A 10-year longitudinal study of deep white matter lesions on magnetic resonance imaging.

PURPOSE: Deep white matter lesions (DWMLs), T2 high-intensity areas in the subcortical white matter on magnetic resonance imaging (MRI), are a clinical phenotype of cerebral small vessel disease. Factors such as age and hypertension have been reported to significantly contribute to the presence and severity of DWMLs in cross-sectional studies. We herein report a 10-year longitudinal study on DWMLs in elderly Japanese subjects to reveal the clinical variables contributing to the progression of DWMLs. METHODS: A total of 469 Japanese subjects were invited to participate in the study. Of the participants at baseline, 259 subjects completed the revisit MRI study 10 years later. In those 259 subjects, we evaluated the correlation between the progression of DWMLs and clinical variables, such as the gender, age, and overt vascular risk factors. To clarify the role of hypertension, 200 subjects with grade 1 DWMLs at baseline were categorized into three groups according to their status of hypertension and its treatment. RESULTS: Of the 200 subjects with grade 1 DWMLs, 47 subjects (23.5%) showed progression of DWMLs (progression group). In the progression group, the percentage of subjects with hypertension and the systolic blood pressure values were higher than in the non-progression group. In addition, subjects ≥ 60 years old at baseline tended to show deterioration of DWMLs in the group with hypertension without antihypertensive treatment. CONCLUSION: The results of this 10-year longitudinal study imply a positive correlation between long-standing hypertension and the progression of DWMLs.

Serum albumin to globulin ratio is related to cognitive decline via reflection of homeostasis: a nested case-control study.

BACKGROUND: Recent research suggests that several pathogenetic factors, including aging, genetics, inflammation, dyslipidemia, diabetes, and infectious diseases, influence cognitive decline (CD) risk. However, no definitive candidate causes have been identified. The present study evaluated whether certain serum parameters predict CD. METHODS: A total of 151 participants were assessed for CD using the Mini-Mental State Examination (MMSE), and 34 participants were identified as showing CD. RESULTS: Among CD predictive risk factors, Helicobacter pylori seropositivity was significantly predictive of CD risk, more so than classical risk factors, including white matter lesions and arterial stiffness [adjusted odds ratio (OR) = 4.786, 95% confidence interval (CI) = 1.710-13.39]. A multivariate analysis indicated that the albumin to globulin (A/G) ratio was the only factor that significantly lowered CD risk (OR = 0.092, 95% CI = 0.010-0.887). A/G ratio also was positively correlated with MMSE scores and negatively correlated with disruption of homeostatic factors (i.e., non-high-density lipoprotein, hemoglobin A1c, and high-sensitive C-reactive protein). CONCLUSIONS: The current study results suggest that the A/G ratio is related to cognitive decline and may reflect homeostatic alterations.

CD62-mediated activation of platelets in cerebral white matter lesions in patients with cognitive decline.

BACKGROUND: Vascular dementia is related to intracranial arteriosclerosis associated with deep white matter lesions (DWMLs). DWMLs have been linked to thrombogenesis due to sustained platelet activation; therefore, an accurate hematological marker is needed. This study was done to evaluate the usefulness of a new method to examine the function of activated platelets in order to assess DWMLs associated with cognitive decline. METHODS: A total of 143 individuals (70.4 ± 6.1 years old) who underwent hospital-based health screening using head MRI were evaluated. DWLs were evaluated on T2-weighted and FLAIR images by semi-quantitatively grading them from Grade 0 (none) to Grade 3 (severe) using the Fazekas classification. Cognitive function was evaluated using the MMSE and the word fluency test. Platelet activation was assessed using fluorescence-labeled anti-human platelet monoclonal antibodies and semi-quantitatively determining PAC-1- and CD62P-positive rates by flow cytometry. RESULTS: Significant increases in hypertension and CD62P levels were observed with increasing DWML grade (2.6% in Group 0, 3.1% in Group 1, 4.1% in Group 2, and 5.0% in Group 3). CD62P levels were defined as elevated when they were above the mean+2SD of the Grade 0 group, and the odds ratio of the Grade 2+3 group was 3.03. A significant negative correlation was observed between CD62P levels and word fluency tests or the MMSE score. CONCLUSION: Elevations in CD62P levels, which reflect platelet function activation, were associated with white matter lesions accompanied by a decline in cognitive function. CD62P levels may be useful as a sensitive clinical marker for the early detection of DWMLs with cognitive decline.

TGF-beta1 is associated with the progression of intracranial deep white matter lesions: a pilot study with 5 years of magnetic resonance imaging follow-up.

OBJECTIVES: Elevated expression of transforming growth factor (TGF)-beta1 has been reported in hereditary cerebral small-vessel (HCSV) disease. The aim of this study was to clarify whether TGF-beta1 is a risk factor for intracranial deep white matter lesions (DWLs) and their progression in a general elderly population. METHODS: The subjects included 81 participants (Groups DWL, DWLP, and C) who had voluntarily undergone a health examination and brain magnetic resonance imaging (MRI) in 2003 and 2008 and 43 age-matched patients with previous symptomatic brain infarctions. Deep white matter lesions were graded from Grade 0 to 3 according to the Fazekas classification. Group DWL (23 subjects) was defined as DWLs with no progression in the grade level, and Group DWLP (progression of DWL) (12 subjects) was defined as DWLs with an increase in one or more grade number and an apparent worsening of Grade 3. Forty-six age-matched control subjects with consistent normal brain MRI were included in Group C. The associations between DWLs and various vascular risk factors, including peripheral blood TGF-beta1 levels, were examined. RESULTS: In addition to the classical risk factors, the highest TGF-beta1 levels were found in Group DWLP. The TGF-beta1 levels were significantly higher in Group DWLP than in Group DWL, and DWLP was significantly correlated with elevated TGF-beta1 levels (odds ratio [OR]  =  1·72). CONCLUSIONS: The present data suggest that TGF-beta1 may be important in the pathogenesis and progression of DWLs, and it is expected to be useful as a clinical indicator reflecting the presence of intracranial white matter lesions.

[Case of successful management with mirtazapine for prolonged pain after esophagectomy].

This case report describes a successful outcome of mirtazapine treatment in a patient with difficult post-thoracotomy pain. A 63-year-old man received thoracotomy for the resection of esophageal tumor. The pain continued 2 years after the operation. Allodynia was present in the region of the intercostal nerves from the surgical wound. Remedies such as clonazepam, amitriptyline, gabapentin, and acetaminophen were not effective, and epidural block effect was only temporal. The patient experienced a reduction in shooting pain after taking pregabalin; however, he still suffered from persistent pain and, mirtazapine was additionally administrated. One month after this, shooting and persistent pain was reduced, and the patient's appetite was improved, which had been present since the thoracotomy. Since then, his weight slightly increased and the administration of mirtazapine was stopped in accordance with the patient's request. The pain became worse again. Therefore, mirtazapine, commonly used as an antidepressant agent, was considered to be beneficial for neuropathic pain as an analgesic adjuvant.

Use of the Pentax-AWS in 293 patients with difficult airways.

BACKGROUND: Several case reports have shown that the Pentax-AWS (Hoya Corporation, Tokyo, Japan), a new video laryngoscope, is useful in patients with difficult airways. METHODS: We assessed the effectiveness of the Pentax-AWS in two groups. Group 1 included 270 patients in whom direct laryngoscopy using a Macintosh laryngoscope had been difficult. Group 2 included 23 patients with predicted difficult intubation and difficult mask ventilation without previous use of the Macintosh laryngoscope. RESULTS: In group 1, the view of the glottis with the Macintosh laryngoscope was Cormack and Lehane grade 2 in 14 patients, grade 3 in 208 patients, and grade 4 in 48 patients. In 256 patients in whom the grade was 3 or 4 with the Macintosh laryngoscope, the view with the Pentax-AWS was either grade 1 or 2 in 255 patients (99.6%; 95% confidence intervals 97.8-100%). Tracheal intubation was successful with the Pentax-AWS in 268 of 270 patients (99.3%; 95% confidence interval 97.4-100%), and it failed (after two attempts) in two patients. In group 2, tracheal intubation was successful in 22 of 23 patients, and it failed in one patient. The reasons for failed intubation using the Pentax-AWS were failure to position the blade toward the glottic side of the epiglottis, inability to maneuver the endotracheal tube away from the arytenoids and into the trachea, and bleeding and swelling of the oropharynx. CONCLUSION: The success rate of tracheal intubation using the Pentax-AWS was high in patients with difficult laryngoscopy with a Macintosh laryngoscope and in patients with predicted difficult intubation.

[TruViewEVO2 videolaryngoscope].

TruViewEVO2 videolaryngoscope (Truphatek, Israel) is a modified version of the Truphatek 1. We used this device in four patients with difficult airways. A 77-year-old obese woman, scheduled for nasal surgery, had short neck and small jaw. After induction of anesthesia and neuromuscular blockade, laryngoscopy was attempted using a Macintosh blade, but the epiglottis, but not the glottis, was seen. A full view of the glottis was obtained when the TruView was used, and the trachea was easily intubated. In another two patients, in whom laryngoscopy with a Macintosh blade had failed, and in one patient with limited mouth opening, the TruView allowed us to see the glottis and to intubate the trachea without difficulty. Therefore, we believe that the TrueViewEVO2 videolaryngoscope is useful in patients with difficult airways.

Comparison of genomic and cDNA sequences of guinea pig CYP2B18 and rat CYP2B2: absence of a phenobarbital-responsive enhancer module in the upstream region of the CYP2B18 gene.

Potential mechanisms were investigated whereby CYP2B18, a cytochrome P450 gene exhibiting high constitutive expression but only low levels of phenobarbital-inducibility in the guinea pig liver, may be differentially regulated versus the highly inducible rat CYP2B2 gene. To comparatively assess potential regulatory sequences associated with CYP2B18, a guinea pig genomic library was screened enabling isolation of the CYP2B18 gene. The genomic screening process resulted in the identification of at least four closely-related CYP2B18 genes, designated here as CYP2B18A-D. Of these isolates, CYP2B18A exhibited sequence identical to that of the CYP2B18 cDNA. Further, the deduced amino acid sequence of the CYP2B18 cDNA was identical to that of N-terminal and internally-derived peptide sequences obtained in this investigation from CYP2B18 protein isolated from guinea pig liver. Genomic structural sequences were derived for CYP2B18A, together with the respective 5'-upstream and intronic regions of the gene. Comparison of the CYP2B18A and CYP2B2 gene sequences revealed the lack of repetitive LINE gene sequences in CYP2B18A, putative silencing elements that effect neighboring genes, although these sequences were present in both 5'-upstream and 3'-downstream regions of CYP2B2. We determined that the phenobarbital-responsive enhancer module was absent from the 5'-upstream region as well as the intronic regions of CYP2B18A gene. We hypothesize that the compromised phenobarbital inducibility of CYP2B18A stems from its lack of a functional phenobarbital responsive enhancer module.

[Comparison of analgesic effects of intravenous flurbprofen and suppository indomethacin after laparoscopic cholecystectomy].

BACKGROUND: Epidural analgesia may not be necessary after laparoscopic cholecystectomy, but analgesics, such as non-steroidal anti-inflammatory drugs, may often be required postoperatively. There have been only a few studies comparing different NSAIDs in this situation. METHODS: After laparoscopic cholecystectomy under general anesthesia using intravenous propofol, nitrous oxide and fentanyl 3 micrograms.kg-1, 40 patients were randomly allocated to receive either intravenous flurbprofen 50 mg or suppository indomethacin 50 mg. Visual analogue scales of postoperative pain at 0, 10, 20, 30 and 60 min after surgery (at rest and at coughing), use of rescue analgesics, and the presence or absence of complications were recorded. RESULTS: Pain score at rest was markedly reduced (> 15% reduction from the baseline value) in 13 of 20 patients after injection of flurbiprofen and in five patients after indomethacin during the initial 60 min after surgery (P < 0.05), whereas there was no significant difference between the two groups for the pain score during coughing. There was no difference in the need of rescue analgesics within the initial 60 min, but the flurbiprofen group required significantly more rescue analgesics than the indomethacin group during 1-24 h after surgery (P < 0.005). The incidence of complications was low in both groups. CONCLUSIONS: Compared with suppository indomethacin, intravenous flurbiprofen is more effective in acute postoperative pain but the duration of its analgesic effect is shorter.

Effects of FK317, a novel anti-cancer agent, on survival of mice bearing B16BL6 melanoma and Lewis lung carcinoma.

The effects of FK317 (11-acetyl-8-carbamoyloxymethyl-4-formyl-6-methoxy-14- oxa-1,11-diazatraacylo[7.4.1.0(2.7).0(10.2)]-tetradeca-2,4,6-trien-9-yl acetate), a novel anti-cancer agent, and mitomycin C (MMC) on survival time of mice bearing B16BL6 melanoma and Lewis lung carcinoma (LLC), induced by intravenous inoculation of the tumor, were investigated. Treatment with FK317 resulted in a significant prolongation of survival time in both tumor models. Four of ten mice bearing B16BL6 were disease-free following FK317 treatment. In contrast, MMC was not effective in prolonging survival time. Overall, this study demonstrated that FK317 shows more potent survival extension in mice bearing B16BL6 and LLC than MMC, suggesting that FK317 may have therapeutic utility for cancer chemotherapy.

Role of the Tsc1-Tsc2 complex in signaling and transport across the cell membrane in the fission yeast Schizosaccharomyces pombe.

Heterozygous inactivation of either human TSC1 or TSC2 causes tuberous sclerosis (TSC), in which development of benign tumors, hamartomas, occurs via a two-hit mechanism. In this study, fission yeast genes homologous to TSC1 and TSC2 were identified, and their protein products were shown to physically interact like the human gene products. Strains lacking tsc1(+) or tsc2(+) were defective in uptake of nutrients from the environment. An amino acid permease, which is normally positioned on the plasma membrane, aggregated in the cytoplasm or was confined in vacuole-like structures in Deltatsc1 and Deltatsc2 strains. Deletion of tsc1(+) or tsc2(+) also caused a defect in conjugation. When a limited number of the cells were mixed, they conjugated poorly. The conjugation efficiency was improved by increased cell density. Deltatsc1 cells were not responsive to a mating pheromone, P-factor, suggesting that Tsc1 has an important role in the signal cascade for conjugation. These results indicate that the fission yeast Tsc1-Tsc2 complex plays a role in the regulation of protein trafficking and suggest a similar function for the human proteins. We also show that fission yeast Int6 is involved in a similar process, but functions in an independent genetic pathway.