Differential role of MyD88 and Mal/TIRAP in TLR2-mediated gastric tumourigenesis.

Signalling by the toll-like receptor (TLR) family of pathogen recognition receptors has emerged as a key molecular component in the pathogenesis of an increasing number of inflammatory-related cancers, among which gastric cancer rates as the second most lethal cancer world-wide. The myeloid differentiation factor 88 (MyD88) adapter molecule has a critical role in mediating innate immune signalling by members of the TLR and interleukin (IL)-1 families, and has been associated with either pro- or antitumourigenic responses in various cancer models. However, little is known about the in vivo role of MyD88 adapter-like (Mal)/TIR-domain containing adapter protein (TIRAP), which is restricted to facilitating TLR4 and TLR2 signalling. To interrogate the role of these innate immune signalling components in gastric tumourigenesis, here we have employed the spontaneous gastric cancer gp130(F/F) mouse model, in which TLR2 promotes the growth of gastric tumours. Genetic ablation of Myd88 in gp130(F/F) mice suppressed tumourigenesis and was associated with increased apoptosis and reduced proliferation in the gastric tumour epithelium, comparable to that observed previously upon deletion of Tlr2 in gp130(F/F) mice. By contrast, the tumour burden in gp130(F/F):Mal(-/-) mice was equivalent to their gp130(F/F) littermates. At the molecular level, suppressed tumourigenesis in gp130(F/F):Myd88(-/-) mice correlated with reduced expression and activation of TLR2-regulated protumourigenic genes and signalling pathways, respectively. Consistent with the previously defined non-essential role for TLR2 in gastric tumour inflammation, the extent of inflammatory cell infiltrates in gastric tumours from gp130(F/F):Mal(-/-) and gp130(F/F):Myd88(-/-) mice remained unaltered compared with gp130(F/F) mice. Collectively, our data reveal a differential, but inflammation-independent, requirement for Mal and MyD88 during TLR2-promoted gastric tumourigenesis.

N-ethyl-N-nitrosourea (ENU) mutagenesis and male fertility research.

Male infertility affects about 1 in 25 men in the western world. Conversely, there is an urgent requirement for additional male-based contraceptives, yet progress in both areas has been severely hampered by a lack of knowledge of the biochemistry and physiology of male reproductive function. It is only through a thorough knowledge of these processes that we can hope to insightfully regulate male reproductive function. Without doubt, mouse models will form an important foundation in any future process. In recent years, the chemical mutagen N-ethyl-N-nitrosourea (ENU) has been used widely to identify genes essential for a range of biological systems including male infertility. These studies have shown random mutagenesis is an attractive means of identifying key genes for male fertility. This technique has distinct, but complementary advantages compared to knockout technologies. Specifically, it allows the removal of researcher bias whereby only pre-conceived genes are tested for function; it produces mice with a guaranteed phenotype and allows for the production of allelic series of mice to dissect all aspects of gene function. ENU mouse mutagenesis programs will enable advances in the diagnosis and treatment of human male infertility and ultimately aid in the development of novel male-based contraceptives.

A repository of ENU mutant mouse lines and their potential for male fertility research.

Many of the proteins and their encoding genes involved in spermatogenesis are unknown, making the specific diagnosis and treatment of infertility in males difficult and highlighting the importance of identifying new genes that are involved in spermatogenesis. Through genome-wide chemical mutagenesis using N-ethyl-N-nitrosourea (ENU) and a three-generation breeding scheme to isolate recessive mutations, we have identified mouse lines with a range of abnormalities relevant to human male fertility. Abnormal phenotypes included hypospermatogenesis, Sertoli cell-only (SCO) seminiferous tubules, germ-cell arrest and abnormal spermiogenesis and were accompanied, in some, with abnormal serum levels of reproductive hormones. In total, from 65 mouse lines, 14 showed a reproductive phenotype consistent with a recessive mutation. This study shows that it is feasible to use ENU mutagenesis as an effective and rapid means of generating mouse models relevant to furthering our understanding of human male infertility. Spermatozoa and genomic DNA from all mouse lines, including those with abnormal reproductive tract parameters, have been cryopreserved for the regeneration of lines as required. This repository will form a valuable resource for the identification and analysis of key regulators of multiple aspects of male fertility.

Chronic fatigue syndrome: sociodemographic subtypes in a community-based sample.

Most chronic fatigue syndrome (CFS) studies are based on information about patients from primary or tertiary care settings. These patients might not be typical of patients in the general population. This investigation involved examinations of individuals with CFS from a community-based study. A random sample of 18,675 in Chicago was interviewed by telephone. Individuals with chronic fatigue and at least four minor symptoms associated with CFS were given medical and psychiatric examinations. A group of physicians then diagnosed individuals with CFS, who were then subclassified based on three sociodemographic categories--gender, ethnicity, and work status. Sociodemographic subgroups were analyzed in terms of symptom severity, functional disability, coping, optimism, perceived stress, and psychiatric comorbidity. Women, minorities, and nonworking individuals with CFS reported greater levels of functional disability, symptom severity, and poorer psychosocial functioning than men, Caucasians, and working individuals, suggesting sociodemographic characteristics may be associated with poorer outcomes in urban, community-based samples of CFS individuals.

Chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivities in a community-based sample of persons with chronic fatigue syndrome-like symptoms.

OBJECTIVE: The aim of this study was to determine illness comorbidity rates for individuals with chronic fatigue syndrome (CFS), fibromyalgia (FM), and multiple chemical sensitivities (MCS). An additional objective was to identify characteristics related to the severity of fatigue, disability, and psychiatric comorbidity in each of these illness groups. METHODS: A random sample of 18,675 residents in Chicago, Illinois, was first interviewed by telephone. A control group and a group of individuals with chronic fatigue accompanied by at least four minor symptoms associated with CFS received medical and psychiatric examinations. RESULTS: Of the 32 individuals with CFS, 40.6% met criteria for MCS and 15.6% met criteria for FM. Individuals with MCS or more than one diagnosis reported more physical fatigue than those with no diagnosis. Individuals with more than one diagnosis also reported greater mental fatigue and were less likely to be working than those with no diagnosis. Individuals with CFS, MCS, FM, or more than one diagnosis reported greater disability than those with no diagnosis. CONCLUSIONS: Rates of coexisting disorders were lower than those reported in prior studies. Discrepancies may be in part attributable to differences in sampling procedures. People with CFS, MCS, or FM endure significant disability in terms of physical, occupational, and social functioning, and those with more than one of these diagnoses also report greater severity of physical and mental fatigue. The findings illustrate differences among the illness groups in the range of functional impairment experienced.

Chronic fatigue syndrome: occupation, medical utilization, and subtypes in a community-based sample.

Most studies of chronic fatigue syndrome (CFS) have been based on patients recruited from primary or tertiary care settings. Patients from such settings might not be typical of patients in the general population. The present investigation involved examining individuals with CFS from a community-based study. A random sample of 18,675 respondents in Chicago was first interviewed by telephone. A group of individuals with chronic fatigue accompanied by at least four minor symptoms associated with CFS were given medical and psychiatric examinations. From this sample, a physician review group diagnosed individuals with CFS. Those diagnosed with CFS were subclassified based on a variety of categories, including duration of illness, mode of illness onset, and presence or absence of a stressful life event directly preceding onset. In addition, we examined medical utilization among those diagnosed with CFS, as well as whether individuals with CFS were disproportionately represented in health care professions. Important differences emerged on measures of sociodemographics, symptoms, and functional disability. The implications of these findings and others are discussed.

Yeast alcohol dehydrogenase bound to membranes: surface and microenvironment effects on activity and stability.

The enzyme, yeast alcohol dehydrogenase, was adsorbed to porous nitrocellulose and nylon membranes. The two membranes provide different surface chemistries as indicated by the results of the streaming potential, enzyme adsorption, and fluorescein isothiocyanate adsorption experiments. The stability of the enzyme, as determined by continually measuring the extent of coenzyme reduction as a function of time, appeared to be much less for the enzyme adsorbed to the positively charged membrane surface. Moreover, the enzyme adsorbed to the positively charged membrane was the least responsive to pulses of the reducing agent, dithiothreitol, and appeared to exhibit the highest transition temperature when subjected to differential scanning calorimetry analysis. These results indicate that the entropically spreading process observed for other adsorbed proteins may be occurring and the process is more rapid and extensive when enzyme is adsorbed to the nylon than the nitrocellulose membrane. In addition to the relative stability of the enzyme on two different surfaces being examined, the effect of the microenvironment on modulating the activity of the enzyme was investigated by using the reversibility of the enzyme-catalyzed reaction as a probe of the average local environment of the enzyme. It was found that a threshold buffer concentration existed that, once exceeded, the effect of proton production by the reaction could be suppressed.

The use of myocutaneous flaps following radical excision of the external genitalia.

Myocutaneous and fascio-cutaneous flaps have enabled single stage combined surgical resections and reconstructive procedures to be carried out for locally advanced, non-metastatic carcinoma of the external genitalia. The need for delayed repair procedures with their associated morbidity and prolonged hospital stay is minimised. Functional loss resulting from the removal of the supporting muscle is rarely a problem.

The significance of scrotal interference in stage I testicular cancer managed by orchiectomy and surveillance.

Of 210 patients with clinical Stage I testicular tumours managed by orchiectomy and surveillance, 36 had scrotal interference at or prior to removal of their primary tumour. None developed inguinoscrotal relapse during a mean observation period of 37 months. The overall relapse rate of 4/36 (11%) compared favourably with that of the surveillance series as a whole (18%).

The accuracy of CT scanning prior to para-aortic lymphadenectomy in patients with bulky metastases from testicular teratoma.

The accuracy of CT scanning prior to para-aortic lymphadenectomy was assessed in 108 patients with metastatic testicular teratoma. In 106 its presence was confirmed by surgery. The site was accurately predicted in 95%. A good correlation (P less than 0.0025) was found between mean tumour cross-sectional area assessed by CT scanning and that measured in the excised pathological specimens.

The treatment of oestrogen-escaped carcinoma of the prostate with estramustine phosphate.

30 patients with oestrogen-escaped carcinoma of the prostate have been treated with estramustine phosphate (Estracyt). 27% showed a partial objective response and 33% had a subjective response. The terms used for defining a response are challenged and it is recommended that comparative controlled trials are necessary to judge the place of this drug in the management of advanced prostatic cancer.