Nonlinearity and facilitation in phosphoinositide signaling studied by the use of caged inositol trisphosphate in Xenopus oocytes

The phosphoinositide signaling pathway, which mediates neurotransmitter responses, was studied in Xenopus oocytes by recording membrane currents evoked using lightflash photolysis of caged inositol trisphosphate (caged IP3) to produce rapid and reproducible transients in intracellular IP3 levels. Photolysis of caged IP3 evoked currents which were carried largely by chloride ions and depended upon intracellular, but not extracellular, calcium. A given light flash evoked larger responses when the amount of caged IP3 loaded into the oocyte was increased, and illumination of the vegetal hemisphere gave larger responses than the animal. Long (10 sec) light exposures produced oscillatory currents, resembling responses to serotonin and other agonists, which became larger, more transient, and of shorter latency as the light intensity was increased. Brief (ca. 100 msec) flashes evoked a single "spike" of current. The caged IP3 response showed a threshold, in that light flashes had to be greater than a certain intensity and duration before currents could be detected. Associated with this, sub- and suprathreshold light flashes caused a long-lasting (seconds or minutes) potentiation of responses to subsequent test flashes. The lightflash response was also potentiated by a preceding intracellular injection of IP3 and by extracellular application of an agonist thought to induce IP3 liberation. However, intracellular injections of calcium depressed the response. We conclude that the liberation of calcium from intracellular stores varies nonlinearly with the intracellular level of IP3. This phenomenon may explain earlier observations, including the long latency of currents evoked by low doses of agonists such as acetylcholine and serotonin, and the nonlinear facilitation seen between these agonists. Further, it suggests a mechanism for "chemical integration," which may be important in the functioning of neurons and other cells which use IP3 as an intracellular messenger.     

Neisseria sicca osteomyelitis.

Neisseria sicca was identified as the cause of vertebral osteomyelitis in a male patient who had previously suffered a nonpenetrating, traumatic back injury. The identifying characteristics and antimicrobial susceptibility patterns are presented for this rare human pathogen, which heretofore has not been reported as a cause of infection localized to bone.     

Respiratory syncytial virus infection does not increase allergen-induced type 2 cytokine production, yet increases airway hyperresponsiveness in mice

Severe respiratory syncytial virus (RSV)-induced disease is associated with childhood asthma and atopy. We combined murine models of allergen-sensitization and RSV infection to explore the interaction of allergic and virus-induced airway inflammation and its impact on airway hyperresponsiveness (AHR). We found that RSV infection during ova-sensitization (OVA/RSV) increased and prolonged AHR compared to mice only RSV-infected (RSV) or ova-sensitized (OVA). AHR is known to be associated with an increase in Type 2 cytokines (IL-4, IL-5, and IL-13) in allergen-sensitized mice. Therefore, we hypothesized that RSV-induced enhancement of AHR was a result of potentiating the Type 2 cytokine profile promoted by ova-sensitization. Surprisingly, we found that Type 2 cytokines induced by ova-sensitization were not increased by RSV infection despite the increase in AHR, and in some cases were diminished. RNAse protection assay revealed no difference in IL-4 and IL-5 mRNA levels between the OVA and OVA/RSV groups, and IL-13 mRNA was significantly decreased in the OVA/RSV mice compared to the OVA group. Flow cytometric analysis of Type 2 cytokines demonstrated the same frequency of IL-4 and IL-5 production in lung-derived T lymphocytes from the OVA/RSV and OVA groups. Direct cytokine ELISA measurements of lung supernatant showed the level of IL-13 was significantly decreased in the OVA/RSV group compared to OVA mice, while there was no difference in either IL-4 or IL-5 between these two groups. These data indicate that the enhanced and prolonged AHR caused by the interaction of allergic airway inflammation and virus-induced immune responses is a complex process that can not be explained simply by augmented production of Type 2 cytokines.     

Risk and protective factors for suicidal behavior in abused African American women

This study examined risk and protective factors that differentiate low-income, abused African American women (N = 200) who attempted suicide from those who had never made a suicide attempt. Results from multivariate analyses revealed that numerous and/or severe negative life events, a history of child maltreatment, high levels of psychological distress and depression, hopelessness about the future, and alcohol and drug problems were factors associated with attempter status. Protective factors associated with nonattempter status included hopefulness, self-efficacy, coping skills, social support, and effectiveness in obtaining material resources. Culturally competent intervention approaches for abused women should target increasing their protective factors and reducing their risk factors to decrease the likelihood that these women engage in suicidal behavior.     

Sea blue histiocytosis in a patient with chronic non-neuropathic Niemann-Pick disease.

A patient with Niemann-Pick disease is reported together with family studies. Her liver and bone marrow were shown to be infiltrated with sea blue histiocytes. Other organs, spleen and lung, were presumably also involved but histological proof was not obtained. Enzyme assay of leucocytes, lymphocytes, and cultured skin fibroblasts showed the patient to be deficient in sphingomyelinase activity. In fibroblasts, activity was 5% of normal while for the parents activity was about 50% of normal. The expected partial deficiency was not found using leucocytes or lymphocytes from the parents. Heat stability studies on fresh fibroblast extracts from the propositus indicated that residual sphingomyelinase activity was slightly more labile than that of the controls. It seems clear that chronic Niemann-Pick disease without neurological involvement is associated with sea blue histiocytosis.     

Ability of an avirulent mutant of Vibrio cholerae to colonize in the infant mouse upper bowel.

Vibrio cholerae strain 3083 (biotype El Tor, serotype Ogawa) and Texas Star-SR (SR), a mutant derived from 3083 that produces the B (binding) but not the A (toxic) subunit of choleragen, were compared in their abilities to: (i) associate with the infant mouse upper bowel; (ii) survive and multiple there; and (iii) induce diarrhea. Vibrios labeled with 35SO4 were used to determine association with the upper bowel and ability to multiply. The parental strain associated significantly better than SR, although viable mutant cells were found in the infant mouse intestine 16 to 18 h after challenge. Addition of exogenous toxin enhanced the rate at which labeled SR (but not 3083) was cleared, further suggesting that SR associates less well with the upper bowel. Both SR and 3083 multiplied in the upper bowel but, due perhaps to slight net killing during the first 3 h and its more rapid rate of clearance, SR achieved a population size only 10% that of 3083 by 8 h postchallenge. Strain 3083 elicited diarrhea in infant mice but SR did not, even after 10 successive passages through the infant mouse intestine. Strain SR was slightly temperature sensitive at 37 and 40 degrees C. Its potential use as a live vaccine is discussed.     

Relationship between conjugate lateral eye movements and alexithymia.

The relationship between conjugate lateral eye movements (CLEMs) and alexithymia was investigated in a group of 60 (23 male and 37 female) right-handed university students. Subjects completed the Toronto Alexithymia Scale (TAS), the Schalling-Sifneos Personality Scale, and the Basic Personality Inventory, which measures 12 basic dimensions of personality and psychopathology, CLEMs were recorded while subjects were asked 20 general knowledge questions that have no tendency to elicit eye movements predominantly in one direction. A series of gender by CLEM preference (left vs. right mover) ANOVAs were conducted with the various measures. There was a significant relationship between right CLEM preference and higher scores on the TAS, but no relationships between CLEMs and any of the other measures. These results suggest that alexithymia is associated with left cerebral lateralization, and support the hypothesis that alexithymic characteristics reflect a variation in brain organization.     

Absence of simian virus 40 (SV40) DNA in lymphoma samples from Tasmania, Australia

AIMS: It has been postulated that the recent world-wide increase in the incidence of non-Hodgkin's lymphoma (NHL) may have been caused by human infection with simian virus 40 (SV40) (a lymphotropic monkey virus that was introduced to man from contaminated poliovirus vaccines between 1955 and 1963); therefore, we set out to determine the incidence of SV40 DNA positivity in lymphoma samples from patients in Tasmania, Australia. METHODS: One hundred lymph node samples, 50 from patients with lymphomas and 50 from controls, were tested using PCR amplification of three SV40-specific primer pairs followed by dot-blot hybridisation. RESULTS: All of the samples tested contained amplifiable DNA, but none contained amplifiable SV40 sequences with any of the primer sets used. CONCLUSIONS: Our results demonstrate absence of SV40 in the lymphoid tissues of our study population in Tasmania, Australia. SV40 does not explain the increasing incidence of NHL in our population.     

Confidentiality and serious harm in genetics - preserving the confidentiality of one patient and preventing harm to relatives

Genetics can pose special challenges to the principle of confidentiality within the health professional-patient relationship, since genetic information is by its nature both individual and familial. Most professional guidelines allow confidentiality to be broken in rare circumstances, where it will prevent a 'serious', 'imminent' and 'likely' harm. We argue that the types of harms that may result from genetic medicine are particularly diverse. Using clinical examples, we explore ethical issues that arise when balancing individual and family member interests. As genetic testing becomes more, widespread situations will arise where clinicians are faced with a choice between preserving the confidentiality of one patient and preventing harm to another. Professionals need to incorporate the notion of familial implications in their counseling of individuals. Since such dilemmas have been relatively rare in the pre-genetic age, we call for a wider debate on the balance between confidentiality and harm to others.