Isolated cortical tuber in an infant with genetically confirmed tuberous sclerosis complex 1 presenting with symptomatic West syndrome

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disorder caused by mutations in either TSC1 on chromosome 16 or TSC2 on chromosome 9, clinically characterized mainly by facial angiofibroma, epilepsy, and intellectual disability. Cortical dysplasias, subependymal nodules, and subependymal giant cell astrocytoma are characteristic central nervous system lesions among 11 major features in the current clinical diagnostic criteria for TSC. We encountered an unusual case of genetically confirmed TSC1 presenting with symptomatic West syndrome due to an isolated cortical dysplasia in the left occipital lobe of a six‐month‐old male infant who did not meet the clinical diagnostic criteria for TSC. The patient underwent left occipital lesionectomy at age 11 months and has been seizure‐free for nearly six years since then. Histological examination of the resection specimen revealed cortical neuronal dyslamination with abundant dysmorphic neurons and ballooned cells, consistent with focal cortical dysplasia (FCD) type IIb. However, the lesion was also accompanied by unusual features, including marked calcifications, dense fibrillary gliosis containing abundant Rosenthal fibers, CD34‐positive glial cells with abundant long processes confined to the dysplastic cortex, and multiple nodular lesions occupying the underlying white matter, consisting exclusively of ballooned cell and/or balloon‐like astrocytes with focal calcifications. Genetic testing for TSC1 and TSC2 using the patient's peripheral blood revealed a germline heterozygous mutation in exon 7 (NM_000368.5: c.526dupT, p.Tyr176fs) in TSC1. Isolated FCD with unusual features such as calcification, dense fibrillary gliosis, Rosenthal fibers and/or subependymal nodule‐like lesions in the white matter may indicate the possibility of a cortical tuber even without a clinical diagnosis of TSC. Identification of such histopathological findings has significant implications for early and accurate diagnosis and treatment of TSC, and is likely to serve as an important supplementary feature for the current clinical diagnostic criteria for TSC.     

Prevalence and diversity of Hepatozoon canis in naturally infected dogs in Japanese islands and peninsulas

Canine hepatozoonosis is a worldwide protozoal disease caused by Hepatozoon canis and Hepatozoon americanum and is transmitted by ixodid ticks, Rhipicephalus and Amblyomma spp., respectively. H. canis infection is widespread in Africa, Europe, South America, and Asia, including Japan. The objective of this study was to study the distribution pattern and diversity of H. canis in naturally infected dogs in nine Japanese islands and peninsulas. Therefore, 196 hunting dogs were randomly sampled during the period from March to September 2011 and the ages and sexes were identified. Direct microscopy using Giemsa-stained blood smears revealed H. canis gametocytes in the peripheral blood of 45 (23.6 %) dogs. Polymerase chain reaction (PCR) was performed on EDTA-anticoagulated blood, initially with the common primer set (B18S-F and B18S-R) amplifying the 1,665-bp portion of the 18S rRNA gene, and then with the specific primer set (HepF and HepR) amplifying about 660 bp fragments of the same gene. Based on PCR, 84 (42.9 %) dogs were positive using the common primer and 81 (41.3 %) were positive using the specific primer. The current investigation indicated that all screened areas, except for Sado Island and Atsumi Peninsula, were infected. Yaku Island had the highest infection rate (84.6 % in males and 100.0 % in females), while Ishigaki Island showed the lowest infection rates (8.3 % in males and 17.7 % in females). Both sexes were infected with no significant difference. However, diversity of infection among the surveyed islands and peninsulas was significantly different (P?<?0.05). Although H. canis has previously been reported in dogs in Japan, the higher infection rate described in the current study and the diversity of infection in a wide range of islands strongly encourage prospective studies dealing with the prevention and treatment of the infection in dogs, as well as control of ticks.     

Bacterial concentration and composition in liquid baby formula and a baby drink consumed with an artificial nipple

ObjectivesTo clarify the characteristics and growth of bacteria that may infiltrate liquid baby formula during feeding and after storage for more than 3 h, the transfer of oral bacteria through artificial nipples, and bacterial survival in liquid baby formula and a baby drink were examined immediately after drinking and after storage at 4 °C for 12 h and 24 h.MethodsThirteen human subjects (aged 19–24 years) were asked to drink approximately 50 mL of liquid baby formula and a baby drink, via the artificial nipple of a baby bottle. Samples of the remaining liquid after storage at 4 °C for 12 h and 24 h were inoculated onto blood agar plates and incubated anaerobically at 37 °C for 7 days. Genomic DNA was extracted from individual colonies, and the bacterial species were identified by 16S rRNA gene sequencing.ResultsThe mean concentrations of bacteria in the liquid baby formula were (2.6 ± 2.8) × 10⁴ and (4.1 ± 6.6) × 10⁴ colony-forming unit/mL after storage at 4 °C for 12 h and 24 h, respectively. Streptococcus (43.2%), Veillonella (9.3%), and Schaalia (8.2%) species were recovered from the remaining liquid baby formula after storage at 4 °C for 12 h. In contrast, no bacteria were detected in the remaining baby drink after storage at 37 °C for 24 h.ConclusionsThe levels of bacteria immediately after drinking and after storage at 4 °C for 12 h or 24 h were similar, suggesting that remaining liquid baby formula may be preserved safely in a refrigerator for more than 3 h.     

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.     

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.