Abdominal T-cell non-Hodgkin's lymphoma of the gamma/delta type in a patient with selective immunoglobulin A deficiency

A 28-year-old man presented with selective immunoglobulin A deficiency and severe diarrhea responding to a gliadin-free diet. Biopsy samples of the small intestine showed dense T-cell infiltrations in the lamina propria and a slight increase of intraepithelial T-lymphocytes. No clonal rearrangement of the T-cell receptor c-beta chain genes was detectable by Southern blotting. Four years later, at the age of 32, the patient was hospitalized again with liver failure, abdominal lymphadenopathy, pancytopenia, and recurrent bacterial infections. Retrospective polymerase chain reaction analysis of formalin-fixed tissues of the intestinal biopsy samples obtained 4 years earlier showed monoclonal T-cell receptor gamma-chain gene rearrangement. Lymphoid cells of the peripheral blood showed an immunophenotype of CD3-positive gamma/delta T cells with a negativity for CD4 and CD8. A clonally rearranged T-cell receptor delta chain gene and a germline configuration of the c-beta chain genes was found by Southern blotting. Cytogenetics showed an abnormal karyotype with unbalanced translocations t(1;5) and t(9;13). The patient died of extensive lung infiltrations by gamma/delta T cells; autopsy showed a peripheral T-cell lymphoma of the gamma/delta type in the enlarged abdominal lymph nodes. This is the first report of an abdominal T-cell lymphoma of the gamma/delta type in a patient with selective immunoglobulin A deficiency.     

Crystal structure of TNF-alpha mutant R31D with greater affinity for receptor R1 compared with R2

Crystal structures have been determined of recombinant human tumor necrosis factor-alpha (TNF-alpha) and its R31D mutant that preferentially binds to TNF receptor R1 with more than seven times the relative affinity of binding to receptor R2. Crystals of the wild-type TNF were of space group P4(1)2(1)2 and had unit cell dimensions of a = b = 94.7 and c = 117.4 A. Refinement of the structure gave an R-factor of 22.3% at 2.5 A resolution. The crystals of TNF R31D mutant diffracted to 2.3 A resolution, and were of identical space group to the wild type with unit cell dimensions of a = b = 95.4 and c = 116.2 A, and the structure was refined to an R-factor of 21.8%. The trimer structures of the wild-type and mutant TNF were similar with a root mean square (r.m.s.) deviation of 0.56 A for Calpha atoms; however, the subunits within each trimer were more variable with an average r.m.s. deviation of 1.00 A on Calpha atoms for pairwise comparison of subunits. Model complexes of TNF with receptors R1 and R2 have been used to predict TNF-receptor interactions. Arg31 in all three subunits of wild-type TNF is predicted to form an ionic interaction with the equivalent glutamic acid in both receptors R1 and R2. Asp31 of the TNF R31D mutant is predicted to interact differently with the two receptors. The side chain of Asp31 in two subunits of the TNF mutant is predicted to form hydrogen bond interactions with Ser59 or Cys70 of R1, while it has no predicted interactions with R2. The loss of three strong ionic interactions of Arg31 and the electrostatic repulsion of Asp31 with Glu in the receptors is consistent with the reduced binding of the R31D mutant to both receptors relative to wild-type TNF. The replacement of these ionic interactions by two weaker hydrogen bond interactions between Asp31 of the R31D mutant and R1, compared with no interactions with R2, is in agreement with the observed preferential binding of the R31D mutant to R1 over R2. Analysis of the structure and function of receptor-discriminating mutants of TNF will help understand the biological role of TNF and facilitate its use as an antitumor agent.      

Human immunodeficiency virus 1 (HIV-1)-specific reverse transcriptase (RT) inhibitors may suppress the replication of specific drug-resistant (E138K)RT HIV-1 mutants or select for highly resistant (Y181C-->C181I)RT HIV-1 mutants

Mutant HIV-1 that expresses a Glu138-->Lys substitution in its RT [(E138K)RT] is resistant to the HIV-1-specific RT inhibitor 2',5'-bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"- oxathiole-2",2"-dioxide)pyrimidine (TSAO). However, cell cultures infected with this mutant were completely protected against virus-mediated destruction by micromolar concentrations of the HIV-1-specific RT inhibitors tetrahydroimidazo[4,5,1-jk][1,4]benzodiazepin-2(1H)-one and -thione (TIBO), nevirapine, and bis(heteroaryl)piperazine (BHAP). In contrast, cells infected with a virus mutant that expresses a Tyr181-->Cys substitution in its RT [(Y181C)RT] were not protected by nevirapine and TIBO and were only temporarily protected by BHAP. HIV-1 mutant that emerged under the latter conditions contained a Cys181-->Ile substitution in their RT [(LC181I)RT]. This mutant proved highly resistant to all HIV-1-specific RT inhibitors tested, except for several 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivatives. When recombinant (C181I)RT was evaluated for susceptibility to the HIV-1-specific RT inhibitors, it was resistant to all inhibitors except the HEPT compounds. Since a (Y181F)RT HIV mutant strain was isolated from cells infected with (Y181C)RT HIV-1 and treated with BHAP, we postulate that the Ile codon was derived from a Cys-->Phe transversion mutation (TGT-->TTT), followed by a Phe-->Ile transversion mutation (TTT-->ATT).     

The unanticipated difficult airway with recommendations for management

PURPOSE: To review the current literature and generate recommendations on the role of newer technology in the management of the unanticipated difficult airway. METHODS: A literature search using key words and filters of English language and English abstracted publications from 1990-96 contained in the Medline, Current Contents and Biological Abstracts databases was carried out. The literature was reviewed and condensed and a series of evidence-based recommendations were evolved. CONCLUSIONS: The unanticipated difficult airway occurs with a low but consistent incidence in anaesthesia practice. Difficult direct laryngoscopy occurs in 1.5-8.5% of general anaesthetics and difficult intubation occurs with a similar incidence. Failed intubation occurs in 0.13-0.3% general anaesthetics. Current techniques for predicting difficulty with laryngoscopy and intubation are sensitive, non-specific and have a low positive predictive value. Assessment techniques which utilize multiple characteristics to derive a risk factor tend to be more accurate predictors. Devices such as the laryngeal mask, lighted stylet and rigid fibreoptic laryngoscopes, in the setting of unanticipated difficult airway, are effective in establishing a patient airway, may reduce morbidity and are occasionally lifesaving. Evidence supports their use in this setting as either alternatives to facemask and bag ventilation, when it is inadequate to support oxygenation, or to the direct laryngoscope, when tracheal intubation has failed. Specifically, the laryngeal mask and Combitube have proved to be effective in establishing and maintaining a patent airway in "cannot ventilate" situations. The lighted stylet and Bullard (rigid) fibreoptic scope are effective in many instances where the direct laryngoscope has failed to facilitate tracheal intubation. The data also support integration of these devices into strategies to manage difficult airway as the new standard of care. Training programmes should ensure graduate physicians are trained in the use of these alternatives. Continuing medical education courses should allow physicians in practice the opportunity to train with these alternative devices.     

Love and dating experience in early and middle adolescence: grade and gender comparisons

The experience of being "in love" was studied in a sample of 186 early to middle adolescent males and 199 early to middle adolescent females. Results indicated that amount of dating experience of adolescents varied widely at each age. Being "in love" co-occurred with a reciprocal on-going relationship about half the time. Boys fell in love earlier and more often than girls, and both genders seemed to employ an increasingly narrow prototypical conception of being "in love". Qualitative analyses suggested that early and middle adolescents are actively reasoning about the nature and meaning of romantic feelings and experiences. Results are interpreted from the standpoint of psychosocial developmental theory, and implications for interventions with adolescents are discussed.     

Reduced brain serotonin transporter availability in major depression as measured by [123I]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane and single photon emission computed tomography

BACKGROUND: Prior research has suggested reductions in the density of serotonin transporter (SERT) binding sites in blood platelets and post-mortem brain tissue of depressed patients. We sought to determine whether patients with unipolar major depression have diminished SERT availability as assessed by both brainstem [123I] beta-CIT SPECT and platelet [3H]paroxetine binding. METHODS: Drug-free depressed and healthy subjects were injected with 211 +/- 22 MBq [123I] beta-CIT and imaged 24 +/- 2 h later under equilibrium conditions. A ratio of specific to nonspecific brain uptake (V3" = (brainstem-occipital)/occipital), a measure proportional to the binding potential (Bmax/Kd), was used for all comparisons. RESULTS: Results showed a statistically significant reduction in brainstem V3" values in depressed as compared to healthy subjects (3.1 +/- .9 vs. 3.8 +/- .8, p = .02). Platelet [3H]paroxetine binding was not altered (Bmax = 2389 +/- 484 vs. 2415 +/- 538 fmol/mg protein, p = .91) and was not significantly correlated with brainstem [123I] beta-CIT binding (r = -0.14, p = .48). CONCLUSIONS: These data are the first to suggest reductions in the density of brain SERT binding sites in living depressed patients. These findings provide further support for a preeminent role for alterations in serotonergic neurons in the pathophysiology of depression.     

The need to quantify right-to-left shunt in acute ischemic stroke: a case-control study

BACKGROUND AND PURPOSE: Although right-to-left shunt (RLSh) has been reported to be significantly more frequent in young stroke patients with cryptogenic stroke, its relevance in a nonselected population of acute ischemic stroke is not well known. The aim of this study was to determine the importance of the RLSh magnitude as a risk factor for stroke in nonselected patients. METHODS: Two hundred eight patients hospitalized consecutively with transient ischemic attack or acute cerebral infarction and 100 healthy control subjects were studied. Transcranial Doppler ultrasonography (TCD) was performed in both middle cerebral arteries (MCAs) after intravenous application of agitated saline solution. The magnitude of RLSh was quantified by counting the number of signals in 1 MCA during a Valsalva maneuver. RLSh was classified as "no shunt," "small" (< 10 signals), and "large" (> 10 signals), with the latter including the "shower" (> 25 signals) and "curtain" (uncountable signals) patterns. Extensive investigations, including contrast transesophageal echocardiography, were carried out on patients diagnosed as suffering from stroke of an uncertain etiology. The importance of RLSh for stroke was assessed by logistic regression analysis. RESULTS: Contrast TCD detected a large RLSh in 40 (19.7%) patients and in 21 (21%) control subjects, all with cardiac RLSh characteristics. A large RLSh was present in 4.7% of atherothrombotic strokes, 10.5% of cardioembolic strokes, 15.4% of lacunar strokes, and 45.3% of cryptogenic strokes (P<0.001). Although the overall frequency of RLSh was not significantly different between patients and control subjects, the detection of curtain or shower patterns by contrast TCD was associated with a higher risk of stroke (odds ratio, 3.5; 95% confidence interval, 1.29 to 9.87), particularly with cryptogenic stroke (odds ratio, 12.4; 95% confidence interval, 4.08 to 38.09) after adjustment for concomitant vascular risk factors. CONCLUSIONS: It is essential to quantify RLSh by contrast TCD during the Valsalva maneuver given that only those with shower and curtain patterns are associated with a higher risk of ischemic stroke in a nonselected population.