Biomedical subjects
Publications and source records attributed to W T Miller.
The full range of mediastinal and pleural effects of a variety of drugs both therapeutic and illicit has been reviewed. The importance of clinical information in making the diagnosis of these drug-induced disorders is emphasized.
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BACKGROUND: Pulmonary infection and tumor in the AIDS population has a variable clinical and radiographic presentation. The association between the radiographic presentation of pulmonary tuberculosis and CD4 T lymphocyte count in the HIV-infected patient is investigated in order to provide an empirical approach for early diagnosis, treatment, and isolation of infected subjects. METHODS: A retrospective analysis of chest radiographs, CD4 T lymphocyte counts, and clinical history of 35 subjects from 3 urban hospitals was performed. All subjects were HIV-seropositive and had culture-proven pulmonary tuberculosis. Radiographs were evaluated for the presence of either a pattern characteristic of post-primary tuberculosis (typical pattern) or a pattern uncharacteristic of post-primary infection (atypical pattern). RESULTS: Twenty-one of 26 subjects with a CD4 T lymphocyte count less than 0.20 x 10(9) cells/L, whereas only 1 of 9 subjects with a CD4 T lymphocyte count of 0.20 x 10(9) cells/L or more presented with an atypical pattern of pulmonary tuberculosis (p < 0.001). The mean CD4 T lymphocyte counts of those subjects presenting with atypical versus typical radiographic pattern of post-primary pulmonary tuberculosis were 0.069 x 10(9) cells/L (n = 22) and 0.323 x 10(9) cells/L (n = 13), respectively (p < 0.01). Twenty-one of the 22 subjects with an atypical radiographic pattern of pulmonary tuberculosis were significantly immunosuppressed (CD4 < 0.20 x 10(9) cells/L). Atypical radiographic pattern included diffuse and lower lobar opacities, pleural effusion, mediastinal adenopathy, interstitial nodules, and a normal chest radiograph. CONCLUSION: AIDS patients presenting with CD4 count less than 0.20 x 10(9) cells/L and an atypical radiographic pattern for pulmonary tuberculosis are at risk for tuberculous infection requiring appropriate treatment and isolation until the diagnosis of pulmonary tuberculosis has been excluded.
Bronchiectasis is characterized by irreversible dilatation of the airways. Associated with a variety of underlying disorders, the common pathway for the development of bronchiectasis is chronic or recurrent infection. Bronchiectasis can occur in the normal host after a bout of severe infection or bronchial obstruction. Currently, it is more commonly seen in patients with abnormal host defenses including impaired clearance of secretions and disorders of cellular and humoral immunity. Historically, bronchography has been the imaging tool used for the evaluation of bronchiectasis. This procedure has been replaced by high resolution computed tomography, which is currently the modality of choice for imaging patients with bronchiectasis.
Photoaffinity labeling and site-directed mutagenesis have been used to identify amino acid residues of the phospholipase C gamma 1 (PLC gamma 1) N-terminal SH2 domain involved in recognition of the activated epidermal growth factor receptor (EGFR). The photoactive amino acid p-benzoylphenylalanine (Bpa) was incorporated into phosphotyrosine-containing peptides derived from EGFR autophosphorylation sites Tyr992 and Tyr1068. Irradiation of these labels in the presence of SH2 domains showed cross-linking which was time-dependent and specific; labeling was inhibited with non-Bpa-containing peptides from EGFR in molar excess. The phosphotyrosine residue on the peptides was important for SH2 recognition, as dephosphorylated peptides did not cross-link. Radiolabeled peptides were used to identify sites of cross-linking to the N-terminal SH2 of PLC gamma 1. Bpa peptide-SH2 complexes were digested with trypsin, and radioactive fragments were purified by HPLC and analyzed by Edman sequencing. These experiments showed Arg562 and an additional site in the alpha A-beta B region of the SH2 domain, most likely Glu587, to be labeled by the Tyr992-derived peptide. Similar analysis of the reaction with the Tyr1068-derived photoaffinity label identified Leu653 as the cross-linked site. Mutation of the neighboring residues of Glu587 decreased photo-cross-linking, emphasizing the importance of this region of the molecule for recognition. These results are consistent with evidence from the v-Src crystal structure and implicate the loop spanning residues Gln640-Ser654 of PLC gamma 1 in specific recognition of phosphopeptides.
Phosphorylation of c-Src at carboxyl-terminal Tyr-527 suppresses tyrosine kinase activity and transforming potential, presumably by facilitating the intramolecular interaction of the C terminus of Src with its SH2 domain. In addition, it has been shown previously that occupancy of the c-Src SH2 domain with a phosphopeptide stimulates c-Src kinase catalytic activity. We have performed analogous studies with v-Src, the transforming protein from Rous sarcoma virus, which has extensive homology with c-Src. v-Src lacks an autoregulatory phosphorylation site, and its kinase domain is constitutively active. Phosphopeptides corresponding to the sequences surrounding c-Src Tyr-527 and a Tyr-Glu-Glu-Ile motif from the hamster polyoma virus middle T antigen inhibit tyrosine kinase activity of baculovirus-expressed v-Src 2- and 4-fold, respectively. To determine the mechanism of this regulation, the Tyr-527 phosphopeptide was substituted with the photoactive amino acid p-benzoylphenylalanine at the adjacent positions (N- and C-terminal) to phosphotyrosine. These peptides photoinactivate the v-Src tyrosine kinase 5-fold in a time- and concentration-dependent manner. Furthermore, the peptides cross-link an isolated Src SH2 domain with similar rates and specificity. These data indicate that occupancy of the v-Src SH2 domain induces a conformational change that is transmitted to the kinase domain and attenuates tyrosine kinase activity.
To search for peptides which serve as substrates for protein kinases, an approach based on peptide libraries has been developed. These peptide libraries are chemically synthesized by a modified "divide-couple-recombine" strategy. After reaction with the kinase of interest, the most highly phosphorylated substrate (selected from the library) is identified using on-line liquid chromatography-electrospray mass spectrometry (LC-ESMS). Negative ion LC-ESMS with stepped collision energy is used to identify phosphorylated peptides in the enzyme reactions. As predicted, the cAMP-dependent protein kinase is shown to preferentially phosphorylate Kemptide (Leu-Arg-Arg-Ala-Ser-Leu-Gly) in a library consisting of 19 variants of Kemptide substituted at position 2. Additional experiments have been carried out on the nonreceptor tyrosine kinase v-Abl using a peptide library based on the v-Src autophosphorylation site (Arg-Arg-Leu-Ile-Glu-Asp-Ala-Glu-Tyr-Ala-Ala-Arg-Gly). These results indicate that Ile is the optimal residue at the position N-terminal to tyrosine. Individual peptides containing the Glu-Asp-Ala-Ile-Tyr motif have Vmax/Km values 6-fold higher than the peptide based on the autophosphorylation site itself, confirming the results of the library experiments. This motif has been identified in several tyrosine kinases at a position in the sequence not previously reported to serve as a phosphorylation or autophosphorylation site.
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PURPOSE: To organize pulmonary nontuberculous mycobacterial (NTMB) infections into a classification system based on clinical and radiographic features. MATERIALS AND METHODS: Scientific literature was reviewed and organized into a framework of clinical-radiographic syndromes of NTMB infection. RESULTS: NTMB infection was classified into five clinical-radiographic syndromes. The "classical" form radiographically mimics tuberculosis. It is seen predominantly in white male patients with underlying chronic obstructive lung disease. "Nonclassical" disease radiographically appears as nodular infiltrates and bronchiectasis in a sporadic distribution. It characteristically occurs in elderly women without underlying chronic illness. Asymptomatic nodules are another manifestation. Immunocompromised individuals develop disseminated infection, often with few or no pulmonary symptoms but various chest radiographic manifestations. Patients with achalasia have a radiographic appearance that most often resembles aspiration pneumonia. CONCLUSION: Most pulmonary NTMB infections can be classified into one of five categories, which helps in the understanding of these wide-ranging manifestations.
Clinicians are frequently faced with patients in whom the radiographic resolution of community-acquired pneumonia seems delayed. Previous studies of radiographic resolution of the disease have yielded conflicting results. We prospectively assessed the radiographic resolution of pneumonia in 81 non-immuno-compromised patients, presenting to the emergency room and ambulatory clinics of a large university hospital, who met clinical and radiographic criteria for pneumonia. Serial chest radiographs were obtained every 2 wk for an initial period of 8 wk, and then every 4 wk until 24 wk had passed, or until all radiographic abnormalities had cleared. Forty-one of the 81 patients (50.6%) demonstrated complete clearance after 2 wk. Fifty of the 75 patients (66.7%) followed to 4 wk demonstrated complete clearance. The rate of clearance was inversely correlated with age (p < 0.001) and involvement of single versus multiple lobes (p < 0.0001) (log-rank test). Clearance was faster in those patients treated as outpatients (3.8 wk versus 9.1 wk, p = 0.03) and in patients who were nonsmokers (4.5 wk versus 8.4 wk, p = 0.05) (log-rank test). Multivariate regression analysis demonstrated that only age (relative risk for clearance, +0.79 per decade) and single versus multiple lobes involved (relative risk for clearance, 0.55 for more than one lobe) had independent predictive value (Cox proportional hazards regression model). The radiographic resolution of pneumonia occurs more rapidly in younger patients and in those with only a single lobe involved.(ABSTRACT TRUNCATED AT 250 WORDS)
OBJECTIVE: To evaluate the clinical and radiographic features of pulmonary aspergillosis as they present in AIDS patients; in particular, to determine similarities and differences between Aspergillus infection in patients with AIDS vs those without AIDS. SUBJECTS AND METHODS: Six new cases of confirmed or probable pulmonary aspergillosis were discovered during a search of hospital records. These are reviewed with 30 previously reported cases with special attention to radiographic appearance of disease and how radiographic appearance influences clinical outcome. RESULTS: Symptoms of pulmonary aspergillosis in AIDS were nonspecific, most often including fever, cough, and dyspnea, and less commonly, chest pain or hemoptysis. Major risk factors for the development of pulmonary aspergillosis in patients with AIDS were steroid administration and neutropenia. Neutropenia was often a complication of therapies for AIDS, in particular, ganciclovir and zidovudine. Radiographic appearance of disease could be divided into three general categories. One third of the patients (13/36) presented with cavitary upper lobe disease resembling noninvasive or chronic necrotizing aspergillosis. Fatal hemoptysis occurred in 42 percent of patients with this form of disease. Twenty-two percent (8/36) of the cases presented as a nondescript focal alveolar opacity similar to invasive aspergillosis. In several patients, the focal infiltrate remained stable for several months, a feature that is unusual for aspergillosis in non-AIDS patients. The air crescent sign was present in none of the 36 reported cases. Patients with only focal disease had the best prognosis of patients with pulmonary aspergillosis. Bilateral alveolar or interstitial disease similar to invasive aspergillosis was present in 23 percent (9/36) of the patients. Bilateral disease appears to be a marker for disseminated infection and was associated with a high mortality due to aspergillosis. Two new forms of bronchial aspergillosis (5/36 cases) have been described previously. These patients presented with either obstructing fungal casts or bronchial pseudomembranes demonstrated bronchoscopically. In some patients with the bronchial forms of aspergillosis, transient alveolar opacities were seen on chest radiographs. These opacities may represent regions of atelectasis due to airway obstruction. One patient who had bilateral pneumothoraces without parenchymal opacities did not correspond to any of the three previously mentioned categories. Mortality due to aspergillosis was greater than 50 percent among AIDS patients. Death was subsequent to fatal hemoptysis or widespread pulmonary or systemic infection. CONCLUSION: Unlike other risk groups that tend to contract only one form of pulmonary aspergillosis, AIDS patients can develop the whole spectrum of aspergillosis-related pulmonary disorders, including chronic cavitary, invasive, and bronchial forms of aspergillosis. Clinical symptoms are nonspecific and major risk factors include neutropenia, which is often a side effect of various therapies for AIDS, and steroid administration. Patients with the chronic cavitary form of disease have an unusually high mortality due to fatal hemoptysis. Patients with bilateral pulmonary infiltrates and aspergillosis have a high mortality due to disseminated infection.
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Tuberculosis, an ancient disease undergoing recent control by public hygiene and drug therapy, has experienced a recrudescence in the United States. Factors leading to the increased incidence of tuberculosis include the high incidence of tuberculosis among the AIDS population, an increase in Asian immigrants, and the emergence of drug-resistant strains of tuberculosis. Radiographically, the picture also has changed with a much higher incidence of primary tuberculosis in the adult population.
Several tyrosine phosphorylation sites in the insulin receptor kinase substrate IRS-1 are predicted to be within Tyr-Met-X-Met (YMXM) motifs, and synthetic peptides corresponding to these sequences are excellent substrates for the insulin receptor kinase in vitro (Shoelson, S. E., Chatterjee, S., Chaudhuri, M., and White, M. F. (1992) Proc. Natl. Acad. Sci. U. S. A. 89, 2027-2031). In this study, YMXM-containing peptides are shown to act as substrates for two members of the nonreceptor subfamily of tyrosine kinases, v-Src and v-Abl (the transforming gene products of Rous sarcoma virus and Abelson murine leukemia virus, respectively). For v-Src, a baculovirus expression system was used which was capable of producing milligram quantities of pure 60-kDa v-Src in Spodoptera frugiperda (Sf9) cells. The source of v-Abl was an Escherichia coli expression vector that produces a fusion protein of glutathione S-transferase with the abl catalytic domain. The synthetic YMXM-containing peptides had among the highest apparent affinities described to date for either tyrosine kinase, with Km values as low as 97 microM for v-Src and v-Abl. Comparisons with the results obtained with the insulin receptor kinase revealed differences in substrate specificity among the enzymes. In particular, v-Src was more tolerant of substitutions at the Met+1 and Met+3 positions in the YMXM motif than either v-Abl or the insulin receptor kinase but was more dependent on the presence of a preceding acidic amino acid. For v-Abl, the presence of threonine at any position in the YMXM motif caused a reduction in catalytic efficiency. Phosphorylated YMXM motifs are recognition elements for binding to the src homology 2 domains of phosphatidylinositol 3'-kinase and additional proteins; hence, differences in specificity of tyrosine kinases toward YMXM-containing proteins may have relevance to downstream signaling events.