Long term outcomes of nonmyeloablative allogeneic stem cell transplantation with TSEB TLI and ATG for Mycosis Fungoides and Sezary Syndrome.

Advanced stage (IIB-IVB) Mycosis Fungoides (MF) and Sezary Syndrome (SS) have a poor prognosis with median survival <5 years. We report long-term outcomes of a non-myeloablative allogeneic stem cell transplantation regimen consisting of total skin electron beam therapy, total lymphoid irradiation and antithymocyte globulin. Our prospective cohort consisted of 41 patients with a higher proportion of MF (34MF, 7SS). Acute GVHD Grade 2 to 4 was seen in 31.7% and chronic GVHD Grade 2 to 4 in 24%. The cumulative incidence of non-relapse mortality was 9.8% at 1 year and 12.6% at 2 years. At Day +90 post-transplant 66% of patients had a complete response (CR). With a median post-transplant follow up of 5.27 years, the 5-year overall survival rate was 37.7% (MF 36.7%, SS 57.1%). The 5-year cumulative incidence of progressive disease or relapse was 52.7% in all patients but only 20.8% in those with CR at transplant compared to 70.6% in those not in CR at transplant (p = 0.006). Long term survival is possible in advanced MF and SS with non-myeloablative transplantation and outcomes are improved in patients with CR at transplant.

The Effects of N-terminal Mutations on ß-amyloid Peptide Aggregation and Toxicity.

Human amyloid ß1-42 (hAß1-42) peptides are known to self-aggregate into oligomers that contribute to the degeneration of neurons and development of Alzheimer's disease (AD) pathology. Unlike humans, rodents do not develop AD, possibly due to differences in three amino acids (R5G, Y10F and H13R) within the hydrophilic N-terminal domain of Aß1-42. This is partly supported by evidence that hAß1-42 is more prone to fibrillization and has a higher cellular toxicity than rodent Aß1-42 (rAß1-42). Mutagenesis studies, however, have shown that correlation between fibrillization potential and toxicity is not always direct. Thus, to understand better how N-terminal mutations can affect hAß1-42 toxicity through oligomerization, we evaluated fibrillization kinetics, oligomer sizes and toxicity profiles of double mutant (human toward rodent) Aß1-42. Additionally, we tested the mutant peptides in combination with hAß1-42, to assess effects on hAß1-42 aggregation/toxicity. Our results clearly show that double mutations to humanize rAß1-42 result in a significantly reduced efficiency of fibril formation, as determined by Thioflavin-T aggregation assays and confirmed with electron micrographic studies. Interestingly, the mutants are still able to aggregate into oligomers, which are predominantly larger than those comprised of hAß1-42. Our cell viability experiments further showed a rank order of oligomer toxicity of hAß1-42 > rAß1-42 ≫ mutant Aß1-42, suggesting that toxicity can be influenced by N-terminal Aß1-42 mutations via reduction of fibril formation and/or alteration of oligomer size. These results, taken together, confirm that N-terminal mutations can affect Aß fibril and oligomer formation with reduced toxicity despite lying outside the core amyloid region of Aß peptide.

Evaluating elderly patients with syncope.

Age-related physiologic changes together with high prevalence of chronic illness and the use of multiple medications predispose older adults to syncope. The causes of many of these patients' syncope are unexplained and most remained symptomatic. A thoughtful diagnostic strategy is essential to pinpoint the cause in each patient. The initial assessment includes a comprehensive medical history, preferably with an eye witness account, and a thorough physical examination. The decision for further diagnostic tests often depends on whether there is evidence of underlying structural heart disease. In the absence of heart disease, tilt table testing and the related autonomic function testing are usually most productive. Various cardiac studies will be more appropriate for those with suspected structural heart disease. A cause of syncope can only be concluded if there is a sufficiently strong correlation between syncopal symptoms and the detected abnormalities on investigations. A strategic evaluation of syncope of the elderly subjects should allow a correct diagnosis and appropriate management.

Environmental temperature and the percutaneous absorption of a cholinesterase inhibitor, VX.

S-(2-diisoproplaminoethyl) 0-ethyl methylphosphonothioate (VX), an anticholinesterase liquid of low volatility, was applied to the skin of 139 men at environmental temperatures of -18 degrees, 2 degrees, 18 degrees, or 46 degrees C. The skin was decontaminated after 3 hr and the men spent the next 21 hr at about 27 degrees C. The amount of VX penetrating the skin was estimated from the inhibition of red blood cell cholinesterase. The decimal fraction of the dose that penetrated in 3 hr ranged from 0.04 at -18 degrees C to 0.32 at 46 degrees C for the cheek and from 0.004 at +18 degrees C to 0.029 at 46 degrees C for the forearm. Further increase in cholinesterase inhibition after decontamination was evidence of a deposit of VX in the skin. The amount of VX remaining in the skin after decontamination was greater in the forearm and less in the cheek at higher temperatures.

Attempt to induce cataracts in rabbits by cutaneous application of acetone.

Acetone is used as a solvent for chemicals in skin sensitization studies. Its low cost, high solvent powers, and comparative lack of toxicity make it one of the most widely used industrial solvents. Absorption of acetone through the skin is not considered hazardous; however, in an earlier study we found that acetone caused cataracts in a large group of guinea pigs when small multiple doses were administered either topically or intracutaneously on the backs of these animals. No cataracts were found when two rabbits were tested. The purpose of the present study is to repeat the earlier study using more rabbits. Here, none of the 10 experimental rabbits or the 10 control rabbits developed any lens abnormalities. Those drugs and toxic substances that have produced cataracts in rabbits are described.