An analog-AI chip for energy-efficient speech recognition and transcription.

Models of artificial intelligence (AI) that have billions of parameters can achieve high accuracy across a range of tasks1,2, but they exacerbate the poor energy efficiency of conventional general-purpose processors, such as graphics processing units or central processing units. Analog in-memory computing (analog-AI)3-7 can provide better energy efficiency by performing matrix-vector multiplications in parallel on 'memory tiles'. However, analog-AI has yet to demonstrate software-equivalent (SWeq) accuracy on models that require many such tiles and efficient communication of neural-network activations between the tiles. Here we present an analog-AI chip that combines 35 million phase-change memory devices across 34 tiles, massively parallel inter-tile communication and analog, low-power peripheral circuitry that can achieve up to 12.4 tera-operations per second per watt (TOPS/W) chip-sustained performance. We demonstrate fully end-to-end SWeq accuracy for a small keyword-spotting network and near-SWeq accuracy on the much larger MLPerf8 recurrent neural-network transducer (RNNT), with more than 45 million weights mapped onto more than 140 million phase-change memory devices across five chips.

Diagnostic features of acquired dermal melanocytosis of the face and extremities.

Acquired dermal melanocytosis of the face and extremities (ADMFE) is an unusual form of acquired dermal melanocytosis (ADM). In this paper, we report a case of ADMFE and review the published literature. Our review highlights several clinical differences between ADMFE and ADM: (i) more frequent involvement of the nasal alae in ADMFE than in ADM, (ii) less frequent involvement of the cheeks in ADMFE than in ADM, (iii) limbs affected in all cases of ADMFE but in few cases of ADM, and (iv) frequent involvement of conjunctiva and/or gingiva in ADMFE but very rare involvement in ADM. These findings strongly support the hypothesis that ADMFE is clinically distinct from the classic form of ADM, and gaining an understanding of its phenotype will enable accurate diagnosis and early intervention by Q-switched laser therapy, which should benefit those patients with disease-related cosmetic issues.

Immune responses against norovirus GII.4 virus-like particles in mice.

Norovirus (NoV) is a causative agent of gastroenteritis in children and adults worldwide. To evaluate the safety and effectiveness of a NoV vaccine candidate, 100 µg of GII.4 NoV-like particles (VLPs) was challenged orally (oral and intrabuccal administration) and by subcutaneous injection without adjuvant in mice. The subcutaneous injection induced IgG in sera, but not IgA in feces. The oral delivery method induced IgA in both sera and feces, but not IgG in sera. However, challenging by the intrabuccal administration induced IgG in sera and IgA in both sera and feces, especially by 2-dose immunization. The peak of specific immune responses by the intrabuccal administration was detected later than that of the oral delivery method. Heterologous immune responses against other genotypes were also recognized. NoV-specific IFN-γ was detected after the intrabuccal administration. These findings indicated that the administration of NoV VLPs by intrabuccal administration could induce the best immune responses against NoV in mice.

Male sexual function after laparoscopic total mesorectal excision.

AIM: The aim of this prospective study was to clarify the frequency of male sexual dysfunction after laparoscopic total mesorectal excision (LTME) and to examine the relationship between pelvic autonomic nerve (PAN) preservation status and functional outcomes. METHOD: Candidates for LTME were included in this study. PAN preservation status after LTME was examined in detail by video review. Patients completed a functional questionnaire (the International Index of Erectile Function) before and 3, 6 and 12 months after the operation. RESULTS: Twenty-six patients who underwent LTME were assessable. Detailed video reviews identified inadvertent PAN damage during surgery. PAN injury was observed in 11 cases (41%), including eight cases (32%) of inadvertent PAN damage (incomplete preservation group). There was a trend toward increasing inadvertent PAN injury rate in patients with high body mass index and large tumours. The results from all patients who underwent LTME showed no deterioration in total International Index of Erectile Function or its domain scores 12 months after surgery. In the incomplete preservation group, these scores temporarily decreased (3 and 6 months after surgery), but such deterioration was not observed in the complete preservation group. Most of the 12 patients with potentially active erectile function before the operation recovered this function, and only one patient (7%) with PAN injury was still judged as inactive 12 months after surgery. CONCLUSION: The proportion of patients with sexual dysfunction after LTME is low. With the enhanced visibility of the laparoscope, inadvertent PAN injury was detected in a significant number of cases and associated with transient deterioration of sexual function.

Efficacy and safety of multitarget therapy with mizoribine and tacrolimus for systemic lupus erythematosus with or without active nephritis.

The prognosis of lupus nephritis (LN) has improved since the introduction of immunosuppressant therapies, but the safety and effectiveness of treatments can also be improved. We retrospectively assessed the treatment courses of 12 patients with systemic lupus erythematosus who were treated with glucocorticoid, mizoribine (MZR) and tacrolimus. This regimen was used as initial therapy for active LN in six patients (mean glucocorticoid dose, 66.6 mg); four of these six patients also received pulse methylprednisolone therapy. The starting doses of MZR and tacrolimus were 150 and 3 mg, respectively, and they were titrated as required. Five of six patients achieved complete remission and one achieved partial remission at 6 months. Five patients who completed 12-month analysis achieved complete remission. Another six patients were given the combination regimen for treating minor flares or for steroid sparing. The mean prednisolone doses were reduced from 11.0 mg at baseline to 6.6 mg at 12 months. Six patients experienced minor adverse events, including three minor infections. One patient stopped tacrolimus because of suspected toxicity. All 12 patients were successfully treated, and none experienced severe adverse events. Multitarget therapy combining glucocorticoid, MZR and tacrolimus may have the potential to become a treatment option which is effective and safe.

Blockade of cysteinyl leukotriene-1 receptors suppresses airway remodelling in mice overexpressing GATA-3.

BACKGROUND: We demonstrated previously that GATA-3 overexpression markedly enhanced allergen-induced airway inflammation and airway remodelling, including subepithelial fibrosis, and smooth muscle cell hyperplasia, in transgenic mice. OBJECTIVE: Because cysteinyl leukotrienes (cysLTs) have been shown to be involved in such structural changes, the effects of a specific cysLT1 receptor antagonist, montelukast, were evaluated in a mouse model of chronic asthma. METHODS: GATA-3-overexpressing mice and wild-type Balb/c mice were sensitized and repeatedly challenged by ovalbumin (OVA) or saline. The effects of montelukast on the development of airway remodelling were compared between the two mouse genotypes. RESULTS: CysLTs in the lung were increased after repeated allergen challenges, and significantly enhanced in GATA-3-overexpressing mice. The enhanced cysLT levels were accompanied by the development of eosinophilia, smooth muscle cell hyperplasia, and increased stromal cell-derived factor-1 gene expression with a small increase in pro-collagen gene expression in OVA-challenged GATA-3-overexpressing mice, but not in wild-type mice. Montelukast significantly decreased lung cysLT levels and inhibited the GATA-3-overexpression-related airway remodelling, potently preventing smooth muscle cell hyperplasia, but partially suppressed the increased pro-collagen gene expression and eosinophilic inflammation. Increases in the levels of IL-4, IL-5, IL-13, and eotaxin in bronchial lavage and TGF-ß gene expression in the lungs were induced by OVA in both mouse genotypes. Montelukast treatment also significantly reduced these levels to the levels seen after saline challenges in GATA-3-overexpressing mice. CONCLUSION: Montelukast efficaciously prevented airway inflammation and remodelling in a GATA-3-overexpression antigen challenge mouse model by decreasing the cysLT-driven Th2 cytokine cycle of amplification of airway pathologies.

Risk factors of mid-term mortality of patients with infective endocarditis.

In-hospital and long-term mortality of infective endocarditis (IE) are well noted, but the studies for mid-term (90-day) mortality of IE is still limited. We determine the mid-term mortality rate of IE and its significant predictors. Seventy patients with IE were hospitalised at St. Luke's International Hospital between January 1996 and March 2009, of whom 62 consecutive patients could be followed up for 90 days after diagnosis. We then calculated Kaplan-Meier (KM) estimates and performed time-to-event analysis. The mean (standard deviation, SD) age was 66.6 (15.3) years. Thirty-five patients (56%) were male. Blood cultures were positive in 87%. Causative microorganisms were: viridans group streptococci (23%), ß-streptococci (16%), Staphylococcus aureus (15%), including methicillin-resistant S. aureus (MRSA) (5%). Thirty-three cases (53%) had at least one complication such as heart failure (34%), central nervous system (CNS) complication (29%) or emboli peripheral to CNS (6%). KM estimates (95% CI) of the 90-day mortality was 14.5% (7.8-25%). In multiple regression analysis using the Cox proportional hazards model, hazard ratios of at least one complication for the 90-day mortality was 8.2 (1.4-155). Mid-term mortality of IE continues to be high and the presence of at least one complication may be considered as an independent risk factor of mid-term mortality.

NEMO mutation as a cause of familial occurrence of Behçet's disease in female patients.

Behçet's disease is a chronic, relapsing, multisystem inflammatory disease of unknown etiology. Nuclear factor κB (NF-κB) essential modulator (NEMO) that is required for the activation of NF-κB plays an important role in inflammation. To investigate the role of NEMO in the pathogenesis of Behçet's disease, we analyzed NEMO gene and its expression pattern in tissues in a family with Behçet's disease. We found a heterozygous mutation (1217A> T, D406V) in a 6-year-old girl and her mother. Skewed X-chromosome inactivation was not observed in the peripheral blood mononuclear cells as well as in oral and intestinal mucosa of the patients. Accordingly, there was a significant proportion of peripheral blood monocytes that did not produce sufficient intracellular tumor necrosis factor-α with the stimulation of lipopolysaccharide. Heterozygous NEMO mutation is a cause of familial occurrence of Behçet's disease in female patients.

[Surgical treatment of aortic root disease].

We reviewed aortic root disease and operative procedures. Between January 1982 and December 2008, aortic root operation was performed for 58 patients with various aortic root disease. We chose Bentall type operations in extensive root destructive cases and urgent or reoperative cases. Overall in-hospital mortality was 8.6% (5/58). Four patients (7.5% of survivors) died during the period of followup. Actuarial survival at 15 years was 92%. Freedom from cardiovascular event at 10 and 15 years was 81% and 27%, respectively. Of 5 reoperations in 5 patients, only 1 was required due to complications of the initial Bentall type operation. The Bentall type operations resulted in a durable result. Although, in Marfan syndrome, freedom from cardiovascular event was lower than that in non-Marfan syndrome, actuarial survival rate was equal with non-Marfan syndrome. Close observation is necessary for detecting cardiovascular event, especially in Marfan syndrome.

Association study of the tumor necrosis factor-alpha gene and its 1A receptor gene with methamphetamine dependence.

Recent preclinical findings that repeated treatment with methamphetamine (METH) induced an increase in tumor necrosis factor-alpha (TNF-alpha) mRNA in some brain regions and that TNF-alpha blocked METH neurotoxicity and rewarding effects suggest TNF-alpha, a multifunctional pro-inflammatory cytokine, may be involved in METH dependence. We hypothesized that genetic polymorphisms of the TNF-alpha gene and its receptor genes may be associated with vulnerability to METH dependence. Genetic association of -308G>A and -857C>T in the promotor region of the TNF-alpha gene, and 36A>G in exon 1 of the TNF receptor 1A gene (TNFR-SF1A), were analyzed in patients with METH dependence (n = 185) and healthy controls (n = 221) in a Japanese population. No significant association of alleles or haplotypes of the TNF-alpha or TNFR-SF1A genes with METH dependence was found. Neither was any significant association of clinical phenotype with METH dependence found. These results suggest that genetic variations in the TNF-alpha gene and its receptor genes may not be involved in individual vulnerability to METH dependence.

No association between CART (cocaine- and amphetamine-regulated transcript) gene and methamphetamine dependence.

Cocaine- and amphetamine-regulated transcript (CART) was originally discovered as a peptide that increased in the rat striatum after injection of a psychostimulant drug, such as cocaine or amphetamine, and is suggested to play potential roles in drug dependence. We tested the genetic association between the CART gene and methamphetamine (METH) dependence and/or psychosis. The subjects were 203 patients with METH dependence and 239 age- and gender-matched healthy controls. Two single nucleotide polymorphisms (SNPs) of the CART gene, -156A>G and IVS1 + 224G>A, were examined . There were no significant differences in genotype and allele distributions of the polymorphisms between patients with METH dependence and/or psychosis and controls. Neither were significant differences in subgroups of clinical phenotypes, for example, age at first consumption of METH, latency to onset of psychotic symptoms after the first consumption of METH, prognosis of psychosis after therapy, complication of spontaneous relapse to a psychotic state, or multisubstance abuse status, observed. The present findings suggest that the CART gene may not play a pivotal role in the development of METH dependence and psychosis, at least in a Japanese population.

Phenotypic and genetic analyses of T-cell-mediated immunoregulation in patients with Type 1 diabetes.

AIMS: To investigate the contribution of regulatory T cells and co-stimulatory molecules in CD4(+) T cells to the development of Type 1 diabetes (T1D). METHODS: Twelve patients with T1D, nine patients with systemic lupus erythematosus (SLE), and 12 age-matched healthy control subjects participated. We analysed the proportions of CD25(+)CD4(+) T cells and natural killer T cells (NKT cells), and the expression levels of Foxp3, CTLA-4, CD28, ICOS, PD-1 and BTLA in peripheral blood mononuclear cells and purified CD4(+) T cells. RESULTS: There were no significant differences in the proportions of CD25(+) CD4(+) T cells or NKT cells among the three groups. PD-1 expression levels of peripheral CD4(+) T cells from T1D patients were significantly lower than those from healthy control subjects (P = 0.00066). In contrast, PD-1 expression levels were similar in SLE patients and healthy control subjects. The expression levels of Foxp3, CTLA-4, CD28, ICOS and BTLA were similar in the three groups. CONCLUSIONS: Decreased expression of the PD-1 gene in CD4(+) T cells may contribute to the development and/or maintenance of autoimmune T1D. As the population studied was small and heterogeneous, further studies are required to confirm the findings.

The relation of pepsinogen group II (PGII) expression to intestinal metaplasia and gastric cancer.

AIMS: A substantial minority of intestinal metaplasia (IM)-associated stomach cancers express a gastric product-pepsinogen group II (PGII). The aim of this study was to examine PGII expression as it relates to IM and to tumour heterogeneity. METHODS AND RESULTS: The extent of IM was divided into four levels: none, minimal, moderate, extensive. Stomach specimens (N = 165) were stained for PGII and two tumour markers, epidermal growth factor receptor (EGFr) and p53. PGII was more likely to be expressed with moderate or extensive IM than with minimal or no IM (P = 0.05). Cancers that expressed PGII were more likely to be of high stage than those that did not (P = 0.035). Of 25 cases that expressed all three markers (PGII, EGFr, p53), 20 (80%) had stage 3 or 4 disease, compared with 11 (37%) advanced cancers expressing none of the markers (P = 0.001). Cancers expressing one or two markers were between these extremes. CONCLUSIONS: PGII+ cancers in IM-associated gastric cancers may derive from residual gastric glands, or may arise from postinduction reversion to a gastric phenotype from intestinalized cells. This is supported by the more frequent association of PGII expression with the most extensive degrees of IM and its association with high-stage cancers that display heterogeneity in tumour marker expression.

Novel roles of osteopontin and CXC chemokine ligand 7 in the defence against mycobacterial infection.

Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced human monocyte-derived macrophage (GM-Mphi) or macrophage CSF (M-CSF)-induced human monocyte-derived Mphi (M-Mphi) are distinct in terms of the resistance to Mycobacterium tuberculosis. To elucidate the role of molecules involved in the functional differences between these Mphis, we investigated the gene expression profiles using microarray. After culture of CD14+ monocytes with CSFs, Mphis were cultured with or without bacillus Calmette-Guérin (BCG) (GM-Mphi-BCG and M-Mphi-BCG). The gene expression profiles from these cells were compared. Chemokines highly expressed in M-Mphis were selected and evaluated for anti-mycobacterial activity and superoxide production. FN1 and FCGR2B were the most up-regulated genes in GM-Mphi and M-Mphi, respectively. After stimulation with BCG, three chemokine genes (Osteopontin (SPP1), CXC chemokine ligand 7 (CXCL7) and CC chemokine ligand 11 (CCL11)) were highly expressed in M-Mphi-BCG when compared to those in GM-Mphi-BCG. A significantly increased resistance to M. tuberculosis H37Ra was observed after the stimulation of GM-Mphi with SPP1 or CXCL7. Superoxide production levels of SPP1- or CXCL7-stimulated GM-Mphis were higher than those of GM-Mphis without stimulation. These results indicate that both SPP1 and CXCL7 might have a role in the resistance against mycobacteria, at least in part, through augmenting reactive oxygen intermediate production in Mphis.

Distinct gene expression patterns of peripheral blood cells in hyper-IgE syndrome.

Hyper-immunoglobulin E (IgE) syndrome (HIES) is one of the primary immunodeficiency syndromes. Although the cytokine dysregulation is suggested to play a role in its pathophysiology, the causative gene has not yet been identified. To investigate the pathophysiology and candidate genes involved in this disease, we performed microarray analysis of unstimulated peripheral CD4+ T cells and CD14+ cells, as well as peripheral blood mononuclear cells (PBMNC) stimulated with Staphylococcus aureus isolated from HIES patients and healthy controls. By microarray analysis, 38 genes showed over 2-fold differences between the HIES patients and healthy controls in purified CD14+ cells, although only small differences in the gene expression profiles were observed between the two groups in purified CD4+ T cells. RGC32 expression levels showed the greatest difference between the two groups, and were significantly elevated in HIES compared with those in severe atopic dermatitis or healthy controls using real-time PCR. A significantly larger number of lysosome-related genes were up-regulated, and significantly larger number of genes related to cell growth and maintenance were down-regulated in HIES. After the stimulation of PBMNC with Staphylococcus aureus, 51 genes showed over 3-fold differences between HIES patients and healthy controls. A significantly large number of immunoglobulin-related genes were up-regulated in HIES. The distinct patterns of gene expression profiles and RGC32 expression levels will be useful for understanding the pathophysiology and for diagnosis of HIES, respectively.

Association analysis of tissue inhibitor of metalloproteinase2 gene polymorphisms with COPD in Egyptians.

Proteinase/antiproteinase imbalance is recognized to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). A relative increase in the activities of matrix metalloproteinases might be caused by mutations of tissue inhibitor of metalloproteinase2 (TIMP2). Recently, two polymorphisms of the TIMP2 gene, +853 G/A and -418 G/C (+551 and -720 from the translation initiation site), have been shown to be associated with the development of COPD in the Japanese population. In this study, a case-control association analysis for these polymorphisms was conducted in the Egyptian population using 106 COPD patients and 72 healthy controls. The genotype frequency of +853 G/A was significantly different between the patient and the control groups (P = 0.029), although no significant difference was detected in the allele frequency between the two groups. These results suggest that the +853 G/A polymorphism of the TIMP2 gene might be associated with COPD across ethnicities. In contrast, neither the distributions of genotype nor allele frequencies of -418 G/C were significantly different between the two groups, raising the possibility that a combination of different genetic factors contributes to the development of COPD in different ethnic groups.

Transport of prostaglandin E1 across the blood-brain barrier in rats.

The transport of prostaglandin E(1) (PGE(1)) across the blood-brain barrier (BBB) was characterized using an in-situ rat brain perfusion technique. The uptake of [(3)H]PGE(1) was not affected by shortchain monocarboxylic acids (butyric acid and valeric acid). On the other hand, uptake of [(3)H]PGE(1) was significantly inhibited by medium-chain monocarboxylic acids such as hexanoic acid, enanthic acid and octanoic acid. These medium-chain monocarboxylic acids showed a more potent inhibitory effect on [(3)H]PGE(1) uptake with increasing number of carbon atoms. In contrast, there was no decrease in [(3)H]PGE(1) transport by any dicarboxylic acids with 5-8 carbon atoms. Valproic acid decreased [(3)H]PGE(1) uptake, whereas p-aminohippuric acid, a substrate for the organic anion transporter family, did not inhibit [(3)H]PGE(1) transport. Bromocresol green, an inhibitor of prostaglandin transporter (PGT), strongly decreased [(3)H]PGE(1) transport across the BBB. In addition, digoxin and taurocholate, substrates for organic anion transporting polypeptide subtype 2 (Oatp2), significantly inhibited [(3)H]PGE(1) uptake. RT-PCR analysis revealed that PGT mRNA and Oatp2 mRNA are expressed in a capillary-rich fraction from rat brain. Thus, it is suggested that PGE(1) transport across the BBB is mediated by some specific transport systems, possibly by the members of the Oatp family.