A comprehensive classification of mandibular fractures: a preliminary agreement validation study.

This study evaluates a comprehensive classification system for mandibular fractures based on imaging analysis. The AO/ASIF scheme, defining three fracture types (A, B, C), three groups within each type (e.g. A1, A2, A3) and three subgroups within each group (e.g. A1.1, A1.2, A1.3) with increasing severity from A1.1 (lowest) to C3.3 (highest) was used. The mandible is divided into two vertical units (I and V), two lateral horizontal units (II and IV) and one central unit (III) comprising the symphyseal and parasymphyseal region. Type A fractures are non-displaced, type B are displaced and type C are multifragmentary/defect injuries. Groups and subgroups are further defined in the classification system. Two classification sessions using semi-automatic software with 7 and 9 surgeons were performed to evaluate 100 fracture cases in the first session and 50 in the second. Inter-observer reliability and individual rater's accuracy were evaluated by kappa coefficient and latent class analysis, respectively. The analysis of inter-observer agreement for the detailed coding showed kappa coefficients around 0.50 with higher agreement among raters in the vertical units. This system allows standardization of documentation of mandibular fractures, although improvement in the definition of categories and their application is required.

Pathogenic effects of bullous pemphigoid autoantibodies on rabbit corneal epithelium.

Bullous pemphigoid (BP) is associated with circulating autoantibodies reactive with an antigen(s) of the basement membrane zone (BMZ) of skin and mucosae. The pathogenicity of these autoantibodies, although suspected, is unconfirmed. We have investigated the effects of BP autoantibodies on a closely related tissue, the corneal epithelium of the rabbit. IgG fractions from the sera of seven patients with BP were purified by (a) ammonium sulfate precipitation, (b) ion exchange chromatography, or (c) gel filtration. Control IgG was prepared by ion exchange chromatography of pooled normal human gamma globulins. 32 rabbits received corneal intrastromal injections of BP IgG fractions (50 microliter, 0.95-2.05 mg total dose) in one eye, and control IgG (50 microliter, 1.8 mg) in the contralateral cornea. 28 of 32 BP IgG injections produced corneal inflammatory lesions, 10 of which developed visible blisters. Histologically, lesions showed polymorphonuclear cells clustering along the BMZ, and subepithelial blister formation. Immunofluorescence showed in vivo bound IgG and C3 at the BMZ. The intensity of inflammation was dose dependent and correlated often with in vitro complement fixation titers of the fractions. None of 32 corneas injected with control IgG became inflamed. BP IgG fractions injected intradermally into the ear skin of rabbits failed to produce inflammation. This may be due to slow clearance of IgG in the cornea, and optimal binding by the corneal epithelium. The intracorneal injections of BP IgG reproduce the clinical, histological, and immunological features of BP. This study provides evidence that BP autoantibodies are pathogenic.

Dpc4 transcriptional activation and dysfunction in cancer cells.

Dpc4 (Smad4) is implicated in mediation of signals from transforming growth factor (TGF) beta and related ligands, and wild-type Dpc4 mediates TGF-beta-stimulated gene transcription at specific DNA sequences bound by Dpc4 [Smad binding element (SBE)]. We characterized panels of DPC4 tumor mutations and cancer cell lines. Amino acid substitutions within the NH2-terminal third of Dpc4 weakened or ablated SBE-mediated gene regulation by a disruption of DNA binding. An interaction of the COOH-terminal end with the DNA-binding domain of Dpc4 was evident but was not required to explain the functional impairment produced by NH2-terminal DPC4 mutations. Both substitution and truncation mutations of the COOH-terminal half of DPC4 lacked the ability to regulate transcription while retaining the sequence-specific DNA-binding function, but through differing mechanisms. A modular domain to redistribute Dpc4 to the nuclear compartment allowed SBE-mediated transcriptional activation in a cell line having a TGF-1 receptor defect and was sufficient to restore SBE-mediated transactivation ability to COOH-terminal DPC4 missense mutants. Cells harboring DPC4 alterations had a universal impairment of the TGF-beta-stimulated SBE transcriptional response. These studies identify the loss of SBE-mediated gene regulation as a uniform outcome of the selection for DPC4 alterations during tumorigenesis. They raise the possibility of restoration of some Dpc4-associated transcriptional events in cancer cells through the targeted redistribution of wild-type and some missense mutant forms of Dpc4 to the nucleus.

Nd:YAG capsulotomy rates after use of the AcrySof acrylic three piece and one piece intraocular lenses.

BACKGROUND/AIM: Acrylic lens size and shape may influence the rate of posterior capsule opacification (PCO) and need for Nd:YAG capsulotomy. The aim of this study is to compare the Nd:YAG capsulotomy rate of the three piece acrylic/PMMA AcrySof MA series lens with the one piece acrylic AcrySof SA series lens. METHODS: 434 eyes of 329 patients who had cataract extraction and implantation of one of four types of intraocular lenses (IOLs) were evaluated for rate of Nd:YAG capsulotomy. 176 eyes received the acrylic AcrySof MA30AC IOL, 71 eyes the acrylic AcrySof MA60AC IOL, 45 eyes the acrylic AcrySof SA30AL IOL, and 142 eyes the acrylic AcrySof SA60AT IOL. RESULTS: The rates of Nd:YAG capsulotomy with the three piece IOL (MA30AC/MA60AC) and the one piece IOL (SA30AL/SA60AT) were 1.2% and 2.1% at 6 months, 2.8% and 5.9% at 12 months, and 3.6% and 7.5% at 24 months, respectively. The incidence of Nd:YAG capsulotomy was higher in patients who received the one piece IOL (p=0.01, log rank test). There was no difference in Nd:YAG capsulotomy rates when comparing lens optic size, age, sex, history of pars plana vitrectomy, and diabetes mellitus. CONCLUSIONS: This study shows a greater incidence of Nd:YAG capsulotomy in patients who receive one piece acrylic AcrySof lenses when compared to those who receive three piece acrylic AcrySof lenses.

Characterization of murine bronchoalveolar macrophage respiratory burst: comparison of soluble and particulate stimuli.

Stimulation of the respiratory burst of murine bronchoalveolar macrophages obtained by lung lavage was studied using four different stimuli and different assay conditions. One soluble stimulus, phorbol myristate acetate (PMA), two intracellular particles, zymosan and Blastomyces dermatitidis conida, and one extracellular particle, B. dermatitidis yeast, were incubated with either freshly obtained macrophages in suspension or 2- and 48-hour macrophage monolayers. Suspension cultures were incubated with stimuli for 90 minutes and monolayers for 10 minutes before O2- was assayed. PMA did not elicit O2- production in macrophage suspensions or 2-hour macrophage monolayers, but 48-hour macrophage monolayers exhibited a 13-fold increase above control values (P = .0001). On the other hand, zymosan elicited an increase in O2- production in both suspensions and monolayers, although monolayers incubated for 48 hours produced almost fourfold more O2- than the other systems (P = .025). Opsonization had no effect on the ability of zymosan to elicit respiratory burst. B. dermatitidis conidia resulted in a two- to threefold increase in O2- production in macrophage suspensions and a five- to eightfold increase in 48-hour monolayers, representing significantly less respiratory burst stimulation than with either zymosan or PMA. Similarly, B. dermatitidis yeasts demonstrated similar submaximal stimulation of O2-, 3-4 times that over control values, and again this was less than zymosan and PMA. We conclude that 1) freshly obtained murine bronchoalveolar macrophages do not respond to PMA with an increase in O2- production, but that responsiveness is evident after 48 hours of incubation in monolayers; 2) B. dermatitidis conidia and yeasts do not stimulate respiratory burst activity to the same degree as zymosan or PMA; and 3) opsonization of zymosan is not necessary for stimulation of the murine bronchoalveolar macrophage oxidative burst, confirming previous data that functional complement receptors are not present on these cells.

Immunological activation of polymorphonuclear neutrophils for fungal killing: studies with murine cells and blastomyces dermatitidis in vitro.

The interaction of elicited murine polymorphonuclear neutrophils (PMN) and the thermally dimorphic fungal pathogen Blastomyces dermatitidis in vitro was studied. The PMN elicited intraperitoneally with thioglycollate, in normal mice or mice immune to B dermatitidis, failed to reduce colony forming units (CFU) of B dermatitidis in the inoculum in a 4-hr in vitro assay, even in the presence of 10% fresh immune serum. In contrast, PMN elicited intraperitoneally in immune mice by injection of nonviable B dermatitidis cells significantly reduced inoculum CFU (60 +/- 5%) under the same conditions. Furthermore, nonviable B dermatitidis intraperitoneally (i.p.) in normal mice or nonviable Candida albicans i.p. in immune mice failed to elicit peritoneal exudate cells that reduced inoculum CFU in this system. These results support the concept that PMN, elicited in a site by means of an immunological reaction, acquired enhanced microbicidal activity. The fungicidal activity of immunologically elicited PMN was shown to be most effective at high effector to target cell ratios (1,000:1), maximal within 2 hr of coculture, and significantly enhanced in the presence of fresh immune serum compared to heat-inactivated immune serum, normal mouse serum, or fetal bovine serum. Such PMN also had significantly enhanced fungicidal activity against C albicans compared to normal PMN. Fungicidal activity was abrogated in the presence of catalase, implicating hydrogen peroxide generation as the killing mechanism in the activated cells.

The iron-hydrogen peroxide-iodide system is fungicidal: activity against the yeast phase of Blastomyces dermatitidis.

A series of experiments show the potency of a newly described microbicidal system, involving iron, H2O2, and halide, in killing a fungus (Blastomyces dermatitidis). B dermatitidis has previously been shown susceptible to the myeloperoxidase-H2O2-halide system. The present studies show killing of either of two strains in 1 hour if Fe++ at 5 X 10(-5)M, H2O2 at 5 X 10(-5)M and Kl at 5 X 10(-4)M are all present (P less than 0.001). EDTA, a Fe++ chelator, abrogates killing. The mechanism presumably utilizes hydroxyl radical, since an inhibitor, ethanol, also neutralizes the system. The bactericidal and fungicidal system is of great potential importance in vivo.

Empiric treatment of fungal infections in the neutropenic host. Review of the literature and guidelines for use.

Persistent fever that is refractory to broad-spectrum antibacterials is common in neutropenic patients undergoing induction chemotherapy of acute leukemia. Clinical experience suggests that many of these patients are infected with fungi. Until recently, data supporting the role of empiric antifungal therapy in this setting were limited to small groups of patients or postmortem reports. Evolving evidence in larger patient populations supports data from smaller series: febrile neutropenic patients who have failed to respond to a 4- to 7-day course of broad-spectrum antibacterials may benefit from the early initiation of antifungal therapy. Patients with fungal colonization or pulmonary infiltrates and adult patients who have not received previous fungal prophylaxis may especially benefit from the early use of antifungal drugs. Amphotericin B has been the "gold standard" for empiric antifungal therapy, although the newer azoles may be useful in certain situations.

Ketoconazole-induced increase in estradiol-testosterone ratio. Probable explanation for gynecomastia.

Ketoconazole, an antifungal drug, causes gynecomastia in some patients. It also inhibits androgen and glucocorticoid synthesis. In four volunteer male subjects, 600-mg doses of ketoconazole depressed serum testosterone concentrations markedly, but serum estradiol to a much lesser degree. The bound and free percentages of both hormones were not significantly altered. The net result was a significant elevation of the estradiol-testosterone ratio, expressed as either total circulating hormone or free hormone. In five male patients receiving long-term high-dose ketoconazole therapy, the testosterone concentrations fell, but the effect on estradiol was variable. In these patients the estradiol-testosterone ratio was persistently increased. Since gynecomastia appears to be the result of an elevated estradiol-testosterone ratio, the selective hormonal effect demonstrated may explain the side effect of gynecomastia after ketoconazole therapy.

Toxoplasma encephalitis in patients with the acquired immunodeficiency syndrome.

Among 504 cases of AIDS diagnosed between 1983 and 1990, there were 86 patients (17%) with toxoplasma encephalitis (TE). All were symptomatic at the time of diagnosis. General signs such as fever, neck stiffness, or headache were present in 87.2%, and 75.6% had focal signs. The primary means of diagnosis was computerized tomographic scanning, revealing 169 lesions of which 80% were immediately contrast-enhancing. All patients had IgG antibodies against Toxoplasma gondii either before (74 of 75 evaluable patients) or at the time of diagnosis of TE (73 of 75). Elevated antibody titers were present in 44% of evaluable patients, compared to 11% of patients with AIDS and other opportunistic infections. Initial treatment was pyrimethamine plus sulfonamides in 65 patients, and pyrimethamine plus clindamycin in 12 patients, with other combinations or no treatment accounting for the remainder. Life-table analysis of the time to discontinuation of treatment because of suspected side effects suggested that sulfadiazine was significantly more toxic, with 48% of patients experiencing an interruption in treatment after 30 days, than pyrimethamine (12%) or clindamycin (24%). The 30-day mortality rate was 12%, and median survival was 310 days after diagnosis, 530 in patients treated with zidovudine and 190 days in those not so treated. Of 82 evaluable patients, 16 relapsed once and 4 of these more than once. The risk of relapse was 27% 1 year after diagnosis of a first episode of TE.

Oral fluconazole as suppressive therapy of disseminated cryptococcosis in patients with acquired immunodeficiency syndrome.

PURPOSE: Because of the increasing numbers of patients with acquired immunodeficiency syndrome (AIDS) who will require treatment for cryptococcosis and because of the problems associated with long-term administration of intravenous amphotericin B, an alternative therapeutic approach in the form of an efficacious and easily administered oral antifungal drug would be of great benefit. Fluconazole, a new triazole antifungal agent, represents such an alternative. We therefore conducted an open, non-randomized trial of oral fluconazole as maintenance suppressive therapy of disseminated cryptococcosis in patients with AIDS. PATIENTS AND METHODS: Twenty patients with AIDS, 19 of whom had cryptococcal meningitis, were studied. Patients were followed for up to 21 months. All patients received amphotericin B as primary therapy, from 20 to 257 days prior to entry (500 to 5,080 mg total dose). Eight also received flucytosine. After administration of amphotericin B for acute disseminated cryptococcosis, and prior to initiation of fluconazole therapy, Cryptococcus neoformans was isolated from the cerebrospinal fluid (CSF) in two patients and from the blood in one patient. Fluconazole was given once daily, in doses of 50 to 200 mg/day. RESULTS: Following initiation of fluconazole, results of CSF and blood cultures continued to be negative, except for the CSF culture in one patient who had a relapse in the 32nd week of therapy. Fluconazole therapy has been successfully continued in nine patients, for a median of 11 months (nine to 21 months). Seven patients died; five had no evidence of active cryptococcosis at the time of death. Two patients had a relapse, although the CSF culture showed growth of the fungus in only one patient. One patient was lost to follow-up after five months of therapy and one was unevaluable. Fluconazole had to be discontinued in only one patient in whom thrombocytopenia developed, and then resolved when the drug was stopped. CONCLUSION: We conclude that oral fluconazole represents a significant advance in the management of cryptococcal meningitis and should be useful in the long-term suppressive therapy of this opportunistic infection in patients with AIDS.

Experience with ketoconazole in three major manifestations of progressive coccidioidomycosis.

Forty-seven courses of oral ketoconazole therapy administered to 46 patients with progressive coccidioidomycosis were evaluated. Responses, of varying degrees evaluated by a point system, occurred in 81, 94, and 91 percent of courses evaluated for skeletal, chronic pulmonary, and cutaneous disease, respectively. Presumed side effects occurred in 26 percent of courses and were generally minor and reversible. Relapse occurred in 33, 33, and 11 percent of evaluable responding patients with skeletal, chronic pulmonary and cutaneous disease, respectively. From this experience, ketoconazole appears to be an important advance in the therapy of chronic coccidioidomycosis. Whether cure is possible will require further study and follow-up.

NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis.

BACKGROUND: Invasive aspergillosis is the most common invasive mould infection and a major cause of mortality in immunocompromised patients. Response to amphotericin B, the only antifungal agent licensed in the United States for the treatment of aspergillosis, is suboptimal. METHODS: A multicenter open study with strict entry criteria for invasive aspergillosis evaluated oral itraconazole (600 mg/d for 4 days followed by 400 mg/d) in patients with various underlying conditions. Response was based on clinical and radiologic criteria plus microbiology, histopathology, and autopsy data. Responses were categorized as complete, partial, or stable. Failure was categorized as an itraconazole failure or overall failure. RESULTS: Our study population consisted of 76 evaluable patients. Therapy duration varied from 0.3 to 97 weeks (median 46). At the end of treatment, 30 (39%) patients had a complete or partial response, and 3 (4%) had a stable response, and in 20 patients (26%), the protocol therapy was discontinued early (at 0.6 to 54.3 weeks) because of a worsening clinical course or death due to aspergillosis (itraconazole failure). Twenty-three (30%) patients withdrew for other reasons including possible toxicity (7%) and death due to another cause but without resolution of aspergillosis (20%). Itraconazole failure rates varied widely according to site of disease and underlying disease group: 14% for pulmonary and tracheobronchial disease, 50% for sinus disease, 63% for central nervous system disease, and 44% for other sites; 7% in solid organ transplant, 29% in allogeneic bone marrow transplant patients, and 14% in those with prolonged granulocytopenia (median 19 days), 44% in AIDS patients, and 32% in other host groups. The relapse rates among those who completed therapy and those who discontinued early for possible toxicity were 12% and 40%, respectively; all were still immunosuppressed. CONCLUSION: Oral itraconazole is a useful alternative therapy for invasive aspergillosis with response rates apparently comparable to amphotericin B. Relapse in immunocompromised patients may be a problem. Controlled trials are necessary to fully assess the role of itraconazole in the treatment of invasive aspergillosis.

The phacoemulsification procedure. III. Corneal complications.

Persistent corneal edema is one of the complications of phacoemulsification. Five patients underwent this procedure 6 to 8 months before keratoplasty was performed. In addition to bullous keratopathy, two corneas had corneal scarring due to probe overheating or corneal vascularization of the anterior chamber. Electron microscopy of corneal specimens showed that four cases had Fuch's dystrophy without warts and one had guttata. Endothelial cell destruction varied from lessions of small size (15 to 50 mu) to large abrasions. Cases with severe edema and vitreous adhesion showed retrocorneal membrane formation. Surgical trauma seemed to have precipitated decompensation of these dystrophic corneas.

Dependence on antibody for induction of chemiluminescence in polymorphonuclear leukocytes by herpes simplex virus.

The induction of luminol-dependent chemiluminescence in rabbit polymorphonuclear leukocytes (PMN) by a stromal keratitis causing strain (RE) of herpes simplex virus type 1 (HSV-1) was examined. Virus alone and virus infected rabbit corneal cells were unable to stimulate chemiluminescence. However, when the virus or virus infected cells were incubated in the presence of HSV-1 specific immune serum or purified IgG, a gradual chemiluminescent response was observed. Virus and virus infected cells incubated with normal rabbit serum or IgG produced little or no activity. No impairment of chemiluminescent response was observed in experiments in which rabbit PMN were exposed to HSV prior to the addition of opsonized zymosan or HSV-antibody complexes. Results suggest PMN exert antiviral activity in the presence of specific antibody and may be important factors in the inflammatory process resulting from ocular HSV infection.

Distribution of pemphigus and pemphigoid antigens, laminin, and type IV collagen in corneal epithelium.

Dog corneas were studied by indirect immunofluorescence with antibodies specific for pemphigus and pemphigoid antigens, laminin, and type IV collagen. The distribution of these antigens was similar to that observed in other squamous epithelia and skin. This study provides further evidence for close immunochemical similarities between these tissues.

Overview: antifungal combination therapy.

We have yet to realize the clinical benefits of combination antifungal therapy, but the literature is beginning to show the potential positive and negative aspects of this approach. Detailed laboratory-based study of each new antifungal compound will be required in order to define the interactions between the different drugs. Most important in this discussion is that a determination of the most appropriate experimental design and parameters to reflect the outcomes in the treatment of human mycoses is required. That will be the challenge for the next several years. In the meantime, combination antifungal therapy should be approached carefully and be initiated on a case-by-case basis following consideration of all the options available for the patient.

Herpes zoster ophthalmicus and granulomatous angiitis. An ill-appreciated cause of stroke.

The syndrome of granulomatous angiitis related to varicella zoster virus infection often manifests as herpes zoster ophthalmicus followed by contralateral hemiplegia. Forty-five cases have been reported to date, and the authors' experience with two additional cases seen in a one-year period is described. Given the frequency of both stroke and herpes zoster ophthalmicus in an aging population, the authors postulate that granulomatous angiitis is underdiagnosed. There is need for increased awareness of this disease by the non-neurologist. Diagnostic and therapeutic considerations are reviewed.

The effect of removing running sutures on astigmatism after penetrating keratoplasty.

To evaluate astigmatic change after removal of the double running sutures used in penetrating keratoplasty, all patients (N = 131) in the Michigan Corneal Transplantation Patient Registry, Ann Arbor, whose eyes were phakic after penetrating keratoplasty were evaluated. The primary reasons for surgery in this group were keratoconus (n = 44, 34%) and Fuchs' corneal dystrophy (n = 19, 15%). The average effect of 10-0 suture removal in 58 eyes with documented keratometry readings was a 0.30-diopter (D) decrease in astigmatism, with 59% showing 2 D or less of astigmatic change. In 83 eyes with keratometry readings before and after 11-0 suture removal, an average increase of 0.37 D of astigmatism was observed, with 81% showing less than 2 D of astigmatic change. In eyes that were highly astigmatic (greater than 6 D) before suture removal, a reduction in astigmatism exceeding 2 D was observed in 39% and 11% after 10-0 and 11-0 suture removal, respectively.

Predictive factors for endothelial cell loss after penetrating keratoplasty.

To assess the influence of donor age, donor endothelial cell density, recipient age, and diagnosis on loss of endothelial cell density after penetrating keratoplasty, we evaluated endothelial cell density data from specular endothelial images collected during the follow-up penetrating keratoplasty surgeries performed from 1980 through 1985 at one center. Univariate and multivariate analyses of information from 265 grafts showed consistent and statistically significant associations between 1-year postoperative loss of endothelial cell density and donor age, donor endothelial cell density, and recipient age. Corneas obtained from older donors, corneas with higher donor endothelial cell density, and corneas transplanted to older recipients demonstrated greater percentage of loss of endothelial cell density 1 year after surgery. These three factors accounted for 17% of the total variance in percentage of loss of endothelial cell density 1 year after surgery.