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.

Transabdominal levatorplasty technique in laparoscopic mesh rectopexy for rectal prolapse.

Rectal prolapse is characterized by a full-thickness intussusception of the rectal wall and is associated with a spectrum of coexisting anatomic abnormalities. We developed the transabdominal levatorplasty technique for laparoscopic rectopexy, inspired by Altemeier's procedure. In this method, following posterior mesorectum dissection, we expose the levator ani muscle just behind the anorectal junction. Horizontal sutures, using nonabsorbable material, are applied to close levator diastasis associated with rectal prolapse. The aim of the transabdominal levatorplasty is to (i) reinforce the pelvic floor, (ii) narrow the anorectal hiatus, and (iii) reconstruct the anorectal angle. We report a novel transabdominal levatorplasty technique during laparoscopic rectopexy for rectal prolapse. The laparoscopic mesh rectopexy with levatorplasty technique was performed in eight cases: six underwent unilateral Orr-Loygue procedure, one modified Wells procedure, and one unilateral Orr-Loygue procedure combined with sacrocolpopexy for uterine prolapse. The median follow-up period was 178 (33-368) days, with no observed recurrences. Six out of seven patients with fecal incontinence experienced symptomatic improvement. Although the sample size is small and the follow-up period is short, this technique has the potential to reduce the recurrence rate and improve functional outcomes, as with levatorplasty of Altemeier's procedure. We believe that this technique may have the potential to become an option for rectal prolapse surgery.

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.

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.

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.

Inactivation of two Dictyostelium discoideum genes, DdPIK1 and DdPIK2, encoding proteins related to mammalian phosphatidylinositide 3-kinases, results in defects in endocytosis, lysosome to postlysosome transport, and actin cytoskeleton organization.

Phosphatidylinositide 3-kinases (PI3-kinases) have been implicated in controlling cell proliferation, actin cytoskeleton organization, and the regulation of vesicle trafficking between intracellular organelles. There are at least three genes in Dictyostelium discoideum. DdPIK1, DdPIK2, and DdPIK3, encoding proteins most closely related to the mammalian 110-kD PI-3 kinase in amino acid sequence within the kinase domain. A mutant disrupted in DdPIK1 and DdPIK2 (delta ddpik1/ddpik2) grows slowly in liquid medium. Using FITC-dextran (FD) as a fluid phase marker, we determined that the mutant strain was impaired in pinocytosis but normal in phagocytosis of beads or bacteria. Microscopic and biochemical approaches indicated that the transport rate of fluid-phase from acidic lysosomes to non-acidic postlysosomal vacuoles was reduced in mutant cells resulting in a reduction in efflux of fluid phase. Mutant cells were also almost completely devoid of large postlysosomal vacuoles as determined by transmission EM. However, delta ddpik1/ddpik2 cells functioned normally in the regulation of other membrane traffic. For instance, radiolabel pulse-chase experiments indicated that the transport rates along the secretory pathway and the sorting efficiency of the lysosomal enzyme alpha-mannosidase were normal in the mutant strain. Furthermore, the contractile vacuole network of membranes (probably connected to the endosomal pathway by membrane traffic) was functionally and morphologically normal in mutant cells. Light microscopy revealed that delta ddpik1/ddpik2 cells appeared smaller and more irregularly shaped than wild-type cells; 1-3% of the mutant cells were also connected by a thin cytoplasmic bridge. Scanning EM indicated that the mutant cells contained numerous filopodia projecting laterally and vertically from the cell surface, and fluorescent microscopy indicated that these filopodia were enriched in F-actin which accumulated in a cortical pattern in control cells. Finally, delta ddpik1/ddpik2 cells responded and moved more rapidly towards cAMP. Together, these results suggest that Dictyostelium DdPIK1 and DdPIK2 gene products regulate multiple steps in the endosomal pathway, and function in the regulation of cell shape and movement perhaps through changes in actin organization.

[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.

Tubulointerstitial injury induced in rats by a monoclonal antibody that inhibits function of a membrane inhibitor of complement.

The kidney widely expresses membrane-associated complement regulatory proteins (membrane inhibitors of complement). The aim of this work was to evaluate the roles of these molecules in rat kidneys in vivo. To suppress functions of rat membrane inhibitors of complement, two mAbs, 512 and 6D1, were used. 5I2 and 6D1 inhibit functions of membrane inhibitors of complement at C3 level (rat Crry/p65) and C8/9 level (rat CD59), respectively. F(ab')2 fragment of 5I2 or 6D1 was perfused in the left kidneys, and perfusate was discarded from the renal vein. After perfusion, the left kidneys were connected to systemic circulation. In rats perfused with 5I2, mouse IgG was found in glomeruli, peritubular capillaries, vascular bundles, and tubules 15 min after recirculation. Binding of C3 and C5b-9 was evident in these areas. 1 d after perfusion with 5I2, cast formation, dilatation of tubular lumen, and tubular cell degeneration were observed. At day 4 through day 7, significant mononuclear cell infiltration and proximal tubule damage were observed. These changes were completely prevented by complement depletion. Rats perfused with 6D1 showed the binding of mouse IgG in the similar areas as 5I2, but C3 or C5b-9 deposition was not observed. Rats perfused with 6D1 or vehicle only did not show any pathology in the left kidneys. These results suggest that rat Crry/p65 plays protective roles against spontaneously occurring indiscriminate attack to tubulointerstitial tissues by autologous complement and that rat Crry/p65 is one of the important factors to maintain normal integrity of the kidney in rats.

A ubiquitin-conjugating enzyme is essential for developmental transitions in Dictyostelium.

We have identified a developmentally essential gene, UbcB, by insertional mutagenesis. The encoded protein (UBC1) shows very high amino acid sequence identity to ubiquitin-conjugating enzymes from other organisms, suggesting that UBC1 is involved in protein ubiquitination and possibly degradation during Dictyostelium development. Consistent with the homology of the UBC1 protein to UBCs, the developmental pattern of protein ubiquitination is altered in ubcB-null cells. ubcB-null cells are blocked in the ability to properly execute the developmental transition that occurs between the induction of postaggregative gene expression during mound formation and the induction of cell-type differentiation and subsequent morphogenesis. ubcB-null cells plated on agar form mounds with normal kinetics; however, they remain at this stage for approximately 10 h before forming multiple tips and fingers that then arrest. Under other conditions, some of the fingers form migrating slugs, but no culmination is observed. In ubcB-null cells, postaggregative gene transcripts accumulate to very high levels and do not decrease significantly with time as they do in wild-type cells. Expression of cell-type-specific genes is very delayed, with the level of prespore-specific gene expression being significantly reduced compared with that in wild-type cells. lacZ reporter studies using developmentally regulated and cell-type-specific promoters suggest that ubcB-null cells show an unusually elevated level of staining of lacZ reporters expressed in anterior-like cells, a regulatory cell population found scattered throughout the aggregate, and reduced staining of a prespore reporter. ubcB-null cells in a chimeric organism containing predominantly wild-type cells are able to undergo terminal differentiation but show altered spatial localization. In contrast, in chimeras containing only a small fraction of wild-type cells, the mature fruiting body is very small and composed almost exclusively of wild-type cells, with the ubcB-null cells being present as a mass of cells located in extreme posterior of the developing organism. The amino acid sequence analysis of the UbcB open reading frame (ORF) and the analysis of the developmental phenotypes suggest that tip formation and subsequent development requires specific protein ubiquitination, and possibly degradation.

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.

Relationship of ethnicity and other prognostic factors to breast cancer survival patterns in Hawaii.

The survival experience of 2,956 invasive breast carcinoma cases identified among the 5 major ethnic groups in Hawaii between 1960 and 1979 was studied. The study population consisted of 1,174 Caucasian, 972 Japanese, 458 Hawaiian, 226 Chinese, and 126 Filipino women. A multivariate analysis based on the proportional hazards regression model revealed that after simultaneous adjustment for stage of disease, age, and socioeconomic status (SES), Filipino and Hawaiian patients had significantly poorer survival than Japanese and Caucasian patients. Hawaiian women also had a significantly poorer survival than Chinese women. Survival was higher in patients between the ages of 45 and 54 years compared to those younger or older, in patients with localized tumors compared to those with more advanced tumors, and in patients with middle or high SES compared to those with the low SES. Histology and marital status were not associated with survival. The possibility that other factors such as obesity, estrogen receptor status, treatment, and nutritional and hormonal status could explain the remaining observed racial differences in breast cancer survival is discussed.