Abnormal motor cortical plasticity as a useful neurophysiological biomarker for Alzheimer's disease pathology.

OBJECTIVE: Amyloid-beta (Aß) and tau accumulations impair long-term potentiation (LTP) induction in animal hippocampi. We investigated relationships between motor-cortical plasticity and biomarkers for Alzheimer's disease (AD) diagnosis in subjects with cognitive decline. METHODS: Twenty-six consecutive subjects who complained of memory problems participated in this study. We applied transcranial quadripuse stimulation with an interstimulus interval of 5 ms (QPS5) to induce LTP-like plasticity. Motor-evoked potentials were recorded from the right first-dorsal interosseous muscle before and after QPS5. Cognitive functions, Aß42 and tau levels in the cerebrospinal fluid (CSF) were measured. Amyloid positron-emission tomography (PET) with11C-Pittsburg compound-B was also conducted. We studied correlations of QPS5-induced plasticity with cognitive functions or AD-related biomarkers. RESULTS: QPS5-induced LTP-like plasticity positively correlated with cognitive scores. The degree of LTP-like plasticity negatively correlated with levels of CSF-tau, and the amount of amyloid-PET accumulation at the precuneus, and correlated with the CSF-Aß42 level positively. In the amyloid-PET positive subjects, non-responder rate of QPS5 was higher than the CSF-tau positive rate. CONCLUSIONS: Findings suggest that QPS5-induced LTP-like plasticity is a functional biomarker of AD. QPS5 could detect abnormality at earlier stages than CSF-tau in the amyloid-PET positive subjects. SIGNIFICANCE: Assessing motor-cortical plasticity could be a useful neurophysiological biomarker for AD pathology.

Unidirectional titanium fiber-reinforced porous titanium with mechanical properties suitable for load-bearing biomaterials.

Biomaterials for load-bearing implants are expected to exhibit mechanical biocompatibility of low stiffness and high strength for avoiding stress shielding and failure of the implants in vivo, respectively. This study aimed to develop porous titanium (Ti) reinforced with long Ti fibers so that the porous Ti exhibited low Young's modulus and high tensile strength. The unidirectional Ti fiber-reinforced porous Ti with porosities (p) of 40%-58% and volume percentages of Ti fiber (Vf) of 3%-33% has been successfully fabricated via the space holder technique. Mechanical testing revealed that its strength was improved, compared with uniform porous Ti because Ti fibers prevent microscopic damage progress. The porous Ti with p = 40% and Vf = 33% exhibited the strength of 233 MPa and Young's modulus of 26 GPa, which were higher than and comparable to those of natural bones, respectively. Hence, the Ti fiber-reinforced porous Ti exhibited ideal mechanical properties for implant applications.

Association between reduced left ventricular ejection fraction and peritoneal dialysis related peritonitis: a single center retrospective cohort study in Japan.

We present a single-center retrospective analysis of 228 Japanese patients with peritoneal dialysis, in which we examined whether reduced left ventricular ejection fraction (LVEF) is a risk factor for peritonitis development. Time-dependent multivariable-adjusted Cox proportional hazards models revealed that reduced LVEF (LVEF < 50% vs. preserved LVEF ≥ 50%, hazard ratio (HR) 2.10; 95% confidence interval (CI) 1.16-3.82) was associated with peritonitis. Qualitatively, similar associations with reduced LVEF (< 50%) were observed for enteric peritonitis (adjusted HR 7.68; 95% CI 2.51-23.5) but not for non-enteric peritonitis (adjusted HR 1.15; 95% CI 0.54-2.44). Reduced LVEF is associated with a significantly higher risk of subsequent peritonitis, particularly enteric peritonitis. These results indicate that patients with reduced LVEF may be at risk of enteric peritonitis from bowel sources caused by intestinal involvement due to cardiac dysfunction.

Wavefront accuracy of mechanically assembled all-cordierite reflective optical system for cryogenic applications.

Although a reflective optical system can theoretically realize ideal optical designs, it is not always the optimal choice compared with a refractive one because of the difficulty in achieving high wavefront accuracy. A promising solution is to build reflective optical systems by mechanically assembling all the optical and structural components made of cordierite, which is a ceramic with a very low thermal expansion coefficient. Interferometric evaluations of an experimental product demonstrated that diffraction-limited performance in the visible wavelength was achieved and maintained even after cooling to 80 K. This new technique may be the most cost-effective method for utilizing reflective optical systems, especially for cryogenic applications.

[Efficacy and Safety of Trastuzumab Biosimilars in Combination with Pertuzumab].

Although trastuzumab biosimilars have been approved based on clinical studies on their use as monotherapy or in combination with chemotherapy, clinical studies on their combination with pertuzumab are lacking. Data on the efficacy and safety of this combination are scarce. We evaluated the efficacy and safety of trastuzumab biosimilars in combination with pertuzumab. Progression-free survival was 10.5 months(95% confidence interval[CI]: 3.3-16.3)for a reference biological product and 8.7 months(2.1-not applicable)for biosimilars with a hazard ratio of 0.96(95%CI: 0.29-3.13, p=0.94); however, no statistically significant difference was observed. The incidence of adverse events was not significantly different between the reference biological product and biosimilars, and no increase was observed for any adverse events after switching to the biosimilars. The results of this study verify that a combination of trastuzumab biosimilars with pertuzumab is sufficiently effective and safe in clinical practice.

Osteoarticular infections at a pediatric emergency core hospital in Japan.

OBJECTIVES: Osteomyelitis (OM) and septic arthritis (SA) in childhood might cause complications, sequelae, or even death if diagnosis and treatment are delayed. Here, we examined the outcomes of OM/SA at a pediatric emergency core hospital in Japan. METHODS: This was a single-center, retrospective, observational cohort study at a pediatric emergency core hospital in Japan. Pediatric outpatients who underwent magnetic resonance imaging at the hospital in the period 2012?2020 were recruited. Primary outcomes were sequelae, recurrent symptoms, chronicity, and death. RESULTS: Fifteen OM/SA patients (9 OM, 4 SA, 2 OM+SA) were recruited. The identified major pathogens included methicillin-susceptible Staphylococcus aureus (40.0 %, n=6) and methicillin-resistant S. aureus (13.3 %, n=2). Mean time from onset to first hospital visit, hospitalization, and initiation of effective antibiotics was 2 days, 3.9?±?1.8 days, and 4.9±2.2 days, respectively. All OM/SA patients recovered without complications or sequelae. CONCLUSIONS: In this study, all patients with OM/SA showed a good prognosis. Despite the small sample size, this pilot study suggests that the pediatric emergency core system in Japan provides early treatment and a good prognosis for patients diagnosed with OM/SA. J. Med. Invest. 70 : 236-240, February, 2023.

Pre-treatment hematuria and crescents predict estimated glomerular filtration rate trajectory after methylprednisolone pulse therapy with tonsillectomy for IgA nephropathy.

BACKGROUND: Glomerular hematuria and proteinuria are typical manifestations of IgA nephropathy (IgAN). However, hematuria severity is not considered a useful marker of the potential benefits of corticosteroid administration as proteinuria severity only is included in the current guidelines. METHODS: In this retrospective cohort study, we enrolled 133 patients diagnosed with IgAN through biopsy. We calculated the 2-year estimated glomerular filtration rate (eGFR) slope (mL/min/1.73m2/year) and eGFR trajectory after methylprednisolone pulse therapy using mixed effects models stratified by the Oxford classification and three categories of pre-treatment hematuria: mild [urinary red blood cells (URBCs) < 10/high-power field (HPF)], moderate (URBCs 10-30/HPF), and severe (URBCs ≥ 30/HPF). RESULTS: The severe pre-treatment hematuria group showed a significantly higher likelihood of having crescents (odds ratio (OR), 4.3; 95% confidence interval (CI), 1.7-10.9). In the longitudinal analysis of 103 patients, most of whom underwent tonsillectomy, the severe pre-treatment hematuria group had a significantly higher 2-year eGFR slope after methylprednisolone pulse therapy than the mild and moderate hematuria groups (mild, -0.52 ± 1.97; moderate, -0.32 ± 1.99; severe, 1.44 ± 3.20 mL/min/1.73m2/year). Patients with C2 scores showed a significantly higher 2-year eGFR slope after methylprednisolone pulse therapy than those with C0 and C1 scores (C0, -0.38 ± 1.74; C1, 0.81 ± 3.02; C2, 3.29 ± 3.68 mL/min/1.73m2/year). Analyses of eGFR trajectory after methylprednisolone pulse therapy revealed that the eGFR improved only in patients with severe pre-treatment hematuria or C2 score (Pinteraction with time < 0.001). CONCLUSIONS: The eGFR is likely to improve after methylprednisolone pulse therapy with tonsillectomy in IgAN patients with severe pre-treatment hematuria or a high percentage of crescents.

The expression of prosaposin and its receptors, GRP37 and GPR37L1, are increased in the developing dorsal root ganglion.

Prosaposin (PSAP), a highly conserved glycoprotein, is a precursor of saposins A-D. Accumulating evidence suggests that PSAP is a neurotrophic factor, as well as a regulator of lysosomal enzymes. Recently, the orphan G-protein-coupled receptors GPR37 and GPR37L1 were recognized as PSAP receptors, but their functions have not yet been clarified. In this study, we examined the distribution of PSAP and its receptors in the dorsal root ganglion (DRG) during development using specific antibodies, and showed that PSAP accumulates primarily in lysosomes and is dispersed throughout the cytoplasm of satellite cells. Later, PSAP colocalized with two receptors in satellite cells, and formed a characteristic ring shape approximately 8 weeks after birth, during a period of rapid DRG development. This ring shape, which was only observed around larger neurons, is evidence that several satellite cells are synchronously activated. We found that sortilin, a transporter of a wide variety of intracellular proteins containing PSAP, is strongly localized to the inner side of satellite cells, which contact the neuronal surface. These findings suggest that PSAP and GPR37/GPR37L1 play a role in activating both satellite and nerve cells.

Prosaposin in the rat oviductal epithelial cells.

Prosaposin (PSAP) has two forms: a precursor and a secreted form. The secreted form has neurotrophic, myelinotrophic, and myotrophic properties. The precursor form is a precursor protein of saposins A-D. Although the distribution of PSAP in male reproductive organs is well known, its distribution in female reproductive organs, especially in the oviduct, is unclear. Immunoblots and immunohistochemistry of oviducts showed that oviductal tissues contain PSAP proteins, and a significant increase in PSAP was observed in the estrus-metestrus phase compared to the diestrus-proestrus phase in the ampulla. To identify PSAP trafficking in cells, double-immunostaining was performed with antibodies against PSAP in combination with sortilin, mannose 6 phosphate receptor (M6PR), or low-density lipoprotein receptor-related protein 1 (LRP1). PSAP and sortilin double-positive reactions were observed near the nuclei, as well as in the apical portion of microvillous epithelial cells, whereas these reactions were only observed near the nuclei of ciliated epithelial cells. PSAP and M6PR double-positive reactions were observed near the nuclei of microvillous and ciliated epithelial cells. PSAP and M6PR double-positive reactions were also observed in the apical portion of microvillous epithelial cells. PSAP and LRP1 double-positive reactions were observed in the plasma membrane and apical portion of both microvillous and ciliated epithelial cells. Immunoelectron staining revealed PSAP immunoreactive small vesicles with exocytotic features at the apical portion of microvillous epithelial cells. These findings suggest that PSAP is present in the oviductal epithelium and has a pivotal role during pregnancy in providing an optimal environment for gametes and/or sperm in the ampulla.

Proton pump inhibitor use increases the risk of peritonitis in peritoneal dialysis patients.

Peritonitis is a major and the most significant complication of peritoneal dialysis (PD). Although some predictors of peritonitis in PD patients are known, the association between proton pump inhibitor (PPI) use and peritonitis has not been characterized. Here, we examined whether PPI use is a risk factor for the development of peritonitis, based on a single-center retrospective analysis of 230 consecutive Japanese PD patients at Narita Memorial Hospital. We assessed the association between PPI use and subsequent first episode of peritonitis using multivariate Cox proportional hazards models, following adjustment for clinically relevant factors. The median follow-up period was 36 months (interquartile range, 19-57 months). In total, 86 patients (37.4%) developed peritonitis. Analysis with multivariate Cox proportional hazards models revealed the following significant predictors of peritonitis: PPI use (adjusted hazard ratio [HR] = 1.72, 95% confidence interval [CI]: 1.11-2.66; P = 0.016) and low serum albumin level (per g/dl adjusted HR = 0.59, 95% CI: 0.39-0.90; P = 0.014). Thus, PPI use was independently associated with PD-related peritonitis. The results suggest that nephrology physicians should exercise caution when prescribing PPIs for PD patients.

Growth promotion of three microalgae, Chlamydomonas reinhardtii, Chlorella vulgaris and Euglena gracilis, by in situ indigenous bacteria in wastewater effluent.

BACKGROUND: Microalgae are a promising biomass feedstock for biofuels production. The use of wastewater effluent as a nutrient medium would improve the economics of microalgal biofuels production. Bacterial communities in aquatic environments may either stimulate or inhibit microalgal growth. Microalgal productivity could be enhanced if the positive effects of indigenous bacteria could be exploited. However, much is unknown about the effects of indigenous bacteria on microalgal growth and the characteristics of bacterial communities associated with microalgae in microalgae-effluent culture. To assess the effects of the indigenous bacteria in wastewater effluent on microalgal growth, three microalgae, Chlamydomonas reinhardtii, Chlorella vulgaris, and Euglena gracilis, were cultured in two municipal wastewater effluents and one swine wastewater effluent with and without indigenous bacteria for 7 days. RESULTS: All microalgae grew better in all effluents with indigenous bacteria than without bacteria. Biomass production of C. reinhardtii, C. vulgaris, and E. gracilis increased > 1.5, 1.8-2.8, and > 2.1-fold, respectively, compared to the axenic cultures of each microalga. The in situ indigenous bacterial communities in the effluents therefore promoted the growth of the three microalgae during 7-day cultures. Furthermore, the total numbers of bacterial 16S rRNA genes in the 7-day microalgae-effluent cultures were 109‒793 times the initial numbers. These results suggest that the three microalgae produced and supplied organic carbon that supported bacterial growth in the effluent. At the phylum and class levels, Proteobacteria (Alphaproteobacteria and Betaproteobacteria) and Bacteroidetes (Sphingobacteriia and Saprospirae) were selectively enriched in all microalgae-effluent cultures. The enriched core bacterial families and genera were functions of the microalgal species and effluents. These results suggest that certain members of the bacterial community promote the growth of their "host" microalgal species. CONCLUSION: To enhance their own growth, microalgae may be able to selectively stimulate specific bacterial groups from among the in situ indigenous bacterial community found in wastewater effluent (i.e., microalgae growth-promoting bacteria: MGPB). The MGPB from effluent cultures could be used as "probiotics" to enhance microalgal growth in effluent culture. Wastewater effluent may therefore be a valuable resource, not only of nutrients, but also of MGPB to enable more efficient microalgal biomass production.

Prosaposin and its receptors are differentially expressed in the salivary glands of male and female rats.

Salivary glands produce various neurotrophins that are thought to regulate salivary function during normal and pathological conditions. Prosaposin (PSAP) is a potent neurotrophin found in several tissues and various biological fluids and may play roles in the regulation of salivary function. However, little is known about PSAP in salivary glands. As the functions of salivary glands are diverse based on age and sex, this study examines whether PSAP and its receptors, G protein-coupled receptor 37 (GPR37) and GPR37L1, are expressed in the salivary glands of rats and whether sex and aging affect their expression. Immunohistochemical analysis revealed that PSAP and its receptors were expressed in the major salivary glands of rats, although their expression varied considerably based on the type of gland, acinar cells, age and sex. In fact, PSAP, GPR37 and GPR37L1 were predominantly expressed in granular convoluted tubule cells of the submandibular gland and the intensity of their immunoreactivity was higher in young adult female rats than age-matched male rats, which was more prominent at older ages (mature adult to menopause). On the other hand, weak PSAP, GPR37 and GPR37L1 immunoreactivity was observed mainly in the basal layer of mucous cells of the sublingual gland. Triple label immunofluorescence analysis revealed that PSAP, GPR37 and GPR37L1 were co-localized in the basal layer of acinar and ductal cells in the major salivary glands. The present findings indicate that PSAP and its receptors, GPR37 and GPR37L1, are expressed in the major salivary glands of rats and their immunoreactivities differ considerably with age and sex.

A year-round evidence-based medicine-learning course organized by medical students at Ehime University.

To resolve the problem that evidence-based medicine (EBM) courses are not sufficiently taught in Japanese medical schools, we organized a year-round EBM-learning course. This study was an observational study and was designed to evaluate the participants' understanding of EBM using an original survey. The survey was given three times. In total, 18 students responded to our survey. Of those 18 students, six students answered both the first and the last surveys, and their mean score increased 1.17 of 4.00 (95% CI: 0.72-1.65). These results suggest our course improved students' ability to read clinical articles.

Membranous glomerulonephropathy in a patient with bullous pemphigoid.

Bullous pemphigoid (BP) is a common autoimmune blistering disease that can be complicated by autoimmune disorders. We describe a patient with BP who developed membranous glomerulonephropathy (MN). Proteinuria decreased during the clinical course as anti-BP180 antibody titers decreased. This finding suggested an association between the pathogenesis of these two diseases in terms of immunological disorders.

Enhancement of Thermosensitivity of Gel-Immobilized Tunable Colloidal Photonic Crystals with Anisotropic Contraction.

A thermosensitive poly(N-isopropylacrylamide) (PNIPAM) circular gel film containing single-crystalline colloidal crystals was prepared, and the circular edge was pinched with washers to restrain the in-plane shrinkage of the gel film. Upon heating, the film shrunk in the thickness direction selectively, resulting in a change in the crystal structure of colloids embedded in the anisotropic shrunken gel. This led to the manipulation of the optical stop-band wavelength of the colloidal photonic crystals with a higher thermosensitivity and over a wider range of wavelengths covering a wide margin on either side of the visible-light region. The present method for enhancement of the sensitivity is very simple, and the principle should also be applicable to the gel-immobilized colloidal crystals that respond to stimuli other than temperature changes. The present findings contribute to the progress of practical applications of gel-immobilized colloidal photonic crystals as tunable photonic crystals and biological and chemical sensors.

Interneurons secrete prosaposin, a neurotrophic factor, to attenuate kainic acid-induced neurotoxicity.

Prosaposin (PS) is a secretory neurotrophic factor, as well as a regulator of lysosomal enzymes. We previously reported the up-regulation of PS and the possibility of its axonal transport by GABAergic interneurons after exocitotoxicity induced by kainic acid (KA), a glutamate analog. In the present study, we performed double immunostaining with PS and three calcium binding protein markers: parvalbumin (PV), calbindin, and calretinin, for the subpopulation of GABAergic interneurons, and clarified that the increased PS around the hippocampal pyramidal neurons after KA injection existed mainly in the axons of PV positive interneurons. Electron microscopy revealed PS containing vesicles in the PV positive axon. Double immunostaining with PS and secretogranin or synapsin suggested that PS is secreted with secretogranin from synapses. Based on the results from in situ hybridization with two alternative splicing forms of PS mRNA, the increase of PS in the interneurons was due to the increase of PS + 0 (mRNA without 9-base insertion) as in the choroid plexus, but not PS + 9 (mRNA with 9-base insertion). These results were similar to those from the choroid plexus, which secretes an intact form PS + 0 to the cerebrospinal fluid. Neurons, especially PV positive GABAergic interneurons, produce and secrete the intact form of PS around hippocampal pyramidal neurons to protect them against KA neurotoxicity.

Randomized double-blind placebo-controlled multicenter trial of Yokukansan for neuropsychiatric symptoms in Alzheimer's disease.

AIM: Yokukansan (YKS), a traditional herbal medicine, has been used to treat behavioral and psychological symptoms of dementia (BPSD). The present study is the first double-blind, randomized, placebo-controlled trial to determine the efficacy and safety of YKS for the treatment of BPSD in Alzheimer's disease (AD). METHODS: A total of 22 sites consisting of clinics, hospitals and nursing homes participated. A total of 145 patients with AD were randomized. Active YKS (7.5 g/day) and placebo were supplied to 75 and 70 participants, respectively. The primary outcome measure was the 4-week change in total score of the Neuropsychiatric Inventory Brief Questionnaire Form (NPI-Q), an instrument that evaluates BPSD. Secondary outcome measures included 12-week changes in NPI-Q scores, changes in NPI-Q subcategory scores and total scores of the Mini-Mental-State Examination. RESULTS: Four-week changes in NPI-Q total scores did not differ significantly between the treatment and placebo groups. There were also no significant differences between groups in 12-week changes in total NPI-Q scores, NPI-Q subcategory scores or total Mini-Mental-State Examination scores. However, a subgroup with fewer than 20 points on the Mini-Mental-State Examination at baseline showed a greater decrease in "agitation/aggression" score in the YKS group than in the placebo group (P = 0.007). No serious adverse effects were observed during the study. CONCLUSIONS: Our data did not reach statistical significance regarding the efficacy of YKS against BPSD; however, YKS improves some symptoms including "agitation/aggression" and "hallucinations" with low frequencies of adverse events. Geriatr Gerontol Int 2017; 17: 211-218.

Unusual case of tacrolimus vascular toxicity after deceased donor renal transplantation.

We report a case of tacrolimus vascular toxicity found on a protocol biopsy shortly after a deceased donor renal transplantation. The patient was immunologically high-risk and acute antibody-mediated rejection during post-transplant dialysis phase was suspected on the protocol biopsy. Although the patient was stable after treatment of rejection, a further examination showed a very rare but specific side-effect of tacrolimus. It is sometimes difficult to make a differential diagnosis during postoperative dialysis period among AMR, primary non-functioning, drug toxicity, infection or just prolonged recovery from the damage of a long agonal phase on the non-heart beating donor. Although the possibilities of coexistence of rejection or other causes such as infection have not been completely excluded, it is important to be aware of this unusual side effect of tacrolimus.

Streptococcal Infection-related Nephritis (SIRN) Manifesting Membranoproliferative Glomerulonephritis Type I.

We herein report the case of an 18-year-old boy who developed nephrotic syndrome and hypertension after upper airway inflammation. Post-streptococcal acute glomerulonephritis was diagnosed on the basis of a high antistreptolysin O titer, hypocomplementemia, proteinuria, and microscopic hematuria. A renal biopsy was performed due to persistent proteinuria, and the pathological diagnosis was membranoproliferative glomerulonephritis (MPGN) type I. Glomeruli showed positive staining for nephritis-associated plasmin receptor (NAPlr), a nephritogenic group A streptococcal antigen, and plasmin activity was found in a similar distribution as NAPlr deposition. This rare case of streptococcal infection-related nephritis (SIRN) manifesting MPGN type I supports the histological diversity of SIRN.

Machined immersion grating with theoretically predicted diffraction efficiency.

An immersion grating composed of a transmissive material with a high refractive index (n>2) is a powerful device for high-resolution spectroscopy in the infrared region. Although the original idea is attributed to Fraunhofer about 200 years ago, an immersion grating with high diffraction efficiency has never been realized due to the difficulty in processing infrared crystals that are mostly brittle. While anisotropic etching is one successful method for fabricating a fine groove pattern on Si crystal, machining is necessary for realizing the ideal groove shape on any kind of infrared crystal. In this paper, we report the realization of the first, to the best of our knowledge, machined immersion grating made of single-crystal CdZnTe with a high diffraction efficiency that is almost identical to that theoretically predicted by rigorous coupled-wave analysis.