Artificial intelligence for the automated single-shot assessment of psoriasis severity.

BACKGROUND: PASI score is globally used to assess disease activity of psoriasis. However, it is relatively complicated and time-consuming, and the score will vary due to the inconsistent subjectivity between dermatologists. Therefore, an AI system capable of assessing psoriasis severity will be useful. OBJECTIVES: To propose a simplified PASI system (Single-Shot PASI) and associated AI models capable of assessing psoriasis severity. METHODS: Overall, 705 psoriasis images of the trunk's front and back were used in our research. Considering the relatively small number of images, we used data augmentation techniques to expand the data. A psoriasis expert's scores were used as teacher data. Various convolutional neural network models and hyperparameters were adjusted using a fivefold cross-validation. From these adjustments, we discovered that fine-tuning Imagenet2012-pretrained InceptionV3 whose last linear layer was replaced by a two-layer perceptron (30 hidden units and five output units) exhibited the best performance. RESULTS: To validate our deep learning system, 10 images were selected as test sets and were excluded from the training sets. The AI assessment of Single-Shot PASI was almost consistent with the clinical severity. We examined whether AI assistance would affect human scoring. In this study, 13 dermatologists and 9 medical students were invited as evaluators. Mean absolute differences from AI scores and standard deviation among evaluators reduced with AI assistance. In addition, the evaluator's scores got close to the teacher's score with AI's assistance. CONCLUSIONS: We proposed a Single-Shot PASI system and developed an associated AI system capable of assessing psoriasis severity simply by uploading a single clinical image. An easy-to-use scoring system and our freely available AI software would help dermatologists and patients with psoriasis.

Punctate Administration of Ficin as a human and animal model of non-histaminergic itch.

BACKGROUND: Ficin, a cysteine protease derived from fig-tree latex, has been reported to elicit itch and nociceptive sensations, though quantitative sensory studies are lacking. Cowhage containing the pruritic cysteine Mucunain, on the contrary, has been widely studied as activating polymodal nociceptors and eliciting a histamine-independent itch. OBJECTIVES: We tested whether ficin in heat-inactivated cowhage spicules would elicit itch and nociceptive sensations in humans, and analogous behaviours in mice, which are similar to those evoked by native cowhage, and whether these behaviours in mice were dose-dependent when ficin was injected intradermally. METHODS: Human volunteers rated the magnitude of itch and nociceptive sensations evoked by either native cowhage spicules or heat-inactivated spicules soaked in 1, 10 or 100 mg/mL ficin (0.03, 0.3 and 3 ng of ficin in spicule tip), applied to forearm. In mice, itch-like scratching and nociceptive-like wiping were recorded in response to either native cowhage, to heat-inactivated spicules that were either inactive or contained 100 mg/mL ficin, or to intradermal injections of 1.25, 2.5 or 5 µg/ 5 µL, each treatment applied to the cheek. RESULTS: The dose of 100 mg/mL ficin in spicules evoked comparable magnitudes of itch, nociceptive sensations and areas of cutaneous dysesthesia as native cowhage in humans and comparable itch-like scratching and pain-like wiping behaviours in mice. But to elicit similar behaviours when injected intradermally in mice a greater amount of ficin (1.25 µg) was required. CONCLUSION: Spicule delivery or intradermal injection of ficin elicits behaviours in mice that model itch and nociceptive sensations in humans, suggesting that ficin may be useful in translating mechanistic research on the neural mechanisms of pruritic and nociceptive effects of cysteine proteases between the two species.

An outbreak of food poisoning due to Escherichia coli serotype O7:H4 carrying astA for enteroaggregative E. coli heat-stable enterotoxin1 (EAST1).

In June 2020, a large-scale food poisoning outbreak involving about 3000 elementary and junior high school students occurred in Yashio, Saitama, Japan. A school lunch was the only food stuff ingested by all of the patients. Escherichia coli serotype O7:H4 carrying the astA gene for enteroaggregative E. coli (EAggEC) heat-stable enterotoxin 1 (EAST1) was detected in faecal specimens from the patients, and sample inspection revealed its presence in a seaweed salad and red seaweed (Gigartina tenella) as one of the raw materials. Analysis of the antibiotic sensitivity of the isolates revealed resistance to ampicillin and cefotaxime. All isolates were confirmed to be of the same origin by pulsed-field gel electrophoresis after digestion with the restriction enzyme XbaI, and single nucleotide polymorphism analysis using whole genome sequencing. To our knowledge, this is the first report of a large-scale food poisoning caused by E. coli O7:H4, which lacks well-characterized virulence genes other than astA.

Cartilage and subchondral bone distributions of the distal radius: a 3-dimensional analysis using cadavers.

OBJECTIVE: To quantify the spatial distributions of cartilage and subchondral bone thickness of the distal radius. DESIGN: Using 17 cadaveric wrists, three types of 3-dimensional models were created: a cartilage-bone model, obtained by laser scanning; a bone model, rescanned after dissolving the cartilage; and a subchondral bone model, obtained using computed tomography. By superimposing the bone model onto the cartilage-bone and the subchondral bone models, the cartilage and subchondral bone thickness were determined. Measurements along with the spatial distribution were made at fixed anatomic points including the scaphoid and lunate fossa, sigmoid notch and interfossal ridge, and compared at each of these four regions. RESULTS: Cartilage thickness of the interfossal ridge (0.89 ± 0.23 mm) had a larger average thickness compared to that of the scaphoid fossa (0.70 ± 0.18 mm; p = 0.004), lunate fossa (0.75 ± 0.17 mm; p = 0.044) and sigmoid notch (0.64 ± 0.13 mm; p < 0.001). Subchondral bone was found to be thickest at the scaphoid (2.18 ± 0.72 mm) and lunate fossae (1.94 ± 0.93 mm), which were both thicker than that of sigmoid notch (1.63 ± 1.06 mm: vs scaphoid fossa, p = 0.020) or interfossal ridge (1.54 ± 0.84 mm: vs scaphoid fossa, p = 0.004; vs lunate fossa, p = 0.048). In the volar-ulnar sub-regions of the scaphoid and lunate fossa, the subchondral bone thickened. CONCLUSIONS: Our data can be applied when treating distal radius fractures. Cartilage thickness was less than 1 mm across the articular surface, which may give an insight into threshold for an acceptable range of step-offs. The combined findings of subchondral bone appreciate the importance of the volar-ulnar corner of the distal radius in the volar locking plate fixation.

Cartilage wear patterns in severe osteoarthritis of the trapeziometacarpal joint: a quantitative analysis.

OBJECTIVE: The present quantitative study aimed to assess the three-dimensional (3-D) cartilage wear patterns of the first metacarpal and trapezium in the advanced stage of osteoarthritis (OA) and compare cartilage measurements with radiographic severity. DESIGN: Using 19 cadaveric trapeziometacarpal (TMC) joints, 3-D cartilage surface models of the first metacarpal and trapezium were created with a laser scanner, and 3-D bone surface model counterparts were similarly created after dissolving the cartilage. These two models were superimposed, and the interval distance on the articular surface as the cartilage thickness was measured. All measurements were obtained in categorized anatomic regions on the articular surface of the respective bone, and we analyzed the 3-D wear patterns on the entire cartilage surface. Furthermore, we compared measurements of cartilage thickness with radiographic OA severity according to the Eaton grading system using Pearson correlation coefficients (r). RESULTS: In the first metacarpal, the cartilage thickness declined volarly (the mean cartilage thickness of the volar region was 0.32 ± 0.16 mm, whereas that of the dorsal region was 0.53 ± 0.18 mm). Conversely, the cartilage evenly degenerated throughout the articular surface of the trapezium. Measurements of the categorized regions where cartilage thinning was remarkable exhibited statistical correlations with radiographic staging (r = -0.48 to -0.72). CONCLUSIONS: Our findings indicate that cartilage wear patterns differ between the first metacarpal and trapezium in the late stage of OA. There is a need for further studies on cartilage degeneration leading to symptomatic OA in the TMC joint.

A novel 5HT3 receptor-IGF1 mechanism distinct from SSRI-induced antidepressant effects.

Depression is a common mental disorder affecting around 350 million people worldwide. Although selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants, a significant proportion of depressed patients do not achieve remission with SSRIs. In this study, we show that a serotonin type 3 receptor (5HT3R) agonist induces antidepressant effects as well as hippocampal neurogenesis independent of fluoxetine (a commonly used SSRI). Notably, our histological analysis reveals that 5HT3R and insulin-like growth factor 1 (IGF1) are expressed in the same neurons in the subgranular zone of the hippocampal dentate gyrus. Furthermore, our in vivo microdialysis analysis shows that 5HT3R regulates hippocampal extracellular IGF1 levels, and we also show that 5HT3R-dependent hippocampal neurogenesis is mediated by increased IGF1 levels. Altogether, our findings suggest a novel 5HT3R-IGF1 mechanism that is distinct from fluoxetine-induced responses and that provides a new therapeutic target for depression, especially bringing significant benefits for SSRI-resistant depressed patients.

Surgical starting time in the morning versus the afternoon: propensity score matched analysis of operative outcomes following laparoscopic colectomy for colorectal cancer.

BACKGROUND: The number of colorectal cancer cases is increasing, and so the number of laparoscopic colectomy procedures being performed is also increasing, leading to an increased workload for surgeons. However, operating for prolonged time periods may cause surgeons to lose their concentration and develop fatigue. We hypothesized that there is a time-of-day variation in outcome for patients with colorectal cancer who undergo laparoscopic colectomy. The present study aimed to compare the operative outcome between laparoscopic colectomy for colorectal cancer performed in the morning versus the afternoon. METHODS: This was a single-center, retrospective study. All 1961 consecutive patients who underwent laparoscopic surgery for colorectal cancer between 2007 and 2017 were included; 1006 of these patients underwent morning surgery, while 955 underwent afternoon surgery. These patients were analyzed using propensity score matching, giving 791 patients in each group. The short- and long-term outcomes in both groups were compared. RESULTS: Before propensity score matching, the morning group had a larger mean tumor size than the afternoon group (30 cm vs 35 cm; P = 0.0035). After matching, the two groups did not significantly differ in any patient characteristics. Compared with the afternoon group, the morning group had a significantly lesser incidence of intra-operative organ injury (0.25% vs 1.13%; P = 0.027), and a significantly greater incidence of post-operative abdominal abscess (2.03% vs 0.75% P = 0.028). The incidences of other complications and morbidities were similar in both groups. The median operative time in the morning group (201 min) was significantly longer than that in the afternoon group (193 min; P = 0.0124). The two groups did not differ in 5-year overall survival rates and 5-year disease-free rates within any disease stage. CONCLUSIONS: Surgical start times are correlated with surgical outcomes. Our data will help to ensure the safest possible surgeries.

The 5-HT3 receptor is essential for exercise-induced hippocampal neurogenesis and antidepressant effects.

Exercise has a variety of beneficial effects on brain structure and function, such as hippocampal neurogenesis, mood and memory. Previous studies have shown that exercise enhances hippocampal neurogenesis, induces antidepressant effects and improves learning behavior. Brain serotonin (5-hydroxytryptamine, 5-HT) levels increase following exercise, and the 5-HT system has been suggested to have an important role in these exercise-induced neuronal effects. However, the precise mechanism remains unclear. In this study, analysis of the 5-HT type 3A receptor subunit-deficient (htr3a(-/-)) mice revealed that lack of the 5-HT type 3 (5-HT3) receptor resulted in loss of exercise-induced hippocampal neurogenesis and antidepressant effects, but not of learning enhancement. Furthermore, stimulation of the 5-HT3 receptor promoted neurogenesis. These findings demonstrate that the 5-HT3 receptor is the critical target of 5-HT action in the brain following exercise, and is indispensable for hippocampal neurogenesis and antidepressant effects induced by exercise. This is the first report of a pivotal 5-HT receptor subtype that has a fundamental role in exercise-induced morphological changes and psychological effects.

Allergen-specific basophil reactivity exhibits daily variations in seasonal allergic rhinitis.

It remains poorly understood how symptoms in allergic rhinitis are most severe during overnight or early in the morning. The circadian clock consisting of a network of several 'clock genes' including Clock drives daily rhythms in physiology. This study showed that allergen-induced surface CD203c expression on basophils in seasonal allergic rhinitis caused by Japanese cedar pollen exhibited a time-of-day-dependent variation associated with temporal variations in canonical circadian clock gene expression. We also found that bone-marrow-derived basophils (BM basophils) generated from wild-type mice exhibited a time-of-day-dependent variation in IgE-mediated IL-4 and histamine production, which was not observed in BM basophils generated from Clock-mutated mice. Therefore, allergen-specific basophil reactivity shows daily variations depending on the circadian clock activity in basophils, which could partly explain temporal symptomatic variations in allergic rhinitis. Additionally, circadian variations in CD203c expression should be considered for interpretation of this biomarker in clinical research.

Circulating microRNAs as biomarkers for early detection of diffuse-type gastric cancer using a mouse model.

BACKGROUND: Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and a poor prognosis. There are no effective serum biomarkers for early detection of DGC. We have established an E-cadherin/p53 double conditional knockout (DCKO) mouse line that recapitulates human DGC morphologically and molecularly. In this study we tried to identify circulating microRNAs (miRNAs) as non-invasive biomarkers for DGC diagnosis using DCKO mice. METHODS: We performed miRNA microarray and quantitative reverse transcription-PCR analyses of tissue and serum samples from DCKO mice with DGC and age-matched littermate controls. RESULTS: Comparative analyses showed that mouse and human primary gastric cancers have similar miRNA expression patterns. Next, we selected some candidate miRNAs highly expressed in sera and cancer tissues of DCKO mice for further evaluation. TaqMan quantitative RT-PCR analyses indicated that four of them, miR-103, miR-107, miR-194 and miR-210, were significantly upregulated in sera of both early and advanced-stage DGC-bearing mice compared with in corresponding controls. Receiver-operating characteristic curve analyses demonstrated that these four miRNAs can discriminate DGC-positive cases from normal ones with high sensitivity and specificity. CONCLUSION: These observations suggest that this mouse model of DGC is useful for identifying serum biomarkers, and we found circulating miRNAs that can accurately detect DGC at an early stage.

Mutation analysis of BRAF and KIT in circulating melanoma cells at the single cell level.

BACKGROUND: The availability of molecular-targeted therapies for the treatment of melanoma has emphasised the need to identify mutations in target genes such as BRAF and KIT. Circulating tumour cells (CTC) are present in the peripheral blood of a significant proportion of cancer patients. METHODS: High molecular weight melanoma-associated antigen (HMW-MAA) was used to isolate melanoma cells from peripheral blood as it is selectively expressed at high levels on melanomas. The HMW-MAA-positive cells were isolated using immunomagnetic beads. After removing CD45(+) cells, CTC were identified by staining with MART-1- and gp100-specific antibodies (HMW-MAA(+), CD45(-), MART-1/gp100(+)). Single, isolated CTC were then subjected to BRAF and KIT mutational analysis. RESULTS: CTC (HMW-MAA(+), CD45(-), MART-1/gp100(+)) were isolated from the blood of 11 patients and BRAF and KIT were sequenced in nine and four patients, respectively. The BRAF sequences identified in the CTC were inconsistent with those identified in autologous melanoma tumours in three patients and the KIT sequences were inconsistent in three patients. In addition, polyclonal BRAF mutations were identified in one patient and concomitant mutations in BRAF and KIT were identified in another patient. CONCLUSION: Melanoma cells show clonal heterogeneity. Therefore, CTC genotyping may be crucial for successful molecular-targeted therapy.

Marked response to imatinib mesylate in metastatic acral lentiginous melanoma on the thumb.

We report a case of melanoma that had a marked response to treatment with imatinib mesylate (IM). The patient was a 61-year-old man who presented with a small red nodule on the thumb and destruction of the nail plate. On histological examination, this lesion was diagnosed as a melanoma, and computed tomography revealed lymph-node swelling in the left axilla and nodules in both lung fields. Although the patient received intratumoral injections of interferon-ß and systemic administration of dacarbazine, both primary and metastatic lesions increased in size. Immunochemistry detected a KIT mutation, which was confirmed by DNA sequencing analysis, and patient was given IM. Within 2 weeks of starting the IM regimen, the size of the nodule on the nail plate markedly decreased, and the axillary lymph-node swelling and lung-nodule formation regressed. This case suggests that IM may be a promising treatment option for KIT mutation-positive melanoma.

Preferential usage of the Fc receptor gamma chain in the T cell antigen receptor complex by gamma/delta T cells localized in epithelia.

zeta and eta chains of the T cell antigen receptor (TCR) complex and the gamma chain of Fc receptors (FcR gamma) constitute a family of proteins important for the expression of, and signal transduction through, these receptors in hematopoietic cells. In zeta-deficient mice, TCR expression was reduced in most T cells. By contrast, CD8 alpha alpha + TCR-gamma/delta + intestinal intraepithelial lymphocytes in these mice expressed a normal level of TCR. Biochemical analysis of the TCR complex in these cells from zeta-deficient as well as normal mice revealed the predominant usage of FcR gamma. Furthermore, gamma/delta + T cells in epithelia of the skin and female reproductive organs from zeta-deficient mice also showed relatively high TCR expression, indicating the usage of FcR gamma. These observations demonstrate the preferential usage of FcR gamma by gamma/delta + T cells localized in epithelia of normal mice.

Intradermal injections of polyarginine-containing immunogenic antigens preferentially elicit Tc1 and Th1 activation and antitumour immunity.

Background We previously have shown that nona-arginine protein transduction domain (R9-PTD) induced efficient protein-antigen (Ag) transduction of dendritic cells (DCs) in vitro, resulting in the efficient induction of strong Ag-specific immune responses mediated by CD8+ and CD4+ T cells and in superior antitumour effects in vivo in cancer-bearing mice. Objectives The Ag-specific immune responses caused by intradermal (i.d.) injections of R9-PTD-containing protein Ags without DC preparation were investigated. We also investigated the antitumour effects by intratumoral (i.t.) injections of rR9-containing protein Ags. Methods Synthesized SIINFEKL peptide, or recombinant ovalbumin fusion proteins (rOVA, rR9-OVA), were directly injected into abdominal skin in naïve C57BL/6 mice. OVA-specific cytotoxic T lymphocyte (CTL) activity, serum IgG titre and cytokine profiles were investigated. Histopathological analyses were also performed. In a cancer vaccination model, EG.7 (OVA-cDNA transfectants thymoma) cells were inoculated intradermally in C57BL/6 mice, and the antitumour effects were evaluated by i.t. injections of rR9-OVA in a treatment setting. Results i.d. injections of rR9-OVA into naïve C57BL/6 mice elicited OVA-specific CTLs and produced IgG2-dominant immunoglobulin. The i.d. injections of rR9-OVA also induced inflammatory cell infiltrates containing neutrophils, monocytes and lymphocytes, as well as production of inflammatory cytokines such as interferon (IFN)-gamma, interleukin-2 and IFN-inducible protein 10, with presenting SIINFEKL epitopes on major histocompatibility complex (MHC) class I molecules at the injection area. i.t. injections of rR9-OVA into EG.7 tumour mass significantly suppressed tumour growth, and these effects were completely abrogated by the depletion of CD8+ T cells. These antitumour effects were superior to those elicited by i.t. injections of rR9-OVA-treated DCs. Conclusions i.d. injections of rR9-containing immunogenic Ag without adjuvants simultaneously induce dual immunological effects: the induction of Tc1- and Th1-dominant immune responses, and the induction of inflammatory and CTL-mediated immune responses at the injection area by expressing Ag epitopes on MHC class I molecules as targets. This simple vaccination approach with R9-PTD-containing fusion proteins might be useful as prophylactic immunotherapy for cancer or infectious diseases.

Antifungal steroid glycoside from sea cucumber.

An antifungal steroid glycoside, holotoxin, has been isolated from the sea cucumber Stichopus japonicus (Selenka). In vitro, it exhibits high activity against various fungi, including vegetable pathogens, but has scarcely any activity against Gram-positive and Gram-negative bacteria and mycobacteria in vitro.