Cyclosporin A mediated immunosuppression in vitro: effect on high affinity interleukin-2 receptor expression and -turnover

The effect of in vitro administration of Cyclosporin A (CsA) during mitogen, antigen and alloantigen activation of human T-lymphocytes on high affinity interleukin-2 (IL-2) receptor expression and -turnover and IL-2 production was investigated. The presence of CsA reduced 3H-thymidine incorporation and binding of radiolabelled human recombinant (ala125) IL-2 to high-affinity receptors in a dose-dependent fashion, although a pronounced inter- and intra-individual variation in sensitivity to CsA mediated immunosuppression was observed. Maximum inhibition was obtained when antigen and CsA were added to culture medium simultaneously. Preincubation with CsA did not influence the response. Although the number of IL-2 receptors was reduced, the turnover of the remaining high affinity IL-2 receptors on CsA treated cells was unaffected. Thus, binding, internalization and degradation were qualitatively unaltered by CsA administration. Finally, T cell activation in the presence of CsA reduced radioimmuno detectable IL-2 in cell culture supernatants to about 20%. CsA, added during antigen activation, reduced the number of Tac antigen presenting cells, but anti-Tac was unable to detect variations in the expression of high affinity IL-2 receptors. The present data indicate that CsA mediates immunosuppression by affecting early events during T-cell activation, and that variations in high affinity IL-2 receptor expression and IL-2 production are secondary to this affection.     

Anatomy and developmental chronology of the rat inferior alveolar nerve

This report describes the anatomy of the inferior alveolar neuroascular bundle in the adult rat and provides a quantitative analysis of the developing inferior alveolar nerve (IAN). Soon after its entrance in the mandibular canal, the IAN splits into a mental nerve (MN) and an inferior dental nerve (IDN), which course in separate bony compartments. The MN passes unbranched through the mandibular canal. The IDN sends branches to the incisor, the first molar, and the second molar. The third molar (M₃) is supplied by a separate IAN branch. The adult rat IAN contains 8,000–10,000 axons, 70% of which are myelinated. The MN accounts for 70% of all IAN axons, the IDN 26%, and 4% form the M₃ branch. The proportion of large myelinated axons is lower in the MN than in the IDN. Following chemical sympathectomy, the IAN axon number does not change in a statistically sigificant way. The total number of IAN axons, which is high prenatally and neonatally, has decreased to the adult level about 1 week after birth. De novo myelination commences at birth and is complete 3–4 weeks later. The size spectrum of the myelinated fibres is narrow and unimodal during the first postnatal weeks. By 1 month, the largest fibres reach diameters of ～6 μm, and a bimodal pattern is emerging. From 3 months and on, the size range reaches up to 10–12 μm, and the distribution is bimodal. These data provide a basis for further studies on developmental tooth-nerve interactions. © 1992 Wiley-Liss, Inc.     

Campylobacter pylori detected by indirect immunohistochemical technique

An immunohistochemical assay for staining C. pylori is described. The method is compared with cultivation of C. pylori and observation of campylobacter-like organisms (CLOs) in hematoxyline-eosine (HE) stained sections. Eighteen biopsies from which C. pylori was cultivated but not seen in HE stained sections and three culture negative biopsies with CLOs seen in HE stained sections were selected from 331 biopsies including 113 culture positive biopsies. There were agreements between cultivation of C. pylori and CLOs seen in HE stained sections in the remaining 310 biopsies. Fourteen of the 18 and one of the three biopsies were found positive by the immunohistochemical assay. In addition 21 culture-positive control biopsies and one of 18 culture-negative control biopsies were also found positive. When the immunohistochemical assay was compared with cultivation the predictive value of positive result is 93% and of negative result 89%. By this method we were able to detect single organisms and no cross-reactions to other curved bacteria on the gastric epithelium were observed.     

Comparison of weight loss achieved after laparoscopic adjustable gastric banding between Afro-Caribbean,Caucasian and South Asian adult female patients in a London bariatric centre

Introduction

It has been shown that following laparoscopic adjustable gastric banding (LAGB) procedures, Afro-Caribbeans achieve poorer weight loss compared with Caucasians. The reasons for this are multifactorial. However, studies have been based on mainly female patients from the US and none to date have been from the UK. Furthermore, South Asians have not previously been compared. The aim of this study was to compare excess weight loss percentage (%EWL) outcomes up to five years following LAGB in Afro-Caribbean, Caucasian and South Asian females in a London-based teaching hospital.

Methods

An analysis was carried out of prospectively collected data of female patients aged ≥16 years of Afro-Caribbean, Caucasian or South Asian origin who underwent LAGB between October 2000 and December 2011. Data included demographics, co-morbidities and anthropometrics.

Results

Overall, 596 females underwent LAGB; 316 Caucasians (53.0%), 64 Afro-Caribbeans (10.8%) and 27 South Asians (4.5%) formed the majority of those who disclosed ethnicities. Age and initial body mass index (BMI) were comparable between Afro-Caribbeans and Caucasians (mean BMI: 47.3kg/m² [standard deviation [SD]: 7.5kg/m², range: 37.0–78.3kg/m²] vs 45.8kg/m² [SD: 7.1kg/m², range: 24.7–79.8kg/m²], p=0.225). A non-significant trend suggested less %EWL in Afro-Caribbeans than in Caucasians at 6 months, and at 1, 2, 3, 4 and 5 years (21.4% vs 24.4%, p=0.26; 27.4% vs 31.3%, p=0.27; 33.0% vs 36.8%, p=0.15; 39.0% vs 45.8%, p=0.14; 34.2% vs 45.3%, p=0.16; 37.1% vs 47.6%, p=0.67). South Asians and Caucasians had a similar age and preoperative BMI (mean BMI: 43.6kg/m² [range: 32.5–59.1kg/m²] vs 45.8kg/m² [range: 24.7–79.8kg/m²], p=0.08). The %EWL was greatest at three and four years among South Asians although numbers were small (n=4 and n=3 respectively).

Conclusions

A non-significant trend suggests poorer weight loss outcomes in Afro-Caribbeans compared with Caucasians in our cohort. Discussion of realistic weight loss outcomes as well as enhanced follow-up and dietary modifications are required for Afro-Caribbean patients. Low numbers prevent definitive conclusions regarding South Asians. Multicentre studies across England are required to better define any differences between ethnicities.     

Acute and long-term effects of massive balloon dilation on the aortic wall and vasa vasorum

To investigate the acute and long-term effects on the vasa vasorum after massive overdilation, canine aortic segments were dilated with Gruentzig balloon catheters to more than 100% over normal size. In the acute study, the significant lumen increase was the result of intimal and medial rupture with stretching and thinning of the adventitia. In these areas, the vasa vasorum were stretched and severed, causing adventitial hemorrhage. In the chronic study, areas of previous subtotal wall rupture with adventitial thinning were repaired by scar tissue. This repair included formation of a neomedia, hyperplasia of the adventitia, and proliferation of the vasa vasorum. No progression of luminal dilatation was seen. This study showed that in subtotal aortic wall rupture, even a severely damaged adventitia is capable of preserving the lumen from further dilatation and rupture until healing. Blood flow to the damaged vessel wall was reestablished by revascularization via capillary budding in the aortic wall.     

Systematic review and stratified meta-analysis of the efficacy of carnosine in animal models of ischemic stroke

Carnosine is a naturally occurring pleotropic dipeptide which influences multiple deleterious mechanisms that are activated during stroke. Numerous published studies have reported that carnosine has robust efficacy in ischemic stroke models. To further evaluate these data, we have conducted a systematic review and meta-analysis of published studies. We included publications describing in vivo models of ischemic stroke where the neuroprotective efficacy of carnosine was being evaluated through the reporting of infarct volume and/or neurological score as outcomes. Overall efficacy was evaluated using weighted mean difference random effects meta-analysis. We also evaluated for study quality and publication bias. We identified eight publications that met our inclusion criteria describing a total of 29 comparisons and 454 animals. Overall methodological quality of studies was moderate (median = 4/9). Carnosine reduced infarct volume by 29.4% (95% confidence interval (CI), 24.0% to 34.9%; 29 comparisons). A clear dose-response effect was observed, and efficacy was reduced when carnosine was administered more than 6 h after ischemia. Our findings suggest that carnosine administered before or after the onset of ischemia exhibits robust efficacy in experimental ischemic stroke. However, the methodological quality of some of the studies was low and testing occurred only in healthy young male animals.     

NCAM-induced intracellular signaling revisited

The neural cell adhesion molecule (NCAM) plays a crucial role in neuronal development, synaptic plasticity, and regeneration. NCAM works as "smart glue" that not only mediates cell-cell adhesion but also induces activation of a complex network of intracellular signaling cascades on homophilic or heterophilic binding. Stimulation of NCAM by homophilic interactions induces neuronal differentiation through activation of a number of signaling molecules, including the fibroblast growth factor receptor, non-receptor kinases Fyn and focal adhesion kinase, growth-associated protein-43, the mitogen-activated protein kinase pathway, intracellular Ca(2+), and protein kinases A, C, and G. This review presents and discusses the current knowledge in the area of NCAM signaling with a focus on the events involved in NCAM-mediated neurite outgrowth.     

Effectiveness of the ketogenic diet in a broad range of seizure types and EEG features for severe childhood epilepsies

Background –  Ketogenic diet (KD) is an effective treatment for pharmacoresistant epilepsy: more than half of the patients show a greater than 50% reduction in seizures.
Objective –  To identify clinical or electroencephalogram (EEG) variables predicting the response to KD.
Methods –  Clinical and EEG data were retrospectively analysed from 50 consecutive patients treated by KD for severe, pharmacoresistant epilepsy. Most of the patients (70%) had retarded mental and motor development.
Results –  Three months after the start of the KD two-thirds (33) of the patients were responders (had a more than 50% reduction in seizure frequency). The presence of epileptiform EEG discharges in the temporal region correlated with an unfavourable response ( P  = 0.03). The presence of bilateral synchronous epileptiform discharges, and the presence of complex partial seizures approached significance but all other variables did not.
Conclusions –  Our results further support that KD is efficient in a wide variety of epileptic patients with a broad range of EEG features. However, patients with epileptiform discharges in the temporal region are less likely to achieve therapeutic response.     

Individual differences in psychotic effects of ketamine are predicted by brain function measured under placebo

The symptoms of major psychotic illness are diverse and vary widely across individuals. Furthermore, the prepsychotic phase is indistinct, providing little indication of the precise pattern of symptoms that may subsequently emerge. Likewise, although in some individuals who have affected family members the occurrence of disease may be predicted, the specific symptom profile may not. An important question, therefore, is whether predictive physiological markers of symptom expression can be identified. We conducted a placebo-controlled, within-subjects study in healthy individuals to investigate whether individual variability in baseline physiology, as assessed using functional magnetic resonance imaging, predicted psychosis elicited by the psychotomimetic drug ketamine and whether physiological change under drug reproduced those reported in patients. Here we show that brain responses to cognitive task demands under placebo predict the expression of psychotic phenomena after drug administration. Frontothalamic responses to a working memory task were associated with the tendency of subjects to experience negative symptoms under ketamine. Bilateral frontal responses to an attention task were also predictive of negative symptoms. Frontotemporal activations during language processing tasks were predictive of thought disorder and auditory illusory experiences. A subpsychotic dose of ketamine administered during a second scanning session resulted in increased basal ganglia and thalamic activation during the working memory task, paralleling previous reports in patients with schizophrenia. These results demonstrate precise and predictive brain markers for individual profiles of vulnerability to drug-induced psychosis.