A Survey of the FAERS Database Concerning the Adverse Event Profiles of α1-Adrenoreceptor Blockers for Lower Urinary Tract Symptoms

Purpose: Current guidelines recommend α1-adrenoreceptor blockers (A1Bs) for treating lower urinary tract symptoms suggestive of benign prostatic hyperplasia, but their adverse effects can be problematic. In this study, reports submitted to the US Food and Drug Administration Adverse Event Reporting System (FAERS) between 1997 and 2011 were reviewed to assess the safety profiles of A1Bs.Methods: After deleting duplicated submissions and revising arbitrary drug names, reports involving A1Bs for male patients were analyzed. Data mining algorisms were used for the quantitative detection of signals, where a signal represents an association between a drug and an adverse event or a drug-associated adverse event, including the proportional reporting ratio, reporting odds ratio, information component given by a Bayesian confidence propagation neural network, and empirical Bayes geometric mean.Results: The total number of reports used was 1,260,182. Signal scores suggested the associations of alfuzosin, doxazosin, tamsulosin, and terazosin with dizziness/vertigo, orthostatic hypotension, erectile dysfunction, ejaculation dysfunction (EjD), thirst/dry mouth, and constipation; however, reports on naftopidil, silodosin, and urapidil were not enough to compare with the other 4 A1Bs. Signal scores for EjD were higher for tamsulosin, and those for dizziness/vertigo were lower for doxazosin than for the other 3 drugs.Conclusions: Tamsulosin-associated EjD, which was found in clinical studies, was reproduced in this analysis with markedly higher signal scores, and these results strongly suggest the necessity of well-organized clinical studies on A1B-associated adverse events.     

In vitro activities and spectrum of lascufloxacin（KRP-AM1977）against anaerobes

The in vitro antibacterial spectra and activities of five antimicrobial agents, including lascufloxacin (LSFX) and two quinolones, were investigated against 69 species of anaerobes in 31 genera and 188 strains in 9 genera, respectively.In this study, minimum inhibitory concentrations (MICs) of lascufloxacin against the reference strains associated with respiratory and head and neck infections. LSFX inhibited the growth of 33 gram-positive and gram-negative reference strains at ≤0.015–2 μg/mL, except for Leptotrichia buccalis. MICs ranges of LSFX against the clinical isolates of 44 Porphyromonas spp., 45 Prevotella spp., 25 Fusobacterium spp., 7 Leptotrichia spp., 25 Parvimonas micra, 25 other gram-positive anaerobic cocci, and 17 Veillonella spp., were ≤0.015–4, 0.125–4, 0.06–0.5, 2, 0.25–16, ≤0.015–2, ≤0.015–16 μg/mL, respectively.LSFX demonstrated potent antibacterial efficacy against a wide range of species isolated from specimens involved in respiratory as well as head and neck infections.     

Colonoscopic Stigmata of 1 mm or Deeper Submucosal Invasion in Colorectal Cancer

Purpose  This study was designed to identify colonoscopic stigmata, indicating substantial invasion into the submucosa by T1 colorectal cancer with sessile morphology, including both flat and protruded types. Methods  A total of 111 Tis or T1 colorectal cancers were studied retrospectively. The lesions were divided into two groups: Group A (n = 83), Tis or T1 cancers with <1 mm submucosal invasion; and Group B (n = 28), T1 cancers with a ≥1 mm submucosal invasion. Printed photographs of the lesions were reviewed by five experienced colonoscopists who were blinded to histology. Deep depression, irregular surface, ulceration or erosion, fold convergence, and spontaneous bleeding were independently evaluated. Findings considered present by three or more reviewers were defined as positive. Kappa analysis was used to measure inter/intraobserver variability. Results  Positive rates of four findings but not fold convergence were significantly higher in Group B than in Group A. Irregular surface and spontaneous bleeding were significant independent predictors of ≥1 mm submucosal invasion, with diagnostic accuracies of 85.6 and 76.6 percent, respectively. Kappa analysis demonstrated fair-to-good inter/intraobserver agreement for spontaneous bleeding and fair-to-good intraobserver agreement for irregular surface. Conclusions  Irregular surface and spontaneous bleeding were colonoscopic stigmata, indicating ≥1 mm submucosal invasion in T1 colorectal cancer.     

Single serum cortisol values at 09:00 h can be indices of adrenocortical function in children with Kawasaki disease treated with intravenous immunoglobulin plus prednisolone

Combination treatment with intravenous immunoglobulin (IVIG) plus prednisolone is effective for prevention of cardiovascular complications in children with Kawasaki disease (KD). However, administration of prednisolone for approximately 20 d in this regimen causes adrenocortical suppression in a high proportion of treated children. To establish a simple method to screen for this suppression, we performed a prospective study on 72 children with KD treated with this regimen in our institution from February 2012 to March 2014. By performing ROC analysis of 21 initial patients treated between February and June 2012, a serum cortisol value at 09:00 h of 5 mcg/dL was established as a threshold for intact adrenocortical function, which is equivalent to a peak serum cortisol value of higher than 15 mcg/dL in the CRH stimulation test. Then, we applied this screening test to 51 subsequent patients treated between July 2012 and March 2014. Approximately 90% of the patients with morning serum cortisol values above 5 mcg/dL 2 to 6 mo after the cessation of initial prednisolone treatment had peak serum cortisol values exceeding 15 mcg/dL, suggesting the efficacy of this approach.     

Natural resistance to worms exacerbates bovine tuberculosis severity independently of worm coinfection

Pathogen interactions arising during coinfection can exacerbate disease severity, for example when the immune response mounted against one pathogen negatively affects defense of another. It is also possible that host immune responses to a pathogen, shaped by historical evolutionary interactions between host and pathogen, may modify host immune defenses in ways that have repercussions for other pathogens. In this case, negative interactions between two pathogens could emerge even in the absence of concurrent infection. Parasitic worms and tuberculosis (TB) are involved in one of the most geographically extensive of pathogen interactions, and during coinfection worms can exacerbate TB disease outcomes. Here, we show that in a wild mammal natural resistance to worms affects bovine tuberculosis (BTB) severity independently of active worm infection. We found that worm-resistant individuals were more likely to die of BTB than were nonresistant individuals, and their disease progressed more quickly. Anthelmintic treatment moderated, but did not eliminate, the resistance effect, and the effects of resistance and treatment were opposite and additive, with untreated, resistant individuals experiencing the highest mortality. Furthermore, resistance and anthelmintic treatment had nonoverlapping effects on BTB pathology. The effects of resistance manifested in the lungs (the primary site of BTB infection), while the effects of treatment manifested almost entirely in the lymph nodes (the site of disseminated disease), suggesting that resistance and active worm infection affect BTB progression via distinct mechanisms. Our findings reveal that interactions between pathogens can occur as a consequence of processes arising on very different timescales.

Interactions between pathogens cooccurring within a single host can have profound effects on infection outcomes, ranging from the severity of clinical disease in individual hosts to the rate of disease spread across populations (1–3). Because most hosts are commonly infected by more than one type of pathogen at a time (4), understanding the consequences of pathogen interactions during concurrent infection (or coinfection) is essential for effective disease management and control. While many studies focus on pathogen interactions that are the result of one pathogen responding to the simultaneous presence of another (5), two pathogens need not overlap in time to interact with one another. For example, heterologous immunity, where prior exposure or infection with one pathogen modifies the immune response to another, can drive both positive and negative interactions between pathogens (6). This phenomenon highlights how modifications of the host immune system by one pathogen that occur during the lifetime of a host (i.e., in ecological time) can shape future responses to secondary pathogens. Likewise, strong selection pressure imposed by pathogens on hosts, particularly on immune function (7), can result in modifications of the host immune system that occur over generations (i.e., in evolutionary time), a process which should also affect responses to secondary infections. In this case, a historical population-level response to selection by one pathogen may generate heritable differences among individuals in contemporary responses to another. Crucially, ecological- vs. evolutionary-scale interactions between pathogens may operate for different reasons, so distinguishing between the two is integral to understanding both the mechanistic basis and consequences of these interactions.Helminths, or parasitic worms, and tuberculosis (TB) are involved in one of the most geographically extensive of pathogen interactions (2, 8). Both pathogens affect approximately one-third of the world’s human population and are widespread in domestic and wild animals (9–11). Caused by bacteria in the Mycobacterium tuberculosis complex, including M. tuberculosis (Mtb), the causative agent of human TB, and Mycobacterium bovis (Mb), the causative agent of bovine TB, TB is responsible for 2 million human deaths (12) and 25% of all disease-related cattle deaths (13) annually. In humans, about 10% of individuals infected with Mtb progress to active pulmonary disease, but the mechanisms underlying progression to active TB are poorly defined (14). Accumulating evidence suggests that coinfection with worms may be a factor in TB disease progression (2, 15), although some studies do not support this link, highlighting the complex nature of worm–TB interactions (16). Interestingly, research in laboratory animals suggests that enhanced immunity (i.e., resistance) to worms can compromise a host’s ability to control TB even in the absence of active worm infection (17–20), implying that evolved defenses against worms may independently affect the response to TB. Considered in light of widespread worm resistance in human and animal populations (21, 22) and the broad geographic coincidence of worms and TB, worm–TB interactions may represent an illustrative case where variation in evolved resistance to one pathogen (worms) contributes to variable responses to another (TB).In this study, we tested the hypothesis that resistance to worms modifies the host response to TB. To do this, we monitored gastrointestinal (GI) worm (specifically strongyle nematode) and Mb infections in a cohort of wild African buffalo (Syncerus caffer) to assess the effects of natural variation in worm resistance on the incidence, severity, and progression of bovine TB (BTB). In previous work, we demonstrated the presence of an ecological interaction between worms and BTB in buffalo by showing that clearance of active worm infection via anthelmintic treatment reduces BTB-associated mortality (23). Thus, we took advantage of the fact that half of our study animals were subject to long-term deworming to compare the relative effects of worm coinfection vs. natural worm resistance on BTB outcomes. We found evidence of a genetic basis to worm resistance in buffalo and that buffalo with resistance to worms were more severely affected by BTB in terms of both mortality risk and disease progression. However, the mechanisms by which natural variation in the host response to worms was associated with BTB progression appeared to be distinct from the effects of anthelmintic treatment. Our results suggest that negative effects of worms on BTB outcomes occur as a result of both concurrent worm infection and genetically based differences in host responsiveness to worms. This discovery fundamentally alters our understanding of the timescales over which worms and TB interact in real-world populations.     

Activity of lower limb muscles during treadmill running at different velocities

[Purpose] The present study aimed to determine changes in muscle activity while moving on a treadmill at various speeds. [Subjects] The activities of the left vastus lateralis, vastus medialis, hip adductors, lateral head of gastrocnemius, medial head gastrocnemius, soleus, and tibialis anterior of 10 healthy male university students were analyzed. [Methods] University students walked, jogged, and ran for 10 minutes each in random order, and then myogenic potentials were measured 10 minutes later for 30 seconds. The flexion angle of the lower limb upon initial contact, mid stance, and toe off were measured. [Results] The average walking, jogging, and running speeds were 3.6 ± 0.4, 6.7 ± 0.6, and 10.4 ± 1.3 km/h, respectively. The average electromyographic activities of the vastus medial, tibialis anterior, medial head of gastrocnemius, and lateral head of gastrocnemius significantly differed. All muscles were more active during jogging and running than walking. Only the soleus was more active during running than walking, and the activities of the hip adductors and vastus lateralis did not significantly differ. [Conclusion] Velocity is faster and the angles of the lower limbs and ground reaction force (GRF) are larger during running than walking. The vastus medialis and soleus worked more easily according to the angle of the knee joint, whereas the tibialis anterior worked more easily at faster velocities and the medial and lateral heads of the gastrocnemius worked more easily with an increased GRF.Key words: Walking, Running, Skeletal muscle     

Worldwide Distribution of Four SNPs in X‐Ray and Repair and Cross‐Complementing Group 1 (XRCC1)

Purpose

X‐ray repair cross‐complementing group 1 (XRCC1) repairs single‐strand breaks in DNA. Several reports have shown the association of single nucleotide polymorphisms (SNPs) (Arg194Trp, Pro206Pro, Arg280His, Arg399Gln) in XRCC1 to diseases. Limited population data are available regarding SNPs in XRCC1, especially in African populations. In this study, genotype distributions of four SNPs in worldwide populations were examined and compared with those reported previously.

Materials and Methods

Four SNPs (Arg194Trp, Pro206Pro, Arg280His, Arg399Gln) in XRCC1 from genomic DNA samples of 10 populations were evaluated by using polymerase chain reaction followed by restriction fragment length polymorphism analysis.

Results

The frequency of the minor allele corresponding to the Trp allele of XRCC1Arg194Trp was higher in Asian populations than in African and Caucasian populations. As for XRCC1Pro206Pro, Africans showed higher minor allele frequencies than did Asian populations, except for Tamils and Sinhalese. XRCC1 Arg280His frequencies were similar among Africans and Caucasians but differed among Asian populations. Similarly, lower mutant XRCC1 Arg399Gln frequencies were observed in Africans.

Conclusions

This study is the first to show the existence of a certain genetic heterogeneity in the worldwide distribution of four SNPs in XRCC1.