While age and the APOE ε4 allele are major risk factors for Alzheimer’s disease (AD), a small percentage of individuals with these risk factors exhibit AD resilience by living well beyond 75 years of age without any clinical symptoms of cognitive decline.
Objective To investigate whether symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is non-inferior to antibiotics in the treatment of uncomplicated lower urinary tract infection (UTI) in women, thus offering an opportunity to reduce antibiotic use in ambulatory care.Design Randomised, double blind, non-inferiority trial.Setting 17 general practices in Switzerland.Participants 253 women with uncomplicated lower UTI were randomly assigned 1:1 to symptomatic treatment with the NSAID diclofenac (n=133) or antibiotic treatment with norfloxacin (n=120). The randomisation sequence was computer generated, stratified by practice, blocked, and concealed using sealed, sequentially numbered drug containers.Main outcome measures The primary outcome was resolution of symptoms at day 3 (72 hours after randomisation and 12 hours after intake of the last study drug). The prespecified principal secondary outcome was the use of any antibiotic (including norfloxacin and fosfomycin as trial drugs) up to day 30. Analysis was by intention to treat.Results 72/133 (54%) women assigned to diclofenac and 96/120 (80%) assigned to norfloxacin experienced symptom resolution at day 3 (risk difference 27%, 95% confidence interval 15% to 38%, P=0.98 for non-inferiority, P<0.001 for superiority). The median time until resolution of symptoms was four days in the diclofenac group and two days in the norfloxacin group. A total of 82 (62%) women in the diclofenac group and 118 (98%) in the norfloxacin group used antibiotics up to day 30 (risk difference 37%, 28% to 46%, P<0.001 for superiority). Six women in the diclofenac group (5%) but none in the norfloxacin group received a clinical diagnosis of pyelonephritis (P=0.03).Conclusion Diclofenac is inferior to norfloxacin for symptom relief of UTI and is likely to be associated with an increased risk of pyelonephritis, even though it reduces antibiotic use in women with uncomplicated lower UTI.Trial registration ClinicalTrials.gov NCT01039545.
Solitary rectal ulcer syndrome (SRUS) is a benign and chronic disorder well known in young adults and less in children. It is often related to prolonged excessive straining or abnormal defecation and clinically presents as rectal bleeding, copious mucus discharge, feeling of incomplete defecation, and rarely rectal prolapse. SRUS is diagnosed based on clinical symptoms and endoscopic and histological findings. The current treatments are suboptimal, and despite correct diagnosis, outcomes can be unsatisfactory. Some treatment protocols for SRUS include conservative management such as family reassurance, regulation of toilet habits, avoidance of straining, encouragement of a high-fiber diet, topical treatments with salicylate, sulfasalazine, steroids and sucralfate, and surgery. In children, SRUS is relatively uncommon but troublesome and easily misdiagnosed with other common diseases, however, it is being reported more than in the past. This condition in children is benign; however, morbidity is an important problem as reflected by persistence of symptoms, especially rectal bleeding. In this review, we discuss current diagnosis and treatment for SRUS.
Hair-pulling disorder (trichotillomania, HPD) is a disabling condition that is characterized by repetitive hair-pulling resulting in hair loss. Although there is evidence of structural grey matter abnormalities in HPD, there is a paucity of data on white matter integrity. The aim of this study was to explore white matter integrity using diffusion tensor imaging (DTI) in subjects with HPD and healthy controls. Sixteen adult female subjects with HPD and 13 healthy female controls underwent DTI. Hair-pulling symptom severity, anxiety and depressive symptoms were also assessed. Tract-based spatial statistics were used to analyze data on fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). There were no differences in DTI measures between HPD subjects and healthy controls. However, there were significant associations of increased MD in white matter tracts of the fronto-striatal-thalamic pathway with longer HPD duration and increased HPD severity. Our findings suggest that white matter integrity in fronto-striatal-thalamic pathways in HPD is related to symptom duration and severity. The molecular basis of measures of white matter integrity in HPD deserves further exploration.
Chronic day-to-day symptoms of orthostatic intolerance are the most notable features of postural orthostatic tachycardia syndrome (POTS). However, we have encountered patients with such symptoms and excessive tachycardia but with no symptoms during the tilt-table test (TTT). We aimed to investigate whether POTS patients with chronic orthostatic intolerance always present orthostatic symptoms during the TTT and analyze the factors underlying symptom manifestation during this test.
Mucopolysaccharidosis type II (MPS II) is an inherited X-linked disease associated with a deficiency in the enzyme iduronate 2-sulfatase due to iduronate 2-sulfatase gene (IDS) mutations. Recent studies in MPS II carriers did not find clinical involvement, but these were mainly performed by anamnesis and patients' self-reported description of signs and symptoms. So although it is rare in heterozygous carriers, investigations in other types of inherited X-linked disorders suggest that some clinical manifestations may be a possibility. The aim of this study was to evaluate the clinical pattern in female carriers of MPS II and to determine whether clinical symptoms were associated with the X-chromosome inactivation (XCI) pattern and age.
BACKGROUND: To assess the clinical and laboratory parameters, response to therapy and development of antituberculosis (TB) drug resistance in pulmonary TB (PTB) patients with diabetes mellitus (DM) and without DM. METHODS: Using a prospective design, 227 of 310 new cases of culture-positive PTB diagnosed at the Queen Savang Vadhana Memorial Hospital and the Chonburi Hospital between April 2010 and July 2012 that met the study criteria were selected. Data regarding clinical and laboratory parameters, drug susceptibility and treatment outcomes were compared between PTB patients with DM and those without DM. To control for age, the patients were stratified into two age groups (< 50 and ≥ 50 years) and their data were analysed. RESULTS: Of the 227 patients, 37 (16.3%) had DM, of which 26 (70.3%) had been diagnosed with DM prior to PTB diagnosis and 11 (29.7%) had developed DM at PTB diagnosis. After controlling for age, no significant differences were found between the two groups regarding mycobacterium burden, sputum-culture conversion rate, evidence of multidrug-resistant tuberculosis, frequency of adverse drug events from anti-TB medications, treatment outcomes and relapse rate. The presenting symptoms of anorexia (p = 0.050) and haemoptysis (p = 0.036) were observed significantly more frequently in PTB patients with DM, while the presenting symptom of cough was observed significantly more frequently in PTB patients without DM (p = 0.047). CONCLUSIONS: Plasma glucose levels should be monitored in all newly diagnosed PTB patients and a similar treatment regimen should be prescribed to PTB patients with DM and those without DM in high TB-burden countries.
Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches.
Japanese encephalitis virus (JEV) causes acute central nervous system (CNS) disease in humans, in whom the clinical symptoms vary from febrile illness to meningitis and encephalitis. However, the mechanism of severe encephalitis has not been fully elucidated. In this study, using a mouse model, we investigated the pathogenetic mechanisms that correlate with fatal JEV infection. Following extraneural infection with the JaOArS982 strain of JEV, infected mice exhibited clinical signs ranging from mild to fatal outcome. Comparison of the pathogenetic response between severe and mild cases of JaOArS982-infected mice revealed increased levels of TNF-α in the brains of severe cases. However, unexpectedly, the mortality rate of TNF-α KO mice was significantly increased compared with that of WT mice, indicating that TNF-α plays a protective role against fatal infection. Interestingly, there were no significant differences of viral load in the CNS between WT and TNF-α KO mice. However, exaggerated inflammatory responses were observed in the CNS of TNF-α KO mice. Although these observations were also obtained in IL-10 KO mice, the mortality and enhanced inflammatory responses were more pronounced in TNF-α KO mice. Our findings therefore provide the first evidence that TNF-α has an immunoregulatory effect on pro-inflammatory cytokines in the CNS during JEV infection and consequently protects the animals from fatal disease. Thus, we propose that the increased level of TNF-α in severe cases was the result of severe disease, and secondly that immunopathological effects contribute to severe neuronal degeneration resulting in fatal disease. In future, further elucidation of the immunoregulatory mechanism of TNF-α will be an important priority to enable the development of effective treatment strategies for Japanese encephalitis.
Celiac disease is an autoimmune systemic disease having among its clinical manifestations frequent symptoms common to rheumatologic diseases such as musculoskeletal pain, asthenia, and cognitive fatigue. It is associated with other autoimmune diseases like Sjögren disease. It is a well-characterized disease with specific diagnostic tests. Non-celiac gluten sensitivity is an emerging entity with symptoms similar to celiac disease, but without specific diagnostic tests. The concept of non-celiac gluten sensitivity and its diagnostic problems are reviewed, and the hypothesis of its association with fibromyalgia, spondyloarthritis, and autoimmune conditions is proposed. Clinical observations supporting the hypothesis are described, highlighting the benefit of treating non-celiac gluten sensitivity.