STAT4-associated natural killer cell tolerance following liver transplantation.

OBJECTIVE: Natural killer (NK) cells are important mediators of liver inflammation in chronic liver disease. The aim of this study was to investigate why liver transplants (LTs) are not rejected by NK cells in the absence of human leukocyte antigen (HLA) matching, and to identify a tolerogenic NK cell phenotype. DESIGN: Phenotypic and functional analyses on NK cells from 54 LT recipients were performed, and comparisons made with healthy controls. Further investigation was performed using gene expression analysis and donor:recipient HLA typing. RESULTS: NK cells from non-HCV LT recipients were hypofunctional, with reduced expression of NKp46 (p<0.05) and NKp30 (p<0.001), reduced cytotoxicity (p<0.001) and interferon (IFN)-γ secretion (p<0.025). There was no segregation of this effect with HLA-C, and these functional changes were not observed in individuals with HCV. Microarray and RT-qPCR analysis demonstrated downregulation of STAT4 in NK cells from LT recipients (p<0.0001). Changes in the expression levels of the transcription factors Helios (p=0.06) and Hobit (p=0.07), which control NKp46 and IFNγ expression, respectively, were also detected. Hypofunctionality of NK cells was associated with impaired STAT4 phosphorylation and downregulation of the STAT4 target microRNA-155. Conversely in HCV-LT NK cell tolerance was reversed, consistent with the more aggressive outcome of LT for HCV. CONCLUSIONS: LT is associated with transcriptional and functional changes in NK cells, resulting in reduced activation. NK cell tolerance occurs upstream of major histocompatibility complex (MHC) class I mediated education, and is associated with deficient STAT4 phosphorylation. STAT4 therefore represents a potential therapeutic target to induce NK cell tolerance in liver disease.

The influence of surgery on the onset of symptomatic coronary artery disease.

We speculated that asymptomatic patients undergoing routine surgery might be at higher risk of subsequent cardiac events. We studied 183,534 patients with no prior admission for heart disease, aged 50-75 years, admitted electively for one of five operations considered medium to low risk of peri-operative cardiac morbidity, between January 1997 and December 2005. Controls were generated from linked records. Within 3 years 3444 (1.9%) patients undergoing operations had subsequent myocardial infarction/acute coronary syndrome (MI/ACS) compared with 3708 (2.0%) controls (p < 0.001). Overall 8406 (4.6%) patients undergoing surgery had MI/ACS compared with 9306 (5.1%) controls (p < 0.001). Of patients undergoing surgery, 20.2% died compared with 25.7% of controls (p < 0.001). Patients undergoing certain surgical procedures did not have a higher incidence of readmission for cardiac events, but had a general survival benefit compared with other elective hospital admissions. Assessment for surgery may represent a health benefit beyond the original surgery.

Development, validation, and utilization of a novel antibody specific to the type III chicken gonadotropin-releasing hormone receptor.

Two gonadotropin-releasing hormone receptors (GnRH-Rs) have been characterized in chickens to date: cGnRH-R-I and cGnRH-R-III, with cGnRH-R-III being the predominant pituitary form. The purpose of the present study was to first validate a novel antibody for the specific detection of cGnRH-R-III and second, using this antibody, detect changes in cGnRH-R-III protein levels in the pituitary gland of male and female chickens during a reproductive cycle. The localization of cGnRH-R-III within the anterior pituitary gland was also determined. Western blotting of pituitary extracts and transiently transfected COS-7 cell lysates revealed that our antibody is highly specific to cGnRH-R-III protein. Similarly, when used in immunocytochemistry, this antibody specifically detects cells expressing cGnRH-R-III and not cGnRH-R-I. Western blot analyses of chicken pituitary gland homogenates show that cGnRH-R-III protein levels are significantly greater in sexually mature birds than in immature birds or birds at the end of a reproductive cycle (P < 0.0001). A similar pattern was observed for both males and females. Additionally, the antibody was able to detect cGnRH-R-III in cells along the periphery of the cephalic and caudal lobes of the anterior pituitary where the cells containing the gonadotropins are located. In summary, we successfully validated a novel antibody to cGnRH-R-III and showed levels of cGnRH-R-III protein in the pituitary fluctuate with respect to the reproductive status in both male and female chickens.

The Scottish Audit of Surgical Mortality: a review of areas of concern related to anaesthesia over 10 years.

The Scottish Audit of Surgical Mortality is a voluntary, peer reviewed, critical event analysis of patients who die under the care of consultant surgeons in acute hospitals in Scotland. The anaesthetic contribution to surgical mortality over a 10-year period from 1996 was reviewed. The total number of deaths was 44 230 or 1.5% of all admissions. Forty thousand, eight hundred and ninety-six deaths (92%) were audited. Deaths after elective surgery declined over 10 years. Over 80% of deaths followed emergency admission. The number of deaths where an anaesthetist was present was 16 981 or 0.6% of all admissions. Anaesthetic areas of concern were identified in 8% of deaths. Of these, 43% were related to pre-operative assessment. Anaesthesia also played a part in a further 18% of deaths where decision making was shared with the surgical team. Of these, 41% were related to access to critical care. A further 24% related to communication failures, principally when the operation should not have been done or was unnecessary.

Autism-like behavioral phenotypes in BTBR T+tf/J mice.

Autism is a behaviorally defined neurodevelopmental disorder of unknown etiology. Mouse models with face validity to the core symptoms offer an experimental approach to test hypotheses about the causes of autism and translational tools to evaluate potential treatments. We discovered that the inbred mouse strain BTBR T+tf/J (BTBR) incorporates multiple behavioral phenotypes relevant to all three diagnostic symptoms of autism. BTBR displayed selectively reduced social approach, low reciprocal social interactions and impaired juvenile play, as compared with C57BL/6J (B6) controls. Impaired social transmission of food preference in BTBR suggests communication deficits. Repetitive behaviors appeared as high levels of self-grooming by juvenile and adult BTBR mice. Comprehensive analyses of procedural abilities confirmed that social recognition and olfactory abilities were normal in BTBR, with no evidence for high anxiety-like traits or motor impairments, supporting an interpretation of highly specific social deficits. Database comparisons between BTBR and B6 on 124 putative autism candidate genes showed several interesting single nucleotide polymorphisms (SNPs) in the BTBR genetic background, including a nonsynonymous coding region polymorphism in Kmo. The Kmo gene encodes kynurenine 3-hydroxylase, an enzyme-regulating metabolism of kynurenic acid, a glutamate antagonist with neuroprotective actions. Sequencing confirmed this coding SNP in Kmo, supporting further investigation into the contribution of this polymorphism to autism-like behavioral phenotypes. Robust and selective social deficits, repetitive self-grooming, genetic stability and commercial availability of the BTBR inbred strain encourage its use as a research tool to search for background genes relevant to the etiology of autism, and to explore therapeutics to treat the core symptoms.

Reduced ultrasonic vocalizations in vasopressin 1b knockout mice.

The neuropeptides oxytocin and vasopressin have been implicated in rodent social and affiliative behaviors, including social bonding, parental care, social recognition, social memory, vocalizations, territoriality, and aggression, as well as components of human social behaviors and the etiology of autism. Previous investigations of mice with various manipulations of the oxytocin and vasopressin systems reported unusual levels of ultrasonic vocalizations in social settings. We employed a vasopressin 1b receptor (Avpr1b) knockout mouse to evaluate the role of the vasopressin 1b receptor subtype in the emission of ultrasonic vocalizations in adult and infant mice. Avpr1b null mutant female mice emitted fewer ultrasonic vocalizations, and their vocalizations were generally at lower frequencies, during a resident-intruder test. Avpr1b null mutant pups emitted ultrasonic vocalizations similar to heterozygote and wildtype littermates when separated from the nest on postnatal days 3, 6, 9, and 12. However, maternal potentiation of ultrasonic vocalizations in Avpr1b null and heterozygote mutants was absent, when tested at postnatal day 9. These results indicate that Avpr1b null mutant mice are impaired in the modulation of ultrasonic vocalizations within different social contexts at infant and adult ages.

M100,907, a selective 5-HT(2A) antagonist, attenuates dopamine release in the rat medial prefrontal cortex.

Previous research has suggested that serotonin 5-HT(2A) receptors modulate the functioning of the mesocortical dopamine (DA) pathway. However, the specific role of 5-HT(2A) receptors localized within the medial prefrontal cortex (mPFC) is not known. The present study employed in vivo microdialysis to examine the role of this receptor in the modulation of basal and K(+)-stimulated (Ca(2+)-dependent) DA release. The selective 5-HT(2A) antagonist M100,907 was infused directly into the mPFC of conscious rats. This resulted in a concentration-dependent blockade of K(+)-stimulated DA release. Intracortical application of M100,907 also blocked increases in DA release produced by the systemic administration of the 5-HT(2A/2C) agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). These findings demonstrate that local 5-HT(2A) antagonism has an inhibitory effect on stimulated, Ca(2+)-dependent DA release. They suggest that cortical 5-HT(2A) receptors potentiate the phasic release of mesocortical DA.

Prospective study of high dependency care requirements and provision.

BACKGROUND AND PURPOSE OF THE STUDY: To compare the level of post-operative care requested for surgical patients with that provided in a Scottish teaching hospital. METHODS: A three months pragmatic prospective observational study was undertaken which included patients undergoing major surgery excluding gynaecological and elective orthopaedic surgery. A study specific questionnaire was used to collate the information. The data were inputted to DataEase 4.5 and subsequently exported to SPSSWIN version 6.1.3 for analysis. The main outcome measure was the level of care requested and the level of care actually received. MAIN FINDINGS: Among 1363 patients a total of 1395 operations were performed. The median age was 59 years with a male: female ratio of 1.1:1. The type of admission was elective in 58% and emergency in 42% of cases. The operations were elective in 44% and nonelective in 56% of cases. The ASA score was 3 or greater in 33% of patients. The optimum level of care requested by surgeons and anaesthetists was intensive therapy unit (ITU) in 9.7% and high dependency unit (HDU) in 23.6% of patients. Twenty-one (15.9%) of 132 ITU requests and 256 (73.8%) of 349 HDU requests were not met immediately post-operatively. Overall mortality was 1.5%. For those patients who received optimum requested care mortality was 1.2% and, in those patients who did not receive optimum requested care, mortality was 3.1% (p < 0.038: Chi-square). CONCLUSION: This study confirms a significant lack of access to properly staffed and equipped HDU facilities in a major teaching hospital with a consequent increase in mortality in those not receiving optimal post-operative care.

Prediction of a small internal jugular vein by external jugular vein diameter.

The relationship between internal jugular vein diameter as measured with an ultrasound imaging machine (SiteRite, Dymax) and external jugular vein diameter was studied in 50 anaesthetised patients undergoing elective cardiac surgery. There was an inverse correlation between external jugular vein diameter and internal jugular vein diameter (r = -0.47, p < 0.001). All patients with an external jugular vein diameter of 7 mm or greater had an internal jugular vein diameter of less than 15 mm. No patient with an external jugular vein diameter of less than 7 mm had an internal jugular vein diameter of less than 20 mm. No other patient dimension (height, weight, body mass index, neck circumference) predicted internal jugular vein size. These results suggest that a large external jugular vein (i.e. 7 mm or greater in external diameter) may be associated with a small internal jugular vein. A size 5.0-mm internal diameter tracheal tube may be used to provide a rapid assessment of external jugular vein diameter.

Isoflurane for removal of chest drains after cardiac surgery.

Thirty-five patients who had undergone uncomplicated cardiac surgery were randomly allocated to receive either Entonox or isoflurane 0.25% in Entonox as inhalational analgesia for the removal of their two chest drains. The gases were presented premixed in high-pressure cylinders and were self-administered by means of a demand valve. The removal of the second drain was more painful than the first but that pain was better controlled by isoflurane 0.25% in Entonox than by Entonox alone.

Theatre usage for emergency surgery--use or abuse?

A prospective study was performed to characterise the activity in the designated Emergency Operating Theatre of a fourteen hundred bed teaching hospital. The main conclusion was that a large group of non-emergency but non-elective patients undergo surgery in this facility. The study has shown that in this hospital, despite apparently adequate emergency facilities including a separate orthopaedic trauma theatre, additional theatre time equivalent to six designated theatre sessions would be required to optimise the management of these patients who are often elderly and require major surgery.

DSP-4 treatment influences olfactory preferences of developing rats.

Control cagemates of rats treated with the norepinephrine (NE) neurotoxin DSP-4, showed normal olfactory learning as infants, but abnormal aversion to home-cage odors as juveniles. Neither age nor social housing conditions influenced the odor preferences of DSP-4-treated rats: they showed tolerance or attraction to familiar odors at both developmental stages. Controls, but not DSP-4-treated juveniles, housed in mixed treatment groups, showed elevated concentrations of a serotonin metabolite and reduced NE concentrations in the hippocampus, suggesting that this social situation was particularly stressful for the controls. DSP-4-treated juveniles, but not infants, produced odors that were discriminable from controls'. Thus, conflicting olfactory signals in the home-cages of mixed juvenile groups may have led to the development of stress in controls. NE depletion appeared to lessen social stress effects in their DSP-4-treated cagemates. These findings support other data suggesting that NE modulates the biobehavioral effects of the social environment.

Existence of a silent gene for pseudocholinesterase in a Trinidad population.

Although the values reported were higher than those reported for Caucasians, differences in dibucaine number for pseudocholinesterase values among the three ethnic groups in Trinidad and Tobago, were not significant. Eight individuals had intermediate dibucaine number values between 40 and 70; one of them was African, 3 were East Indians, and 4 Mixed. Two of the Mixed group were of Portuguese lineage and had significantly lower dibucaine numbers and enzyme concentration. Two sisters of East Indian origin had an inestimable dibucaine number and their pseudocholinesterase values were just detectable, suggesting the presence of a 'silent gene' for pseudocholinesterase. These studies, which are being extended, suggest that the dibucaine number should be estimated prior to succinylcholine administration in patients in Trinidad and Tobago who are at risk of apnoea.

Anaesthesia and the new generation monoamine oxidase inhibitors.

The new generation monoamine oxidase inhibitors are short acting and specific for monoamine oxidase A. Evidence to date suggests that there is little potential for significant interaction with most drugs used in anaesthesia.

Fibrous histiocytoma of the larynx.

Fibrous histiocytoma has a variable, unpredictable behaviour and potential for malignancy. The treatment of choice is wide local excision, which, in the larynx, entails total laryngectomy. A case of fibrous histiocytoma of the larynx, treated successfully by radiotherapy, is presented. A recurrence was treated with cryosurgery and the patient is well at 10-year follow-up. The pathological characteristics of fibrous histiocytoma and the difficulties of classification are reviewed.

Unsuspected factors in 'self-limiting' ailments.

An unsuspected subtotally perforated eardrum treated with wax softening drops shows how clinical findings do not always correlate with symptoms or history. Attention is drawn to the dilemma posed by delegating matters such as diagnosis and prescribing which have been considered to be purely in the medical sphere.