Quality Control of Procollagen in Cells.

Collagen is the most abundant protein in mammals. A unique feature of collagen is its triple-helical structure formed by the Gly-Xaa-Yaa repeats. Three single chains of procollagen make a trimer, and the triple-helical structure is then folded in the endoplasmic reticulum (ER). This unique structure is essential for collagen's functions in vivo, including imparting bone strength, allowing signal transduction, and forming basement membranes. The triple-helical structure of procollagen is stabilized by posttranslational modifications and intermolecular interactions, but collagen is labile even at normal body temperature. Heat shock protein 47 (Hsp47) is a collagen-specific molecular chaperone residing in the ER that plays a pivotal role in collagen biosynthesis and quality control of procollagen in the ER. Mutations that affect the triple-helical structure or result in loss of Hsp47 activity cause the destabilization of procollagen, which is then degraded by autophagy. In this review, we present the current state of the field regarding quality control of procollagen.

Interactome Screening Identifies the ER Luminal Chaperone Hsp47 as a Regulator of the Unfolded Protein Response Transducer IRE1α.

Maintenance of endoplasmic reticulum (ER) proteostasis is controlled by a dynamic signaling network known as the unfolded protein response (UPR). IRE1α is a major UPR transducer, determining cell fate under ER stress. We used an interactome screening to unveil several regulators of the UPR, highlighting the ER chaperone Hsp47 as the major hit. Cellular and biochemical analysis indicated that Hsp47 instigates IRE1α signaling through a physical interaction. Hsp47 directly binds to the ER luminal domain of IRE1α with high affinity, displacing the negative regulator BiP from the complex to facilitate IRE1α oligomerization. The regulation of IRE1α signaling by Hsp47 is evolutionarily conserved as validated using fly and mouse models of ER stress. Hsp47 deficiency sensitized cells and animals to experimental ER stress, revealing the significance of Hsp47 to global proteostasis maintenance. We conclude that Hsp47 adjusts IRE1α signaling by fine-tuning the threshold to engage an adaptive UPR.

Comparative study of eating behavior between patients with mental illness and healthy controls using the Japanese version of the Dutch Eating Behavior Questionnaire.

BACKGROUND AND OBJECTIVES: To examine the reliability and validity of the Japanese version of the Dutch Eating Behavior Questionnaire (DEBQ-J) for patients with mental illness, and to determine the characteristics of eating behavior among these patients when compared with healthy controls. METHODS AND STUDY DESIGN: In May 2018, 120 outpatients with mental illness and 132 healthy controls were surveyed. First, exploratory factor analysis was conducted on the DEBQ-J statement responses for both patients and healthy controls. Next, reliability coefficients were calculated for the eating behavior scale scores (emotional, restrained, and external eating) extracted from the factor analysis. The association between BMI and eating behavior was examined using Student's t-test and Pearson's correlation coefficient. RESULTS: The DEBQ-J had a similar factor structure to that of the original DEBQ for healthy controls, with a cumulative contribution of 52.4% for the three factors, and alpha coefficients ranging from 0.87 to 0.91. For patients, factor analysis showed that four statements classified as emotional eating items in the original DEBQ were recategorized as external eating items, and the percentage of patients with obesity (BMI≥25) was 57.5%, compared with only 25.4% among the healthy controls. The patients with obesity tended to score higher on the external eating scale than did those with BMI<25. CONCLUSIONS: Patients tended to blur the distinction between emotional feelings of mental irritability or anxiety and feelings in response to external stimuli. Monitoring of the DEBQ-J external eating score and appropriate intervention among patients living with mental illness may help to prevent obesity.

Simulations of cortical networks using spatially extended conductance-based neuronal models.

The Hodgkin-Huxley model of action potential generation and propagation, published in the Journal of Physiology in 1952, initiated the field of biophysically detailed computational modelling in neuroscience, which has expanded to encompass a variety of species and components of the nervous system. Here we review the developments in this area with a focus on efforts in the community towards modelling the mammalian neocortex using spatially extended conductance-based neuronal models. The Hodgkin-Huxley formalism and related foundational contributions, such as Rall's cable theory, remain widely used in these efforts to the current day. We argue that at present the field is undergoing a qualitative change due to new very rich datasets describing the composition, connectivity and functional activity of cortical circuits, which are being integrated systematically into large-scale network models. This trend, combined with the accelerating development of convenient software tools supporting such complex modelling projects, is giving rise to highly detailed models of the cortex that are extensively constrained by the data, enabling computational investigation of a multitude of questions about cortical structure and function.

Nonlinear visuoauditory integration in the mouse superior colliculus.

Sensory information from different modalities is processed in parallel, and then integrated in associative brain areas to improve object identification and the interpretation of sensory experiences. The Superior Colliculus (SC) is a midbrain structure that plays a critical role in integrating visual, auditory, and somatosensory input to assess saliency and promote action. Although the response properties of the individual SC neurons to visuoauditory stimuli have been characterized, little is known about the spatial and temporal dynamics of the integration at the population level. Here we recorded the response properties of SC neurons to spatially restricted visual and auditory stimuli using large-scale electrophysiology. We then created a general, population-level model that explains the spatial, temporal, and intensity requirements of stimuli needed for sensory integration. We found that the mouse SC contains topographically organized visual and auditory neurons that exhibit nonlinear multisensory integration. We show that nonlinear integration depends on properties of auditory but not visual stimuli. We also find that a heuristically derived nonlinear modulation function reveals conditions required for sensory integration that are consistent with previously proposed models of sensory integration such as spatial matching and the principle of inverse effectiveness.

Infant drug exposure via breast milk.

More than half of women take medications during breastfeeding, predisposing their infants to medication exposure via breast milk. As a result, adverse drug reactions may emerge in the infant, although they are rarely reported. Disposition of maternal drugs in breast milk is described with several key parameters, which include relative infant dose (RID): infant drug intake via milk (weight- and time-adjusted) expressed as a percentage of the similarly adjusted mother's dose. Most drugs show RID values of <10%, indicating that drug concentrations in infant serum do not reach a level known to be therapeutic in adults unless drug clearance is markedly lower than the adult level on a weight basis. RID is a function of milk-to-(maternal) plasma drug concentration ratio (MP ratio) and maternal drug clearance. Therefore, MP ratio between drugs must be interpreted not by itself but with maternal drug clearance of each drug. This is why some drugs such as phenobarbital show an MP ratio of <1 but an RID as high as 50-70%, while morphine shows an MP ratio of 2 but an RID in the range of 5%. Using RID, we interpreted case reports of infant adverse outcomes, and we observed cases with relatively low infant serum concentrations of drug, consistent with low RID, as well as those with near- or above-adult therapeutic serum concentrations, with or without increased drug intake (i.e. high RID). It is important to consider both pharmacokinetic and pharmacodynamic factors in interpreting adverse outcomes in infants breastfed by a mother taking medications.

Population pharmacokinetics of vancomycin in paediatric patients with febrile neutropenia and augmented renal clearance: development of new dosing recommendations.

OBJECTIVES: The purpose of this study was to evaluate the influence of augmented renal clearance (ARC) on vancomycin clearance and provide dosage recommendations for paediatric patients with febrile neutropenia following HSCT. METHODS: A population pharmacokinetic analysis was performed based on a two-compartment model structure using a non-linear mixed-effect modelling approach. Monte Carlo simulations were conducted as a target attainment analysis of AUC between 400 mg·h/L and 650 mg·h/L for MRSA at an MIC of 1 mg/L. RESULTS: A total of 165 paediatric patients and 276 vancomycin serum concentrations were analysed in this study. Age, body weight, estimated glomerular filtration rate (eGFR) and fever (≥38.0°C) were identified as factors that significantly influenced vancomycin clearance. The median eGFR of the population was 143 mL/min/1.73 m2 and 34% of patients showed an eGFR ≥160 mL/min/1.73 m2, which may be classified as ARC. Our simulations showed that current dosing recommendations result in poor target attainment. In particular, children aged 6 months old to 6 years old with ARC require an initial vancomycin dose up to 35%-65% higher than the current dosing guidelines. CONCLUSIONS: ARC is frequently observed in paediatric patients with post-HSCT febrile neutropenia, resulting in a significant increase in vancomycin clearance. We propose a vancomycin dosing strategy for children with febrile neutropenia following HSCT based on eGFR, age, weight and body temperature.

Cognitive and behavioral risk factors for low quality of life in survivors of childhood acute lymphoblastic leukemia.

BACKGROUND: With high survival rates for pediatric acute lymphoblastic leukemia (ALL), long-term quality of life is a prominent consideration in treatment. We concurrently evaluated cognition, behavior, and quality of life in child and adolescent ALL survivors and determined associations between them. METHODS: The sample included 83 controls (mean age: 12.5 years) and 71 ALL survivors (mean age: 11.9 years, mean age at diagnosis: 3.8 years). Participants completed measures of general intellectual abilities, math achievement, and fine motor skills. Parents and teachers completed a survey assessing child participants' cognitive, behavioral, and emotional function. Parents additionally completed a survey about their child's quality of life. RESULTS: Survivors had lower scores on measures of working memory, processing speed, timed math, and fine motor skills (effect size 0.5-1, p < 0.001). Parents identified more problems with executive function and learning in survivors than controls (effect size > 0.7, p < 0.001), and indicated a lower quality of life in all categories evaluated (effect size > 0.7, p < 10-4). Reduced quality of life was associated with lower math achievement scores and with inattention and executive function problems. CONCLUSIONS: ALL survivors experience diffuse cognitive, behavioral, and motor impairments, which are associated with reduced quality of life. These findings underscore the need to address these challenges in ALL survivors. IMPACT: Compared with cancer-free peers, parents of childhood acute lymphoblastic leukemia survivors treated with chemotherapy only reported reduced quality of life. Math difficulties and behavioral problems increased the risk for reduced quality of life. Reduced quality of life is associated with mild cognitive and behavioral difficulties, suggesting that even relatively mild impairments have broad implications for ALL survivors. Screening and early intervention targeting cognitive and behavioral function may enhance quality of life for ALL survivors.

Accuracy and Trending Ability of Cardiac Index Measured by the CNAP System in Patients Undergoing Abdominal Aortic Aneurysm Surgery.

OBJECTIVES: The CNAP system is a noninvasive monitor that provides a continuous arterial pressure waveform using an inflatable finger cuff. The authors hypothesized that dramatic changes in systemic vascular resistance index during abdominal aortic aneurysm (AAA) surgery might affect the accuracy of noninvasive pulse contour monitors. The aim of this study was to evaluate the accuracy and trending ability of cardiac index derived by the CNAP system (CICN) in patients undergoing AAA surgery. DESIGN: Prospective clinical study. SETTING: Cardiac surgery operating room in a single cardiovascular center. PARTICIPANTS: Twenty patients who underwent elective AAA surgery. INTERVENTIONS: CICN and cardiac index measured using 3-dimensional images (CI3D) were determined simultaneously at 8 points during the surgery. At aortic clamping and unclamping, the authors tested the trending ability of CICN using 4-quadrant plot analysis and polar plot analysis. MEASUREMENTS AND MAIN RESULTS: The authors found a wide limit of agreement between CICN and CI3D (percentage error: 85.0%). The cubic splines, which show the relationship between systemic vascular resistance index and percentage CI discrepancy [(CICN-CI3D)/CI3D], were sloped positively. Four-quadrant plot analysis showed poor trending ability for CICN at both aortic clamping and unclamping (concordance rate: 29.4% and 57.9%, respectively). In the polar plot analysis, the concordance rates at aortic clamping and unclamping were 15.0% and 35.0%, respectively. CONCLUSIONS: CICN is not interchangeable with CI3D in patients undergoing AAA surgery. The trending ability for CICN at aortic clamping and unclamping was below the acceptable limit. These inaccuracies might be secondary to the high systemic vascular resistance index during AAA surgery.

Using Brexanolone for Postpartum Depression Must Account for Lactation.

On March 19, 2019, Brexanolone (Zulresso ™) was released as the first-ever FDA-approved medication specifically for the treatment of postpartum depression by Sage Therapeutics, Inc. Unfortunately, its use in breastfeeding mothers was not evaluated and is being restricted. An efficacious drug for postpartum depression stands to benefit many families. However, the lack of guidance for breastfeeding patients, and the resultant restrictions on breastfeeding by insurance companies is deeply troubling. Conversely, withholding this medication from a lactating mother is ethically problematic. From a public health perspective, we aim to foster continuous breastfeeding among depressed women while they are being treated for depression. We therefore aim to address concerns about Brexanolone's effects on the breastfed child, as exposed through breastmilk, as well as the impact this medication may have on lactation.

Roles of the endoplasmic reticulum-resident, collagen-specific molecular chaperone Hsp47 in vertebrate cells and human disease.

Heat shock protein 47 (Hsp47) is an endoplasmic reticulum (ER)-resident molecular chaperone essential for correct folding of procollagen in mammalian cells. In this Review, we discuss the role and function of Hsp47 in vertebrate cells and its role in connective tissue disorders. Hsp47 binds to collagenous (Gly-Xaa-Arg) repeats within triple-helical procollagen in the ER and can prevent its local unfolding or aggregate formation, resulting in accelerating triple-helix formation of procollagen. Hsp47 pH-dependently dissociates from procollagen in the cis-Golgi or ER-Golgi intermediate compartment and is then transported back to the ER. Although Hsp47 belongs to the serine protease inhibitor (serpin) superfamily, it does not possess serine protease inhibitory activity. Whereas general molecular chaperones such as Hsp70 and Hsp90 exhibit broad substrate specificity, Hsp47 has narrower specificity mainly for procollagens. However, other Hsp47-interacting proteins have been recently reported, suggesting a much broader role for Hsp47 in the cell that warrants further investigation. Other ER-resident stress proteins, such as binding immunoglobulin protein (BiP), are induced by ER stress, whereas Hsp47 is induced only by heat shock. Constitutive expression of Hsp47 is always correlated with expression of various collagen types, and disruption of the Hsp47 gene in mice causes embryonic lethality due to impaired basement membrane and collagen fibril formation. Increased Hsp47 expression is associated with collagen-related disorders such as fibrosis, characterized by abnormal collagen accumulation, highlighting Hsp47's potential as a clinically relevant therapeutic target.

A BRET-based assay reveals collagen-Hsp47 interaction dynamics in the endoplasmic reticulum and small-molecule inhibition of this interaction.

Molecular chaperones perform pivotal roles in proteostasis by engaging in protein-protein interactions (PPIs). The collagen-specific molecular chaperone Hsp47 (heat shock protein 47) interacts with procollagen in the endoplasmic reticulum (ER) and plays crucial roles in collagen synthesis. PPIs between Hsp47 and collagen could offer a therapeutic target for fibrosis, which is characterized by abnormal collagen accumulation in the extracellular matrix of fibrotic organs. Herein, we established a bioluminescence resonance energy transfer (BRET) system for assessing Hsp47-collagen interaction dynamics within the ER. After optimization and validation of the method, we could demonstrate inhibition of the interaction between Hsp47 and collagen by a small molecule (Col003) in the ER. Using the BRET system, we also found that Hsp47 interacts not only with the Gly-Pro-Arg motif but also weakly with Gly-Pro-Hyp motifs of triple-helical collagen in cells. Moreover, we found that the serpin loop of Hsp47 (SerpinH1) contributes to its binding to collagen. We propose that the method developed here can provide valuable information on PPIs between Hsp47 and collagen and on the effects of PPI inhibitors important for the management of fibrotic disorders.

Model-based detection of putative synaptic connections from spike recordings with latency and type constraints.

Detecting synaptic connections using large-scale extracellular spike recordings presents a statistical challenge. Although previous methods often treat the detection of each putative connection as a separate hypothesis test, here we develop a modeling approach that infers synaptic connections while incorporating circuit properties learned from the whole network. We use an extension of the generalized linear model framework to describe the cross-correlograms between pairs of neurons and separate correlograms into two parts: a slowly varying effect due to background fluctuations and a fast, transient effect due to the synapse. We then use the observations from all putative connections in the recording to estimate two network properties: the presynaptic neuron type (excitatory or inhibitory) and the relationship between synaptic latency and distance between neurons. Constraining the presynaptic neuron's type, synaptic latencies, and time constants improves synapse detection. In data from simulated networks, this model outperforms two previously developed synapse detection methods, especially on the weak connections. We also apply our model to in vitro multielectrode array recordings from the mouse somatosensory cortex. Here, our model automatically recovers plausible connections from hundreds of neurons, and the properties of the putative connections are largely consistent with previous research.NEW & NOTEWORTHY Detecting synaptic connections using large-scale extracellular spike recordings is a difficult statistical problem. Here, we develop an extension of a generalized linear model that explicitly separates fast synaptic effects and slow background fluctuations in cross-correlograms between pairs of neurons while incorporating circuit properties learned from the whole network. This model outperforms two previously developed synapse detection methods in the simulated networks and recovers plausible connections from hundreds of neurons in in vitro multielectrode array data.

CYP2C9, VKORC1, and CYP4F2 polymorphisms and pediatric warfarin maintenance dose: a systematic review and meta-analysis.

Studies on the effect of cytochrome P450 2C9 (CYP2C9), vitamin K epoxide reductase complex subunit 1 (VKORC1), and cytochrome P450 4F2 (CYP4F2) polymorphisms on warfarin maintenance dose in children are conflicting. We conducted a systematic review and meta-analysis to evaluate the effect of these polymorphisms on warfarin maintenance dose in children. We searched relevant literature using the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trial libraries without any language restrictions from their inception to 23 July 2017. Dose differences are expressed as standardized mean difference (SMD) or mean difference (MD) with 95% confidence intervals (CI). This review was registered in the PROSPERO prospective register of systematic reviews (CRD42015016172). We included a total of nine studies (745 participants) in the meta-analysis. Patients with CYP2C9 *1/*2, *1/*3, *2/*2, *2/*3, or *3/*3 required a lower warfarin maintenance dose compared with patients with CYP2C9 *1/*1 (SMD = -0.610, 95% CI: -0.802 to -0.419, I2 = 0%). Patients with VKORC1-1639GA or AA required a lower warfarin maintenance dose compared with patients with VKORC1-1639GG (SMD = -0.666, 95% CI: -0.887 to -0.445, I2 = 33%). However, no associations were observed between CYP4F2 polymorphisms and warfarin maintenance dose (MD = 0.005 mg/kg/day, 95% CI: -0.006 to 0.015, I2 = 0%). These results were not affected by a sensitivity analysis. Our meta-analysis provides evidence that CYP2C9 and VKORC1 variant statuses affect warfarin maintenance dose in children, but not CYP4F2.

Towards therapeutic drug monitoring of TNF inhibitors for children with juvenile idiopathic arthritis: a scoping review.

OBJECTIVES: Before a clinician decides whether treatment with TNF inhibition in children with JIA has failed, one should ensure adequate systemic exposure has been achieved. Therapeutic drug monitoring might allow for improved treatment outcome with lower treatment-associated costs. However, this requires understanding of the pharmacokinetic (PK) characteristics, and the pharmacokinetic/pharmacodynamic (PK/PD) relationship for children with JIA. We performed a scoping review to summarize the available literature and identify areas for future research. METHODS: A systematic search was conducted of the Medline, EMBASE, Web of Science and Cochrane databases as well as the clinicaltrials.gov registry. In total, 3959 records were screened and 130 publications were selected for full text assessment. RESULTS: Twenty publications were included and divided into three categories: PK (n = 9), PK/PD (n = 3) and anti-drug antibodies (n = 13). Industry involvement was significant in 14 publications. Although data are limited, systemic exposure to TNF inhibitors is generally lower in younger children but meta-analysis is not possible. The PK/PD relationship has had limited study but there is partial evidence for infliximab. Anti-drug antibodies are common, and are related to impaired clinical outcome with adalimumab and infliximab therapy. CONCLUSION: The current knowledge about the PK and PK/PD of TNF inhibitors in the treatment of children with JIA is limited, which prevents the introduction of TDM. Re-analysis of available data from previous trials, incorporation of pharmacologic assessments into existing biorepository studies as well as new prospective PK and PK/PD trials are required to obtain this knowledge.

In Vitro Effects of Paclitaxel and Cremophor EL on Human Riboflavin Transporter SLC52A2.

Paclitaxel, a mitotic inhibitor with anti-cancer effects, is dissolved in Cremophor EL (CrEL). However, peripheral neuropathy is a known side effect. As one of the mechanisms of the neuropathy, mitochondrial dysfunction has been proposed, while peroxidation products are involved in the cause of CrEL-induced neurotoxicity. Riboflavin is an essential nutrient required for ATP production in mitochondria and has an antioxidant role as a coenzyme for glutathione. Therefore, riboflavin transporters might play a key role to mitigate neuropathy. However, it is unclear whether paclitaxel and CrEL affect these transporters. In this study, human riboflavin transporter SLC52A2 was used to analyze the effects of paclitaxel and CrEL. CrEL, but not paclitaxel, inhibited uptake of riboflavin in human embryonic kidney 293 cells transfected with the SLC52A2 expression vector, suggesting that altered riboflavin disposition may be involved in the pathogenesis of paclitaxel/CrEL toxicity.

Accuracy and Trending Ability of Blood Pressure and Cardiac Index Measured by ClearSight System in Patients With Reduced Ejection Fraction.

OBJECTIVES: To investigate the accuracy and trending ability of ClearSight (Edwards Lifesciences, Irvine, CA) in patients with reduced ejection fraction (<55%) undergoing off-pump coronary artery bypass graft (CABG) surgery by comparing the ClearSight-derived cardiac index (CICS) with the cardiac index measured with thermodilution using a pulmonary artery catheter. In addition, the accuracy and trending ability of ClearSight for blood pressure measurement was investigated by comparing the mean arterial pressure (MAP) derived by ClearSight (MAPcs) with invasive intra-arterial pressure. DESIGN: Prospective clinical study. DESIGN: Cardiac surgery operating room in a single cardiovascular center. PARTICIPANTS: The study comprised 20 patients who underwent elective CABG surgery. INTERVENTIONS: MAP and cardiac index were measured simultaneously at 6 time points intraoperatively. Trending ability was investigated at the following 2 points: (1) before and after placing the patient in the Trendelenburg position and (2) before and after atrial pacing with a targeted heart rate increase of 20%. MEASUREMENTS AND MAIN RESULTS: Bland-Altman analysis showed that the percentage error between CICS and the cardiac index measured with thermodilution was 40.2% and the percentage error between MAPcs and MAP was 24.6%. Four-quadrant plot analysis showed that the tracking ability of CICS with the Trendelenburg position and atrial pacing was below the good trending ability cutoff (92%). However, the concordance rate of the 4-quadrant plot analysis showed a good trending ability for MAPcs. The polar plot analysis showed the same trend. CONCLUSIONS: CICS was not sufficiently accurate in patients with reduced ejection fraction undergoing off-pump CABG surgery. However, ClearSight was clinically acceptable for MAP regarding its accuracy and trending ability in patients with reduced ejection fraction.

Structure-Activity Relationship Study on Col-003, a Protein-Protein Interaction Inhibitor between Collagen and Hsp47.

This study demonstrates the structure-activity relationship of Col-003, a potent collagen-heat-shock protein 47 (Hsp47) interaction inhibitor. Col-003 analogues were successfully synthesized by Pd(0)-catalyzed cross-coupling reactions of 5-bromosalicylaldehyde derivatives with alkyl-metal species, and the inhibitory activities of the synthetic analogues were evaluated using surface plasmon resonance analysis (BIAcore). We succeeded in discovering two potent inhibitors that showed 85 and 81% inhibition at a concentration of 1.9 µM against the collagen-Hsp47 interaction. This indicates that elongation of an alkyl linker between two aromatic rings could considerably improve inhibitory activity due to the adjustment of a pendant phenyl moiety to an appropriate position, in addition to the hydrophobic interaction with an alkyl linker moiety.

The relationship between perceived difficulty and reflection in the practice of discharge planning nurses in acute care hospitals: A nationwide observational study.

AIMS AND OBJECTIVES: To clarify the characteristics and practice of discharge planning nurses in acute care hospitals and to elucidate the relationship between subjective difficulty perceived in practice and reflection. BACKGROUND: The importance of discharge planning for an effective transition from the hospital to a care facility is increasing. In acute care hospitals, however, it is not clear what discharge planning nurses are doing for patients who are highly dependent on medical treatment, the subjective difficulties they perceive in practical activities, and whether reflection by nurses can be expected to mitigate those difficulties. DESIGN: Cross-sectional survey. METHODS: This survey was conducted in 2,379 acute care hospitals in Japan from 1 June-30 June 2018. The survey of discharge planning practice activities examined nine factors. A nurse who answered that he/she did reflect on his/her practices was defined as a self-reflecting nurse. The STROBE statement checklists were completed. RESULTS: Questionnaires were collected from 760 respondents (response rate = 32.1%). The discharge planning nurses had fewer than 36 months of experience with discharge planning. Among the nurses who had been involved in hospital discharge support for 13 months or more, the self-reflecting nurses had fewer perceived difficulties in their practice activities than the non-self-reflecting nurses did. CONCLUSIONS: It was shown that discharge planning nurses with 13 months or more of experience and who practiced reflection on their practical activities perceived less subjective difficulty. Reflection in daily practice may mitigate the subjective difficulty of practical activities experienced by discharge planning nurses, and the establishment of an effective training method that promotes such reflection is required. RELEVANCE TO CLINICAL PRACTICE: In the future, it will be necessary to construct and evaluate an effective education programme for discharge planning nurses that includes self-reflection on practice cases.

Biology of Hsp47 (Serpin H1), a collagen-specific molecular chaperone.

Hsp47, a collagen-specific molecular chaperone that localizes in the endoplasmic reticulum (ER), is indispensable for molecular maturation of collagen. Hsp47, which is encoded by the SERPINH1 gene, belongs to the serpin family and has the serpin fold; however, it has no serine protease inhibitory activity. Hsp47 transiently binds to procollagen in the ER, dissociates in the cis-Golgi or ER-Golgi intermediate compartment (ERGIC) in a pH-dependent manner, and is then transported back to the ER via its RDEL retention sequence. Hsp47 recognizes collagenous (Gly-Xaa-Arg) repeats on triple-helical procollagen and can prevent local unfolding and/or aggregate formation of procollagen. Gene disruption of Hsp47 in mice causes embryonic lethality due to impairments in basement membrane and collagen fibril formation. In Hsp47-knockout cells, the type I collagen triple helix forms abnormally, resulting in thin and frequently branched fibrils. Secretion of type I collagens is slow and plausible in making aggregates of procollagens in the ER of hsp47-knocked out fibroblasts, which are ultimately degraded by autophagy. Mutations in Hsp47 are causally associated with osteogenesis imperfecta. Expression of Hsp47 is strongly correlated with expression of collagens in multiple types of cells and tissues. Therefore, Hsp47 represents a promising target for treatment of collagen-related disorders, including fibrosis of the liver, lung, and other organs.