Enhancement of disease and pathology by synergy of Trichuris suis and Campylobacter jejuni in the colon of immunologically naive swine

Campylobacter jejuni, a leading cause of bacterial gastroenteritis, has different age distribution and disease expression in developing and developed countries, which may be due to the endemnicity of infection and the age of acquisition of immunity. Differences in disease expression are not solely dependent on the C jejuni strain or virulence attributes. Another modulating factor in developing countries may be endemic nematode infections such as Trichuris, which drive type 2 cytokine responses and down-regulate type 1 immune responses. In this study, three-day-old germ-free pigs given dual infections with Trichuris suis and C jejuni had more frequent, more severe diarrhea and severe pathology than pigs given no pathogens, only T. suis, or only C jejuni. These pigs had significant hemorrhage and inflammatory cell infiltrates in the proximal colon where adult worms were found, and abscessed lymphoglandular complexes in the distal colon with intracellular C jejuni. Pigs given only C jejuni had mild clinical signs and pathology, and bacteria in feces or extracellular sites. Pigs given T. suis or no pathogens had no disease and minimal pathology. Thus, these agents synergized to produce significant disease and pathology, which was site specific.     

A randomized,double‐blind,placebo‐controlled,phase III study of the human anti‐tumor necrosis factor antibody adalimumab administered as subcutaneous injections in Korean rheumatoid arthritis patients treated with methotrexate

Objective: Adalimumab is a fully human, monoclonal, antitumour necrosis factor antibody approved for the treatment of rheumatoid arthritis (RA) in more than 60 countries. We investigated the efficacy and safety of 40 mg every‐other‐week (eow) subcutaneous injections of adalimumab with methotrexate (MTX) versus placebo with MTX in Korean patients with RA with insufficient responses to MTX. Methods: This was a 24‐week, randomized, double‐blind, placebo‐controlled, phase III study conducted at six sites in Korea. The primary efficacy endpoint was a 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Secondary endpoints included ACR50, ACR70, and individual ACR components. Beginning at week 18, non‐responders (< 20% reduction in swollen and tender joint counts) could switch to rescue therapy with open‐label adalimumab 40 mg eow. Results: Of the 128 patients enrolled, 65 received adalimumab and 63 received placebo. An ACR20 response at week 24 was achieved by 61.5% of patients receiving adalimumab versus 36.5% receiving placebo (P < 0.01). ACR50 and ACR70 responses were achieved by 43.1% and 21.5% of adalimumab patients versus 14.3% and 7.9% of placebo patients (P < 0.001 and P < 0.05, respectively). Adalimumab significantly improved all seven ACR core components. Statistically significant improvements in ACR20 were observed with adalimumab as early as week 2. Adalimumab was generally well tolerated; there were no significant differences in incidences of adverse events between groups. Conclusions: In Korean patients with RA with insufficient responses to MTX, combination therapy with adalimumab and MTX was more efficacious than placebo and MTX in reducing RA signs and symptoms.     

The effect of inhaled budesonide on the diurnal variation in airway mechanics, airway responsiveness and serum neutrophil chemotactic activity in Asian patients with predominant nocturnal asthma

The effectiveness of inhaled corticosteroids in the control of daytime symptoms in asthma is well established, but the specific use against nocturnal asthma has not been systematically studied in Asian patients. This study examined the effect of treatment with inhaled budesonide on the nocturnal variation in measurements of airway calibre, bronchial hyperresponsiveness to inhaled histamine and circulating neutrophil chemotactic activity in Asian patients with nocturnal asthma. Thirty patients, with nocturnal asthma, were randomized into a 2-month, double-blind, parallel group study. Twice as many subjects were allocated to the group who received two consecutive months of inhaled budesonide 1600 μg daily as to the group who received placebo followed by budesonide. Spirometry, lung mechanics, bronchial hyperresponsiveness and serum neutrophil chemotactic factor (NCA) were measured at 16.00 h, 22.00 h and at 04.00 h on 3 days and nights, 4 weeks apart before and after either placebo or budesonide. The combined measurements for the two groups at 04.00 h before and after treatment with budesonide were: forced expiratory volume in 1 s (FEV₁) mean (SEM) litres 1.34 (0.17) before, 2.00 (0.19) after; thoracic gas volume (TGV) litres 3.05 (0.32) before, 2.25 (0.14) after; specific airway conductance (sGaw) (cmH20.0 sec)^?1 0.39 (0.07) before, 1.16 (0.17) after; PD₂₀μg geometric mean 1.16 before, 44.74 after; neutrophil chemotactic activity (NCA) in units of graduations of migration 98.8 (4.2) before, 101 (14.2) after. The data showed that short and intermediate term high dose inhaled budesonide is an effective specific treatment for nocturnal asthma in Asian patients, resulting in marked improvements in symptoms and in lung mechanics, and reductions in the diurnal variations in bronchial hyperresponsiveness, before any change could be demonstrated in a circulating marker of airway inflammation.     

Increased factor VIII-related antigen in necrobiosis lipoidica and widespread granuloma annulare without associated diabetes

Factor VIII-related antigen was found to be raised in diabetics, and in patients with necrobiosis lipoidica and widespread granuloma annulare who were not diabetic. It was not increased in patients with solitary lesions of granuloma annulare. The relationship of factor VIII-related antigen to the development of micro-angiopathy in these conditions is discussed.     

Prognosis after local recurrence after conservative surgery and radiation for early-stage breast cancer

PURPOSE: To determine the long-term prognosis of patients who develop a local recurrence (LR) after conservative surgery (CS) and radiation therapy (RT) for early-stage invasive breast cancer. METHODS AND MATERIALS: Between 1970 and 1987, 2102 patients with clinical Stage I-II breast cancer were treated with CS+RT. LR was defined as any recurrence within the ipsilateral breast with or without simultaneous regional nodal or distant metastasis. Patients were at risk for a LR until the first of distant metastases, second nonbreast malignancy, or death (DF/S/D). The final study population comprised 341 patients with LR. The median time to LR was 72 months. The median follow-up time after LR was 85 months. A proportional hazards model of time from LR to DF/S/D was done to investigate the influence of factors at initial diagnosis and at LR on subsequent outcome. RESULTS: The actuarial freedom from DF/S/D 5 years after LR was 65% and the survival was 81%. Variables significantly associated with time to DF/S/D were: LR histology (invasive vs. ductal carcinoma in situ, hazard ratio [HR] = 4.1, p < 0.0001); local therapy for LR (none vs. mastectomy or unknown, HR = 3.2, p < 0.0001; and CS +/- RT vs. mastectomy or unknown, HR = 2.0, p = 0.02); time to LR (< or =2 years vs. >5 years, HR = 2.6, p < 0.0001; and 2-5 years vs. >5 years, HR = 1.8, p = 0.006); and age at initial diagnosis (> or =60 vs. <60, HR = 1.6, p = 0.01). CONCLUSIONS: Many patients with LR after CS+RT have prolonged distant disease-free survival, particularly those able to be treated with mastectomy. Patients with a noninvasive LR, longer interval to LR, or age <60 had a longer time to distant failure, second malignancy, or death than other patients.     

Disruption of the transmembrane dense core vesicle proteins IA-2 and IA-2beta causes female infertility

Female infertility is a worldwide problem affecting 10-15% of the population. The cause of the infertility in many cases is not known. In the present report, we demonstrate that alterations in two transmembrane structural proteins, IA-2 and IA-2beta, located in dense core secretory vesicles (DCV) of many endocrine and neuroendocrine cells, can result in female infertility. IA-2 and IA-2beta are best known as major autoantigens in type 1 diabetes, but their normal function has remained an enigma. Recently we showed in mice that deletion of IA-2 and/or IA-2beta results in impaired insulin secretion and glucose intolerance. We now report that double knockout (DKO), but not single knockout, female mice are essentially infertile. Vaginal smears showed a totally abnormal estrous cycle, and examination of the ovaries revealed normal-appearing oocytes but the absence of corpora lutea. The LH surge that is required for ovulation occurred in wild-type mice but not in DKO mice. Additional studies showed that the LH level in the pituitary of DKO female mice was decreased compared with wild-type mice. Treatment of DKO females with gonadotropins restored corpora lutea formation. In contrast to DKO female mice, DKO male mice were fertile and LH levels in the serum and pituitary were within the normal range. From these studies we conclude that the DCV proteins, IA-2 and IA-2beta, play an important role in LH secretion and that alterations in structural proteins of DCV can result in female infertility.     

Preclinical AD Workgroup staging: pathological correlates and potential challenges

The National Institute on Aging Preclinical Alzheimer's disease Workgroup (PADW) has issued a preliminary report with recommendations for classifying preclinical Alzheimer's disease (pAD) according to 3 early disease stages. Here we examine the PADW recommendations in relation to neuropathological features in a large, consecutive series of cognitively intact elderly persons, autopsied within a year after cognitive testing (n = 126 cognitively intact patients with mean age 83.7 years at death). Subjects were grouped based on a hypothetical construct correlating pathological features with PADW stages. Many cognitively intact individuals were classifiable as pAD (53/126 or 43%), as expected based on epidemiological and biomarker studies. Of these, most (48%) were in “stage 3”, which corresponds to amyloid pathology with early neurodegeneration. As with prior studies, our data indicate that the development of neocortical neurofibrillary tangles is the key pathological event that is not observed in pAD cases: Braak stages III or IV pathology are hence not truly a substrate for “intermediate likelihood” that cognitive impairment is due to Alzheimer's disease (AD). We also stress the importance of comorbid non-Alzheimer's disease brain pathologies (hippocampal sclerosis, neocortical alpha-synucleinopathy, cerebrovascular disease, and brains with hippocampal neurofibrillary tangles but no cortical amyloid plaques) that can contribute to the development of cognitive impairment, or which may serve as confounds in the application of the PADW recommendations. While the final recommendations from the PADW working group have not yet been released, this preliminary analysis provides a perspective on those recommendations from a neuropathological point of view.