Vibriophage VcA-3 as an epidemic strain marker for the U.S. Gulf Coast Vibrio cholerae O1 clone.

Toxigenic and nontoxigenic Vibrio cholerae O1, El Tor biotype strains, which are endemic to the U.S. Gulf Coast, can be lysogenic for bacteriophage VcA-3. To evaluate the presence of VcA-3 as an indicator of toxigenicity and as an epidemic strain marker, phage production and the presence of phage and cholera toxin genes were assayed in 98 strains of V. cholerae O1 (35 U.S. and 63 foreign strains). By using a HindIII chromosomal digest for Southern blot analysis, 39 of the study strains hybridized with the VcA-3 probe in 10 banding patterns. The 15 toxigenic and 6 of the 20 nontoxigenic U.S. isolates gave four VcA-3-related patterns. Among the foreign isolates, 12 of 12 toxigenic classical biotype strains, 1 of 43 toxigenic El Tor biotype strains, and 3 of 8 nontoxigenic atypical strains gave six patterns that were clearly distinct from that of VcA-3. Compared with Southern blot analysis, the phage production assay had a sensitivity of 1.0 and a specificity of 0.48, while the colony hybridization assay had a sensitivity of 1.0 and a specificity of 0.77 for identification of VcA-3. Neither assay reliably identified the toxigenic Gulf Coast clone. The presence of VcA-3, as defined by Southern blot analysis, always separated toxigenic U.S. from foreign isolates and often from nontoxigenic U.S. isolates of V. cholerae O1.     

Randomized controlled trial of brief cognitive behaviour therapy versus treatment as usual in recurrent deliberate self-harm: the POPMACT study

BACKGROUND: We carried out a large randomized trial of a brief form of cognitive therapy, manual-assisted cognitive behaviour therapy (MACT) versus treatment as usual (TAU) for deliberate self-harm. METHOD: Patients presenting with recurrent deliberate self-harm in five centres were randomized to either MACT or (TAU) and followed up over 1 year. MACT patients received a booklet based on cognitive behaviour therapy (CBT) principles and were offered up to five plus two booster sessions of CBT from a therapist in the first 3 months of the study. Ratings of parasuicide risk, anxiety, depression, social functioning and global function, positive and negative thinking, and quality of life were measured at baseline and after 6 and 12 months. RESULTS: Four hundred and eighty patients were randomized. Sixty per cent of the MACT group had both the booklet and CBT sessions. There were seven suicides, five in the TAU group. The main outcome measure, the proportion of those repeating deliberate self-harm in the 12 months of the study, showed no significant difference between those treated with MACT (39%) and treatment as usual (46%) (OR 0.78, 95% CI 0.53 to 1.14, P=0.20). CONCLUSION: Brief cognitive behaviour therapy is of limited efficacy in reducing self-harm repetition, but the findings taken in conjunctin with the economic evaluation (Byford et al. 2003) indicate superiority of MACT over TAU in terms of cost and effectiveness combined.     

Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition

Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders. However, fundamental questions remain about the effects of DBS on neurons surrounding the electrode. Experimental studies have produced apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei. We hypothesized that cell body firing does not accurately reflect the efferent output of neurons stimulated with high-frequency extracellular pulses, and that this decoupling of somatic and axonal activity explains the paradoxical experimental results. We studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to DBS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Stimulation subthreshold for direct activation of TC relay neurons caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train mediated by activation of presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon. This independence of firing in the cell body and axon resolves the apparently contradictory experimental results on the effects of DBS. In turn, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS.     

Interoception: the inside story--a model for psychosomatic processes

OBJECTIVE: To comprehend psychosomatic processes, it will be necessary to understand the brain's influences on bodily functions and also the body's afferent sensory input to the central nervous system, including the effects of this input on behavior and cognitive functions, especially emotion. The objective of this Presidential Address is to review what is known circa the year 2000 of the processes and mechanisms of visceral sensory psychobiology, often called interoception. METHODS: Over 1000 publications that have appeared since the 19th century were reviewed to prepare this review, including a group that are specifically cited here. RESULTS: Factors and data were reviewed that were identified as germane to understanding interoception. These included definitional issues, historical roots, the neural basis, studies and results in the cardiovascular-respiratory and alimentary-gastrointestinal systems, studies of emotion, and studies in people with mental disorders. Drug and hormone effects, pain, proprioception, and phantom limb or organ factors, and the role of awareness were briefly described. Methodological issues, methods of study including functional imaging, and possible future directions for study were identified. CONCLUSIONS: Understanding the physical basis of psychosomatic processes, including the so-called mind-body problem, will require a detailed understanding the psychobiology of interoception.     

Trial of platelet-derived growth factor antagonist,trapidil, in accelerated nephrotoxic nephritis in the rabbit.

The platelet-derived growth factor (PDGF) antagonist, trapidil, which also blocks the thromboxane and/or PG-endoperoxide receptor and is an inhibitor of thromboxane synthetase, was administered during rabbit accelerated nephrotoxic nephritis; the clinical and histological evolution was studied as well as urinary immunoreactive thromboxane (i-TXB2) and immunoreactive prostaglandin E2 (i-PGE2) excretion. Although the dose we used has been shown to be effective in vivo, and it inhibited the urinary i-TXB2 excretion on days 5 and 10, it neither inhibited the enhanced production of i-TXB2 on day 1, nor prevented the glomerular influx of monocytes on days 5 and 10. All clinical and histological data tend to be worse rather than better in trapidil-treated animals on days 5 and 10.     

Immunohistochemical labeling for the Dpc4 gene product is a specific marker for adenocarcinoma in biopsy specimens of the pancreas and bile duct.

We immunohistochemically labeled 72 biopsy specimens from the extrahepatic biliary tree and pancreas for Dpc4 protein and correlated expression with histologic diagnosis and patient follow-up. Specimens were classified histologically as follows: nonneoplastic, 35; neoplastic, 22; atypical, 15. Loss of expression of Dpc4 protein was identified in 12 specimens; 11 were histologically diagnostic of carcinoma. The 12th specimen was from a patient whose biopsy specimen initially was diagnosed as "atypical," but clinical follow-up revealed adenocarcinoma. Of the 12 atypical biopsy specimens with intact expression for Dpc4, follow-up later revealed that 10 were adenocarcinoma. Loss of expression of Dpc4 protein was never identified in a benign specimen. Immunohistochemical labeling for the Dpc4 gene product is a specific marker of carcinoma in biopsy specimens of the pancreas and extrahepatic bile ducts and is marginally helpful in classifying atypical specimens. The sensitivity for carcinoma is low. This latter finding is not unexpected, because the DPC4 tumor suppressor gene is inactivated in only about half of pancreatic and biliary malignant neoplasms. Importantly, loss of Dpc4 expression has been reported in in situ carcinomas, suggesting that loss of expression should not be equated with invasive carcinoma.     

The differentiation capacity of Clara cells isolated from the lungs of rabbits

The purpose of our studies was to determine the growth and differentiation potential of Clara cells isolated from rabbit lungs. The Clara cell preparations were enriched (80 to 85%) by density gradient-elutriation procedures and then were inoculated into rat tracheas denuded of their own epithelium. These tracheas then were transplanted subcutaneously on the backs of nude mice. For purposes of comparison, other denuded tracheas were inoculated with mixed epithelial cells obtained from rabbit tracheas by enzymatic procedures. Control tracheas were inoculated with cell-free media. At 2, 4, and 14 weeks after transplantation, the tracheal grafts were removed from the recipient nude mice and examined by light and electron microscopy. Tracheal grafts not receiving cell inocula contained no epithelial lining, and the tracheal lumens were filled with loose connective tissue. Tracheas inoculated with 2 X 10(4) mixed tracheal cells showed a columnar, pseudostratified epithelium composed of five cell types: (a) poorly-differentiated cells, (b) ciliated cells, (c) mucous cells, (d) Clara-like cells, and (e) typical basal cells. A very different epithelium was established in tracheas repopulated with Clara cell isolates. This epithelium, at all time points examined, was cuboidal, single layered (never pseudostratified), and lacked basal cells. The tracheal lumens were lined with ciliated and nonciliated cells. The latter showed typical features of mature Clara cells (i.e., electron dense granules and smooth endoplasmic reticulum). At 14 weeks, the same two cell types were present, and often they were located on ridges and furrows of the tracheal walls. Mixed tracheal cells inoculated into denuded tracheas gave rise to a normal-appearing pseudostratified mucociliary epithelium, whereas the Clara cells inoculated under identical conditions gave rise to a low cuboidal epithelium resembling that seen in normal bronchioles. Establishment of these two types of epithelial linings occurred in the presence of the same mesenchymal components. Thus, we conclude that Clara cells have considerable self-renewal capacity, and their differentiation potential appears to be quite narrow.