Coexistence of beta-1 and beta-2 adrenergic receptors in the human heart: effects of treatment with receptor antagonists or calcium entry blockers

The properties of the binding of [125I]iodopindolol ([125I]IPIN) to beta adrenergic receptors on plasma membranes prepared from right atrial tissue removed during cardiac bypass surgery were investigated. Some of the patients from whom the tissue was removed had been treated before surgery with either a beta adrenergic receptor antagonist or a calcium entry blocker or both. The specific binding of [125I]IPIN to beta adrenergic receptors was saturable, stereoselective and rapidly reversible. Studies of the inhibition of the specific binding of [125I]IPIN by drugs selective for beta-1 or beta-2 adrenergic receptors suggested that both beta-1 and beta-2 adrenergic receptors are present in the tissue, with approximately 55% of the receptors having the properties of beta-2 adrenergic receptors. The density of receptors in patients not treated with beta adrenergic receptor antagonists or calcium entry blockers was approximately 80 fmol/mg of protein, whereas the density of beta adrenergic receptors in treated patients was increased by approximately 50%. The relative proportion of beta-1 to beta-2 adrenergic receptors in subjects treated with beta adrenergic receptor antagonists and/or calcium entry blockers was not significantly different from that in untreated subjects. Studies were also carried out with a limited number of samples of human ventricular muscle obtained from untreated subjects at the time of surgery. The density of receptors was lower than that observed in studies with atrial tissue. However, as with atrial tissue, approximately half of the receptors appeared to be beta-2 adrenergic receptors.     

Fat embolism syndrome complicating intraarterial chemotherapy with cis-platinum

A 19-year-old man with telangiectatic osteosarcoma of the left proximal femur was started on a course of neoadjuvant chemotherapy consisting of intraarterial administration of cis-platinum. Within 72 hours of receiving the first intraarterial dose, the patient developed signs and symptoms of fat embolism syndrome (FES). A physical examination revealed cyanosis, tachycardia, and seizure activity. Laboratory studies demonstrated a pO2 of less than 65 mmHg, lipuria, and a drop in hematocrit of three percentage points. There was no clinical or roentgenographic evidence of pathologic fracture. Tumor necrosis secondary to intraarterial cis-platinum therapy in this patient with osteosarcoma may have caused a sudden release of free fatty acids and embolization of fat macroglobules that precipitated this episode of FES. FES in association with the intraarterial administration of cis-platinum seems not to have been previously reported.     

Massive acroosteolysis in adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma is a relatively uncommon disease, most often found in Japan, the Caribbean, the southeastern United States, and South America. To date there have been few reports of its skeletal manifestations. A case is reported in a 44-year-old man in which a short history of swelling of the hands and feet and painful motion in the fingers was followed by the rapid development of severe acroosteolysis.     

Photodynamic therapy--a new treatment option for epithelial malignancies of the skin

Photodynamic therapy (PDT) is based on the activation of a photosensitizer by illumination with visible light, leading to photochemical tissue destruction or immunomodulation. The greatest disadvantage of systemic administration of photosensitizers is cutaneous photosensitization of the patients, which lasts for some months. An alternative approach for epithelial precancerous lesions, such as actinic keratoses and Bowen's disease, as well as for superficial skin tumors, such as basal cell carcinomas, is the topical application of sensitizers, especially 5-aminolevulinic acid. Topical PDT causes selective tissue necrosis and tumor destruction and produces excellent cosmetic results. The following article summarizes the main principles of PDT and provides a synopsis of the present status of the use of PDT for epithelial skin malignancies.     

The spectrum of mesenchymal skin neoplasms reflected by the new WHO classification

Mesenchymal tumors are a heterogeneous group of tumors often arising in the skin and soft tissue. The tumors have been reclassified by the WHO in 2002. Benign mesenchymal tumors are about a hundred times more frequent than malignant mesenchymal tumors. Clinically, mesenchymal tumors often present as skin-colored nodes. Overall, elderly persons are more affected than younger individuals. The etiology is often unknown, sometimes there is an association with insults such as radiation, scars, or lymphedematous or venous stasis. Whereas some years ago a wide excision with a margin of 3-5 cm was performed for malignant variants, today micrographic surgery is preferred, as it can avoid mutilating procedures. Early detection and removal is critical since mesenchymal skin tumors often cannot be cured by radiation or chemotherapy.     

The safety and therapeutic effectiveness of human red cells stored at - 80 degrees C for as long as 21 years

Human red cells frozen by various methods have been stored in the frozen state at -80 degrees C for as long as 21 years. This report discusses: red cells frozen with 42 percent weight per volume (wt/vol) glycerol in an ionic medium in a polyvinylchloride (PVC) plastic bag using the Cohn method; red cells frozen with 45 percent wt/vol glycerol in a low ionic medium in a PVC plastic bag using the Huggins method; red cells frozen with 40 percent wt/vol glycerol in an ionic medium in a polyolefin plastic bag using the Meryman-Hornblower method; and red cells frozen with 40 percent wt/vol glycerol in an ionic medium in a standard 600-ml or an elongated 800-ml PVC plastic primary collection bag with an adapter port using the Naval Blood Research Laboratory (NBRL) method. After frozen storage for as long as 21 years by the four methods described above, the thawed red cells were deglycerolized with 50 to 150 ml of 12 percent sodium chloride and 1.5 to 2.0 l of sodium chloride-glucose or sodium chloride-glucose-phosphate solution. After washing and storage at 4 degrees C for 24 hour, the red cells had a mean freeze-thaw-wash recovery value of 90 percent, a mean 24-hour posttransfusion survival value of 85 percent, a mean index of therapeutic effectiveness of 75 percent, normal or slightly impaired oxygen transport function, and minimal hemolysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Challenges of developing and conducting clinical trials in rare disorders

Rare disease drug development is a rapidly expanding field. Clinical researchers in rare diseases face many challenges when conducting trials in small populations. Disease natural history is often poorly understood and the ability to detect clinically meaningful outcomes requires understanding of their rate of occurrence and variability, both of which contribute to difficulties in powering a study. Standard trial designs are not optimized to obtain adequate safety and efficacy data from small numbers of patients, so alternative designs (enrichment, crossover, adaptive, N‐of 1) need to be considered. The affected patients can be hard to identify, especially early in the course of their disease, are generally geographically dispersed, and are often children. Trials are frequently conducted on an international scale and may be subject to complex or multiple regulatory agency oversights and may be affected by local customs, cultures, and practices. A basic understanding of the FDA programs supporting development of drugs for rare diseases is provided by this review and the role of early consultation with the FDA is emphasized. Of recent FDA New Molecular Entities (NME) approvals, 41% (17 approvals) in 2014, 47% (21 approvals) in 2015, and 41% (9 approvals) in 2016 were for rare disease indications. Through effective interactions and collaborations with physicians, institutions, and patient groups, sponsors have been successful in bringing new treatments to market for individuals affected by rare diseases. Challenges to drug development have been overcome through the focused efforts of patients/families, non‐profit patient advocacy groups, drug developers, and regulatory authorities.