Open-label pilot study of interferon gamma-1b in Friedreich ataxia.

OBJECTIVES/AIMS: This is an open-label trial of the safety of interferon gamma-1b (IFN-γ) and its effect on frataxin levels and neurologic measures in 12 children with Friedreich ataxia. MATERIALS AND METHODS: Interferon gamma-1b was administered via subcutaneous injection three times weekly. The dose increased from 10 to 50 mcg/m(2) during the first four weeks and then remained at 50 mcg/m(2) for final eight weeks. Safety assessments included laboratory testing, electrocardiogram, and monitoring of adverse events. The primary efficacy outcome measure was frataxin level in whole blood. Secondary measures included frataxin levels in multiple tissues, frataxin mRNA levels, Friedreich Ataxia Rating Scale (FARS) scores and other neurologic evaluations. Statistical analyses were performed via SAS and STATA. RESULTS: Interferon gamma-1b was well tolerated with no serious adverse events, and only two subjects reporting severe adverse events and subsequent dose reductions. Small but significant changes in frataxin levels were observed in red blood cells, PBMC, and platelets after 12 weeks of treatment. However, the magnitude of change was small and varied between tissues. Mean improvement in FARS score was equivalent to roughly 18 months of disease progression after 12 weeks of treatment (P = 0.008). No other statistically significant changes were observed. No statistically significant relationships were observed between frataxin protein levels, FARS scores, and in vivo IFN-γ levels. CONCLUSIONS: Interferon gamma-1b improved FARS scores without a clear relationship to changes in frataxin levels. Larger, longer placebo-controlled trials including biochemical assessments in affected tissues are necessary to evaluate fully the efficacy and utility of IFN-γ in FRDA.

Changes in DXA and quantitative CT measures of musculoskeletal outcomes following pediatric renal transplantation.

This prospective study evaluated changes in dual energy X-ray absorptiometry (DXA) whole body bone mineral content (WB-BMC) and spine areal bone mineral density (spine-BMD), and tibia quantitative computed tomography (QCT) trabecular and cortical volumetric BMD and cortical area in 56 children over 12 months following renal transplantation. At transplant, spine-BMD Z-scores were greater in younger recipients (<13 years), versus 898 reference participants (p < 0.001). In multivariate models, greater decreases in spine-BMD Z-scores were associated with greater glucocorticoid dose (p < 0.001) and declines in parathyroid hormone levels (p = 0.008). Changes in DXA spine-BMD and QCT trabecular BMD were correlated (r = 0.47, p < 0.01). At 12 months, spine-BMD Z-scores remained elevated in younger recipients, but did not differ in older recipients (≥ 13) and reference participants. Baseline WB-BMC Z-scores were significantly lower than reference participants (p = 0.02). Greater glucocorticoid doses were associated with declines in WB-BMC Z-scores (p < 0.001) while greater linear growth was associated with gains in WB-BMC Z-scores (p = 0.01). Changes in WB-BMC Z-scores were associated with changes in tibia cortical area Z-scores (r = 0.52, p < 0.001), but not changes in cortical BMD Z-scores. Despite resolution of muscle deficits, WB-BMC Z-scores at 12 months remained significantly reduced. These data suggest that spine and WB DXA provides insight into trabecular and cortical outcomes following pediatric renal transplantation.

Cost-effectiveness analysis of pancreatin minimicrospheres in patients with pancreatic exocrine insufficiency due to chronic pancreatitis.

OBJECTIVE: Chronic pancreatitis (CP) is the most common cause of pancreatic exocrine insufficiency (PEI). Management of PEI due to CP is achieved through lifelong treatment with pancreatic enzyme replacement therapy (PERT). To the authors' knowledge, no cost-effectiveness analysis on the benefit of PERT in CP patients with PEI has been performed to date. The objective of this analysis was to examine the cost-effectiveness of Creon (pancreatin minimicrospheres [MMS]), one of the main PERTs available in Poland, in treating patients with CP-related PEI. METHODS: The cost-effectiveness of pancreatin MMS in the treatment of patients with CP-related PEI vs no PERT treatment was estimated using a decision analysis based on clinical data from relevant studies. The model horizon was 20 years. Main outcomes included the percentage of patients with controlled PEI, survival, total medical costs, number of quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). All costs were analysed from the Polish payer perspective. RESULTS: The model included clinical data from 176 patients treated in five pancreatin MMS randomized trials. Treatment with pancreatin MMS resulted in a considerably higher proportion of patients with controlled PEI compared to those not treated with any PERT. Over a horizon of 20 years, the total treatment cost and the ICER for pancreatin MMS was €8223 and €6312 per QALY, respectively. LIMITATIONS: Important limitations include the lack of long-term and comparative clinical data available. The use of 'no PERT treatment' as a comparator against pancreatin MMS treatment may not accurately reflect current practice in Poland. CONCLUSIONS: Treatment of CP-related PEI with pancreatin MMS is cost-effective from a Polish payer perspective, with an ICER below the accepted 'willingness to pay' threshold of 3-times gross domestic product (GDP) per capita. These results are likely to apply to other European countries.

WYSIWYP: What You See Is What You Pick.

Scientists, engineers and physicians are used to analyze 3D data with slice-based visualizations. Radiologists for example are trained to read slices of medical imaging data. Despite the numerous examples of sophisticated 3D rendering techniques, domain experts, who still prefer slice-based visualization do not consider these to be very useful. Since 3D renderings have the advantage of providing an overview at a glance, while 2D depictions better serve detailed analyses, it is of general interest to better combine these methods. Recently there have been attempts to bridge this gap between 2D and 3D renderings. These attempts include specialized techniques for volume picking in medical imaging data that result in repositioning slices. In this paper, we present a new volume picking technique called WYSIWYP ("what you see is what you pick") that, in contrast to previous work, does not require pre-segmented data or metadata and thus is more generally applicable. The positions picked by our method are solely based on the data itself, the transfer function, and the way the volumetric rendering is perceived by the user. To demonstrate the utility of the proposed method, we apply it to automated positioning of slices in volumetric scalar fields from various application areas. Finally, we present results of a user study in which 3D locations selected by users are compared to those resulting from WYSIWYP. The user study confirms our claim that the resulting positions correlate well with those perceived by the user.

An O(N3) implementation of Hedin's GW approximation for molecules.

We describe an implementation of Hedin's GW approximation for molecules and clusters, the complexity of which scales as O(N(3)) with the number of atoms. Our method is guided by two strategies: (i) to respect the locality of the underlying electronic interactions and (ii) to avoid the singularities of Green's functions by manipulating, instead, their spectral functions using fast Fourier transform methods. To take into account the locality of the electronic interactions, we use a local basis of atomic orbitals and, also, a local basis in the space of their products. We further compress the screened Coulomb interaction into a space of lower dimensions for speed and to reduce memory requirements. The improved scaling of our method with respect to most of the published methodologies should facilitate GW calculations for large systems. Our implementation is intended as a step forward towards the goal of predicting, prior to their synthesis, the ionization energies and electron affinities of the large molecules that serve as constituents of organic semiconductors.

Elimination, in electronic structure calculations, of redundant orbital products.

We propose a direct method for reducing the dimension of the space of orbital products that occur, for example, in the calculation of time dependent density functional theory linear response and in Hedin's GW approximation to the electron propagator. We do this by defining, within the linear space of orbital products, a subspace of dominant directions that are associated with a certain eigenvalue problem. These directions span the entire linear space of products with an error that decreases approximately exponentially with their number. Our procedure works best for atomic orbitals of finite range and it avoids the use of extra sets of auxiliary fit functions.

Severe secondary hyperparathyroidism.

The process of managing SHPT requires ongoing evaluation and revision. Although A.M. presented a number of challenges in the course of managing her SHPT, the outcome goals were met. Throughout the course of treatment, the renal dietitian worked collaboratively with the other members of the multidisciplinary team and played an important role in educating the patient as well as monitoring the treatment plan and response to therapy. More aggressive paricalcitol dosing and close patient follow up was shown to be effective in the management of SHPT.

Mechanisms of inotropic responses of the isolated rat hearts to vanadate.

In view of the invariable development of insulin resistance in different types of cardiovascular diseases, considerable attention has been focused on vanadate because of its ability to exert insulin-like effects in the body. Since vanadate, like insulin, has been shown to exert a beneficial effect in diabetic cardiomyopathy, this study was undertaken to examine the mechanisms of its action on the heart. Vanadate, at 5-10 microM concentrations, produced a positive inotropic effect in the isolated perfused rat heart, whereas at higher concentrations (20 microM), it decreased the contractile force development. The positive inotropic effect of 10 microM vanadate was not affected by the pretreatment of animals with reserpine as well as the presence of propranolol or phenoxybenzamine in the perfusion medium. The increase in contractile force development due to vanadate at low (0.3-0.6 mM) concentrations of Ca2+ was markedly augmented, but this agent produced a negative inotropic action at high concentrations of Ca2+ (2.0-3.0 mM). Preperfusion of hearts with verapamil enhanced the positive inotropic effect of vanadate whereas hearts preperfused with ouabain, low sodium or amiloride showed negative inotropic effects of vanadate. Vanadate was found to inhibit sarcoplasmic reticular Ca(2+)-pump and sarcolemmal Ca(2+)-pump as well as Na(+)-K(+)-ATPase activities but the sarcolemmal effects were evident at lower concentrations in comparison to that on the sarcoplasmic reticulum. The actions of vanadate on membrane Ca2+ transport and ATPase systems were specific since this agent exerted no effect on sarcolemmal Na(+)-Ca2+ exchange or myofibrillar ATPase activities. In isolated cardiomyocytes suspended in buffer containing 0.5 or 1.0 mM Ca2+, vanadate increased the intracellular concentration of Ca2+; this increase in intracellular Ca2+ was more pronounced at 0.5 mM Ca2+. These results indicate that increased intracellular concentration of Ca2+ due to inhibition of sarcolemmal Na(+)-K(+)-ATPase and sarcolemmal Ca(2+)-pump may be the primary mechanism of the positive inotropic action of vanadate in the heart. It is suggested that vanadate may serve as an inotropic agent and that this mechanism may contribute towards its beneficial effects on cardiac dysfunction in different cardiovascular diseases.

Ischemic myocardial damage in spontaneously hypertensive rats (SHR) is enhanced after long-term feeding of an alpha-linolenic acid enriched diet.

In this study the influence of long-term feeding of an alpha-linolenic acid (LNA) enriched diet on the sensitivity of SHR to catecholamine-induced myocardial injury was investigated. An enhanced ischemic vulnerability after LNA supplementation was observed as indicated both by a marked decrease of enzyme activities in the myocardium and by a pronounced elevation of plasma enzymes. Distinctly higher TBARS levels in heart tissue and plasma of LNA rich fed SHR suggest that an exaggerated lipid peroxidation might contribute to the increased ischemic vulnerability. Non-enzymatic lipid peroxidation is favoured by a feeding-provoked enrichment in highly unsaturated fatty acids in tissue phospholipids. Under such conditions of enhanced substrate availability for radical-induced lipid peroxidation an increased requirement for antioxidants can be assumed which might not sufficiently be met by tocopherol-supplementation in SHR because of their known defects in antioxidative defense mechanisms.

Skoog versus conventional rhytidectomy.

The Skoog SMAS rhytidectomy has generally been accepted since its introduction as being superior to conventional rhytidectomy. A study is presented comparing major complications and "redo" modalities to determine if one or the other precedure is superior. The study revealed that the Skoog rhytidectomy yields fewer major hematomas but that there is a greater need for "redos" within the first year for unsatisfactory results, as well as a significantly larger number of facial nerve injuries.

Construction of natural appearing female genitalia in the male transsexual.

A surgical technique is presented which gives an excellent appearance and functional result in male-to-female transsexual conversion of genitalia. The complications have been few, and the conversion is done in one operation.

A new method for tightening the orbicularis oculi muscles during blepharoplasty.

Long-term results in 248 patients who underwent electrocoagulation to tighten the orbicular muscles of the eyes have proved that the technique is not only safe but highly satisfactory.

"False bursa" concept in augmentation mammaplasty.

Natural feeling breasts are a primary objective to be achieved in the augmentation mammaplasty procedure. Rather than attempt to totally prevent a fibrous capsule from forming about the implant, it should be converted into a larger "false bursa" containing a freely mobile soft implant of modern design with no fixation patches. This relationship must be maintained through many months of the postoperative period to ensure a lasting result. Failure to achieve the false bursa concept results in a tight immobile noncompressible breast that has an unnatural feel.