Refsum's disease: nature of the enzyme defect.

Two siblings with Refsum's disease, an inherited disorder of lipid metabolism, oxidized intravenously injected uniformly labeled phytanic acid-C(14) at rates less than 5 percent of those found in normal subjects. The defect in oxidation of phytanic acid persisted in cultures of fibroblasts from the patients' skin. The rate of oxidation of the phytanic acid-C(14) was less than 1 percent of that found in cultures of fibroblasts from normal skin. However, pristanic acid, previously shown to be the first product of phytanic acid degradation, was oxidized at a normal rate in the patients' cultures. These results indicate that the enzymatic defect in Refsum's disease is in the first step of the pathway for degradation of phytanic acid, that is, in the unusual alpha-oxidative process that leads to a shortening of phytanic acid by one carbon atom.

Refsum's disease: characterization of the enzyme defect in cell culture.

Refsum's disease (heredopathia atactica polyneuritiformis, HAP) is an inherited neurological disorder associated with storage of the branched-chain fatty acid, phytanic acid (3,7,11,15-tetramethylhexadecanoic acid). Cultured fibroblasts derived from skin biopsies of HAP patients did not contain elevated levels of phytanate, yet showed rates of phytanate-C-(14)C oxidation less than 3% of those seen in cells from control subjects. Cells of control subjects converted phytanate to alpha-hydroxyphytanate, to pristanate (the [n-1] homologue of phytanate) and to 4,8,12-trimethyltridecanoate, compounds previously identified as intermediates on the major pathway for phytanate metabolism in animals, providing the first direct evidence that this same oxidative pathway is operative in human cells. None of these breakdown products could be found after incubation of phytanate with HAP cells. Labeled alpha-hydroxyphytanate and labeled pristanate were oxidized at normal rates by HAP cells. Oxidation of the latter proceeded at normal rates both when added to the medium at very low tracer levels and at levels 100 times greater. Phytanate was incorporated into and released from lipid esters at normal rates by HAP cells. Elevated levels of free phytanate in the medium were no more toxic to HAP cells than to control cells over the 48- to 72-hr exposures involved in these studies, as evidenced by morphologic criteria and by ability to oxidize labeled palmitate. These findings are consistent with the hypothesis that the cells from HAP patients are deficient in a single enzyme involved in the alpha-hydroxylation of phytanate, while the enzymes involved in later steps are present at normal or near-normal levels.

Localization of the oxidative defect in phytanic acid degradation in patients with Refsum's disease.

The rate of oxidation of phytanic acid-U-(14)C to (14)CO(2) in three patients with Refsum's disease was less than 5% of that found in normal volunteers. In contrast, the rate of oxidation of alpha-hydroxyphytanic acid-U-(14)C and of pristanic acid-U-(14)C to (14)CO(2), studied in two patients, while somewhat less than that in normal controls, was not grossly impaired. These studies support the conclusion that the defect in phytanic acid oxidation in Refsum's disease is located in the first step of phytanic acid degradation, that is, in the alpha oxidation step leading to formation of alpha-hydroxyphytanic acid. The initial rate of disappearance of plasma free fatty acid radioactivity after intravenous injection of phytanic acid-U-(14)C (t(1/2) = 5.9 min) was slower than that seen with pristanic acid-U-(14)C (t(1/2) = 2.7 min) or palmitic acid-1-(14)C (t(1/2) = 2.5 min). There were no differences between patients and normal controls in these initial rates of free fatty acid disappearance for any of the three substrates tested. There was no detectable lipid radioactivity found in the plasma 7 days after the injection of palmitic acid-1-(14)C or pristanic acid-U-(14)C in either patients or controls. After injection of phytanic acid-U-(14)C, however, the two patients showed only a very slow decline in plasma lipid radioactivity (estimated t(1/2) = 35 days), in contrast to the normals who had no detectable radioactivity after 2 days. Incorporation of radioactivity from phytanic acid-U-(14)C into the major lipid ester classes of plasma was studied in one of the patients; triglycerides accounted for by far the largest fraction of the total present between 1 and 4 hr.

Chromosome markers and evidence for clone formation in lymphocytes of a patient with Sézary syndrome.

Cytogenetic studies of 222 metaphase lymphocytes stimulated by phytohemagglutinin were carried out on a patient diagnosed clinically as having Sézary syndrome. Twenty-two cells (10%) contained 42 to 100 chromosomes. The remaining 200 cells contained 46 chromosomes and revealed evidence of clone formation; 45 were apparently normal diploid cells, but 155 were pseudodiploid with at least one long submetacentric marker in each cell. This marker was shown to have a consistent banding pattern from cell to cell. Of the 25 pseudodiploid cells karyotyped, there were other types of markers present. Normal chromosomes 2 and 17 were missing in all 25 karyotypes. There were seven set of two cells, each with an identical karyotype, suggesting subclonal formation. Many of the phytohemagglutinin-stimulated nondividing white blood cells had one or more nuclear protrusions. Cytogenetic examination of peripheral lymphocytes may be of value in diagnosing and following the course of this disease.

Use of the Y-body for identification of skin source on a successfully grafted burn patient.

The use of the interphase male Y-body (fluorescent Y chromosome segment) technique with cryostat sections of both fresh and frozen-stored skin biopsies is described. A female burn patient appeared to retain her donor homografts, thereby negating the need for autografts. Since a retained homograft of this sort challenged our understanding of immunologic barriers, we applied the Y-body technique to cutaneous biopsies obtained from the patient's burn area that had been homografted with skin from a male donor, as well as control biopsies from the patient's unburned skin and normal control male and female skin. Based on clinical and cytogenetic observations, it was concluded that the most reasonable explanation for this case was that the regenerating tissue at the graft site was that of the recipient and not that of the originally grafted male skin.

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 host's immune response.

Steroid sulfatase activity in epidermis of acne-prone and non-acne-prone skin of patients with acne vulgaris.

Abnormal keratinization of hair follicles appears to be intimately associated with acne vulgaris. Whether steroid metabolism in follicular wall keratinocytes of acne-prone skin plays a role in the development and maintenance of acne vulgaris is unknown at this time. The enzymatic hydrolysis of dehydroepiandrosterone sulfate to dehydroepiandrosterone and of estrone sulfate to estrone in cultured epidermal keratinocytes has been demonstrated. Thus, we sought to establish whether steroid sulfatase activity in freshly obtained epidermal tissue (greater than 90% keratinocytes) from acne-prone skin in patients with acne vulgaris was altered when compared with that in epidermal tissue from non-acne-prone skin in the same individuals. We found that there were no differences in the rates of enzymatic hydrolysis of steroid sulfates in epidermis of acne-prone and non-acne-prone skin; however, the rate of estrone sulfate hydrolysis was two to eight times greater than that of dehydroepiandrosterone sulfate in all of the tissues evaluated in this study.

Lich myxedematosus. A dermal infiltrative disorder responsive to cyclophosphamide therapy.

Lichen myxedematosus is an uncommon, chronic, cutaneous disease of mucin deposition that has resisted a variety of therapies. The discovery of a unique, basic, homogeneous globulin in the sera of many of the patients with this disorder raised questions concerning the relationships between lichen myxedematosus, multiple myeloma, and amyloidosis. Our patient, who lacked the abnormal serum globulin, was successfully treated with cyclophosphamide.

Ketoconazole treatment of chronic mucocutaneous candidiasis.

Five patients received ketoconazole treatment of chronic mucocutaneous candidiasis. One also had disseminated histoplasmosis and cryptococcosis. Ketoconazole was well absorbed after an oral dose of 200 mg and produced detectable antifungal blood levels for more than eight hours after each dose. Thrush cleared in less than two weeks in all patients. Cutaneous lesions cleared slowly during several months of treatment. A patient with polymycotic infection had a rapid clearing of candidiasis, but her histoplasmosis did not respond to three weeks of treatment. Adverse drug effects were minimal. Ketoconazole is a promising new agent for treatment of chronic mucocutaneous candidiasis.

A cutaneous marker in the Hunter syndrome a report of four cases.

A report of four patients and review of the literature suggest that a cutaneous marker exists for the Hunter syndrome. All previously described patients with this eruption have been males with clear corneas. The distinctive lesions consist of firm ivory-white papules and nodules that may coalesce to form ridges or a reticular pattern. The papules are usually seen in symmetrical areas between the angles of the scapulas and posterior axillary lines, the pectoral regions, the nape of the neck and/or on the lateral aspects of the upper arms and thighs. These lesions are seen in both allelic forms and cannot be used to separate a benign from a rapid course.

Malignant atrophic papulosis of Degos. Report of a patient who failed to respond to fibrinolytic therapy.

A 21-year-old woman with eventually fatal malignant atrophic papulosis (Degos disease) was treated primarily with the fibrinolytic agents phenformin hydrochloride and ethylestrenol. In spite of therapy, primarily central nervous system manifestations led to the patient's death.

Topical metronidazole maintains remissions of rosacea.

BACKGROUND: Rosacea is a chronic skin disease that requires long-term therapy. Oral antibiotics and topical metronidazole successfully treat rosacea. Because long-term use of systemic antibiotics carries risks for systemic complications and adverse reactions, topical treatments are preferred. OBJECTIVE: To determine if the use of topical metronidazole gel (Metrogel) could prevent relapse of moderate to severe rosacea. DESIGN: A combination of oral tetracycline and topical metronidazole gel was used to treat 113 subjects with rosacea (open portion of the study). Successfully treated subjects (n = 88) entered a randomized, double-blind, placebo-controlled study applying either 0.75% topical metronidazole gel (active agent) or topical metronidazole vehicle gel (placebo) twice daily (blinded portion of the study). SETTING: Subjects were enrolled at 6 separate sites in large cities at sites associated with major medical centers. SUBJECTS: One hundred thirteen subjects with at least 6 inflammatory papules and pustules, moderate to severe facial erythema and telangiectasia entered the open phase of the study. Eighty-eight subjects responded to treatment with systemic tetracycline and topical metronidazole gel as measured by at least a 70% reduction in the number of inflammatory lesions. These subjects were randomized to receive 1 of 2 treatments: either 0.75% metronidazole gel or placebo gel. INTERVENTIONS: Subjects were evaluated monthly for up to 6 months to determine relapse rates. MAIN OUTCOME MEASURES: Inflammatory papules and pustules were counted at each visit. Relapse was determined by the appearance of a clinically significant increase in the number of papules and pustules. Prominence of telangiectases and dryness (roughness and scaling) were also observed. RESULTS: In the open phase, treatment with tetracycline and metronidazole gel eliminated all papules and pustules in 67 subjects (59%). The faces of 104 subjects (92%) displayed fewer papules and pustules after treatment, and 82 subjects (73%) exhibited less erythema. In the randomized double-blind phase, the use of topical metronidazole significantly prolonged the disease-free interval and minimized recurrence compared with subjects treated with the vehicle. Eighteen (42%) of 43 subjects applying the vehicle experienced relapse, compared with 9 (23%) of 39 subjects applying metronidazole gel (P<.05). The metronidazole group had fewer papules and/or pustules after 6 months of treatment (P<.01). Relapse of erythema also occurred less often in subjects treated with metronidazole (74% vs 55%). CONCLUSION: In a majority of subjects studied, continued treatment with metronidazole gel alone maintains remission of moderate to severe rosacea induced by treatment with oral tetracycline and topical metronidazole gel.

Tensile properties of the interosseous membrane of the human forearm.

The interosseous membrane is a structure deep in the forearm that joins the radius and the ulna. It is made up of membranous and ligamentous regions. Two main ligamentous structures have been described: a prominent central fiber group, the "central band," and a smaller proximal fibrous band, the "oblique cord." Many authors believe that the central band plays a biomechanical role in the normal and fractured forearm and that it may function much like a ligament. The objective of this study was to determine the tensile properties of the central band. Eighteen fresh frozen forearms from cadavers (45-70 years of age, both sexes) were used. A fiber bundle of the central band was subjected to a uniaxial tensile test to failure in a materials testing machine, and its tensile properties were calculated. Stiffness, ultimate load, and energy absorbed to failure were expressed as a function of specimen width. The central band structure had a stiffness of 13.1 +/- 3.0 N/mm per mm width and an ultimate load of 56.6 +/- 15.1 N per mm width (mean +/- SD). The tissue of the central band displayed a modulus of 608.1 +/- 160.2 MPa, ultimate tensile strength of 45.1 +/- 10.3 MPa, and strain at failure of 9.0 +/- 2.0%. This study demonstrated that the central band is comprised of strong tissue. The material properties of the central band compare with those of patellar tendon: modulus is 120% and ultimate tensile strength is 84% that of patellar tendon. As a structure, the interosseous membrane is stiff and capable of bearing high loads. Although load distribution across the central band is unknown, a 1.7 cm wide, evenly loaded homogenous portion of the central band would possess a stiffness comparable with that of the anterior cruciate ligament. The results of this study provide a basis for future analyses of radioulnar stability and load transfer.

Total joint replacement in the upper extremity.

Prosthetic replacement of the joints of the upper extremity relieves pain, mitigates deformity, and improves function. As newer designs of prostheses are tested, we expand our knowledge of the biomechanics of each joint. Newer materials are rapidly changing the variety of implants on the market and improving prosthetic function. The problem of fixation of the noncemented prostheses to viable bone tissue remains one of the major unanswered questions for orthopedic surgeons today. Extensive research around the world is underway; different means of providing the environment that allows biologic ingrowth with fixation of a prosthesis are being investigated, thus avoiding the use of methyl methacrylate and its inherent problems.

Flexible (silicone) implant arthroplasty of the metacarpophalangeal joint of the thumb.

Forty-four thumbs in thirty-four patients with rheumatoid arthritis were treated with a flexible implant arthroplasty of the metacarpophalangeal joint. After follow-ups ranging from two to six and a half years the results were rated good to excellent in forty-two thumbs since they were not painful, had an increased arc of motion of the metacarpophalangeal joint in a more functional range, and were more effective in the activities of daily living. The results in this series indicated that careful reconstruction of the extensor apparatus is essential, as well as stabilization of the interphalangeal joint either by arthrodesis or by tenodesis if there is a hyperextension deformity. Of the six patients who had a fusion of the metacarpophalangeal joint in one thumb and an arthroplasty in the other, five preferred the arthroplasty because the joint was stable and also had a useful arc of motion, while one noted no difference between the two thumbs.

Radial growth and function of the forearm after excision of the radial head. A study of growing macaque monkeys.

In five immature macaque monkeys, the right radial head was excised and the left forearm served as a control. Growth of each radius, ulna, and proximal and distal physis was followed for eight years. Total radial growth was slightly less on the side that was operated on than it was on the control side. After excision of the radial head, 95 per cent of radial growth came from the distal physis, compared with 71 per cent on the control side. A regenerated radial head, which had an irregular surface of fibrocartilaginous tissue, accounted for the remainder of growth on the side that had been operated on. Incongruous contact of articular surfaces resulted in degenerative changes in the capitellum. The arms that had been operated on were left with a flexion contracture that was an average of 12 degrees greater than that of the normal elbows, and they had a carrying angle that was an average of 6 degrees greater than that on the normal side. The arc of pronation and supination was decreased for the forearms that had been operated on, but motion of the wrist was unaffected. In our study, excision of the radial head in growing monkeys resulted in minimum radial shortening, slight deformity of the elbow, and moderate impairment of rotation of the forearm.

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.

Compression ultrasonography for the detection of deep venous thrombosis in patients who have a fracture of the hip. A prospective study.

The effectiveness of compression ultrasonography in the detection of femoral and popliteal venous thrombosis was determined in a prospective trial over a period of seven months. Forty-two patients who had an isolated intertrochanteric or femoral neck fracture participated, and forty of these patients completed the study. The average age of the patients was 81.6 years. Venography was the standard with which all ultrasonic studies were compared. A total of 112 ultrasonic studies were performed. The incidence of major venous thrombosis, as detected by venography, was 12.5 per cent. All patients were clinically asymptomatic. The compression ultrasonic technique had an accuracy of 97 per cent, a sensitivity of 100 per cent, and a specificity of 97 per cent. Compression ultrasonography appears to be a very effective technique for diagnosing venous thrombosis in patients who have a fracture of the hip. It is safe, well accepted by both patients and staff, and simply and quickly performed, and it carries no inherent risks. It also can be readily repeated, making it ideal for monitoring high-risk patients.

A new methodology to measure load transfer through the forearm using multiple universal force sensors.

Previous approaches to measuring forces in the forearm have made the assumption that forces acting in the radius and ulna are uniaxial near the wrist and elbow. To accurately describe forces in the forearm and the forces in the interosseous ligament, we have developed a new methodology to quantitatively determine the 3-D force vectors acting in forearm structures when a compressive load is applied to the hand. A materials testing machine equipped with a six degree-of-freedom universal force-moment sensor (UFS) was employed to apply a uniaxial compressive force to cadaveric forearms gripped at the hand and humerus. Miniature UFSs were implanted into the distal radius and proximal ulna to measure force vectors there. A 3-D digitizing device was used to measure transformations between UFS coordinate systems, utilized for calculating the force vectors in the distal ulna, proximal radius, and the interosseous ligament (IOL). This method was found to be repeatable to within 3 N, and accurate to within 2 N for force magnitudes. Computer models of the forearm, generated from CT scans, were used to visualize the force vectors in 3-D. Application of this methodology to eight forearm specimens showed that the radius carries most of the load at the wrist while force in the IOL relieves load acting in the radius at the mid-forearm. For a 136 N applied hand force, the force in the IOL was 36 + 21 N. Advantages of this methodology include the determination of 3-D force vectors, especially those in the IOL, as well as computer generated 3-D visualization of results.

Free vascularized fibula transfer for stabilization of the thoracolumbar spine. A case report.

Anterior strut grafting for kyphosis has become an accepted procedure. High stresses are placed across these grafts, however, and it would seem advisable to use a living bone graft that could remodel in response to these stresses, rather than an avascular graft of fibula or rib such as is commonly employed. This case report demonstrates the use of a free, vascularized living bone graft in the treatment of a post-traumatic kyphosis, with successful subsequent incorporation into the anterior fusion mass.