The effects of phorbol esters with different biological activities on protein kinase C

The sapintoxins are a series of naturally occurring fluorescent phorbol esters with a range of selective biological activities (e.g. pro-inflammatory but non-tumour promoting). Their ability to activate protein kinase C (PKC) in vitro has been studied. Both tumour promoting and non-promoting phorbol derivatives activate the enzyme in vitro at low concentrations. 12-deoxyphorbol-13-phenylacetate-20 acetate (DOPPA) acts as a partial agonist in the activation of protein kinase C. Structurally distinct phorbol esters may therefore preferentially activate different forms of protein kinase C. α-sapinine, a biologically inactive compound, binds to protein kinase C without stimulating the enzyme and prevents subsequent activation by phorbol esters such as 12-O-tetradecanoyl phorbol-13-acetate (TPA).     

Segmental intestinal muscular thinning: a possible cause of intestinal obstruction in the newborn

Intestinal obstruction proximal to a transition zone without an interposed physical barrier usually indicates Hirschsprung disease. The authors report one case of focal small bowel muscular thinning just distal to a transition zone that produced clinical and radiographic findings that simulated long-segment Hirschsprung disease in a 2-day-old infant.     

The use of restricted spectral range red lenses for the diagnosis and relief of dazzlement of a rod monochromat

An infant rod monochromat was diagnosed and was then treated with the Younger PLS 550 lens. The comparison in use of PLS 550 and a neutral density lens confirmed the presence of cone dysfunction. The use of this lens takes advantage of the spectral shift in luminosity between rods and cones. Younger PLS 550 and PLS 530 tints are used for the relief of photophobia according to prevailing brightness. This paper discusses patient management with the use of these lenses and some characteristics of the vision of a rod monochromat.     

Interleukin-6 production by astrocytes: Induction by the neurotransmitter norepinephrine

Astrocytes contribute to the immunocompetence of the central nervous system (CNS) via their expression of class II major histocompatibility complex (MHC) antigens and the production of inflammatory cytokines such as interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Of these cytokines, IL-6 is of particular interest because one of its many immune and inflammatory actions is the promotion of immunoglobulin synthesis, and it is thought that IL-6 expression within the brain exacerbates autoimmune diseases of the CNS, which are marked by local immunoglobulin production. Several stimuli induce astrocyte IL-6 expression, including such inducible endogenous factors as IL-1β and TNF-α. We have investigated the possibility that a constitutively present endogenous factor, the neurotransmitter norepinephrine (NE), can induce astrocyte IL-6 production. We report that NE induces both IL-6 mRNA and protein in primary neonatal rat astrocytes, with optimal induction at 10 μM. IL-6 protein induction by NE is comparable to that seen with IL-1β or TNF-α, and NE synergizes with these cytokines for a ten-fold enhanced effect. In contrast to astrocytes, microglia are relatively unresponsive to NE, IL-1β and TNF-α for IL-6 production. Experiments with the β-adrenergic receptor agonist isoproterenol, and α and β-adrenergic receptor antagonists (propranolol, phentolamine, atenolol, and yohimbine) indicate that β₂ and α₁-adrenergic receptors are involved in NE induction of astrocyte IL-6 expression. These results help to further the understanding of neuron-glial interactions, and the role of astrocytes and adrenergic activity in immune responses within the CNS.     

Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy

The dominant cone-rod dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12-p13. The retinal- specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber's congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various cone and cone- rod dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone-rod dystrophy. RETGC-1 is only the fourth gene to be implicated in cone-rod dystrophy and this is the first report of dominant mutations in this gene.      

Natural killer cells and reproductive failure--theory, practice and prejudice

The relationship between peripheral blood natural killer (NK) cells and reproductive failure is one of the most controversial areas in reproductive medicine. Amidst much publicity, peripheral blood NK cell testing is being promoted as a useful diagnostic test to guide the initiation of a variety of immunosuppressive therapies amongst patients with either recurrent miscarriage or infertility. We contend (i) that at present there is no scientific basis for the introduction of NK cell testing into routine clinical practice, and (ii) that the use of immunosuppressant agents based on the results of such testing may potentially be harmful.     

Using simulation to instruct emergency medicine residents in cognitive forcing strategies.

PURPOSE: Recent literature defines certain cognitive errors that emergency physicians will likely encounter. The authors have utilized simulation and debriefing to teach the concepts of metacognition and error avoidance. METHOD: The authors conducted a qualitative study of an educational intervention at Lehigh Valley Hospital during academic year 2002-03. Fifteen emergency medicine residents--eight from postgraduate year three (PGY3) and seven from postgraduate year two (PGY2)--experienced a difficult simulator lab scenario designed to lead them into a cognitive error trap. The debriefing was a PowerPoint with audio format CD-ROM with a didactic on succinylcholine (15 minutes) and cognitive forcing strategies (30 minutes). After debriefing, residents were interviewed by an ethnographer with an 11-question (15-minute) interview and completed an eight-question written survey. RESULTS: The residents ranked this experience second only to direct patient care for educational effectiveness. Survey results (Likert scale, 1 = disagree completely to 5 = agree completely) included "Improved my ability to use succinylcholine" (mean = 4.73), "Improved my ability to diagnose and treat hyperkalemia" (mean = 4.6), and "Cognitive forcing strategies is a useful educational effort" (mean = 4.33). The major interview themes that evolved were that the simulation lab was a positive experience; succinylcholine knowledge was gained; mistakes caused reflection/motivation; the lab was stressful; attending feedback was desired; the lab was realistic; and cognitive forcing strategies were discussed. When asked what they learned, more of the PGY3s commented on cognitive strategies or heuristic techniques (six out of eight), whereas the PGY2s commented on knowledge gained about succinylcholine (five out of seven) and only one PGY2 mentioned cognitive strategies. CONCLUSION: Pilot data suggest that metacognitive strategies can be taught to residents, though they may be better understood by upper-level residents.     

Elastic scattering spectroscopy for intraoperative determination of sentinel lymph node status in the breast

The ability to provide the best treatment for breast cancer depends on establishing whether or not the cancer has spread to the lymph nodes under the arm. Conventional assessment requires tissue removal, preparation, and expert microscopic interpretation. In this study, elastic scattering spectroscopy (ESS) is used to interrogate excised nodes with pulsed broadband illumination and collection of the backscattered light. Multiple spectra are taken from 139 excised nodes (53 containing cancer) in 68 patients, and spectral analysis is performed using a combination of principal component analysis and linear discriminant analysis to correlate the spectra with conventional histology. The data are divided into training and test sets. In test sets containing spectra from only normal nodes and nodes with complete replacement by cancer, ESS detects the spectra from cancerous nodes with 84% sensitivity and 91% specificity (per-spectrum analysis). In test sets that included normal nodes and nodes with partial as well as complete replacement by cancer, ESS detects the nodes with cancer with an average sensitivity of 75% and specificity of 89% (per-node analysis). These results are comparable to those from conventional touch imprint cytology and frozen section histology, but do not require an expert pathologist for interpretation. With automation of the technique, results could be made available almost instantaneously. ESS is a promising technique for the rapid, accurate, and straightforward detection of metastases in excised sentinel lymph nodes.     

Baylisascariasis

The raccoon roundworm, Baylisascaris procyonis, is the most common and widespread cause of clinical larva migrans in animals. In addition, it is increasingly recognized as a cause of devastating or fatal neural larva migrans in infants and young children and ocular larva migrans in adults. Humans become infected by accidentally ingesting infective B. procyonis eggs from raccoon latrines or articles contaminated with their feces. Two features distinguish B. procyonis from other helminthes that cause larva migrans: (i) its aggressive somatic migration and invasion of the central nervous system and (ii) the continued growth of larvae to a large size within the central nervous system. Typically, B. procyonis neural larva migrans presents as acute fulminant eosinophilic meningoencephalitis. Once invasion of the central nervous system has occurred, the prognosis is grave with or without treatment. To date, despite anthelmintic treatment of cases of B. procyonis neural larva migrans, there are no documented neurologically intact survivors. Epidemiologic study of human cases of neural larva migrans demonstrate that contact with raccoon feces or an environment contaminated by infective eggs and geophagia or pica are the most important risk factors for infection. In many regions of the United States, increasingly large populations of raccoons, with high rates of B. procyonis infection, live in close proximity to humans. Although documented cases of human baylisascariasis remain relatively uncommon, widespread contamination of the domestic environment by infected raccoons suggests that the risk of exposure and human infection is probably substantial. In the absence of early diagnosis or effective treatment, prevention of infection is the most important public health measure.