Effect of probucol on repeat revascularization rate after percutaneous transluminal coronary angioplasty (from the Probucol Angioplasty Restenosis Trial [PART])

To address the issue of whether probucol reduces clinical events after percutaneous transluminal coronary angioplasty (PTCA), we surveyed clinical status at 1 year after PTCA of 101 patients who had entered the Probucol Restenosis Angioplasty Trial. Repeat angioplasty at index lesions were required in 5 patients in the probucol group and in 12 in the control group, suggesting that probucol administered beginning 4 weeks before PTCA reduces repeat revascularization rates for 1 year.     

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.     

Interhemispheric difference in emotional response without awareness

To investigate interhemispheric differences concerning unconscious human emotional responses processed, we measured human skin conductance responses (SCRs) to masked (unseen) emotional stimuli presented to left or right visual fields. Backward masking was used to preclude conscious processing of emotional stimuli. Masked negative or neutral emotional pictures from the International Affective Picture System (IAPS) were presented to 11 right-handed male volunteers. Mean SCR for negative emotional stimuli presented to the left visual field was significantly greater than mean SCRs for negative emotional stimuli to the right visual field and for neutral stimuli to the left or right visual fields. Thus, the right rather than the left hemisphere appears to respond to preattentive negative emotional stimuli.     

Development of an enzyme-linked immunosorbent assay for fecal bile acid

It has been suggested that the bile acids in the feces act as a promoter of colon cancer. Among the bile acids, deoxycholic acid (DCA), which is one kind of the secondary bile acid, is said to have strong influence. DCA/cholic acid (CA) ratio in feces is also said to have a diagnostic significance in colon cancer. With this in mind, we created a CA and DCA's monoclonal antibody (MoAb) to measure them through the enzyme linked immunosorbent assay (ELISA) method. Using these MoAb, we were able to measure CA and DCA concentrations with low cross-reaction to other bile acids compared with the method with polyclonal antibody (PoAb). We measured CA and DCA concentrations and calculated the DCA/CA ratios in healthy subjects and patients with colon cancer. All subjects had been screened for colon cancer. We then compared the healthy subjects, the cancer patients before surgery and the same cancer patients after surgery. Cancer patients after surgery had significantly low DCA/CA ratios compared to before surgery, whereas there was no significant difference between healthy subjects and the pre-operative colon cancer patients.     

HIF-1 in T cells ameliorated dextran sodium sulfate-induced murine colitis

HIF-1 is active in hypoxia, such as inflamed mucosa, and HIF-1 in epithelium has been reported to control inflamed mucosa in IBD models. Although T cells play an important role for pathogenesis of IBD, the function of HIF-1 in T cells remains to be elucidated. We aimed to clarify the function of HIF-1 in T cells in IBD with focus on the balance between Treg and Teff. Double immunohistochemistry of colonic mucosa in IBD patients showed that HIF-1 was expressed in T cells infiltrating the inflamed mucosa, suggesting that HIF-1 in T cells is involved in the pathogenesis. DSS administration to T cell-specific HIF-1α KO mice showed more severe colonic inflammation than control mice with the up-regulation of Th1 and Th17. Hypoxic stimulation in vitro increased Treg activation in WT T cells but not in HIF-1-deleted T cells. In contrast, hypoxic stimulation increased Th17 activation, and the degree was higher in HIF-1-deleted cells than in control cells. These results show that hypoxia controls intestinal inflammation by regulating cytokine balance in a HIF-1-dependent manner, suggesting that strengthening HIF-1 induction in T cells at the sites of inflammation might be a therapeutic strategy for IBD regulation.     

Serum Matrix Metalloproteinase-2 Levels Indicate Blood–CSF Barrier Damage in Patients with Infectious Meningitis

Objective Protein components in cerebrospinal fluid (CSF) are maintained at a specific concentration by a dynamic gradient between the capillary and intrathecal spaces via the blood–cerebrospinal fluid barrier (BCB) in the brain and spinal cord. Permeability to proteins increases when there is structural damage to the BCB. Matrix metalloproteinase-2 (MMP-2; gelatinase A) has been shown to degrade type IV collagen, a major component of the cellular basement membrane. We analyzed α2 macroglobulin (α2M) indices and evaluated the relationship between α2M, as an indicator of BCB permeability, and MMP-2, which degrades the extra-cellular matrix in patients with infectious meningitis. Materials and Methods Albumin levels in CSF or serum were determined by turbidimetric immunoassay, or bromcresol green assay, respectively. α2M levels in CSF or serum were measured with enzyme-linked immunosorbent assay, or laser-nephelometry, respectively. Serum MMP-2 levels were determined by enzyme immuno assay. We calculated the α2M index, i.e. the ratio of α2M (CSF / serum) to albumin (CSF / serum; α2M in CSF / α2M in serum × albumin in serum / albumin in CSF). Results α2M indices were significantly increased in infectious meningitis compared to healthy controls (p < 0.05). They were highest in bacterial meningitis, and there was a significant difference between viral or mycotic and bacterial meningitis (p < 0.05). Serum MMP-2 levels were increased in infectious meningitis, being highest in bacterial meningitis, where they were significantly different from healthy controls (p < 0.05). There was a significant positive correlation between serum MMP-2 levels and α2M indices (r = 0.64, p < 0.0001). Conclusion Markedly increased levels of serum MMP-2 in infectious, especially bacterial, meningitis may reflect the degree of damage to the BCB.