Ectopic T cell receptor expression causes B cell immunodeficiency in transgenic mice

Mice expressing transgenic T cell receptors (TCR) are used to explore important questions in immunity. However, transgene expression may have unexpected effects. We previously reported a B cell immunodeficiency, comprising decreased B cell numbers and diminished antibody responses, in mice that express a transgenic TCR specific for nicotinic acetylcholine receptor; the mice were generated using cassette vectors designed specifically for transgenic TCR expression [see Kouskoff et al. J. Immunol. Methods 1995. 180: 273-280]. We now show data suggesting that this defect is due to the expression and accumulation of TCR alpha and beta chains inside B cells and induction of an endoplasmic reticulum stress response, causing apoptosis at the pre B-I and later B cell stage. Thus, inappropriate transgene expression can profoundly affect B cells, leading to a previously undescribed mechanism of immunodeficiency.     

"Could it be asthma?": the impact of a mass media campaign aimed at raising awareness about asthma in Australia

Asthma is a very common chronic illness in Australia; however,unrecognized and undertreated asthma is responsible for muchpreventable morbidity in the community. In 1988, a coalitionof private and public sector agencies was formed to conducta national mass communications program aimed at increasing awarenessabout asthma. This pilot campaign comprised a mailout to allprimary care physicians and a mass media campaign, entitled"Could it be asthma?". The impact of this media-based strategywas assessed using population surveys of 1300 adults beforeand after the campaign. Following the campaign, recall of recentasthma media messages increased from 24 to 49% (P < 0.001)and the proportion who recognized possible asthma symptoms intheir household increased from 3.4 to 5.5% following the campaign.Of those with symptoms, twice as many reported that they visiteda doctor to have their symptoms assessed after the campaign.Knowledge of asthma symptoms was significantly higher followingthe campaign (P < 0.001), after adjustment for age, sex andthe presence of asthma in the respondents family. The campaignappeared to have some success in raising awareness about asthma,and has been followed by the development of a National AsthmaCampaign in Australia focusing on reducing asthma morbidityand improving its management.     

Reconnecting with relational values in highly conflicted separating couples: A narrative therapy-informed relational interviewing teamwork-based supervision approach

This article outlines a new supervision practice of narrative therapy-informed reflecting team-based relational interviewing for a high-conflict stuck case of a separated middle-aged couple. The article demonstrates the supervision method consisting in five parts. First, the supervisor interviews the couples' relationship while the team watches from behind the one-way mirror. Second, the team responds to the interview while the couple and the supervisor witness their conversation. The couple is then invited to respond back to the team. Furthermore, there is a meta-conversation about the supervision in collaboration with the couple. The intervention ends with therapeutic letter writing to the relationship. The couple showed a meaningful shift in their positioning towards a more relational awareness and found valuable ways for continuing their therapy. The theoretical elements of the approach underpinning practice to tackle high conflict are considered through the illustration of the case.     

Rotational behaviour and cGMP responses following manipulation of nigral mechanisms with chlordiazepoxide

Summary Unilateral stereotaxic injections of 1 g of the soluble benzodiazepine chlordiazepoxide hydrochloride into the predominantly GABA-containing zona reticulata of the substantia nigra of amphetamine-pretreated rats induced rotational behaviour similar to that seen following unilateral elevation of nigral GABA levels and amphetamine treatment; this effect was not seen following injections into the vicinity of the predominantly dopamine-containing zona compacta. Chlordiazepoxide-induced rotations were abolished by the GABA-antagonist picrotoxin. Both chlordiazepoxide and GABA depressed production of cyclic 3,5-guanosine monophosphate in samples of nigral tissue in vitro as estimated by radioimmunoassay. It is concluded that chlordiazepoxide may enhance GABA transmission within the substantia nigra, by some as yet unidentified mechanism, to create asymmetric activity in GABA-modulated neurones and hence induce rotation.     

Insulin resistance is associated with decreased clinical status in cystic fibrosis

Patients with cystic fibrosis (CF) frequently have impaired glucose tolerance and progression to diabetes (DM) with clinical features of both insulin-dependent and non-insulin-dependent diabetes. One feature of non-insulin-dependent DM is decreased insulin sensitivity, also known as insulin resistance. The goal of this study was to determine whether patients with CF exhibit insulin resistance and to determine the potential effect of insulin resistance on clinical status. We also sought to determine whether insulin resistance is associated with a specific CF genotype. We studied 18 patients with CF (8 with normal glucose tolerance, 5 with impaired glucose tolerance, 5 with DM), and 20 lean control subjects matched for age, weight, and sex. All control subjects had normal glucose tolerance. The clinical status for each CF patient was determined according to a modified National Institutes of Health scoring system. Each subject underwent a three-step hyperinsulinemic euglycemic clamp (insulin doses of 10, 40, 120 mU/m ² per minute). Results from the 120 mU/m ² per minute infusion defined maximal glucose disposal rate (defined in milligrams per kilogram body weight per minute) at steady state with peripheral insulin levels 195 ± 20 mU/ml. Subjects with CF demonstrated insulin resistance (control subjects = 13.6 ± 1.1, patients with CF = 10.2 ± 1.6 mg/kg per minute; p = 0.003). When each subgroup was compared separately with control subjects, all subgroups were statistically insulin resistant (glucose disposal rate, patients with CF and normal glucose tolerance = 10.8; those with impaired glucose tolerance = 8.4; those with DM = 10.1 mg/kg per minute), and the patients with CF with impaired glucose tolerance were the most insulin resistant. When plotted versus glucose disposal rate, a striking positive correlation between worsened clinical status and insulin resistance ( r = 0.85) is demonstrated. Furthermore, there is no correlation between insulin resistance and fasting blood glucose, subject age, or percent ideal body weight (all r values not significant). In conclusion, patients with CF exhibit insulin resistance that is associated with worsened clinical status. We believe it is the combination of insulin resistance and decreased insulin secretion that is responsible for the high incidence of CF-related diabetes. (J Pediatr 1997;130:948-56)     

Medial prefrontal transection enhances social interaction. II: neurochemical studies

Medial prefrontal cortex (MPFC) transection enhances social interaction in an open arena test. Social interaction enhances dopaminergic activity in the nucleus accumbens (NAC). In the present set of experiments, microdialysis probes were implanted in the NAC, and glutamate, gamma-aminobutyric acid (GABA) and dopamine (DA) were measured during electrical stimulation of the MPFC, after coronal transection caudal to the MPFC and after a systemic injection of amphetamine in transected rats. Electrical stimulation of the MPFC caused a transient enhancement of glutamate release in the NAC, no change in GABA levels and a long lasting increase in DA levels. Medial prefrontal transection did not change basal glutamate or GABA levels in the NAC, but increased basal DA levels. Amphetamine administration decreased GABA levels in medial prefrontal transected rats, had no effect on glutamate and increased DA levels more than in controls. The experiments suggest that glutamatergic activity in the accumbens decreases dopamine release. Medial prefrontal transection reduces glutamatergic tone and enhances dopamine release, which probably decreases GABAergic activity in the NAC. Presumably, GABA inhibition in the NAC enhances social interaction.