Adjunctive corticosteroid therapy for inpatients with <Emphasis Type="Italic">Mycoplasma pneumoniae</Emphasis> pneumonia

Background

There is conflicting evidence regarding the benefit of adjunctive corticosteroid therapy in patients with Mycoplasma pneumoniae pneumonia. We hypothesised that corticosteroid therapy could reduce mortality and length of stay (LOS) in such patients.

Methods

Adult patients with M. pneumoniae pneumonia from January 2010 to December 2013 were identified from the Japanese Diagnosis Procedure Combination inpatient database. The effects of low-dose and high-dose corticosteroid therapies on mortality, LOS, drug costs and hyperglycaemia requiring insulin treatment were evaluated using propensity score analyses.

Results

Eligible patients (n?=?2228) from 630 hospitals were divided into no-corticosteroid (n?=?1829), low-dose corticosteroid (n?=?267) and high-dose corticosteroid (n?=?132) groups. The propensity score-matched pairs were generated from no-corticoid and low-dose corticoid groups (251 pairs), or no-corticoid and high-dose corticosteroid groups (120 pairs). Adjunctive corticosteroid therapy did not decrease 30-day mortality. In addition, both low-dose and high-dose corticosteroid therapies were associated with increases in LOS. Furthermore, hyperglycaemia requiring insulin treatment and drug cost increased with corticosteroid use.

Conclusions

Adjunctive treatment with low-dose or high-dose corticosteroids may not be beneficial in M. pneumoniae pneumonia.

     

Prolonged morphometric study of barnacles grown on soft substrata of hydrogels and elastomers

A long-term investigation of the shell shape and the basal morphology of barnacles grown on tough, double-network (DN) hydrogels and polydimethylsiloxane (PDMS) elastomer was conducted in a laboratory environment. The elastic modulus of these soft substrata varied between 0.01 and 0.47 MPa. Polystyrene (PS) (elastic modulus, 3 GPa) was used as a hard substratum control. It was found that the shell shape and the basal plate morphology of barnacles were different on the rigid PS substratum compared to the soft substrata of PDMS and DN hydrogels. Barnacles on the PS substratum had a truncated cone shape with a flat basal plate while on soft PDMS and DN gels, barnacles had a pseudo-cylindrical shape and their basal plates showed curvature. In addition, a large adhesive layer was observed under barnacles on PDMS, but not on DN gels. The effect of substratum stiffness is discussed in terms of barnacle muscle contraction, whereby the relative stiffness of the substratum compared to that of the muscle is considered as the key parameter.     

High cell‐autonomy of the anterior endomesoderm viewed in blastomere fate shift during regulative development in the isolated right halves of four‐cell stage Xenopus embryos

The isolated right half (RH) or left half (LH) of Xenopus embryos can undergo regulation so as to form well‐proportioned larvae. To assess how the combined actions of maternal determinants and cell–cell interactions contribute to form the well‐proportioned larvae, we quantitatively compared four‐cell stage blastomere fate between normal larvae and regulated larvae from RH embryos. In normal larvae, the clones of the right dorsal blastomere (RD) and right ventral blastomere (RV) were located unilaterally. In contrast, in regulated larvae: (i) the RD clone exclusively occupied the anterior endomesoderm (AE) derivatives, coinciding no RV progeny in those derivatives of normal larvae. The clone bilaterally populated tissues along the dorsal midline, which characteristically included the medial regions of both somites adjoining the notochord, with higher percentages on the right and anterior sides. (ii) The RV clone extensively compensated for the missing left side at the expense of its right side contribution, and bilaterally occupied the ventroposterior and also dorsal regions excluding the AE derivatives. This clone considerably populated, with altered orientations, the derivatives of the left half gastrocoel roof plate (GRP), the left half GRP being essential for laterality determination. These results show that the high cell‐autonomy in the AE constitutes a mechanism common to both normal and regulative development. In regulated larvae, cell–cell interactions shifted the midlines on the dorsal side slightly and the ventral side to a greater extent. The cell lineage difference in the left half GRP could result in a different utilization of maternal determinants in that area.     

Effect of yokukansan on psychophysiological insomnia evaluated using cyclic alternating pattern as an objective marker of sleep instability

In this open-label study using final evaluator blinding, the efficacy of yokukansan (YKS) was evaluated in six psychophysiological insomnia patients using the cyclic alternating pattern (CAP) method. YKS had no influence on objective sleep parameters by the Rechtschaffen & Kales method, but the CAP rate and CAP cycle frequency decreased significantly. In the subjective Visual Analog Scale test, significant improvement was seen in five items: tension, calmness, fatigue, heavy-headedness and lassitude. No adverse reactions were noted. YKS improved sleep quality without influencing sleep structure and showed no adverse reactions, suggesting that YKS is an effective antiinsomnia drug with good tolerability.

     

MyD88 associated ROS generation is crucial for Lactobacillus induced IL-12 production in macrophage

It is well known that some strains of lactic acid bacteria (LAB) can induce IL-12 which plays an important role in modulating immune responses. However, the mechanisms by which LAB induce IL-12 production remain unclear. Here, we examine the role of toll-like receptors (TLR's) and reactive oxygen species (ROS) in IL-12 production by LAB stimulated peritoneal macrophages. Our results indicate that a TLR is not necessary for IL-12 induction by LAB, whilst the universal adaptor protein, MyD88, is essential. Specific strains of LAB induced ROS that correlated with both the frequency of phagocytosis and IL-12 production. Reduction in IL-12 production by NADPH oxidase inhibitors or ROS scavengers demonstrates the crucial role of ROS in IL-12 induction. Interestingly, deficiency of TLR2, 4, 9 or MyD88 did not affect the phagocytosis of LAB strain KW3110, a potent IL-12 inducer, and ROS production was significantly reduced only in MyD88 deficient macrophages. These results suggest the existence of TLR-MyD88 independent LAB recognition and MyD88 related ROS induction mechanisms. We show here the importance of ROS for IL-12 induction and provide new insights into IL-12 induction by LAB.     

Discontinuous LYVE-1 expression in corneal limbal lymphatics: dual function as microvalves and immunological hot spots

LYVE-1(+) corneal lymphatics contribute to drainage and immunity. LYVE-1 is widely accepted as the most reliable lymphatic marker because of its continuous expression in lymphatic endothelium. LYVE-1 expression in corneal lymphatics has not been examined. In this study, we report intact CD31(+) corneal lymphatic capillary endothelial cells that do not express LYVE-1. The number of LYVE-1(-) gaps initially increased until 8 wk of age but was significantly reduced in aged mice. C57BL/6 mice showed a notably higher number of the LYVE-1(-)/CD31(+) lymphatic regions than BALB/c mice, which suggests a genetic predisposition for this histological feature. The LYVE-1(-) lymphatic gaps expressed podoplanin and VE-cadherin but not αSMA or FOXC2. Interestingly, the number of LYVE-1(-) gaps in FGF-2, but not VEGF-A, implanted corneas was significantly lower than in untreated corneas. Over 70% of the CD45(+) leukocytes were found in the proximity of the LYVE-1(-) gaps. Using a novel in vivo imaging technique for visualization of leukocyte migration into and out of corneal stroma, we showed reentry of extravasated leukocytes from angiogenic vessels into newly grown corneal lymphatics. This process was inhibited by VE-cadherin blockade. To date, existence of lymphatic valves in cornea is unknown. Electron microscopy showed overlapping lymphatic endothelial ends, reminiscent of microvalves in corneal lymphatics. This work introduces a novel corneal endothelial lymphatic phenotype that lacks LYVE-1. LYVE-1(-) lymphatic endothelium could serve as microvalves, supporting unidirectional flow, as well as immunological hot spots that facilitate reentry of stromal macropahges.     

Involvement of aquaporin-7 in the cutaneous primary immune response through modulation of antigen uptake and migration in dendritic cells

Dendritic cells (DCs) have the ability to present antigen and play a critical role in the induction of the acquired immune response. Skin DCs uptake antigen and subsequently migrate to regional draining lymph nodes (LNs), where they activate naive T cells. Here we show that the water/glycerol channel protein aquaporin 7 (AQP7) is expressed on epidermal and dermal DCs and involved in the initiation of primary immune responses. AQP7-deficient DCs showed a decreased cellular uptake of low-molecular-mass compounds (fluorescein isothiocyanate and Lucifer yellow) and high-molecular-mass substances (ovalbumin and dextran), suggesting that AQP7 is involved in antigen uptake. AQP7-deficient DCs also exhibited reduced chemokine-dependent cell migration in comparison to wild-type DCs. Consistent with these in vitro results, AQP7-deficient mice demonstrated a reduced accumulation of antigen-retaining DCs in the LNs after antigen application to the skin, which could be attributed to decreased antigen uptake and migration. Coincidentally, AQP7-deficient mice had impaired antigen-induced sensitization in a contact hypersensitivity model. These observations suggested that AQP7 in skin DCs is primarily involved in antigen uptake and in the subsequent migration of DCs and is responsible for antigen presentation and the promotion of downstream immune responses.     

Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and?a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.     

Protective role of cell division cycle 48 (CDC48) protein against neurodegeneration via ubiquitin-proteasome system dysfunction during zebrafish development

Cell division cycle 48 (CDC48), a ubiquitin-dependent molecular chaperone, is thought to mediate a variety of degradative and regulatory processes and maintain cellular homoeostasis. To investigate the protective function of CDC48 against accumulated ubiquitinated proteins during neurodevelopment, we developed an in vivo bioassay technique that detects expression and accumulation of fluorescent proteins with a polyubiquitination signal at the N terminus. When we introduced CDC48 antisense morpholino oligonucleotides into zebrafish embryos, the morphant embryos were lethal and showed defects in neuronal outgrowth and neurodegeneration, and polyubiquitinated fluorescent proteins accumulated in the inner plexiform and ganglion cell layers, as well as the diencephalon and mesencephalon, indicating that the degradation of polyubiquitinated proteins by the ubiquitin-proteasome system was blocked. These abnormal phenotypes in the morphant were rescued by CDC48 or human valosin-containing protein overexpression. Therefore, the protective function of CDC48 is essential for neurodevelopment.