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Children with neurodegenerative disease often have debilitating gastrointestinal symptoms. We hypothesized that this may be due at least in part to underappreciated degeneration of neurons in the enteric nervous system (ENS), the master regulator of bowel function. To test this hypothesis, we evaluated mouse models of neuronal ceroid lipofuscinosis type 1 and 2 (CLN1 and CLN2 disease, respectively), neurodegenerative lysosomal storage disorders caused by deficiencies in palmitoyl protein thioesterase-1 and tripeptidyl peptidase-1, respectively. Both mouse lines displayed slow bowel transit in vivo that worsened with age. Although the ENS appeared to develop normally in these mice, there was a progressive and profound loss of myenteric plexus neurons accompanied by changes in enteric glia in adult mice. Similar pathology was evident in colon autopsy material from a child with CLN1 disease. Neonatal administration of adeno-associated virus-mediated gene therapy prevented bowel transit defects, ameliorated loss of enteric neurons, and extended survival in mice. Treatment after weaning was less effective than treating neonatally but still extended the lifespan of CLN1 disease mice. These data provide proof-of-principle evidence of ENS degeneration in two lysosomal storage diseases and suggest that gene therapy can ameliorate ENS disease, also improving survival.

Perineural spread (PNS) from pelvic carcinoma has been regarded as a pathway to muscle and bone metastasis. However, few cases have been reported, especially in patients with bladder carcinoma. In the present report, we discuss a case of diffuse cancer involvement in the muscle 5 years after radical cystectomy for advanced bladder carcinoma. Careful observation of temporal changes on medical images confirmed PNS as the pathway to muscle metastasis (i.e., primary PNS). Our report presents early and post-treatment CT, MRI and FDG-PET/CT findings of PNS from the bladder carcinoma.

GABAergic interneuron deficits have been implicated in the epileptogenesis of multiple neurological diseases. While epileptic seizures are a key clinical hallmark of CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), the etiology of these seizures remains elusive. Given that Cln2 R207X/R207X mice display fatal spontaneous seizures and an early loss of several cortical interneuron populations, we hypothesized that those two events might be causally related. To address this hypothesis, we first generated an inducible transgenic mouse expressing lysosomal membrane-tethered TPP1 (TPP1LAMP1) on the Cln2 R207X/R207X genetic background to study the cell-autonomous effects of cell-type-specific TPP1 deficiency. We crossed the TPP1LAMP1 mice with Vgat-Cre mice to introduce interneuron-specific TPP1 deficiency. Vgat-Cre ; TPP1LAMP1 mice displayed storage material accumulation in several interneuron populations both in cortex and striatum, and increased susceptibility to die after PTZ-induced seizures. Secondly, to test the role of GABAergic interneuron activity in seizure progression, we selectively activated these cells in Cln2 R207X/R207X mice using Designer Receptor Exclusively Activated by Designer Drugs (DREADDs) in in Vgat-Cre : Cln2 R207X/R207X mice. EEG monitoring revealed that DREADD-mediated activation of interneurons via chronic deschloroclozapine administration accelerated the onset of spontaneous seizures and seizure-associated death in Vgat-Cre : Cln2 R207X/R207X mice, suggesting that modulating interneuron activity can exert influence over epileptiform abnormalities in CLN2 disease. Taken together, these results provide new mechanistic insights into the underlying etiology of seizures and premature death that characterize CLN2 disease.

Vitamin D deficiency during infancy has been associated with increased bone turnover rate and bone mineral loss. However, few studies have examined bone turnover markers (BTMs) for both bone formation and resorption in infants with vitamin D deficiency. Here, we analyzed serum concentrations of 25OHD, intact parathormone (iPTH), and BTMs including total alkaline phosphatase (ALP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), and serum type I collagen N-telopeptide (NTx) as well as basic clinical characteristics of 456 infants (626 samples) aged less than 12 mo born at Saitama City Hospital, Japan (latitude 35.9° North) between January 2021 and December 2022. One hundred sixteen infants (147 samples) were classified as having vitamin D deficiency (25OHD < 12.0 ng/mL), and 340 infants (479 samples) had sufficient vitamin D levels (25OHD ≥ 12.0 ng/mL). In addition to 25OHD and ALP, both TRACP-5b and sNTx were measured in 331 infants (418 samples), while 90 infants (105 samples) had only TRACP-5b measured and 101 infants (103 samples) had only sNTx measured. Statistical comparison of 104 subjects each in the vitamin D deficiency and sufficiency groups after matching for the background characteristics revealed that the vitamin D deficiency group had significantly higher levels of ALP and iPTH compared with the sufficiency group ( P  = <.0001, .0012, respectively). However, no significant differences were found in TRACP-5b and NTx levels between the 2 groups ( P  = .19, .08, respectively). Our findings suggest discordant responses between bone formation and resorption markers in subclinical vitamin D deficiency during infancy., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)

Late-infantile neuronal ceroid lipofuscinosis (LINCL) and juvenile neuronal ceroid lipofuscinosis (JNCL) are inherited neurodegenerative diseases caused by mutations in the genes encoding lysosomal proteins tripeptidyl peptidase 1 (TPP1) and CLN3 protein, respectively. TPP1 is well-understood and, aided by animal models that accurately recapitulate the human disease, enzyme replacement therapy has been approved and other promising therapies are emerging. In contrast, there are no effective treatments for JNCL, partly because the function of the CLN3 protein remains unknown but also because animal models have attenuated disease and lack robust survival phenotypes. Mouse models for LINCL and JNCL, with mutations in Tpp1 and Cln3, respectively, have been thoroughly characterized but the phenotype of a double Cln3/Tpp1 mutant remains unknown. We created this double mutant and find that its phenotype is essentially indistinguishable from the single Tpp1 -/- mutant in terms of survival and brain pathology. Analysis of brain proteomic changes in the single Tpp1 -/- and double Cln3 -/- ;Tpp1 -/- mutants indicates largely overlapping sets of altered proteins and reinforces earlier studies that highlight GPNMB, LYZ2, and SERPINA3 as promising biomarker candidates in LINCL while several lysosomal proteins including SMPD1 and NPC1 appear to be altered in the Cln3 -/- animals. An unexpected finding was that Tpp1 heterozygosity significantly decreased lifespan of the Cln3 -/- mouse. The truncated survival of this mouse model makes it potentially useful in developing therapies for JNCL using survival as an endpoint. In addition, this model may also provide insights into CLN3 protein function and its potential functional interactions with TPP1., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

Vitamin D seasonality has been reported in adults and children, suggesting that sunlight exposure has effects on 25(OH)D production. While vitamin D deficiency among infants has received significant attention, little is known about the extent to which vitamin D status during early infancy is affected by sunlight exposure. Here, we retrospectively analysed serum 25(OH)D levels of 692 samples obtained from healthy infants aged 1-2 months born at Saitama City Hospital, Japan (latitude 35·9° North) between August 2017 and September 2021. Data regarding the frequency of outdoor activities, formula intake and BMI were also collected and analysed. Month-to-month comparisons of vitamin D levels revealed significant variation in 25(OH)D levels in breastfed infants starting at 2 months, with maximal and minimal levels in September and January, respectively. An outdoor activity score of 0 was most common at 1 month (83·9 %) and a score of 3 was most common at 2 months (81·2 %), suggesting an increased amount of sunlight exposure at 2 months. Multiple linear regression analysis revealed the amount of formula intake to be significantly associated with vitamin D status at both 1 ( t = 17·96) and 2 months ( t = 16·30). Our results comprise the first evidence that seasonal variation of vitamin D begins at 2 months among breastfed infants from East Asia, though dietary intake appears to be the major determinant of vitamin D status. These findings provide new insights into the influence of dietary and non-dietary factors on vitamin D status during early infancy.

Background: The etiology of Bednar's aphthae remains unclear. Our aim was to investigate the incidence of, and factors associated with, Bednar's aphthae in a Japanese newborn cohort., Methods: A retrospective cross-sectional study was conducted on neonates discharged from the well-baby nursery at Saitama City Hospital, Japan. The principal investigator carefully examined each neonate's oral cavity, up to and including the pharynx, with a light-emitting diode (LED) headlight to determine the presence of Bednar's aphthae. Maternal and neonatal clinical characteristics were first compared between neonates with and those without Bednar's aphthae by univariate analysis. Variables with significant inter-group differences upon univariate analysis were entered into a multivariable logistic-regression model., Results: This study enrolled 1996 infants. We observed Bednar's aphthae in 9.3% of the Japanese newborn infants who were included. When restricted to infants who were born via vaginal delivery, 13.2% of them had aphthae. Multivariable logistic regression analysis identified vaginal delivery (odds ratio = 6.19, p < 0.0001) in Model 1, and vaginal delivery (odds ratio = 6.73, p < 0.0001) and birth weight (odds ratio = 0.9995, p = 0.034) in Model 2 as independent risk factors for the disease., Conclusion: This is the first report of the prevalence of Bednar's aphthae among Japanese neonates. Vaginal delivery was identified as the strongest risk factor. Although confounding between mode of delivery and mechanical stimuli associated with sucking was not found in this study, the findings pave the way for a better understanding of the etiology of Bednar's aphthae., (© 2023 Japan Pediatric Society.)

CLN1 disease, also called infantile neuronal ceroid lipofuscinosis (NCL) or infantile Batten disease, is a fatal neurodegenerative lysosomal storage disorder resulting from mutations in the CLN1 gene encoding the soluble lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1). Therapies for CLN1 disease have proven challenging because of the aggressive disease course and the need to treat widespread areas of the brain and spinal cord. Indeed, gene therapy has proven less effective for CLN1 disease than for other similar lysosomal enzyme deficiencies. We therefore tested the efficacy of enzyme replacement therapy (ERT) by administering monthly infusions of recombinant human PPT1 (rhPPT1) to PPT1-deficient mice (Cln1-/-) and CLN1R151X sheep to assess how to potentially scale up for translation. In Cln1-/- mice, intracerebrovascular (i.c.v.) rhPPT1 delivery was the most effective route of administration, resulting in therapeutically relevant CNS levels of PPT1 activity. rhPPT1-treated mice had improved motor function, reduced disease-associated pathology, and diminished neuronal loss. In CLN1R151X sheep, i.c.v. infusions resulted in widespread rhPPT1 distribution and positive treatment effects measured by quantitative structural MRI and neuropathology. This study demonstrates the feasibility and therapeutic efficacy of i.c.v. rhPPT1 ERT. These findings represent a key step toward clinical testing of ERT in children with CLN1 disease and highlight the importance of a cross-species approach to developing a successful treatment strategy.

Abstract: Takahashi, K, Shirai, Y, and Nabekura, Y. Stretch-shortening cycle function of lower limbs after cycling in triathletes. J Strength Cond Res 36(9): 2610-2614, 2022-Impaired cardiorespiratory response and changes in biomechanical variables occur when running after cycling relative to isolated running. Nevertheless, little is known about the causes of these changes or the training to prevent them. This study aimed (a) to determine whether stretch-shortening cycle (SSC) function decreases after cycling exercise and (b) to determine whether the decreases in SSC function are related to brick training. Eleven male university triathletes performed hopping tests to measure SSC function before and after cycling (30 minutes of cycling at 110% ventilatory threshold). Stretch-shortening cycle function was calculated as the ratio of the jump height to the time spent in contact with the ground (reactive strength index [RSI]). Brick training was evaluated by the total experience of brick training. The RSI significantly decreased after the cycling exercise (-10.7%; p < 0.01), but changes in RSI after cycling did not significantly correlate with the total experience of brick training, despite a large effect size ( p < 0.10; r = 0.62). These results suggest that SSC function decreases after cycling and that brick training is potentially useful for inhibiting decreases in SSC function after cycling., (Copyright © 2020 National Strength and Conditioning Association.)

Cannabidiol (CBD) has gained attention as a therapeutic agent and is purported to have immunomodulatory, neuroprotective, and anti-seizure effects. Here, we determined the effects of chronic CBD administration in a mouse model of CLN1 disease (Cln1 -/- ) that simultaneously exhibits neuroinflammation, neurodegeneration, and spontaneous seizures. Proteomic analysis showed that putative CBD receptors are expressed at similar levels in the brains of Cln1 -/- mice compared to normal animals. Cln1 -/- mice received an oral dose (100 mg/kg/day) of CBD for six months and were evaluated for changes in pathological markers of disease and seizures. Chronic cannabidiol administration was well-tolerated, high levels of CBD were detected in the brain, and markers of astrocytosis and microgliosis were reduced. However, CBD had no apparent effect on seizure frequency or neuron survival. These data are consistent with CBD having immunomodulatory effects. It is possible that a higher dose of CBD could also reduce neurodegeneration and seizure frequency., (© 2022. The Author(s).)

Background: Several cut-off points for 25-hydroxyvitamin D (25(OH)D) levels have been proposed to determine vitamin D deficiency or insufficiency. However, the level for 25(OH)D deficiency in early infancy remains unclear. The serum 25(OH)D value at which parathyroid hormone level plateaus, called the "inflection point," is considered the most appropriate criterion for defining an adequate vitamin D status., Methods: This was a single-center retrospective study involving 305 1-month-old and 252 2-month-old Japanese infants. Nonlinear segmented regression analysis was performed based on the correlation between 25(OH)D and parathyroid hormone levels to determine vitamin D deficiency cut-off points., Results: Inflection points were 7.90 ng/mL for 1-month-old (95% confidence interval, 6.31-9.49) and 6.74 ng/mL for 2-month-old (95% confidence interval, 5.80-7.68) Japanese infants, which were lower than previously reported. Cut-off values were also lower in the high-body mass index (BMI) group than in the low-BMI group for both 1-month and 2-month-old infants., Conclusion: These results imply the need for nutritional rickets prevention via policy recommendations in most full-term newborns in Japan. Although validation studies are required, these results can still be used to guide vitamin D insufficiency treatment options in early infancy., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

While significant efforts have been made in developing pre-clinical treatments for the neuronal ceroid lipofuscinoses (NCLs), many challenges still remain to bring children with NCLs a cure. Devising effective therapeutic strategies for the NCLs will require a better understanding of pathophysiology, but little is known about the mechanisms by which loss of lysosomal proteins causes such devastating neurodegeneration. Research into glial cells including astrocytes, microglia, and oligodendrocytes have revealed many of their critical functions in brain homeostasis and potential contributions to neurodegenerative diseases. Genetically modified mouse models have served as a useful platform to define the disease progression in the central nervous system across NCL subtypes, revealing a wide range of glial responses to disease. The emerging evidence of glial dysfunction questions the traditional "neuron-centric" view of NCLs, and would suggest that directly targeting glia in addition to neurons could lead to better therapeutic outcomes. This review summarizes the most up-to-date understanding of glial pathologies and their contribution to the pathogenesis of NCLs, and highlights some of the associated challenges that require further research., Competing Interests: JC has received research support from BioMarin Pharmaceutical Inc., Abeona Therapeutics Inc., Regenexbio Inc., and Neurogene. The remaining authors declare that the research was conducted in the absence of any commercial orfinancial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Takahashi, Nelvagal, Lange and Cooper.)

Objectives: Increased cardiorespiratory responses and changes in muscle activity and running kinematics occur in running after cycling compared with isolated running. Nevertheless, little is known about the causes of these changes. Cycling exercise decreases the stretch-shortening cycle (SSC) function, which can influence subsequent running. This study aimed to clarify whether the decrease in SSC function after cycling causes cardiorespiratory and biomechanical changes in subsequent running., Design: Cross-sectional laboratory study. Participants were divided into two groups based on SSC function: an SSC dec group (those with decreased SSC function after cycling) and an SSC non-dec group (those without decreased SSC function after cycling)., Methods: Eighteen participants (10 triathletes and 8 runners) completed maximal aerobic tests for running and cycling. After these sessions, a submaximal run-cycle-run test was performed to compare between control run (no preceding cycle) and transition run (preceded by cycling). A jump test was administered before and after the submaximal cycling. SSC function was calculated as the ratio of the jump height to the time spent in contact with the ground (reactive strength index). Gas exchange measures, heart rate, and gait parameters were collected throughout the test., Results: Oxygen uptake and ventilation were increased by cycling in the SSC dec group but not in the SSC non-dec group. In both groups, there were no significant differences in the gait parameters between control and transition runs., Conclusions: The decrease in SSC function after cycling would increase cardiorespiratory responses in subsequent running., (Copyright © 2021 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Sanfilippo D syndrome (mucopolysaccharidosis type IIID) is a lysosomal storage disorder caused by the deficiency of N-acetylglucosamine-6-sulfatase (GNS). A mouse model was generated by constitutive knockout of the Gns gene. We studied affected mice and controls at 12, 24, 36, and 48 weeks of age for neuropathological markers of disease in the somatosensory cortex, primary motor cortex, ventral posterior nuclei of the thalamus, striatum, hippocampus, and lateral and medial entorhinal cortex. We found significantly increased immunostaining for glial fibrillary associated protein (GFAP), CD68 (a marker of activated microglia), and lysosomal-associated membrane protein-1 (LAMP-1) in Sanfilippo D mice compared to controls at 12 weeks of age in all brain regions. Intergroup differences were marked for GFAP and CD68 staining, with levels in Sanfilippo D mice consistently above controls at all age groups. Intergroup differences in LAMP-1 staining were more pronounced in 12- and 24-week age groups compared to 36- and 48-week groups, as control animals showed some LAMP-1 staining at later timepoints in some brain regions. We also evaluated the somatosensory cortex, medial entorhinal cortex, reticular nucleus of the thalamus, medial amygdala, and hippocampal hilus for subunit c of mitochondrial ATP synthase (SCMAS). We found a progressive accumulation of SCMAS in most brain regions of Sanfilippo D mice compared to controls by 24 weeks of age. Cataloging the regional neuropathology of Sanfilippo D mice may aid in understanding the disease pathogenesis and designing preclinical studies to test brain-directed treatments., Competing Interests: Declaration of Competing Interest Dr. Dickson receives research support from Genzyme and M6P Therapeutics. Dr. Cooper receives research support from Regenexbio and Neurogene., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Screening-based intrapartum antibiotic prophylaxis (IAP) has reduced the prevalence of early-onset group B Streptococcus (GBS) infection in newborns. Nevertheless, early-onset disease still occurs despite IAP, and IAP is not effective in preventing late-onset disease. This study aimed to determine the prevalence and risk factors of GBS neonatal umbilical colonization managed by dry cord care in Japan., Methods: Of 735 healthy newborns in the well-baby nursery at Saitama City Hospital, 353 from whom umbilical bacterial swabs were obtained before discharge were included in the analysis. Maternal and neonatal clinical characteristics were retrospectively reviewed., Results: GBS was detected in 4.2% (15/353) of umbilical swabs; 13/15 (86.8%) were born to GBS-negative mothers. The median (IQR) age at umbilical swab collection was 4.0 (4.0-5.0) days. Comparison of clinical characteristics between GBS-positive and negative neonates revealed a significant difference in the proportion of vaginal deliveries (15/15 [100%] in GBS-positive neonates vs. 115/338 [34.0%] in GBS-negative neonates, p < 0.0001). Of 15 GBS-positive neonates, 10 (66.7%) were also co-colonized with other enteric bacteria such as Escherichia coli., Conclusion: Vaginal delivery was a risk factor associated with GBS neonatal umbilical colonization in Japanese neonates. Co-colonization with multiple enteric bacterial species implicates vertical transmission of GBS from undetected carrier mothers during passage through the birth canal., Competing Interests: Declaration of competing interest None., (Copyright © 2021. Published by Elsevier B.V.)

The timing of exercise plays an important role in the effect of the exercise on physiological functions, such as substrate oxidation and circadian rhythm. Exercise exerts different effects on the glycemic response to exercise and meal intake depending on when the exercise performed. Here, we comprehensively investigated the effects of the timing (morning or afternoon) of exercise on glucose fluctuation on the basis of several indices: glycemic variability over 24 h (24-h SD), J-index, mean amplitude of glucose excursions (MAGE), continuous overall net glycemic action (CONGA), and detrended fluctuation analysis (DFA). Eleven young men participated in 3 trials in a repeated measures design in which they performed a single bout of exercise at 60% of their maximal oxygen uptake for 1 h beginning either at 7:00 (morning exercise), 16:00 (afternoon exercise), or no exercise (control). Glucose levels were measured using a continuous glucose monitoring system (CGMs). Glucose fluctuation was slightly less stable when exercise was performed in the afternoon than in the morning, indicated by higher CONGA at 2 h and α 2 in DFA in the afternoon exercise trial than in the control trial. Additionally, decreased stability in glucose fluctuation in the afternoon exercise trial was supported by the descending values of the other glucose fluctuation indices in order from the afternoon exercise, morning exercise, and control trials. Meal tolerance following exercise was decreased after both exercise trials. Glucose levels during exercise were decreased only in the afternoon exercise trial, resulting in less stable glucose fluctuations over 24 h., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

A metal-free and operationally simple strategy for the generation of various α-monofluoroalkyl radicals has been developed. A combination of 1,4-bis(diarylamino)naphthalene photocatalyst and sulfoximine-based fluoroalkylating reagents is the key to success. The protocol can be applied to modular synthesis of β-monofluoroketones through radical monofluoroalkylation of alkenyl acetates.

Organic photoredox catalysis has become a useful tool for the development of metal-free radical reactions. Recently, we have reported that 1,4-bis(diphenylamino)naphthalene N serves as an efficient photoredox catalyst for radical monofluoromethylation with N -tosyl- S -monofluoromethyl- S -phenylsulfoximine 2 . In this paper, we report the preparation and photo- and electrochemical properties of (diarylamino)naphthalene derivatives, 1,4-bis(di( p - tert -butylphenyl)amino)naphthalene 1a , 1,5-bis(di( p - tert -butylphenyl)amino)naphthalene 1b , and 1-(di( p - tert -butylphenyl)amino)naphthalene) 1c , as supported by density functional theory (DFT) and time-dependent-DFT calculations. In addition, their performance of photocatalysis has been evaluated by means of methoxy-monofluoromethylation of aromatic alkenes. Laser flash photolysis shows that the fluorescence of 1a in the excited state is efficiently quenched by 2 (quenching rate constant k q = ca. 2 × 10 9 M -1 s -1 ). Transient absorption spectroscopic analyses reveal that the excited species of 1a in the presence of 2 starts decreasing in ca. 100 ps, suggesting the occurrence of fast electron-transfer processes. These results lead to the unconventional concept for the catalyst design, that is, long lifetime of the excited state is not always a requisite for efficient photoredox catalysts.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative lysosomal storage disorders (LSDs), traditionally grouped together based on shared clinical symptoms. The recent emergence of new forms of NCL along with an improved understanding of endo-lysosomal system function have necessitated the reassessment of their classification and pathogenesis. Novel clinical findings, as well as observations in various animal models of NCL, have revealed significant pathological changes in regions outside the brain, as well as progression of disease along connected anatomical pathways. The characterization of animal models of NCLs has not only highlighted the vulnerability of certain neuron populations but has also revealed glial cells to be adversely affected and actively contribute to disease progression. While the lysosome has been thought of as being the 'waste-disposal' unit of the cell, recent evidence of the endo-lysosomal system playing a crucial role in nutrient sensing and cellular homeostasis have shown that NCL mutations have far-ranging effects on cellular functions including autophagy and synaptic dysfunction. The discovery of the machinery controlling endo-lysosomal function via transcription factor EB (TFEB) and mTORC1, have also shed light on potential mechanisms by which NCL mutations may exert their effect. While the NCLs share many common down-stream pathologies, there is a growing body of evidence for unique pathogenic pathways in each form. In light of the rapid advances in therapeutic strategies for the NCLs and LSDs, these new lessons learnt about unique NCL pathomechanisms will be key for informing the targeting, timing and strategies for future treatments., Competing Interests: Declaration of competing interest JDC has been in receipt of research support from BioMarin Pharmaceutical Inc., Abeona Therapeutics Inc., Regenexbio Inc. and CereSpir Inc., but none of these projects relate directly to the subject of this review. The other authors have no declarations of interest., (Copyright © 2019. Published by Elsevier B.V.)

Mammals have circadian clocks, which consist of the central clock in the suprachiasmatic nucleus and the peripheral clocks in the peripheral tissues. The effect of exercise on phase of peripheral clocks have been reported in rodents but not in humans. Continuous sampling is necessary to assess the phase of the circadian rhythm of peripheral clock gene expressions. It has been assumed that the expression of the genes in leukocyte may be "an accessible window to the multiorgan transcriptome." The present study aimed to examine whether exercise affects the level and phase of clock gene expression in human leukocytes. Eleven young men participated in three trials, in which they performed a single bout of exercise at 60% V̇o 2max for 1 h beginning either at 0700 (morning exercise) or 1600 (afternoon exercise) or no exercise (control). Blood samples were collected at 0600, 0900, 1200, 1500, 1800, 2100, and 2300 and at 0600 the next morning, to assess diurnal changes of clock gene expression in leukocytes. Brain and muscle ARNT-like protein 1 ( Bmal1 ) expression level increased after morning and afternoon exercise, and Cryptochrome 1 ( Cry1 ) expression level increased after morning exercise. Compared with control trial, acrophase of Bmal1 expression tended to be earlier in morning exercise trial and later in afternoon exercise trial. Acrophase of Cry1 expression was earlier in morning exercise trial but not affected by afternoon exercise. Circadian locomotor output cycles kaput ( Clock ), Period 1-3 ( Per1-3 ), and Cry2 expression levels and those acrophases were not affected by exercise. The present results suggest a potential role of a single bout of exercise to modify peripheral clocks in humans. NEW & NOTEWORTHY The present study showed that a single bout of exercise affected peripheral clock gene expression in human leukocytes and the effect of exercise depended on when it was performed. Brain and muscle ARNT-like protein 1 ( Bmal1 ) expression was increased after exercises performed in the morning and afternoon. Cryptochrome 1 ( Cry1 ) expression was also increased after the morning exercise. The effect of exercise on acrophase of Bmal1 depended on the time of the exercise: advanced after morning exercise and delayed after afternoon exercise.

The lipid cell variant of urethral carcinoma (UC) is rare and poorly understood clinicopathologically. A nodular tumor detected in the bladder of an 87-year-old man with asymptomatic gross hematuria was transurethrally resected, and high-grade UC, lipid cell variant, was diagnosed pathologically. The tumor cells resembled lipoblasts and contained numerous cytoplasmic vacuoles. Immunohistochemically, the tumor cells stained positive for the epithelial markers CK7, CK20, EMA, CAM5.2, and 34betaE12 and negative for vimentin and S100. Focal positivity for adipophilin was detected in cytoplasm but not in the vacuoles. These findings suggest that the patient had lipid-producing UC.

Purpose: Individual variations in response of C-reactive protein (CRP) to acute strenuous exercise are less well known. The purpose of this study was to investigate the relationship between running economy and systemic inflammation following a marathon., Materials and Methods: Sixteen college recreational runners participated in this study. To measure maximal oxygen uptake and running economy, the treadmill running test was performed 1-2 weeks before the marathon race. Running economy was defined as oxygen cost (mL/kg/km) at submaximal running. CRP and muscle damage markers (creatine kinase and lactate dehydrogenase) were measured before and 1, 2, and 3 days after the race., Results: All subjects completed the race in 4 hours 7 minutes 43 seconds±44 minute 29 seconds [mean±SD]. The marathon running significantly increased CRP and muscle damage markers. The levels of inflammation and muscle damage peaked after 1 day and remained high throughout the 3-day recovery period compared to that before the race. Spearman correlation analysis showed that the change in CRP level was significantly positively correlated with oxygen cost ( r =0.619, P =0.011) but not maximal oxygen uptake. There was no significant relationship in responses between muscle damage markers and CRP., Conclusion: These findings suggest that running economy is related to postmarathon race CRP response. Further study to clarify the cause of the relationship and clinical significance of transient increase in CRP is necessary., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Dissolution dynamic nuclear polarization (DNP) has recently gained attention as a method to enhance the sensitivity of liquid NMR spectroscopy and MRI. We demonstrate dissolution of the sample hyperpolarized by DNP using photoexcited triplet electrons in 0.38 T at room temperature. The achieved polarization of 0.8% is 6100 times as high as that at thermal equilibrium under the condition. The result is an important step for DNP using photoexcited triplet electrons to become widely used in chemical and biomedical research.

A 73-year-old man presented with right lower back pain and dysuria. Right hydronephrosis and a large pelvic large mass were seen on computed tomography (CT). Although his prostate-specific antigen (PSA) was 0.5 ng/mL, an irregularly enlarged, stony, hard prostate was palpable on digital rectal examination. A prostate tumor was suspected, and a transrectal prostate biopsy and right transurethral ureteral stent placement were performed. Histological and immunohistochemical studies revealed diffuse large B-cell lymphoma. Positron emission tomography-computed tomography showed abnormal uptake in the stomach, cecum, right obturator lymph nodes, para-aortic lymph nodes, and dorsal left kidney. No abnormal findings were seen on bone marrow histology. Clinical stage IVA was confirmed according to Ann Arbor criteria. The patient achieved a complete response after 8 cycles of combination chemotherapy with rituximab, pirarubicin, cyclophosphamide, vincristine, and prednisolone.

A 28-year-old Japanese male without a significant past medical history presented with new-onset generalized clonic seizure and headache. A brain MRI revealed multiple enhanced lesions on both cerebral hemispheres. Laboratory exams showed no evidence of systemic inflammation or auto-immune antibodies such as ANCAs. Despite four courses of high-dose methylprednisolone pulse therapy and five treatments with plasmapheresis, his symptoms worsened and the MRI lesions progressed rapidly. During these treatments, we performed a targeted brain biopsy, that revealed histological findings consistent with a predominant angiitis of parenchymal and subdural small vessels. He was provided with diagnosis of central nervous system vasculitis (CNSV). Subsequent cyclophosphamide pulse therapy enabled a progressive successful improvement of his symptoms. While diagnostic methods for CNSV remain controversial, histological findings are thought to be more useful in obtaining a more definitive diagnosis than findings in image studies, such as MRI and angiography. We suggest that a brain biopsy should be considered during the early period of cases with suspected CNSV and rapid clinical deterioration. We also detected human herpesvirus 7 (HHV-7) using PCR technology in brain biopsy specimens, however the relationship between CNSV and HHV-7 infection is unknow.

Thermosensitive fluoroalkyl end-capped N-(1,1-dimethyl-3-oxobutyl)acrylamide-acryloylmorpholine cooligomer, which was prepared by the cooligomerization of fluoroalkanoyl peroxide with the corresponding monomers, was applied to the autoreduction of gold ions to afford the fluorinated cooligomeric nanocomposite-encapsulated gold nanoparticles under very mild conditions; although the corresponding non-fluorinated cooligomer was not able to afford the gold nanoparticles at all under similar conditions. These fluorinated cooligomeric nanocomposites exhibited a plasmon absorption band around 520 nm related to the formation of gold nanoparticles in their aqueous solutions. Interestingly, these fluorinated nanocomposite-encapsulated gold nanoparticles can exhibit the thermoswitchable sol-gel transition through the lower critical solution temperature (LCST)-triggered aggregation of the corresponding nanocomposites, and this sol-gel switching behavior is reversible during a heating and cooling cycle., (Copyright 2010 Elsevier Inc. All rights reserved.)

Fluoroalkyl end-capped N-(1,1-dimethyl-3-oxobutyl)acrylamide--acryloylmorpholine co-oligomers were prepared by the co-oligomerizations of fluoroalkanoyl peroxides with the corresponding monomers. These fluorinated co-oligomers exhibited a lower critical solution temperature (LCST) characteristic in aqueous solutions. Of particular interest, a steep time dependence of contact angle values for dodecane was observed from 40 to 60 degrees C to decrease their values, effectively, on the modified PMMA [poly(methyl methacrylate)] film surface treated with fluorinated co-oligomer possessing the LCST: 36 degrees C (in water), although such a steep time dependence was not observed from 20 to 30 degrees C.

While the eradication of Helicobacter pylori has been reported to reduce the frequency of ulcer relapse, the preventative mechanism remains unknown. We investigated the changes in the level of gastric colonization 140 days after inducing gastric ulcer by acetic acid in the antral mucosa of a miniature pig infected with H. pylori. The gastric ulcer was induced endoscopically with 1 mL of 40% acetic acid 12 days after inoculation of H. pylori in a 3-month-old miniature pig. Gastric ulcer was healed by 30 days after ulcer induction and the levels of H. pylori in cardiac and antral mucosa increased gradually from 30 to 71 days. The peak bacterial counts in the cardia and antrum were 6.1 and 6.6 log10 cfu/g, respectively, or about 100-fold higher than the initial levels. The levels of H. pylori in cardiac and antral mucosa steadily decreased until reaching the initial levels at 127 days, while that in the fundic mucosa remained constant throughout the observation period. No ulcer recurrence was detected by endoscopy. These results suggested that the levels of H. pylori colonization increased temporally after healing of the acetic acid-induced gastric ulcer in the miniature pig.

This study was designed to determine whether magnesium ion in water would influence the colonization of Helicobacter pylori in 2-week-old miniature pigs. Groups A (2 pigs) and B (1 pig) were both fed a milk diet dissolved in drinking water, Group C (2 pigs) was fed a milk diet dissolved in deionized distilled water (DDW), and Group D (1 pig) was fed a milk diet dissolved in DDW supplemented with MgCl2. Groups B, C, and D were all challenged with H. pylori, and Group A was not. Necropsy was performed on the pigs on postinfection Day 5, and biopsy specimens were taken from 16 sites of the stomach. H. pylori were recovered from 11 of 16 sites in Group B, 1 of 32 sites in Group C, and 13 of 16 sites in Group D. On the other hand, the degree of lymphocyte infiltration increased in the order of Group A < Group B < Group C < Group D. These observations suggest that magnesium ion in drinking water is essential for the colonization of H. pylori in the pig stomach. Possible mechanisms for the lymphocyte infiltration are discussed.

Our previous study showed that the colonization levels of Helicobacter pylori were higher in the stomachs of 5-day-old miniature pigs than in 2-week-old ones. As dietary factors can cause these differences, we compared two diets, i.e., Weanymilk and a similar formula with a higher concentration of Fe(II), Weanylobulin. The colonization levels in the fundic mucosa were significantly higher in 2-week-old pigs fed Weanylobulin than in those fed Weanymilk. Supplementing Weanylobulin with an iron chelator, deferoxamine mesylate, significantly lowered the bacteria counts in the gastric mucosa. Normal diets supplemented with Fe(II) in 2-month-old pigs caused significantly more sites of bacteria in the antrum compared with normal diets alone. In addition, ranitidine, an inhibitor of gastric acid secretion that reduces Fe(III) to Fe(II) in the stomach, decreased the bacteria counts in 10-month-old pigs. These results suggested that Fe(II) maintained the colonization levels of H. pylori in the stomach of the miniature pigs.