Incidence Rate and Risk Factors Associated with Travelers' Diarrhea in International Travelers Departing from Utah, USA.

Despite knowledge on the causes and prevention strategies for travelers' diarrhea (TD), it continues to be one of the most common illnesses experienced by U.S. international travelers. However, studies of risk factors associated with TD among U.S. travelers are limited. In this study, we aimed to determine the incidence rate of TD, the proportion of travelers who experience TD, and to identify risk factors associated with TD. In this cross-sectional study, we collected and analyzed data from anonymous posttravel questionnaires submitted by international travelers recruited during their pretravel visit at two travel clinics in Salt Lake City, Utah, from October 2016 to March 2020. Of 571 travelers who completed posttravel surveys, 484 (85%) answered the TD question, of which 111 (23%) reported TD, for an incidence rate of 1.1 episodes per 100 travel-days (95% confidence interval [CI]: 0.9-1.4). In a multivariable model, visiting Southeast Asian (odds ratio [OR]: 2.60; 95% CI: 1.45-4.72) and African (OR: 2.06; 95% CI: 1.09-3.93]) WHO regions, having 10 or more individuals in the group (OR: 3.91; 95% CI: 1.50-11.32]), longer trip duration (OR: 1.01; 95% CI: 1.00-1.02), visiting both urban and rural destinations (OR: 1.94; 95% CI: 1.01-3.90), and taking medications/supplements to prevent TD (OR: 2.74; 95% CI: 1.69-4.47) were statistically significantly associated with increased odds of reporting TD. TD continues to be common in international travelers from the United States. Our findings provide insights regarding travelers' behaviors regarding TD in international travelers from high-income countries and shows the need for additional research into prevention strategies for travelers' diarrhea.

CD8 co-receptor promotes susceptibility of CD8+ T cells to transforming growth factor-ß (TGF-ß)-mediated suppression.

CD8+ T cell function depends on a finely orchestrated balance of activation/suppression signals. While the stimulatory role of the CD8 co-receptor and pleiotropic capabilities of TGF-ß have been studied individually, the influence of CD8 co-receptor on TGF-ß function in CD8+ T cells is unknown. Here, we show that while CD8 enhances T cell activation, it also enhances susceptibility to TGF-ß-mediated immune suppression. Using Jurkat cells expressing a full-length, truncated or no αßCD8 molecule, we demonstrate that cells expressing full-length αßCD8 were highly susceptible, αßCD8-truncated cells were partially susceptible, and CD8-deficient cells were completely resistant to suppression by TGF-ß. Additionally, we determined that inhibition of Lck rendered mouse CD8+ T cells highly resistant to TGF-ß suppression. Resistance was not associated with TGF-ß receptor expression but did correlate with decreased Smad3 and increased Smad7 levels. These findings highlight a previously unrecognized third role for CD8 co-receptor which appears to prepare activated CD8+ T cells for response to TGF-ß. Based on the important role which TGF-ß-mediated suppression plays in tumor immunology, these findings unveil necessary considerations in formulation of CD8+ T cell-related cancer immunotherapy strategies.

Muscleblind-like 2 (Mbnl2) -deficient mice as a model for myotonic dystrophy.

Myotonic dystrophy (DM), the most common adult-onset muscular dystrophy, is caused by CTG or CCTG microsatellite repeat expansions. Expanded DM mRNA microsatellite repeats are thought to accumulate in the nucleus, sequester Muscleblind proteins, and interfere with alternative mRNA splicing. Muscleblind2 (Mbnl2) is a member of the family of Muscleblind RNA binding proteins (that also include Mbnl1 and Mbnl3) that are known to bind CTG/CCTG RNA repeats. Recently, it was demonstrated that Mbnl1-deficient mice have characteristic features of human DM, including myotonia and defective chloride channel expression. Here, we demonstrate that Mbnl2-deficient mice also develop myotonia and have skeletal muscle pathology consistent with human DM. We also find defective expression and mRNA splicing of the chloride channel (Clcn1) in skeletal muscle that likely contributes to the myotonia phenotype. Our results support the hypothesis that Muscleblind proteins and specifically MBNL2 contribute to the pathogenesis of human DM.

Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial.

BACKGROUND: Minocycline has anti-apoptotic and anti-inflammatory effects in vitro, and extends survival in mouse models of some neurological conditions. Several trials are planned or are in progress to assess whether minocycline slows human neurodegeneration. We aimed to test the efficacy of minocycline as a treatment for amyotrophic lateral sclerosis (ALS). METHODS: We did a multicentre, randomised placebo-controlled phase III trial. After a 4-month lead-in phase, 412 patients were randomly assigned to receive placebo or minocycline in escalating doses of up to 400 mg/day for 9 months. The primary outcome measure was the difference in rate of change in the revised ALS functional rating scale (ALSFRS-R). Secondary outcome measures were forced vital capacity (FVC), manual muscle testing (MMT), quality of life, survival, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00047723. FINDINGS: ALSFRS-R score deterioration was faster in the minocycline group than in the placebo group (-1.30 vs -1.04 units/month, 95% CI for difference -0.44 to -0.08; p=0.005). Patients on minocycline also had non-significant tendencies towards faster decline in FVC (-3.48 vs -3.01, -1.03 to 0.11; p=0.11) and MMT score (-0.30 vs -0.26, -0.08 to 0.01; p=0.11), and greater mortality during the 9-month treatment phase (hazard ratio=1.32, 95% CI 0.83 to 2.10; p=0.23) than did patients on placebo. Quality-of-life scores did not differ between the treatment groups. Non-serious gastrointestinal and neurological adverse events were more common in the minocycline group than in the placebo group, but these events were not significantly related to the decline in ALSFRS-R score. INTERPRETATION: Our finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocycline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in patients with ALS.

Whole-genome analysis of sporadic amyotrophic lateral sclerosis.

BACKGROUND: Approximately 90% of persons with amyotrophic lateral sclerosis (ALS) have the sporadic form, which may be caused by the interaction of multiple environmental factors and previously unknown genes. METHODS: We performed a genomewide association analysis using 766,955 single-nucleotide polymorphisms (SNPs) found in 386 white patients with sporadic ALS and 542 neurologically normal white controls (the discovery series). Associations of SNPs with sporadic ALS were confirmed in two independent replication populations: replication series 1, with 766 case patients with the disease and 750 neurologically normal controls, and replication series 2, with 135 case patients and 275 controls. RESULTS: We identified 10 genetic loci that are significantly associated (P<0.05) with sporadic ALS in three independent series of case patients and controls and an additional 41 loci that had significant associations in two of the three series. The most significant association with disease in white case patients as compared with controls was found for a SNP near an uncharacterized gene known as FLJ10986 (P=3.0x10(-4); odds ratio for having the genotype in patients vs. controls, 1.35; 95% confidence interval, 1.13 to 1.62). The FLJ10986 protein was found to be expressed in the spinal cord and cerebrospinal fluid of patients and of controls. Specific SNPs seem to be associated with sex, age at onset, and site of onset of sporadic ALS. CONCLUSIONS: Variants of FLJ10986 may confer susceptibility to sporadic ALS. FLJ10986 and 50 other candidate loci warrant further investigation for their potential role in conferring susceptibility to the disease.

Curcuminoids enhance amyloid-beta uptake by macrophages of Alzheimer's disease patients.

Treatment of Alzheimer's disease (AD) is difficult due to ignorance of its pathogenesis. AD patients have defects in phagocytosis of amyloid-beta (1-42) (Abeta) in vitro by the innate immune cells, monocyte/macrophages and in clearance of Abeta plaques [5]. The natural product curcuminoids enhanced brain clearance of Abeta in animal models. We, therefore, treated macrophages of six AD patients and 3 controls by curcuminoids in vitro and measured Abeta uptake using fluorescence and confocal microscopy. At baseline, the intensity of Abeta uptake by AD macrophages was significantly lower in comparison to control macrophages and involved surface binding but no intracellular uptake. After treatment of macrophages with curcuminoids, Abeta uptake by macrophages of three of the six AD patients was significantly (P<0.001 to 0.081) increased. Confocal microscopy of AD macrophages responsive to curcuminoids showed surface binding in untreated macrophages but co-localization with phalloidin in an intracellular compartment after treatment. Immunomodulation of the innate immune system by curcuminoids might be a safe approach to immune clearance of amyloidosis in AD brain.

Ineffective phagocytosis of amyloid-beta by macrophages of Alzheimer's disease patients.

The defective clearance of amyloid-beta (Abeta) in the brain of Alzheimer's disease (AD) patients is unexplained. The immunohistochemical studies of the frontal lobe and hippocampus show perivascular and intraplaque infiltration by blood-borne macrophages containing intracellular Abeta but only inefficient clearance of beta deposits. Neurons and neuronal nuclei, respectively, express interleukin-1beta and the chemokine RANTES, which could induce the inflammatory cell infiltration. To clarify the pathophysiology ofbeta clearance, we examined Abeta phagocytosis by monocytes and macrophages isolated from the blood of age-matched patients and controls. Control monocytes display excellent differentiation into macrophages and intracellular phagocytosis of Abeta followed by beta degradation or export. AD monocytes show poor differentiation and only surface uptake of Abeta and suffer apoptosis. HLA DR and cyclooxygenase-2 are abnormally expressed on neutrophils and monocytes of AD patients. AD patients have higher levels of intracellular cytokines compared to controls. Thus Abeta clearance is not restricted to brain microglia and involves systemic innate immune responses. In AD, however, macrophage phagocytosis is defective, which may elicit compensatory response by the adaptive immune system.

Inflammation in amyotrophic lateral sclerosis spinal cord and brain is mediated by activated macrophages, mast cells and T cells.

Recent studies have shown inflammatory markers in affected neural tissues of amyotrophic lateral sclerosis (ALS) patients. We examined immunocytochemically spinal cord tissues of six patients with ALS, two with corticospinal tract degeneration secondary to cerebral infarcts and three control subjects without neuropathologic abnormalities. ALS spinal cords had dense macrophage infiltration (one log greater than control spinal cords) involving the white and gray matter, with heaviest infiltration of lateral and ventral columns and, in one patient, prefrontal gyrus and the occipital lobes of the brain. Macrophages in ALS spinal cord showed strong expression of cyclooxygenase-2 (COX-2) (one log greater than control tissues) and inducible nitric oxide synthase. In the gray matter, macrophages surrounded and appeared to phagocytize neurons (NeuN-positive) that appeared to be dying. Vessels showed damage to the tight junction protein ZO-1 in relation to perivascular CD40 receptor-positive macrophages and CD40 ligand-positive T lymphocytes. ALS spinal cords, but not control cords, were sparsely infiltrated with mast cells. In control cases with corticospinal tract degeneration following hemispheric cerebral infarction, macrophage infiltration of the white matter was COX-2-negative and restricted to lateral and anterior corticospinal tracts. Our data suggest that inflammation in ALS spinal cord and cortex is based on innate immune responses by macrophages and mast cells and adaptive immune responses by T cells.

Bethlem myopathy in a black creole pedigree.

OBJECTIVES: To analyze the clinical and molecular features of a distinctive muscular dystrophy in a family of black Creole descent. METHODS: We clinically characterized a four-generation pedigree and performed linkage analysis for all relevant autosomal-dominant muscular dystrophies. RESULTS: Affected family members had minor neurologic dissimilarities from previously reported Bethlem myopathy pedigrees and a high incidence of keloid formation. Multipoint linkage analysis traced the family's disease to the region of the collagen genes COL6A1-COL6A2. CONCLUSIONS: We report that Bethlem myopathy was linked to the collagen VIA1-2 region on chromosome 21q22.3 in a black Creole family. This is the first report of molecular-proven Bethlem myopathy in a family of either Creole or African-American descent. Although the correlation of Bethlem myopathy and keloids was not statistically significant, the possible connection between these two abnormalities raises the possibility of a common pathophysiological link involving collage VIA.