interest, and a higher risk of developing cardiovascular disease (hazard ratio = 4.61; 95% confidence interval, 4.07-5.21), type 2 diabetes mellitus (hazard ratio = 3.85; 95% confidence interval, 3.35-4.42), and stroke (hazard ratio = 2.60; 95% confidence interval, 2.32-2.92). R/R AML patients were younger, had lower National Cancer Institute comorbidity scores, lower incidence rates of events of interest, and a longer follow-up time compared to non-R/R AML patients.ConclusionElderly AML patients had more comorbidities and higher rates of complications compared to noncancer controls. Considering comorbidities and complications in elderly AML patients may improve clinical decision making.     

Whole-genome sequencing for optimized patient management

Whole-genome sequencing of patient DNA can facilitate diagnosis of a disease, but its potential for guiding treatment has been under-realized. We interrogated the complete genome sequences of a 14-year-old fraternal twin pair diagnosed with dopa (3,4-dihydroxyphenylalanine)-responsive dystonia (DRD; Mendelian Inheritance in Man #128230). DRD is a genetically heterogeneous and clinically complex movement disorder that is usually treated with l-dopa, a precursor of the neurotransmitter dopamine. Whole-genome sequencing identified compound heterozygous mutations in the SPR gene encoding sepiapterin reductase. Disruption of SPR causes a decrease in tetrahydrobiopterin, a cofactor required for the hydroxylase enzymes that synthesize the neurotransmitters dopamine and serotonin. Supplementation of l-dopa therapy with 5-hydroxytryptophan, a serotonin precursor, resulted in clinical improvements in both twins.