Adult Burkitt's lymphoma presenting as intussusception: first UK case report.

Colonic intussusception is rare in adults and can present with non-specific symptoms that can make diagnosis difficult and delayed. Unlike in children, it is commonly due to a pathological lead point that is often malignant. This case is the first reported case of adult intussusception due to Burkitt's lymphoma in the UK. We describe the case of a 22-year-old woman who presented with 4-week history of intermittent epigastric pain. On the third hospital admission, the diagnosis was made by abdominal computed tomography, which showed the 'target' sign, suggestive of intussusception. A right hemicolectomy was performed and histology later confirmed Burkitt's lymphoma. This case demonstrates the difficulty in diagnosing intussusception in adults, which must be considered in recurrent abdominal pain when more common causes have been ruled out. The rare diagnosis of Burkitt's lymphoma made early diagnosis and treatment important.

Shape instability of a biomembrane driven by a local softening of the underlying actin cortex.

We present a theory showing that local shape instabilities of composite biological membranes, consisting of a lipid bilayer and an underlying actin cortex, can be triggered by a local softening of the membrane-associated cytoskeleton. A membrane containing such cortical defects can form blisters or invaginations, depending on external conditions. The theoretical predictions agree with observations provided by two sets of experiments: (i) microscopic observations of shape changes of giant vesicles with underlying shells of a thin actin network show the formation of local blisters and (ii) micropipet aspiration experiments of Dictyostelium discoideum cells in which we observed the formation of blisters in the aspirated cell part. In the latter experiments, the existence of a hole in the underlying cortex is confirmed by observation of the entrance of cell organelles into the blister. Our model may also be applied to the formation of lobopodia, fast-growing cell protrusions that play an important role in the locomotion and spreading of biological cells.

A micromechanic study of cell polarity and plasma membrane cell body coupling in Dictyostelium.

We used micropipettes to aspirate leading and trailing edges of wild-type and mutant cells of Dictyostelium discoideum. Mutants were lacking either myosin II or talin, or both proteins simultaneously. Talin is a plasma membrane-associated protein important for the coupling between membrane and actin cortex, whereas myosin II is a cytoplasmic motor protein essential for the locomotion of Dictyostelium cells. Aspiration into the pipette occurred above a threshold pressure only. For all cells containing talin this threshold was significantly lower at the leading edge of an advancing cell as compared to its rear end, whereas we found no such difference in cells lacking talin. Wild-type and talin-deficient cells were able to retract from the pipette against an applied suction pressure. In these cells, retraction was preceded by an accumulation of myosin II in the tip of the aspirated cell lobe. Mutants lacking myosin II could not retract, even if the suction pressures were removed after aspiration. We interpreted the initial instability and the subsequent plastic deformation of the cell surface during aspiration in terms of a fracture between the cell plasma membrane and the cell body, which may involve destruction of part of the cortex. Models are presented that characterize the coupling strength between membrane and cell body by a surface energy sigma. We find sigma approximately 0.6(1.6) mJ/m(2) at the leading (trailing) edge of wild-type cells.

Structural mosaicism on the submicron scale in the plasma membrane.

The lateral mobility of the neural cell adhesion molecule (NCAM) was examined using single particle tracking (SPT). Various isoforms of human NCAM, differing in their ectodomain, their membrane anchorage mode, or the size of their cytoplasmic domain, were expressed in National Institutes of Health 3T3 cells and C2C12 muscle cells. On a 6.6-s time scale, SPT measurements on both transmembrane and glycosylphosphatidylinositol (GPI) anchored isoforms of NCAM expressed in 3T3 cells could be classified into mobile (Brownian diffusion), slow diffusion, corralled diffusion, and immobile subpopulations. On a 90-s time scale, SPT studies in C2C12 cells revealed that 40-60% of transfected NCAM was mobile, whereas a smaller fraction (approximately 10-30%) experienced much slower diffusion. In addition, a fraction of approximately 30% of both transfected GPI and transmembrane isoforms and endogenous NCAM isoforms in C2C12 cells experienced transient confinement for approximately 8 s within regions of approximately 300-nm diameter. Diffusion within both these and the slow diffusion regions was anomalous, consistent with movements through a dense field of obstacles, whereas diffusion outside these regions was normal. Thus the membrane appears as a mosaic containing regions that permit free diffusion as well as regions in which NCAM is transiently confined to small or more extended domains. These results, including a large, freely diffusing fraction, similar confinement of transmembrane and GPI isoforms, a significant slowly diffusing fraction, and relatively large interdomain distances, are at some variance with the membrane skeleton fence model (Kusumi and Sako, 1996). Possible revisions to the model that incorporate these data are discussed.

Membrane bending modulus and adhesion energy of wild-type and mutant cells of Dictyostelium lacking talin or cortexillins.

We have employed an interferometric technique for the local measurement of bending modulus, membrane tension, and adhesion energy of motile cells adhering to a substrate. Wild-type and mutant cells of Dictyostelium discoideum were incubated in a flow chamber. The flow-induced deformation of a cell near its adhesion area was determined by quantitative reflection interference contrast microscopy (RICM) and analyzed in terms of the elastic boundary conditions: equilibrium of tensions and bending moments at the contact line. This technique was employed to quantify changes caused by the lack of talin, a protein that couples the actin network to the plasma membrane, or by the lack of cortexillin I or II, two isoforms of the actin-bundling protein cortexillin. Cells lacking either cortexillin I or II exhibited reduced bending moduli of 95 and 160 k(B)T, respectively, as compared to 390 k(B)T, obtained for wild-type cells. No significant difference was found for the adhesion energies of wild-type and cortexillin mutant cells. In cells lacking talin, not only a strongly reduced bending modulus of 70 k(B)T, but also a low adhesion energy one-fourth of that in wild-type cells was measured.

Transient confinement of a glycosylphosphatidylinositol-anchored protein in the plasma membrane.

Glycosylphosphatidylinositol (GPI)-anchored proteins participate in many cell surface functions; however, the molecular associations of these lipid-linked proteins within the plasma membrane are not well understood. Recent biochemical analyses of detergent insoluble membrane fractions have suggested that GPI-anchored proteins may be associated with glycosphingolipid (GSL)-enriched domains that also contain cholesterol and signaling molecules such as Src family kinases and, in some cases, caveolae. The movements of two components of the putative GSL-enriched domains, Thy-1, a GPI-anchored protein, and GM1, a GSL, were followed with single particle tracking on C3H 10T1/2 cell surfaces and categorized into four modes of lateral transport, fast diffusion, slow anomalous diffusion, diffusion confined to 325-370 nm diameter regions, and a fraction of molecules that was essentially stationary on the 6.6 s time scale. Longer observations (60 s) showed that Thy-1 and GM1 are transiently confined for 7-9 s to regions averaging 260-330 nm in diameter. Approximately 35-37% of both Thy-1 and GM1 undergo confined diffusion, whereas only 16% of fluorescein phosphatidylethanolamine, a phospholipid analog which is not expected to be found in the GSL domains, experience confined diffusion to regions averaging approximately 230 nm in diameter. Further, when glycosphingolipid expression was reduced approximately 40% with the glucosylceramide synthase inhibitor, d-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol, the percentage of trajectories exhibiting confinement and the size of the confining domain for Thy-1 were reduced approximately 1.5-fold. In contrast, extraction of cells with Triton X-100 leaves the fraction of molecules confined and the domain sizes of Thy-1 and GM1 unchanged. Our results are consistent with the preferential association of GPI-anchored proteins with glycosphingolipid-enriched domains and suggest that the confining domains may be the in vivo equivalent of the detergent insoluble membrane fractions.

New insights into membrane dynamics from the analysis of cell surface interactions by physical methods.

The physical, chemical and mechanical properties of the cell surface can be probed using a variety of microscopy-based techniques. The movements of membrane components are currently being characterized, and recent experiments have begun to define the structural origins of these modes of transport at a molecular level. However, explicit relationships between new knowledge of membrane structure and complex, linked functions, such as signal transduction and adhesion, remain elusive.

Detection of temporary lateral confinement of membrane proteins using single-particle tracking analysis.

Techniques such as single-particle tracking allow the characterization of the movements of single or very few molecules. Features of the molecular trajectories, such as confined diffusion or directed transport, can reveal interesting biological interactions, but they can also arise from simple Brownian motion. Careful analysis of the data, therefore, is necessary to identify interesting effects from pure random movements. A method was developed to detect temporary confinement in the trajectories of membrane proteins that cannot be accounted for by Brownian motion. This analysis was applied to trajectories of two lipid-linked members of the immunoglobulin superfamily, Thy-1 and a neural cell adhesion molecule (NCAM 125), and the results were compared with those for simulated random walks. Approximately 28% of the trajectories for both proteins exhibited periods of transient confinement, which were < 0.07% likely to arise from random movements. In contrast to these results, only 1.5% of the simulated trajectories showed confined periods. Transient confinement for both proteins lasted on average 8 s in regions that were approximately 280 nm in diameter.

Passive immunotherapy in the treatment of advanced human immunodeficiency virus infection.

To evaluate the safety and efficacy of passive immunotherapy for advanced human immunodeficiency virus (HIV) infection, a randomized, double-blind, controlled trial of human anti-HIV hyperimmune plasma was conducted. Sixty-three subjects with stage IV HIV disease (AIDS) were randomized to received 250 mL of either HIV-immune plasma or HIV antibody-negative plasma every 4 weeks. Although nonsignificant trends toward improved survival and delayed occurrence of a new opportunistic infection were noted, no significant effects on absolute CD4 lymphocyte counts or quantitative HIV viremia were seen. The only notable toxicity was the allergenicity to be expected from infusing plasma products, usually manifesting as urticaria. Thus, results do not rule out the potential usefulness of passive immunization with different preparations, but did fail to demonstrate clinical benefit of the product studied.

The N2 component elicited by stimulus matches and multiple targets.

This paper examines two methodological issues concerning the N2 component of human event-related potentials. The first issue concerns the circumstance that the most common way to obtain N2 in discrimination tasks is with an infrequent deviant stimulus that mismatches a frequent, standard stimulus. In these studies it is not possible to disentangle the effects of stimulus probability and stimulus mismatch on N2. In the present study it was found that, if two stimuli regularly alternate, N2 is elicited by infrequent repetitions of either stimulus. Thus, N2 is elicited by infrequent stimulus matches as well as infrequent stimulus mismatches. The second issue concerns the effect of stimulus probability on N2. Whereas previous research has established that the amplitude of N2 is inversely related to stimulus probability, the present study found that the number of possible targets in a visual discrimination task also has effects on N2 amplitude, with the overall probability of targets kept constant. Increasing the number of targets was associated with an increase in the duration of N2 and a differential enhancement of N2 at fronto-central as opposed to posterior-lateral recording sites. The latter results provide further evidence for the existence of two visual N2 components and tentative grounds for differentiating N2 from N400.

Effects of the amount of stimulus information processed on negative event-related potentials.

Event-related potentials were recorded during simple reaction time and 3 discrimination conditions which varied in the amount of stimulus information that needed to be processed. It was found that NA became longer in duration as the amount of stimulus information that required processing was increased. Using sequential topographic mapping, it was concluded that there are at least 3 overlapping deflections that comprise NA. The experimental effect appeared to be mainly on the third deflection of NA. The problem of overlap between NA and later positive-going components, P380 and P3b, is discussed in terms of their relative latencies and scalp distributions.

Topography of visual event-related potentials during geometric and phonetic discriminations.

Event-related potentials (ERPs) were obtained to letters during 3 tasks that involved a SIMPLE RESPONSE (SR) to each letter presentation, a FORM discrimination of the letters that formed a closed loop, and a RHYME discrimination of the letters that rhymed with the letter 'v'. The first task only required detection of the letters, the FORM task required a visual-spatial analysis, and the RHYME task, a grapheme-phoneme conversion of the letters followed by a determination of rhyming characteristics. The SR ERPs were morphologically different from the discriminative ERPs, notably by the absence of N2 and P3. The difference wave forms between the discrimination and SR conditions and between the targets and non-targets indicated differential topographies of components associated with the FORM and RHYME tasks in the 300 msec latency region. In both of these tasks, components exhibited distributions localized primarily in the occipital regions, whereas in the RHYME task they extended more anteriorly and encompassed temporo-parietal regions. Thus, although the stimulus presentation was visual, the requirement of a visual-auditory conversion in the RHYME task resulted in activity that was more proximal to auditory regions than when only a FORM analysis of the letters was required.

Evoked potentials in the assessment of neurotoxicity in humans.

The present paper reviews strengths and weaknesses of evoked potentials (EPs) as an index of toxic insult to the nervous system. EPs are obtained by averaging successive samples of EEG time-locked to the presentation of stimuli. Components of the resulting waveform can be measured for amplitude, latency, and distribution. Normal ranges of these parameters have been characterized for auditory, visual and somatosensory stimuli. Auditory EPs have been studied in humans exposed to lead, trichloroethylene, and carbon monoxide. Changes in timing of short latency components and in amplitude of later cortical components have been reported. Methyl mercury, n-hexane and carbon monoxide cause complex changes in the waveshape of flash and patterned visual EPs. Similarly, specific components of somatosensory EPs are altered following exposure to carbon monoxide, lead and acrylamide. The current lack of standardized recording and analysis techniques has sometimes generated contradictory results, but the evidence thus far supports the ultimate usefulness of EPs as a neurotoxicological screening tool.

Effects of expectation on negative potentials during visual processing.

ERPs were recorded during several RT tasks: simple RT; oddball choice RT; a LIE condition in which subjects were told stimuli would infrequently change, but did not; differential responding to two equiprobable stimuli that were randomized in one condition and alternated in another condition. Subtracting ERPs elicited during simple RT from those elicited during the other conditions, it was found that a negative component, NA, was enhanced, relative to simple RT, in all the other RT tasks. The data of the LIE condition indicated that NA was enhanced by the expectation that unpredictable stimulus changes would occur, even when they did not. The data of the 50/50 alternating RT condition indicated that stimulus changes by themselves enhance NA, even when they are predictable. There appear to be several deflections that comprise NA. NA was obtained with a variety of subtractions that balanced stimulus probability, the structure of the stimulus sequence and task instructions. Similar results were obtained whether subjects made a finger lift response or counted stimuli.

Manipulation of event-related potential manifestations of information processing stages.

The timing of two event-related potential components was differentially affected by two experimental variables. The earlier component (NA) was affected by degradation of the stimuli and the later component (N2) by the nature of a classification task. The results support the hypothesis that NA and N2 reflect sequential stages of information processing, namely, pattern recognition and stimulus classification.

An electrophysiologic indication of auditory processing defects in autism.

Averaged evoked potentials (EPs) to clicks, random pitch changes (signals), and random deletions of stimuli within a regular train of tones were examined in five autistic and five normal children. Brainstem auditory EPs were abnormal in one of the autistic patients. The early cortical EP components P60 and N100 showed no differences across groups, whereas the P200 component of the cortical responses to clicks, as well as the late positive component (P300) to the pitch changes and deleted stimuli, were significantly smaller in the autistic subjects as a group. Furthermore, when P200 and P300 amplitudes were averaged across conditions for the individual subjects, these components were smaller in every autistic subject than in any of the normal subjects. These results are consistent with the view that there are auditory defects in autism that may sometimes involve lower levels of neural transmission as manifested by abnormalities in the brainstem and auditory EP, but are more consistently manifest in higher aspects of processing that involve the registration and storage of stimulus information. It is suggested that the severe language disorder in childhood autism may be secondary to the basic deficits in higher auditory processing.