Vedolizumab: a review of its use in adult patients with moderately to severely active ulcerative colitis or Crohn's disease.

Vedolizumab (Entyvio™) is a humanized monoclonal antibody α4ß7 integrin-receptor antagonist indicated for the treatment of adult patients with moderately to severely active ulcerative colitis or Crohn's disease. This article reviews the pharmacological properties of intravenous infusions of vedolizumab and its clinical efficacy in adult patients with these diseases. In phase III clinical trials, patients with ulcerative colitis had significantly higher rates of clinical response and clinical remission when treated with vedolizumab than when receiving placebo at both 6 and 52 weeks. However, outcomes with vedolizumab in patients with Crohn's disease were mixed. In a study that evaluated both clinical remission rate and CDAI-100 response rate as primary endpoints, only the clinical remission rate at 6 weeks was significantly higher with vedolizumab than placebo. In another trial, there was no significant between-group difference in the clinical remission rate in TNF-antagonist failure patients at 6 weeks (primary endpoint), although there was a significant difference at 10 weeks. In the Crohn's disease study that included maintenance treatment, vedolizumab was significantly more effective at 52 weeks than placebo in both endpoints (clinical remission was the only primary endpoint in the maintenance study). Vedolizumab was generally well tolerated in these trials. As vedolizumab is a specific α4ß7 integrin antagonist, with gut-specific effects, it is unlikely to be associated with the development of progressive multifocal leukoencephalopathy, a risk observed with the less selective α4ß7/α4ß1 integrin antagonist natalizumab. Vedolizumab is a useful addition to the treatment options available for patients with moderately to severely active ulcerative colitis and Crohn's disease.

The natural history of eczema from birth to adult life: a cohort study.

BACKGROUND: Eczema is common in infancy; however, there is little evidence about its natural history to adulthood. OBJECTIVES: To study the natural history of eczema from birth to young adult life with particular reference to its relation to atopy. METHODS: A birth cohort of children with atopic family histories was followed for 23 years. Clinical examinations were conducted until the age of 7 years, skin-prick tests and serum total IgE were recorded in infancy and at ages 7 and 23 years, and questionnaires about eczema symptoms were completed at 15 and 23 years. RESULTS: Information was obtained on 497 subjects at birth, 482 at 1 year, 440 at 7 years, 363 at 15 years and 304 at 23 years. Eczema usually remitted from age 1 to 7 years but became more persistent from the age of 15 years, especially in those who were atopic. The prevalence of eczema rose in women from age 15 to 23 years but declined in men. Adults with eczema had higher IgE than those without at 3 months (geometric mean 3·0 vs. 1·7 kU L(-1); P=0·01), 7 years (107·9 vs. 45·2 kU L(-1); P=0·01) and 23 years (123·4 vs. 42·3 kU L(-1); P=0·01), and were more likely to have had positive skin-prick tests at 1 year of age. Current eczema was associated with raised IgE in infancy and adulthood but not in childhood. CONCLUSIONS: Predisposed infants and children with eczema usually grow out of the disease, but in adolescence it is more likely to persist. Adult eczema is related to atopy from the age of 3 months.

Immunoendocrine responses over a three week international rugby union series.

AIM: This study evaluated changes in immunoendocrine makers over an international series in professional rugby union players (N.=8). METHODS: Venous bloods were taken on camp-entry, as well as before and after (0, 14 and 38 h) two games spaced over 21-days. Samples were analysed for changes in serum C-reactive protein (CRP), cortisol (C), testosterone (T), blood leukocytes, interleukin 6 (IL-6) and creatine kinase (CK). RESULTS: Significant reductions in CK activity and CRP concentrations were evident on day 5 (pre-game 1) when compared to camp-entry (day 1); P<0.05. A large acute-phase response was observed following both games. Differences in the magnitude of this response appeared dependant on the number of collisions players experienced during play. Compared to camp-entry, sharp increases in C (40%) and decreases (37%) in T were evident after both games; P<0.05. A gradual increase in T/C ratio was observed throughout the tournament; values 35% and 45% higher on days 19 and 21 than those observed at camp-entry (P<0.05). CONCLUSION: Current data suggests that improved physiological recovery can be achieved during an international rugby union series. Monitoring of previous club activity is essential to ensure optimal player readiness prior to participation in international rugby union games.

Workers' exposure to dust, endotoxin and ß-(1-3) glucan at four large-scale composting facilities.

OBJECTIVES: To characterise compost workers' exposure to dust, endotoxin and ß-(1-3) glucan during various operational practices and investigate whether dust concentrations are a useful indicator of endotoxin exposure in compost workers. METHODS: This study assessed inhalable dust fractions, bacterial endotoxin and ß-(1-3) glucan in 117 personal samples and 88 ambient samples from four large-scale composting facilities. RESULTS: Employees' exposures to inhalable dust, endotoxin and ß-(1-3) glucan exhibited a large range. Inhalable dust was found to be generally low (GM 0.99 mg/m(3), GSD 2.99 mg/m(3)). Analysis of the biological component of the dust showed that employees' exposures to endotoxin were elevated (GM 35.10 EU/m(3), GSD 9.97 EU/m(3)). Employees' exposure to ß-(1-3) glucan was low (GM 0.98 ng/m(3), GSD 13.39 ng/m(3)). Dust levels were elevated during manual sorting and screening of waste and high levels of endotoxin and ß-(1-3) glucan were observed during all practices involving the movement of waste. A significant correlation was observed between the personal dust levels and personal endotoxin concentrations (r=0.783, p<0.05) and that personal inhalable dust concentration may be a valuable predictor for personal endotoxin concentration in the sites studied. CONCLUSIONS: Workers at composting sites are exposed to high levels of bacterial endotoxin consistent with adverse respiratory outcomes even though in most cases, their personal dust exposure is below the suggested regulatory levels. Dose-response data for the biological components present in the dust encountered at composting sites are not well established at this time and site operators should adopt precautionary measures when assessing and managing these potential risks.

DPPC regulates COX-2 expression in monocytes via phosphorylation of CREB.

The major phospholipid in pulmonary surfactant dipalmitoyl phosphatidylcholine (DPPC) has been shown to modulate inflammatory responses. Using human monocytes, this study demonstrates that DPPC significantly increased PGE(2) (P<0.05) production by 2.5-fold when compared to untreated monocyte controls. Mechanistically, this effect was concomitant with an increase in COX-2 expression which was abrogated in the presence of a COX-2 inhibitor. The regulation of COX-2 expression was independent of NF-kappaB activity. Further, DPPC increased the phosphorylation of the cyclic AMP response element binding protein (CREB; an important nuclear transcription factor important in regulating COX-2 expression). In addition, we also show that changing the fatty acid groups of PC (e.g. using l-alpha-phosphatidylcholine beta-arachidonoyl-gamma-palmitoyl (PAPC)) has a profound effect on the regulation of COX-2 expression and CREB activation. This study provides new evidence for the anti-inflammatory activity of DPPC and that this activity is at least in part mediated via CREB activation of COX-2.

Depletion of ovarian follicles with age in chimpanzees: similarities to humans.

We retrieved ovarian sections taken from necropsies of 19 captive chimpanzees (Pan troglodytes) aged 0-47 yr, counted the number of primordial follicles in each, and compared the rate of decline in numbers to declines previously documented in humans. The follicular depletion rate in this sample was indistinguishable from that shown across the same ages in classic human data sets. This result supports earlier suggestions that ovarian senescence occurs at the same ages in chimpanzees and humans, implying that the influence of declining ovarian function on other physiologic systems may be distinctively buffered in humans.

Role of leucocytes in damage to the vascular endothelium during ischaemia-reperfusion injury.

During this investigation, a model of tourniquet-induced forearm ischaemia-reperfusion injury is employed to investigate the role of leucocytes in damage to the vascular endothelium during ischaemia-reperfusion injury. Leucocyte entrapment is investigated by measuring the concentration of leucocytes in venous blood leaving the arm. Neutrophil and monocyte leucocyte subpopulations are isolated by density gradient centrifugation techniques. Cell surface expression of CD11b and the intracellular production of hydrogen peroxide are measured via flow cytometry. Plasma concentrations of elastase and von Willebrand factor (vWF) are measured using enzyme-linked immunosorbemt assay (ELISA) techniques. During ischaemia-reperfusion, there was an increase in CD11b cell surface expression on neutrophils (P=0.040) and monocytes (P=0.049), and a decrease in peripheral blood leucocytes (P=0.019). There was an increase in the intracellular production of hydrogen peroxide by leucocyte subpopulations (P=0.027 [neutrophils], P=0.091 [monocytes]) and in the plasma elastase concentration (P=0.05). There was also a trend to increasing plasma concentration of vWF (P=0.0562), which was measured as a marker of endothelial damage. Ischaemia-reperfusion results in increased adhesiveness, entrapment and activation of leucocytes. Even following a mild ischaemic insult, this leucocyte response was followed immediately by evidence of endothelial damage. These results may have important implications for understanding the development of chronic diseases that involve mild ischaemic episodes.

Sperm chromosome aneuploidy as related to male factor infertility and some ultrastructure defects.

Some men have elevated levels of sperm chromosome aneuploidy. In this study, we have evaluated and summarized sperm aneuploidy rates in male infertility patients and control groups. The mean aneuploidy rate for five chromosomes (X, Y, 13, 18, 21) was 1.2 +/- 0.1 for fertile controls, 1.4 +/- 0.1 for a general population control group, and 5.8 +/- 1.14 for the patients. When the patients were classified by the type of male factor infertility, the total aneuploidy rate was 2.6 +/- 0.3 in men with moderately diminished semen quality (n = 7), 4.0 +/- 0.3 patients with severe teratoasthenooligozoospermia, and 15.9 +/- 3.8 for men with rare ultrastructure defects such as round head only syndrome or severe tail agenesis. Some infertility patients have a severely elevated level of sperm chromosome aneuploidy, which may contribute to infertility or diminish the likelihood of a successful outcome from IVF/ICSI. The severity of sperm chromosome aneuploidy appears to be proportional to the severity of abnormal semen quality: in particular, abnormal morphology. The high rates of aneuploidy in patients with severe ultrastructure defects suggest that caution should be employed in counseling those patients prior to IVF/ICSI.

Human leucocyte antigen polymorphisms in nut-allergic patients in South Wales.

BACKGROUND: Peanuts and tree nuts are among the most common foods provoking severe allergic reactions including fatal anaphylaxis. However, little is known of the underlying genetic and immunological mechanisms involved. OBJECTIVE: Based on findings in other allergic diseases, we have investigated whether specific human leucocyte antigens (HLA) are associated with nut allergy. METHOD: Eighty-four patients presenting at the allergy clinic with symptoms of nut allergy were typed for the HLA Class I (HLA-A and B) and Class II (HLA-DRB1 and DQB1) loci by PCR using sequence-specific primers. Carriage frequencies were compared with 82 atopic non-nut-allergic subjects and 1798 random blood donors. RESULTS: The frequency of HLA-B(*)07 (28.57%) and DRB1(*)11 (15.48%) was increased in the nut-allergic patients compared to the atopic controls (12.20% and 3.66%, respectively) but not when compared to the blood donors (28.86% and 10.12%). DRB1(*)13 and DQB1(*)06 were both increased in frequency in the nut allergy patients over both the atopic and blood donor controls. However, none of these increased frequencies were significant when corrected for the number of comparisons undertaken. CONCLUSION: At HLA '2-digit resolution' and with undifferentiated patients with nut allergy, there are no major disturbances in the frequency of HLA-A, B, DRB1 or DQB1 types. However, the difference in frequency of HLA-DRB1(*)11 between the nut allergy patients and the atopic controls merits further investigation as this may represent an important phenotypic relationship.

Honey stimulates inflammatory cytokine production from monocytes.

Clinical observations indicate that honey may initiate or accelerate the healing of chronic wounds and has, therefore, been claimed to have anti-inflammatory properties. The aim of this study was to investigate the effects of honey on the activation state of immunocompetent cells, using the monocytic cell line, MonoMac-6 (MM6), as a model. We investigated the effect of each of the three honeys (manuka, pasture and jelly bush) on the release of important inflammatory cytokines from MM6 cells. These honeys, together with a sugar syrup control (artificial honey), were incubated with MM6 cells at a concentration of 1% (w/v) for 0-24h. Cell culture supernatants were tested using specific ELISA assays for tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta and IL-6. All honeys significantly increased the TNF-alpha, IL-1beta and IL-6 release from MM6 cells (and human monocytes) when compared with untreated and artificial-honey-treated cells (P<0.001). Jelly bush honey significantly induced the maximal release of each cytokine compared with manuka, pasture or artificial honeys (P<0.001). These results suggest that the effect of honey on wound healing may in part be related to the stimulation of inflammatory cytokines from monocytic cells. Such cell types are known to play an important role in healing and tissue repair.

Sperm DNA fragmentation is increased in couples with unexplained recurrent pregnancy loss.

Previous studies have indicated that sperm quality may be related to unexplained recurrent pregnancy loss. This study evaluated the degree of sperm DNA fragmentation using the TUNEL assay on sperm from 24 couples with unexplained recurrent pregnancy loss (RPL) compared to sperm from 2 control groups: donors of known fertility and unscreened men from the general population. The percentage of sperm staining positive for DNA fragmentation was increased (p < .001) in the RPL group (38 +/- 4.2) compared to the donor (11.9 +/- 1.0) or general population (22 +/- 2.0) control groups. In the RPL group, no correlation was observed between semen quality parameters and the TUNEL data. These data indicate that some RPL patients have a significant increase of sperm DNA fragmentation, which may be causative of pregnancy loss in some patients.

Polymorphism in the STAT6 gene encodes risk for nut allergy.

Nut allergy is an important and potentially life threatening food allergy with a prevalence of one in 150 children in the UK population. STAT6 (signal transducer and activator of transcription) is an important molecule in the induction and regulation of an allergic response, which maps to chromosome 12q in a region previously linked with total serum IgE concentration and atopy in different populations. We have examined the frequency of a single nucleotide polymorphism (SNP) in the 3'UTR region of STAT6 gene in 71 UK Caucasoid patients diagnosed with nut allergy and 45 atopic patients without nut allergy using PCR-RFLP and compared these with 184 UK healthy controls. The STAT6 G allele frequency was significantly increased in nut allergy patients compared with blood donor controls (P < 0.0001, OR = 2.9, 95% CI: 1.7-4.9), which was under a recessive model (GG vs GA+AA, P = 0.0001, OR = 3.2, 95% CI: 1.7-5.8) but not in atopic patients without nut allergy. The G allele was most frequent in the severe cases and GG homozygosity was associated with the increased risk of severe reaction (OR = 3.9, 95% CI: 1.9-8.3). We conclude that STAT6 3'UTR polymorphism is associated with susceptibility and severity in nut allergic patients in our population.

Stimulation of TNF-alpha release in monocytes by honey.

Although evidence exists for the antibacterial effects of honey there is limited objective evidence for direct promotion of healing. We investigated the effect of manuka, pasture and an artificial honey on macrophage function. Reactive oxygen intermediate (ROI) production was assessed by luminol enhanced chemoluminescence and tumour necrosis factor-alpha (TNF-alpha) release was determined by immunoassay. ROI production was significantly (P<0.001) decreased by pasture honey and manuka honey. TNF-alpha release was significantly enhanced (P<0.001) in unprimed MM6 cells by manuka and pasture honey but was not altered in primed cells. These results could explain the suggested therapeutic properties of honey in promoting wound healing.

Dipalmitoylphosphatidylcholine modulates inflammatory functions of monocytic cells independently of mitogen activated protein kinases.

Phosphatidylcholine (PC) is the major phospholipid of pulmonary surfactant and it is hypothesized that PC and its subspecies modulate the functions of alveolar macrophages. The most abundant of these subspecies is dipalmitoylphosphatidylcholine (DPPC). This study was undertaken to determine the effect of PC on monocyte function using a human monocytic cell line, MonoMac-6 (MM6). This study showed that preincubation of MM6 cells with DPPC at 125 microg/ml for 2 h inhibited the oxidative response to either zymosan or phorbol-12-myristate-13-acetate (PMA) by 30% (P < 0.001). This inhibition with DPPC was independent of LPS priming. When DPPC was replaced with 1-palmitoyl-2-arachidonoyl phosphatidylcholine (PAPC) there was no inhibition and in contrast a significant increase in oxidant production was observed. We also demonstrated that total PC (tPC; a heterogeneous species of PC from egg) and DPPC but not PAPC significantly inhibited the release of TNF-alpha from MM6 cells (P < 0.05). DPPC did not inhibit phosphorylation of the mitogen activated protein kinases (MAPKs) p44/p42 or p38 in stimulated cells. Measurements of membrane fluidity with spin label EPR spectroscopy indicate that DPPC incorporation significantly alters the membrane fluidity of MM6 cells. These results suggest that DPPC, the major component of pulmonary surfactant, may play a role in modulating leucocyte inflammatory responses in the lung. This may in part be related to membrane effects but does not include alterations in p44/p42 or p38 MAPK signalling.

Prostaglandin E(2) and tumour necrosis factor-alpha release by monocytes are modulated by phospholipids.

The regulation of pro- and anti-mediator release from cells within the alveolar space would represent a desirable mechanism serving to protect this delicate gas-exchanging region of the lung. This study investigates the effect of alveolar surfactant lipids on the regulation of tumour necrosis factor alpha (TNF-alpha), a potent inflammatory cytokine, and prostaglandin E(2)(PGE(2)), a lipid mediator with anti-inflammatory properties. The results of this investigation reveal a marked effect on the release of these two important mediators from a monocytic cell line, MonoMac 6 (MM6), by phosphatidylcholine (PC), phosphatidylethanolamine (PE), cholesterol (Chol) and sphingomyelin (SM). PC, PE and Chol demonstrated marked downregulation of TNF-alpha production at lipid concentrations of 125 and 250 microg/ml. Interestingly, SM significantly up regulated the release of TNF-alpha at these concentrations. However, the release of PGE(2)in MM6 cells incubated with the same lipids was significantly increased with PC and Chol, and significantly decreased in cells pre-treated with SM. This indicates a role for these lipids in alveolar immunoregulation.

Demographic characteristics and primary health care utilization patterns of strictly orthodox Jewish and non-Jewish patients.

BACKGROUND: The importance of providing health care services that are acceptable to different cultural groups is widely acknowledged. Strictly orthodox Jewish communities have particular health care needs that reflect their religious teaching and beliefs. OBJECTIVE: To describe the demographic characteristics and health care usage patterns of the strictly orthodox Jewish population of Gateshead. METHODS: Registration and claims data were used in combination with encounter data from computerized and manual practice records. Jewish patients were identified and comparisons made between Jewish and non-Jewish populations registered at the same practices. RESULTS: The orthodox Jewish population was predominantly young (69% aged under 20). The birth rate in orthodox Jewish women aged 20-44 was much higher (294 per 1000) than non-Jewish women. Rates of uptake of cervical screening and childhood immunizations were significantly lower in the orthodox Jewish population. Uptake of breast screening and attendance at diabetic clinics did not differ significantly. The average number of consultations and home visits per annum was higher in Jewish than in non-Jewish patients. CONCLUSIONS: The demographic and health care utilization patterns of orthodox Jewish and non-Jewish patients in Gateshead are different. There are implications for the provision of primary care services, particularly with regard to preventative health care.

Seasonal variation in interleukin 4 in patients with hayfever.

This study was performed to investigate the value of interleukin 4 as a marker of activity in mild atopic disease. We compared IL-4 levels to eosinophil cationic protein (ECP), a suggested inflammatory marker in allergic disease, in patients with hayfever. Patients with hayfever were assessed during January and then in late June at the height of the grass pollen season, and their levels of serum ECP and IL-4 compared. Serum ECP was determined by radio-immunoassay and serum IL-4 by a high-sensitivity enzyme-linked immunosorbent assay. ECP was found to increase significantly in patients with hayfever during the grass pollen season (P<0.01). Conversely, serum levels of IL-4 were found to decrease significantly over the same period when compared with winter values. ECP and IL-4 were not seen to correlate significantly with each other. The fall in serum IL-4 seen during the grass pollen season in the hayfever patients may reflect allergen driven upregulation of membrane IL-4 receptor expression or sequestration of cytokine producing cells to inflammatory sites. These findings suggest that serum IL-4 is a poor indicator of inflammatory status in allergic disease.