Clinical uses of recombinant human thyrotropin

Recombinant human thyroid-stimulating hormone (rhTSH), used to enhance diagnostic radioiodine whole body scanning and thyroglobulin testing, has dramatically altered the management of patients with thyroid cancer. Withdrawal from thyroid hormone suppression therapy and subsequent hypothyroidism is no longer the only safe and effective method for thyroid cancer surveillance. Currently, rhTSH is only approved for the monitoring of low-risk patients with well-differentiated thyroid cancer and radioactive iodine administration, in selected cases. Additional applications of rhTSH include enhancing the sensitivity of positron emission tomography in thyroid cancer, the management of multinodular goiter, and dynamic testing of thyroid reserve. The diagnostic and therapeutic role of rhTSH in these areas is discussed in this review.     

Dose verification in clinical IMRT prostate incidents

PURPOSE: In view of the need for dose-validation procedures on each individual intensity-modulated radiation therapy (IMRT) plan, dose-verification measurements by film, by ionization chamber, and by polymer gel-MRI dosimetry were performed for a prostate-treatment plan configuration. Treatment planning system (TPS) calculations were evaluated against dose measurements. METHODS AND MATERIALS: Intensity-modulated radiation therapy (IMRT) treatments were planned on a commercial TPS. Kodak EDR-2 films were used for the verification of two-dimensional (2D) dose distributions at 1 coronal and 5 axial planes in a water-equivalent phantom. Full three-dimensional (3D) dose distributions were measured by use of a novel polymer gel formulation and a 3D magnetic resonance imaging (MRI) readout technique. Calculations were compared against measurements by means of isocontour maps, gamma-index maps (3% dose difference, 3-mm distance to agreement) and dose-volume histograms. RESULTS: A good agreement was found between film measurements and TPS predictions for points within the 60% isocontour, for all the examined plans (gamma-index <1 for 96% of pixels). Three-dimensional dose distributions obtained with the polymer gel-MRI method were adequately matched with corresponding TPS calculations, for measurements in a gel phantom covering the planning-target volume (PTV). CONCLUSIONS: Measured 2D and 3D dose distributions suggest that, for the investigated prostate IMRT plan configuration, TPS calculations provide clinically acceptable accuracy.     

Low molecular weight heparins: the optimal treatment for venous thromboembolism

Venous thromboembolism (VTE) is a common vascular complication that requires immediate as well as long-term treatment. Unfractionated heparin (UFH), followed by oral anticoagulants (OAs), is of proved efficacy in the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). However, low molecular weight heparins (LMWHs) have successfully replaced UFH both in the prevention and in the initial treatment of DVT and PE. Recent trials evaluated the efficacy and safety of LMWH therapy as an alternative to vitamin K antagonists in long-term VTE secondary prophylaxis for all patients and in specific subgroups. LMWHs differ considerably from each other. These agents were studied separately, administered according to various protocols, in various doses and for different duration of treatment. Results from prospective randomized trials, conducted during the last decade, indicate that LMWHs are at least as effective and yet safer than OAs in the long-term treatment of VTE. In this brief overview, we consider the potential advantages of treatment with LMWH in patients with VTE.     

Resistance-associated point mutations of organophosphate insensitive acetylcholinesterase,in the olive fruit fly Bactrocera oleae

A 2.2-kb full length cDNA containing an ORF encoding a putative acetylcholinesterase (AChE) precursor of 673 amino acid residues was obtained by a combined degenerate PCR and RACE strategy from an organophosphate-susceptible Bactrocera oleae strain. A comparison of cDNA sequences of individual insects from susceptible and resistant strains, coupled with an enzyme inhibition assay with omethoate, indicated a novel glycine-serine substitution (G488S), at an amino acid residue which is highly conserved across species (G396 of Torpedocalifornica AChE), as a likely cause of AChE insensitivity. This mutation was also associated with a 35-40% reduction in AChE catalytic efficiency. The I199V substitution, which confers low levels of resistance in Drosophila, was also present in B. oleae (I214V) and in combination with G488S produced up to a 16-fold decrease in insecticide sensitivity. This is the first agricultural pest where resistance has been associated with an alteration in AChE, which arises from point mutations located within the active site gorge of the enzyme.     

Role of metastasectomy in the management of thyroid carcinoma: the NIH experience

BACKGROUND AND OBJECTIVES: We studied the impact of metatasectomy on disease outcome in 29 advanced nonmedullary thyroid carcinoma (ThyrCa) patients who were operated on between 1969 and 2001 at NIH to further define its role in the management of this malignancy. METHODS: Data were extracted by retrospective chart review. A Kaplan-Meyer survival curve was constructed, and comparative stratification for various parameters was performed. RESULTS: During 47 surgeries, the following lesions were resected from mid-mediastinum/hila, 17; lung parenchyma, 12; skeleton, 14; kidneys, 2; and brain, 2. All patients received multiple radioiodine (RAI) treatments. External-beam radiotherapy, chemotherapy and other palliative measures were used in selected patients. Six patients (21%) died within 74.7 +/- 54.7 months after the first distant metastasectomy. The outcome of the remaining patients was as follows: complete remission, 3; partial remission, 10; and 10: progressive disease, 10, with a follow-up of 175 patient-years. Metastasectomy led to a decrease of 38% in thyroglobulin levels in 23 patients. Cumulative survival rates were 78.5 +/- 8.4% at 5 years and 50.2 +/- 12.5% at 10 years (mean +/-SEM) after initial distant metastasectomy. CONCLUSIONS: Our data show that extensive targeted metastasectomy in the setting of a tertiary center can be beneficial to patients with disseminated ThyrCa with persistent or recurrent distant disease, when used in conjunction with nonsurgical treatment modalities.     

Neuroprotective,anti-apoptotic effects of apomorphine

There is increasing experimental and clinical evidence that oxidation plays a pivotal role in causing neurodegeneration in general and Parkinson's disease in particular. The protective role of antioxidants in such conditions has not been fully examined, but certain neuroprotective agents that have antioxidant action are now being credited with an ability to prevent oxidation-induced neuronal dysfunction. One such agent is the dopamine agonist apomorphine, which is already in clinical use, providing symptomatic relief in Parkinson's disease patients. Far from having simple antioxidants properties, apomorphine is described as a pluripotent agent that can also afford neuroprotection through mechanisms independent of its antioxidant actions. It can, for example, salvage dopaminergic receptors and terminals, upregulate expression of neurotrophic factors, limit the rate of neuronal loss by interfering with several steps of apoptotic cascades, reduce excitotoxicity by modulating nitric oxide metabolism, and reverse ubiquitine-proteasome dependent pathology. This paper reviews the wide range of apomorphine's neuroprotective benefits, suggesting that it is a promising agent with regards to its potential to prevent, reduce, and retard age-related neurodegeneration.     

Functional characterization of the D188V mutation in neuronal voltage-gated sodium channel causing generalized epilepsy with febrile seizures plus (GEFS)

Mutations in the alpha 1 subunit of the voltage-gated sodium channel (SCN1A) have been increasingly recognized as an important cause of familial epilepsy in humans. However, the functional consequences of these mutations remain largely unknown. We identified a mutation (D188V) in SCN1A segregating with generalized epilepsy with febrile seizures (GEFS) in a large kindred. Compared to wild-type sodium channels, in vitro expression of channels harboring the D188V mutation were found to be more resistant to the decline in amplitude that is normally observed over the course of high frequency pulse trains. This small change on a single aspect of channel function is compatible with an increase in membrane excitability, such as during sustained and uncontrolled neuronal discharges. These data suggest that this specific effect on sodium channel function could be a general mechanism in the pathophysiology of epilepsies caused by mutations in sodium channels in humans.     

A Plackett-Burnam screening design directs the efficient formulation of multicomponent DRV liposomes

A computer-based technique was applied for the optimization of recently described multicomponent protective liposomal formulations. These formulations contain riboflavin in either free form or complexed with gamma-cyclodextrin as a model drug, sensitive to photochemical degradation, as well as various light absorbers and antioxidants incorporated into the lipid bilayer and/or the aqueous phase of liposomes. During the liposomal preparation, a series of 11 factors were isolated as important to affect their effectiveness as stabilization systems. These factors were related, first, to the composition of liposomes and, second, to variations during the preparation procedure. The Plackett--Burnam design described in this study was applied for the isolation of the significant factors in order to concentrate more on them. The stabilization ratio of the vitamin was the response variable of the system to be optimized. In order to assure the presence of the examined components in liposomes, the entrapment values were calculated for all the materials, either spectrophotometrically or using second-order derivative spectrophotometry. The optimum formulation should be characterized from the higher protection of the drug.