James H. Herndon

Gene therapy for rheumatic diseases

Rheumatic diseases are complex and correspondingly difficult to treat. Pharmacologic control has largely rested on the appropriation of preexisting drugs, often, as with methotrexate, as a result of chance observations made while treating other diseases or, as with gold, for reasons based on erroneous, but fortuitous, assumptions about disease mechanisms. During the last 20 years, there has been a dramatic increase in understanding of the basic biology of rheumatic diseases. As a result, it is now possible to design rational new therapeutic strategies based on knowledge, rather than to continue to rely on chance and supposition. Foremost among these new approaches are overlapping efforts to manipulate immune reactivity, cytokine function, and the behavior of inflammatory cells while maintaining the integrity of the affected tissues. The traditional pharmacologic approach to achieving these aims is to design or discover small, diffusible, biomodulatory molecules which can be delivered orally or by injection. Biology provides newer, alternative approaches, including gene therapy. Biologic therapy

Androgen excess in cystic acne.

We measured hormone levels in 59 women and 32 men with longstanding cystic acne resistant to conventional therapy. Affected women had higher serum levels of dehydroepiandrosterone sulfate, testosterone, and luteinizing hormone and lower levels of sex-hormone-binding globulin than controls. Affected men had higher levels of serum dehydroepiandrosterone sulfate and 17-hydroxyprogesterone and lower levels of sex-hormone-binding globulin than controls. To lower dehydroepiandrosterone sulfate, dexamethasone was given to men, and dexamethasone or an oral contraceptive pill, Demulen (or both), was given to women. Of the patients treated for six months, 97 per cent of the women and 81 per cent of the men had resolution or marked improvement in their acne. The dose of dexamethasone required to reduce dehydroepiandrosterone sulfate levels was low, rarely exceeding the equivalent of 20 mg of hydrocortisone per day. We conclude that most patients with therapeutically resistant cystic acne have androgen excess and that lowering elevated dehydroepiandrosterone sulfate results in improvement or remission of acne in most instances.

Distal radius fractures in older women: a 10-year follow-up study of descriptive characteristics and risk factors. The study of osteoporotic fractures.

OBJECTIVES: To determine the incidence of distal radius fractures and the characteristics of those fractures and to identify the key risk factors.

Postoperative infection following orthopaedic surgery in human immunodeficiency virus-infected hemophiliacs with CD4 counts ≤ 200/mm3

Human immunodeficiency virus-infected hemophiliacs are at risk for bacterial and opportunistic infections with worsening immunosuppression. Thus, the risk of postoperative infection following orthopaedic surgery is of considerable concern. A survey of United States hemophilia treatment centers was conducted to determine the incidence of postoperative infection in human immunodeficiency virus-positive hemophiliacs with CD4 counts of 200 mm3 or less undergoing orthopaedic surgery. A total of 115 centers from 37 states reported that postoperative infection occurred in 10 (15.1%) of 66 patients undergoing 74 orthopaedic procedures, between several weeks and 5 months following surgery. In five (50%), pre-operative infection preceded postoperative joint infection. Staphylococcus was the most common organism isolated in a prosthetic joint infection, in 6 of 10 (60.0%), and the knee was the most commonly affected joint, in 9 of 10 (90.0%). Joint arthroplasty appeared to have 10 times the risk of nonarthroplasty procedures for postoperative infection (9 of 34 [26.5%] and 1 of 40 [2.5%], respectively, P < .01). Two subjects developed chronic osteomyelitis. The rate of postoperative infection in human immunodeficiency virus-positive hemophiliacs with CD4 counts of 200/mm3 or less appears to be high, when compared with the general population. Early, vigorous treatment should be instituted for suspected infection, antibiotic prophylaxis considered for invasive procedures, and surgical intervention individualized based on the balance of risks and benefits.

Acute fractures of the scaphoid.

&NA; Nondisplaced fractures of the scaphoid heal with cast immobilization in most cases, but operative treatment is being offered with greater frequency to active patients as an approach to reduce the period of cast immobilization. Computed tomography is more useful for evaluating displacement than standard radiography. Displaced fractures are at greater risk for nonunion and malunion — both of which have been associated with the development of radiocarpal arthritis in long-term studies—and should therefore be treated operatively. Surgical treatment is also recommended for complex fractures (open fractures, perilunate fracture-dislocations, and scaphoid fractures associated with fracture of the distal radius), very proximal fractures, and fractures for which the diagnosis and treatment have been delayed. Operative treatment of fractures of the scaphoid has been simplified by the development of cannulated screws. Internal fixation of fractures of the scaphoid may offer some advantages, including earlier return to athletics or manual labor.

Chronic cutaneous lupus erythematosus (DLE)--a clinical and laboratory investigation of 80 patients.

Clinical and laboratory data are presented from a study of a group of 80 patients with chronic cutaneous discoid lupus erythematosus. These data support the contention that if one selects patients with chronic scarring DLE who have no evidence by history or physical examination of extracutaneous involvement, then only a small percentage of patients will have detectable immunologic derangements. It is apparent that the clinical expression of lupus erythematosus depends, in part, upon the nature of the hosts immune response.

Management of painful neuromas in the hand

A new treatment for painful neuromas in the hand was used on thirtty-three patients. Fifteen of them were partial amputees and the others had unrepairable lesions. The treatment was transfer of the stumps to an unscarred site where the neuroma would not be under pressure when the hand was used. Excellent results were achieved in 82 per cent of patients.

Clinical trials in the gene therapy of arthritis

Gene therapy clinical trials raise important safety issues that complicate their design and require extensive preclinical testing. Human protocols for the treatment of arthritis and most other orthopaedic and rheumatologic indications are complicated additionally by the perception that they are largely acquired, nonlethal conditions. Taking these considerations into account, the first such human study used the local, ex vivo delivery of a gene whose product, the interleukin-1 receptor antagonist, has an outstanding safety profile. This gene was delivered to the metacarpophalangeal joints of postmenopausal women 1 week before these joints were removed during total joint replacement surgery. In addition to providing an additional safety cushion, the surgical removal of the genetically modified joints made available large amounts of tissue to examine for evidence of successful gene transfer and gene expression. This Phase I safety study was approved at the local and federal levels, and its funding was contingent on the establishment of an external monitoring board. This trial now has been completed and a Phase II, efficacy study is being planned. A similar study has begun in Dusseldorf, Germany and results from the first two patients are similar to the results of the American patients. Permission has been given for two additional human trials, one in the United States and one in the Netherlands, in which a gene encoding herpes thymidine kinase will be transferred to the joints of patients with rheumatoid arthritis who then will be administered gancyclovir. This procedure aims to treat the disease by producing a genetic synovectomy. Additional development of human gene therapies for arthritis and other orthopaedic and rheumatic conditions will be aided by the successful completion of these studies.

Perilunate dislocation and fracture dislocation: A critical analysis of the volar-dorsal approach

A combined volar-dorsal approach was used to treat 11 perilunate dislocations and fracture dislocations between 1989 and 1994. The mean average age of the patients was 38 years, and the mean average time between injury and surgery was 13 hours. Outcome was assessed after an average of 30 months. Results were based on measurements of grip strength, range of motion, radiographs, and patient satisfaction. Patient satisfaction was high in 9 of 11 patients. Seven had satisfactory pain relief, and 5 had returned to their previous occupation without limitation. The wrist flexion-extension arc and grip strength averaged 71% and 77%, respectively, compared to the opposite side. Follow-up radiographs demonstrated complete union of all 8 wrist fractures. For all 11 patients, the carpal height ratio averaged 0.50. Neither scapholunate dissociation nor significant dorsal intercalated segmental instability existed, but 1 wrist developed scapholunate advanced collapse arthritis. Although perilunate instability patterns of injury create significant derangement in carpal anatomy and are among the most challenging of traumatic wrist injuries to correct, our results show that a combined volar-dorsal approach can be used safely and effectively to restore normal intercarpal relationships and provide fixation for accompanying fractures. For the majority of patients, the outcome after this procedure is characterized by acceptable pain relief as well as functional motion and grip strength.

Medical Errors in Orthopaedics. Results of an AAOS Member Survey

BACKGROUND There has been widespread interest in medical errors since the publication of To Err Is Human: Building a Safer Health System by the Institute of Medicine in 2000. The Patient Safety Committee of the American Academy of Orthopaedic Surgeons has compiled the results of a member survey to identify trends in orthopaedic errors that would help to direct quality assurance efforts. METHODS Surveys were sent to 5540 Academy fellows, and 917 were returned (a response rate of 16.6%), with 53% (483) reporting an observed medical error in the previous six months. RESULTS A general classification of errors showed equipment (29%) and communication (24.7%) errors with the highest frequency. Medication errors (9.7%) and wrong-site surgery (5.6%) represented serious potential patient harm. Two deaths were reported, and both involved narcotic administration errors. By location, 78% of errors occurred in the hospital (54% in the surgery suite and 10% in the patient room or floor). The reporting orthopaedic surgeon was involved in 60% of the errors; a nurse, in 37%; another orthopaedic surgeon, in 19%; other physicians, in 16%; and house staff, in 13%. Wrong-site surgeries involved the wrong side (59%); another wrong site, e.g., the wrong digit on the correct side (23%); the wrong procedure (14%); or the wrong patient (5% of the time). The most frequent anatomic locations were the knee and the fingers and/or hand (35% for each), the foot and/or ankle (15%), followed by the distal end of the femur (10%) and the spine (5%). CONCLUSIONS Medical errors continue to occur and therefore represent a threat to patient safety. Quality assurance efforts and more refined research can be addressed toward areas with higher error occurrence (equipment and communication) and high risk (medication and wrong-site surgery).