Consequences and costs of noncompliance with iron chelation therapy in patients with transfusion-dependent thalassemia: a literature review

BACKGROUND: Patients with thalassemia major require iron chelation therapy (ICT) to prevent complications from transfusional iron overload. Deferoxamine is effective, but requires administration as a slow continuous subcutaneous or intravenous infusion five to seven times per week. Deferiprone is a three-times-daily oral iron chelator, but has limited availability in the United States. Deferasirox is a once-daily oral iron chelator that was approved in the United States in 2005 for patients older than 2 years of age with transfusional iron overload. STUDY DESIGN AND METHODS: Published evidence on rates of compliance with ICT and the association between compliance, and the incidence and costs of complications of iron overload, in patients with thalassemia major was reviewed. RESULTS: A total of 18 studies were identified reporting data on compliance with ICT, including 7 that examined deferoxamine only, 6 that examined deferiprone only, and 5 that compared deferoxamine and deferiprone; no studies reporting compliance with deferasirox were identified. In studies of deferoxamine only, estimated mean compliance ranged from 59 to 78 percent. Studies of deferiprone generally reported better compliance, ranging from 79 to 98 percent. Results of comparative studies of deferoxamine and deferiprone suggest that compliance may be better with oral therapy. Numerous studies demonstrate that that poor compliance with ICT results in increased risk of cardiac disease and endocrinopathies, as well as lower survival. Although data on the costs of noncompliance are limited, a recent model-based study estimated the lifetime costs of inadequate compliance with deferoxamine to be $33,142. CONCLUSIONS: Inadequate compliance with ICT in thalassemia major is common and results in substantial morbidity and mortality, as well as increased costs.     

Processing abstract auditory features in the human auditory cortex

Using electric and magnetic brain responses we tested whether violations of an abstract auditory regularity are processed in auditory cortex and whether abstract auditory regularities are retained for at least 10 s. The mismatch negativity (MMN) event-related potential and its magnetic counterpart (MMNm) were recorded to infrequent tone pairs of descending pitch (the second tone having a lower frequency than the first one) embedded in a sequence of tone pairs of ascending pitch, whereas the absolute frequency of both ascending and descending tone pairs varied on seven levels. Results showed that the dominant generators of the electromagnetic activity elicited by violations of the pitch-ascension rule lie within auditory cortex. We also found that the memory representation of pitch-ascension is retained for at least 10 s. When short trains of ascending-pitched tone pairs were followed by a silent period of 8-12 s, descending-pitched probe tone pairs elicited the MMN component when a single reminding pair with ascending pitch was presented before the probe. The reactivating effect of the reminder was similar to what has been previously shown for concrete auditory regularities, such as the constancy of tone pitch. The present results support the view that auditory cortical functions can process sensory and categorical information in a similar manner.     

Generators of the intracranial P50 response in auditory sensory gating

Clarification of the cortical mechanisms underlying auditory sensory gating may advance our understanding of brain dysfunctions associated with schizophrenia. To this end, data from nine epilepsy patients who participated in an auditory paired-click paradigm during pre-surgical evaluation and had grids of electrodes covering temporal and frontal lobe were analyzed. A distributed source localization approach was applied to the intracranial P50 response and the Gating Difference Wave obtained by subtracting the response to the second stimuli from the response to the first stimuli. Source reconstruction of the P50 showed that the main generators of the response were localized in the temporal lobes. The analysis also suggested that the maximum neuronal activity contributing to the amplitude reduction in the P50 time range (phenomenon of auditory sensory gating) is localized at the frontal lobe. Present findings suggest that while the temporal lobe is the main generator of the P50 component, the frontal lobe seems to be a substantial contributor to the process of sensory gating as observed from scalp recordings.     

Baseline correction of phase contrast images improves quantification of blood flow in the great vessels.

PURPOSE: Phase-contrast Cardiovascular Magnetic Resonance Imaging (CMR) generally requires the analysis of stationary tissue adjacent to a blood vessel to serve as a baseline reference for zero velocity. However, for the heart and great vessels, there is often no stationary tissue immediately adjacent to the vessel. Consequently, uncorrected velocity offsets may introduce substantial errors in flow quantification. The purpose of this study was to assess the magnitude of these flow errors and to validate a clinically applicable method for their correction. MATERIALS AND METHODS: In 10 normal volunteers, phase-contrast CMR was used to quantify blood flow in the main pulmonary artery (Qp) and the aorta (Qs). Following image acquisition, phase contrast CMR was performed on a stationary phantom using identical acquisition parameters so as to provide a baseline reference for zero velocity. Aortic and pulmonary blood flow was then corrected using the offset values from the phantom. RESULTS: The mean difference between pulmonary and aortic flow was 26 +/- 21 mL before correction and 7.1 +/- 6.6 mL after correction (p = 0.002). The measured Qp/Qs was 1.25 +/- 0.20 before correction and 1.05 +/- 0.07 after correction (p = 0.001). CONCLUSION: Phase-contrast CMR can have substantial errors in great vessel flow quantification if there is no correction for velocity offset errors. The proposed method of correction is clinically applicable and provides a more accurate measurement of blood flow.     

Comparative Study of Tumor Targeting and Biodistribution of pH (Low) Insertion Peptides (pHLIP<Superscript>®</Superscript> Peptides) Conjugated with Different Fluorescent Dyes

Purpose

Acidification of extracellular space promotes tumor development, progression, and invasiveness. pH (low) insertion peptides (pHLIP^® peptides) belong to the class of pH-sensitive membrane peptides, which target acidic tumors and deliver imaging and/or therapeutic agents to cancer cells within tumors.

Procedures

Ex vivo fluorescent imaging of tissue and organs collected at various time points after administration of different pHLIP^® variants conjugated with fluorescent dyes of various polarity was performed. Methods of multivariate statistical analyses were employed to establish classification between fluorescently labeled pHLIP^® variants in multidimensional space of spectral parameters.

Results

The fluorescently labeled pHLIP^® variants were classified based on their biodistribution profile and ability of targeting of primary tumors. Also, submillimeter-sized metastatic lesions in lungs were identified by ex vivo imaging after intravenous administration of fluorescent pHLIP^® peptide.

Conclusions

Different cargo molecules conjugated with pHLIP^® peptides can alter biodistribution and tumor targeting. The obtained knowledge is essential for the design of novel pHLIP^®-based diagnostic and therapeutic agents targeting primary tumors and metastatic lesions.

     

Evidence for neurogenesis in the adult mammalian substantia nigra

New neurons are generated from stem cells in a few regions of the adult mammalian brain. Here we provide evidence for the generation of dopaminergic projection neurons of the type that are lost in Parkinson's disease from stem cells in the adult rodent brain and show that the rate of neurogenesis is increased after a lesion. The number of new neurons generated under physiological conditions in substantia nigra pars compacta was found to be several orders of magnitude smaller than in the granular cell layer of the dentate gyrus of the hippocampus. However, if the rate of neuronal turnover is constant, the entire population of dopaminergic neurons in substantia nigra could be replaced during the lifespan of a mouse. These data indicate that neurogenesis in the adult brain is more widespread than previously thought and may have implications for our understanding of the pathogenesis and treatment of neurodegenerative disorders such as Parkinson's disease.     

Meta-learning approach to neural network optimization

Optimization of neural network topology, weights and neuron transfer functions for given data set and problem is not an easy task. In this article, we focus primarily on building optimal feed-forward neural network classifier for i.i.d. data sets. We apply meta-learning principles to the neural network structure and function optimization. We show that diversity promotion, ensembling, self-organization and induction are beneficial for the problem. We combine several different neuron types trained by various optimization algorithms to build a supervised feed-forward neural network called Group of Adaptive Models Evolution (GAME). The approach was tested on a large number of benchmark data sets. The experiments show that the combination of different optimization algorithms in the network is the best choice when the performance is averaged over several real-world problems.     

Immediate recovery room radiographs after primary total knee arthroplasty—why do we keep doing them?

Recovery room radiographs (RRR) are routinely performed after total knee arthroplasty (TKA). This study investigates the utility of these radiographs. Twenty four arthroplasty surgeons were surveyed to rank the value of RRRs. Since RRRs were primarily valued for educational purposes, we examined the ability of 49 orthopaedic trainees to determine the coronal alignment of TKA performed in cadaveric specimens based on these radiographs in neutral, 10° internal and external rotations. Surgeons rated the quality of the RRRs to be significantly lower than the radiographs taken in the radiology suite (5.5 ± 2.5 versus 8.9 ± 0.9, p < 0.0001). Of an estimated 65,910 TKAs performed by these surgeons, only eight cases (0.01%) required same day revision based on the RRR. Neutral alignment was significantly more accurately (p < 0.0001) interpreted than valgus or varus (69.4% versus 42.9% and 16.3%, respectively). Surprisingly, internal rotation of the limb significantly improved interpretation of both varus (from 16.3% to 40.8%, p = 0.014) and valgus (from 42.9% to 63.3%, p = 0.048). Increased level of orthopaedic training did not significantly affect the accuracy of interpretation (p = 0.46). Interpretation of RRRs for coronal malalignment is inaccurate and has a limited educational value.