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.

Hyperkalemic periodic paralysis and the adult muscle sodium channel alpha-subunit gene.

Hyperkalemic periodic paralysis (HYPP) is an autosomal dominant disorder characterized by episodes of muscle weakness due to depolarization of the muscle cell membrane associated with elevated serum potassium. Electrophysiological studies have implicated the adult muscle sodium channel. Here, portions of the adult muscle sodium channel alpha-subunit gene were cloned and mapped near the human growth hormone locus (GH1) on chromosome 17. In a large pedigree displaying HYPP with myotonia, these two loci showed tight linkage to the genetic defect with no recombinants detected. Thus, it is likely that the sodium channel alpha-subunit gene contains the HYPP mutation.

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.

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.

Multiple myeloma in Jamaica: a study of 40 cases with special reference to the incidence and laboratory diagnosis.

For two years protein abnormality was studied in 40 cases of myelomatosis in Jamaica. Thirty-nine of these were in West Indian Negroes. The minimum incidence of myelomatosis in this group was estimated to be of the order of 50 cases per million per annum which is considerably higher than in Caucasians as reported by previous workers. A larger number showed myeloma protein with beta-globulin mobility and hypogammaglobulinaemia than with gamma-globulin mobility. As in the Caucasians the disease is more common in men than in women and the age incidence in both seems to be the same. Combined serum and urinary electrophoresis was diagnostic in every case, and examination of the urine for Bence-Jones protein by electrophoresis yielded more consistent findings than the classical heat test. It is suggested that combined serum and urine electrophoresis should be done in all cases of suspected myelomatosis.

Waldenström type macroglobulinaemia in a Nigerian with rheumatoid arthritis.

Waldenström type macroglobulinaemia has been found in a Nigerian woman with rheumatoid arthritis and cryoglobulinaemia. Twenty-nine per cent. of the total serum proteins were macroglobulins, consisting of 27% 19 S and 2% 29 S. Agglutination tests for rheumatoid arthritis were positive.

Immunoglobulins in Jamaicans and Nigerians with immunogenetic typing of myeloma and lymphoma in Jamaicans.

Serum IgG concentration was lower in Jamaicans than in Nigerians. The maternalfoetal IgG ratio was also lower in Jamaican sera than in Nigerian sera. It is suggested that endemic malaria in Nigeria may be responsible for these differences. The higher IgM concentration in the Nigerian cord sera may be further evidence of this. Eighteen new cases of myeloma were detected in Jamaicans between August 1966 and May 1967. Based on Gm typing, only two of these showed evidence of mixed white ancestry. All the others had the typical Gm groups of Negroes. Similarly, only two patients out of a total of 17 with malignant lymphoma showed evidence of mixed white ancestry. Twelve of the patients with myeloma showed serum proteins of the IgG type, five were IgA, and one had only light chains in the serum. The majority of the patients had myeloma protein of the kappa type. The Gm typing suggested that six patients had myeloma protein of the gamma1 heavy chain subclass, and one patient had a gamma3 subclass heavy chain, the remainder belonging most likely to the gamma2 heavy chain subclass since gamma2 occurs about four times as frequently as gamma4.

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.

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.

A study of enocrine function in protein-energy malnutrition.

Serum concentration of cortisol, growth hormone, thyroxine, thyroid stimulating hormone, follicle stimulating hormone and luteinising hormone, together with triiodothyronine uptake have been measured in Nigerian children with kwashiorkor and marasmus and compared with controls. In both types of malnutrition the cortisol and growth hormone concentrations are raised, whereas those of thyroxine and thyroid stimulating hormone are lowered compared with the controls. Triiodothyronine uptake is lowered in malnutrition but there is no apparent effect on follicle stimulating hormone or luteinising hormone in this age group.

Specific protein assays in protein-calorie malnutrition.

Assessment of serum protein concentrations in protein-calorie malnutrition was carried out by two specific immunochemical methods, the Single Radial Immunodiffusion technique and the Automated Immunonephelometric procedure. The correlation coefficient (r) between the two methods was above 0.85 for all the serum proteins assayed. The automated nephelometric assay procedure has the advantages that it is rapid and that a large number of samples can be readily processed. The system in its present form could not be readily used to quantitate proteins such as prealbumin whose serum concentration was less than 50 mg/100 ml. The single radial immunodiffusiton technique gave more consitent results for IgA estimation than the automated technique. With the exception of C4 and the immunoglobulins, all the serum proteins assayed were lower in children with protein-calorie malnutrition than in control children. During refeeding in children with protein-calorie malnutrition the first serum protein to show a significant rise was C3. This was followed by transferin, then prealbumin and lastly albumin. C4 did not show any significant change. In experimental protein-calorie malnutrition in rats, the first serum protein to show a significant reduction was C3. This was followed by transferrin and then albumin. On refeeding the rats these serum proteins returned to normal values in the same order.

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.

Studies of lipoproteins and fatty acids in maternal and cord blood of two racial groups in Trinidad.

The high mortality rate from coronary heart disease (CHD) among Indians compared to Negroes in Trinidad led us to test plasma lipid profiles to see whether dietary or genetic factors might be involved. There were no interracial differences in the composition of plasma cholesterol ester fatty acids of the tested women and neonates. This finding suggests that dietary fat does not account for the interracial difference in CHD, nor does the cause appear to be due to genetic differences in lipid profiles, as there was no significant difference between values for plasma triglycerides, total cholesterol, high density lipoprotein (HDL) cholesterol, apo-I, apo-II, apo B or cholesterol ester fatty acids in the cord blood of each racial group. Blood samples were collected from 69 nonpregnant and 71 postpartum, fasted Negro and Indian women. Also taken were 71 umbilical cord blood samples. The mean triglyceride level was significantly lower in the Negro nonpregnant and postpartum women than in the Indians. HDL cholesterol and apo-I values were lower in the Indian women. There were no significant differences in the total cholesterol and apo B measurements. The triglyceride values for postpartum women were higher than those of the nonpregnant Negroes and Indians (75% and 47%, respectively), whereas the total cholesterol and HDL cholesterol, apo A-I and apo A-II ranged from 9% to 29% higher in the postpartum women. Apo B was about 40% higher postpartum in both ethnic groups. The high CHD rate of Indians in Trinidad cannot be explained by dietary factors, plasma total cholesterol or fatty acid composition.(ABSTRACT TRUNCATED AT 250 WORDS)

Unusual cause of intranasal injury.

Intranasal injury without external involvement is not common. To our knowledge this is the first reported case of such an injury, caused by an assailant's two fingers forced up the nostrils of our patient causing severe mucosal laceration and excessive bleeding. The patient died two weeks later.

ACTH--inosine pranobex in the treatment of AIDS. Encouraging results.

Twenty patients with Acquired Immune Deficiency Syndrome (AIDS) received treatment with Inosine Pranobex and specific antibacterial and anti-parasitic therapy. Five died shortly after hospitalization, but a further fifteen who also received ACTH, survived, gained weight and improved clinically, biochemically and haematologically.

Sick sinus syndrome and primary systemic amyloidosis.

A sixty-eight-year-old woman with documented sick sinus syndrome was found to have, five year later, florid clinical features of systemic amyloidosis which only then led to recognition of an underlying IgA, Kappa paraproteinaemia. The literature on this association is outlined. Underlying plasma cell dyscrasias should be excluded in cases of unexplained sick sinus syndrome.

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.

Malignant carcinoid syndrome. Failure of anti-oestrogenic therapy.

A pre-menopausal patient with a six-year history of symptoms of the metastatic carcinoid syndrome leading to progressively worsening carcinoid heart disease is described. The failure of anti-oestrogenic therapy (sequential bilateral oophorectomy and Tamoxifen therapy) to halt progression of disease was documented. Death resulted from right ventricular failure associated with pulmonary and tricuspid valvular disease.

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.