Latest developments in gene transfer technology: achievements, perspectives, and controversies over therapeutic applications.

Over the last decade, more than 300 phase I and phase II gene-based clinical trials have been conducted worldwide for the treatment of cancer and monogenic disorders. Lately, these trials have been extended to the treatment of AIDS and, to a lesser extent, cardiovascular diseases. There are 27 currently active gene therapy protocols for the treatment of HIV-1 infection in the USA. Preclinical studies are currently in progress to evaluate the possibility of increasing the number of gene therapy clinical trials for cardiopathies, and of beginning new gene therapy programs for neurologic illnesses, autoimmuno diseases, allergies, regeneration of tissues, and to implement procedures of allogeneic tissues or cell transplantation. In addition, gene transfer technology has allowed for the development of innovative vaccine design, known as genetic immunization. This technique has already been applied in the AIDS vaccine programs in the USA. These programs aim to confer protective immunity against HIV-1 transmission to individuals who are at risk of infection. Research programs have also been considered to develop therapeutic vaccines for patients with AIDS and generate either preventive or therapeutic vaccines against malaria, tuberculosis, hepatitis A, B and C viruses, influenza virus, La Crosse virus, and Ebola virus. The potential therapeutic applications of gene transfer technology are enormous. However, the effectiveness of gene therapy programs is still questioned. Furthermore, there is growing concern over the matter of safety of gene delivery and controversy has arisen over the proposal to begin in utero gene therapy clinical trials for the treatment of inherited genetic disorders. From this standpoint, despite the latest significant achievements reported in vector design, it is not possible to predict to what extent gene therapeutic interventions will be effective in patients, and in what time frame.

Spontaneous hip fractures in fluoride-treated patients: potential causative factors.

Spontaneous fractures were reported to be rare (less than 1%) in 1664 hospital admissions for hip fracture in the 1950s in Sweden. We report 11 fluoride-treated postmenopausal patients who developed spontaneous fractures of the femoral necks, all subcapital initially. In 7 patients who continued treatment there were later femoral neck or shaft fractures; in 6, these were bilateral (one followed a fall). In all there were 19 spontaneous fractures: 5 were asymptomatic, including 2 with deformity; 12 fractures required surgery. Five were incomplete (stress) fractures. All were treated with supplementary calcium 1 g daily; 10 had vitamin D supplementation. In all patients where the timing was known, the initial and subsequent fractures were preceded by, or associated with increased bone turnover as measured by plasma alkaline phosphatase (pAlP) (i.e., they were all "good responders"). Two had pretreatment hip fractures following falls. We compared these 11 (Group 1) and another identically treated group of 14 patients (Group 2), without spontaneous femoral fractures and not different in mean age, pretreatment vertebral fractures, years since menopause, fluoride dosage, and plasma creatinine. Group 1 had a lower (p less than 0.05) index of cortical bone in the femoral neck, as assessed by the ratio "calcar width/femoral neck minimum width." The 6 biopsied fluorotic patients from Group 1 had a higher (p less than 0.05) bone fluoride content than the 4 biopsied fluorotic patients from Group 2. Furthermore, histological cortical features of thinning, increased porosity, and advanced tunneling resorption characterized Group 1 posttreatment biopsies. There were no significant differences in peak pAlP responses in the two groups. Mild asymptomatic vitamin D excess may have been a contributing factor in three Group 1 patients. Two further treatment groups have been studied more recently by forearm single-photon absorptiometry (SPA) at two sites; a cyclic NaF group (Group 3) and a calcium +/- vitamin D group (Group 4). Neither showed significant changes in forearm cortical bone density on treatment for 2 and 1.5 years, respectively, but Group 3 showed a significant increase in density at an ultradistal (60% trabecular) site. The pAlP response in Group 3 was significantly less than in Group 1. Spontaneous femoral neck or shaft fractures did not occur in either Groups 3 or 4. Therefore, we recommend: (1) Avoidance of sodium fluoride (NaF) treatment if pretreatment femoral fracture or thin femoral neck cortices exist.(ABSTRACT TRUNCATED AT 400 WORDS)

Jamshidi needle biopsy of bone lesions.

The technique and advantages of using a Jamshidi needle for skeletal biopsies are described, together with the results of 50 consecutive biopsies. A combined clinical, radiological and pathological approach to the lesions can provide the diagnosis in the majority of patients.

Assessing the treatment of solar urticaria. The dose-response as a quantifying approach.

The weal and flare produced by monochromatic irradiation in solar urticaria may be treated as a classical dose-response. This has been used to investigate therapy with H1 and H2 antihistamines. The conventional H1 drug proved superior. But from the practical viewpoint, solar urticaria is difficult to suppress even with a relatively efficient H1 Antihistamine, chlorpheniramine; the mean protective factor in 5 patients was only 2, insufficient for satisfactory clinical management.