Role of a mutation at position 167 of CTX-M-19 in ceftazidime hydrolysis

CTX-M-19 is a recently identified ceftazidime-hydrolyzing extended-spectrum beta-lactamase, which differs from the majority of CTX-M-type beta-lactamases that preferentially hydrolyze cefotaxime but not ceftazidime. To elucidate the mechanism of ceftazidime hydrolysis by CTX-M-19, the beta-lactam MICs of a CTX-M-19 producer, and the kinetic parameters of the enzyme were confirmed. We reconfirmed here that CTX-M-19 is also stable at a high enzyme concentration in the presence of bovine serum albumin (20 micro g/ml). Under this condition, we obtained more accurate kinetic parameters and determined that cefotaxime (k(cat)/K(m), 1.47 x 10(6) s(-1) M(-1)), cefoxitin (k(cat)/K(m), 62.2 s(-1) M(-1)), and aztreonam (k(cat)/K(m), 1.34 x 10(3) s(-1) M(-1)) are good substrates and that imipenem (k(+2)/K, 1.20 x 10(2) s(-1) M(-1)) is a poor substrate. However, CTX-M-18 and CTX-M-19 exhibited too high a K(m) value (2.7 to 5.6 mM) against ceftazidime to obtain their catalytic activity (k(cat)). Comparison of the MICs with the catalytic efficiency (k(cat)/K(m)) of these enzymes showed that some beta-lactams, including cefotaxime, ceftazidime, and aztreonam showed a similar correlation. Using the previously reported crystal structure of the Toho-1 beta-lactamase, which belongs to the CTX-M-type beta-lactamase group, we have suggested characteristic interactions between the enzymes and the beta-lactams ceftazidime, cefotaxime, and aztreonam by molecular modeling. Aminothiazole-bearing beta-lactams require a displacement of the aminothiazole moiety due to a severe steric interaction with the hydroxyl group of Ser167 in CTX-M-19, and the displacement affects the interaction between Ser130 and the acidic group such as carboxylate and sulfonate of beta-lactams.     

MR features of the substantia innominata and therapeutic implications in dementias

We measured the thickness of the substantia innominata using magnetic resonance imaging in 122 patients with Alzheimer's disease (AD), 31 patients with dementia with Lewy bodies (DLB) and 34 patients with vascular dementia (VaD), and examined the correlates of cognitive response to donepezil. Although all dementia groups showed significant atrophy of the substantia innominata compared to 28 age-matched controls, atrophy was greater in the DLB group, but less in the VaD group than the AD group. Mini-Mental State Examination score changes at 12 weeks after donepezil administration inversely and significantly correlated with the thickness of the substantia innominata in patients with AD (n=103, r=-0.43, p<0.0001) and in patients with DLB (n=24, r=-0.57, p<0.01), but not in patients with VaD (n=12, r=-0.22, p>0.1). There may be some differences in cholinergic impairment among AD, DLB and VaD, reflecting cholinergic neuropathology. Clinical response to cholinergic therapy may be partly attributable to damaged cholinergic neurons in AD and DLB, but not in VaD, suggesting differences in the therapeutic implication of cholinergic system degeneration.     

Social anxiety predicts unconsciously provoked emotional responses to facial expression

Previous psychometric studies using a visual search task suggested that interpersonal fear in individuals with social anxiety disorder (SAD) may be processed by unconscious preattentive mechanisms. However, little is known about relationships between social anxiety and preattentive emotional responses. We explored whether social anxiety is associated with preattentive emotional responses to facial expression. Groups with high and low social anxiety were selected from 125 healthy volunteers according to scores on the Social Phobia Inventory. Fearful and happy faces were presented subliminally using backward masking, with skin conductance responses (SCRs) being measured as an autonomic index of emotional responses. SCRs to these two facial expressions were compared between groups. The group with high social anxiety showed significantly greater differences in SCRs between masked fearful and happy faces than the group with low social anxiety. Social anxiety was associated with unconscious autonomic responses to fearful faces. A preattentive interpersonal threat evaluation system may be an important factor in SAD.     

Effect of hypoxia on gene expression of bone marrow-derived mesenchymal stem cells and mononuclear cells

MSC have self-renewal and multilineage differentiation potential, including differentiation into endothelial cells and vascular smooth muscle cells. Although bone marrow-derived mononuclear cells (MNC) have been applied for therapeutic angiogenesis in ischemic tissue, little information is available regarding comparison of the molecular foundation between MNC and their MSC subpopulation, as well as their response to ischemic conditions. Thus, we investigated the gene expression profiles between MSC and MNC of rat bone marrow under normoxia and hypoxia using a microarray containing 31,099 genes. In normoxia, 2,232 (7.2%) and 2,193 genes (7.1%) were preferentially expressed more than threefold in MSC and MNC, respectively, and MSC expressed a number of genes involved in development, morphogenesis, cell adhesion, and proliferation, whereas various genes highly expressed in MNC were involved in inflammatory response and chemotaxis. Under hypoxia, 135 (0.44%) and 49 (0.16%) genes were upregulated (>threefold) in MSC and MNC, respectively, and a large number of those upregulated genes were involved in glycolysis and metabolism. Focusing on genes encoding secretory proteins, the upregulated genes in MSC under hypoxia included several molecules involved in cell proliferation and survival, such as vascular endothelial growth factor-D, placenta growth factor, pre-B-cell colony-enhancing factor 1, heparin-binding epidermal growth factor-like growth factor, and matrix metalloproteinase-9, whereas the upregulated genes in MNC under hypoxia included proinflammatory cytokines such as chemokine (C-X-C motif) ligand 2 and interleukin-1alpha. Our results may provide information on the differential molecular mechanisms regulating the properties of MSC and MNC under ischemic conditions. Disclosure of potential conflicts of interest is found at the end of this article.     

Supraglottic subepithelial benign mass lesions: Focus on clinical features of sialolipoma-like lesion

ObjectivesSialolipoma has been classified as a benign soft tissue lesion in the 2017 World Health Organization classification of head and neck tumors. To our knowledge, only one case of laryngeal sialolipoma has been reported in the English literature. We conducted a retrospective study to identify clinical characteristics of supraglottic sialolipoma-like lesion and differentiate it from other supraglottic subepithelial masses.MethodsMedical records of 16 patients with supraglottic subepithelial benign mass lesions who underwent histological evaluation between 2003 and 2019 were retrospectively analyzed. Sialolipoma-like lesion was defined as a local finding of a well-circumscribed gross mass with pathological presence of salivary gland-like parenchymal lobules with evenly interspersed adipose tissue.ResultsEight patients showed histological positivity for sialolipoma-like lesion, 3 for amyloidosis, 2 for hemangioma, and 1 each for cyst, lymphoid hyperplasia, and chondrometaplasia. Sialolipoma-like lesion tended to be predominant among men; those affected had a mean age of 52.8 (range, 39–74) years. By contrast, among patients with amyloidosis, the ratio of men to women was 1:2 (100% vs. 33%; p = 0.055). Fiberscopic examination of all patients with sialolipoma-like lesions identified well-circumscribed, yellowish masses, closely resembling local amyloidosis findings. Sialolipoma-like lesion was associated with a significantly higher body-mass index (BMI; 27.4 ± 2.8 kg/m²) than amyloidosis (21.6 ± 1.4 kg/m²; p = 0.014). The transoral approach was used for lesion resection in all patients with sialolipoma-like lesion. No patient experienced postoperative recurrence.ConclusionLaryngeal sialolipoma-like lesion might be more prevalent than was previously reported, and histological examination is important to differentiate it from amyloidosis. Supraglottic sialolipoma-like lesion must be differentially diagnosed in patients with high BMI presenting with well-circumscribed, yellowish supraglottic masses.